Held (2009) stated in his book, Quirks of Human Anatomy*, "how much neural rewiring was needed to convert a quadrupedal simian to a bipedal hominin? Maybe not much: (1) a single mutation in an axon-guidance gene can make a mouse hop like a rabbit (cf. kangaroo rats), and (2) a human syndrome (due to one allele?) was found in Turkey where affected adults revert to walking on all fours [Tan 2006]! Can evolution rewire locomotion faster than arousal cues?"* Ghika (2008) stated in his article: *"In a way, a demented patient with language dysfunction returns to the level of thinking and communication of an early primate, like the Uner Tan syndrome walks like a primate quadruped with curved fingers during wrist walking with arm and leg ratios of human-like apes and possess primitive language and mental abilities."* Therefore the quadrupedalism was proposed to be a phenotypic example of evolution in reverse (see Tan, 2010a), i.e., *"the reacquisition of the same character states as those of ancestor populations by derived populations" (Teotonio & Rose, 2001). On the other hand, Tan (2010a) also suggested that "UTS may be considered within the framework of phylogenetic diseases associated with phylogenetic regression (Bailey, 1978), and this*

The ancestral characteristics of the UTS cases, such as habitual quadrupedal locomotion, no speech but one or two sounds, very limited vocabulary in dysarthric cases with no conscious experience, standing with bent knees and trunk (flexor posture contrary to extensor posture in modern humans), and heavy supraorbital tori, fist walking with bent fingers, and nonopposable thumb observed in some cases, may be associated with atavism or reverse evolution, which, in turn, were considered under Darwinian or phylogenic diseases (see above). Atavism, or evolutionary throwback, was defined as "*the reappearance of a 'lost character' (either morphological or behavioral) that was typical of remote ancestors"* (Tomic & Meyer-Rochow, 2011). This definition is relevant to human quadrupedalism, which is not only one of the main symptoms of UTS, but it can also be observed in individuals with entirely normal brains (Tan, 2007a; Tan & Tan, 2009). Accordingly, the cases with the novel syndrome were first reported as live cases for backward evolution in human beings (Tan, 2005d; Tan, 2006a, b, c). This may be associated with mutation in a single gene: "*Unertan Syndrome suggests that the erect posture of our ancestors may have occurred by a punctuated evolution, as a result of a mutation in a single gene or*

14H shows the MRI skull of a modern man, which shows no supraorbital tori.

*facial regions on brow ridge length during ontogeny."*

*may in turn be related to the theory of human backward evolution."*

**7. Atavism (reverse evolution)**

*in a gene pool"* (Tan, 2005d). And*, "The genetic nature of this syndrome suggests a backward stage in human evolution, which is most probably caused by a genetic mutation"* (Tan, 2006a). Consistent with this hypothesis, single gene mutations were recently identified in single families: VLDLR in the Antep and Canakkale families (Ozcelik et al., 2008a), CA8 in the Iraqi family (Türkmen et al., 2009, WDR81 in the Iskenderun family (Gulsuner et al., 2011). These single genes were associated with the synthesis of proteins responsible for the structural and functional organization of the brain, including the cerebellum, which controls locomotor coordination and especially truncal balance. It was proposed that these mutations were most likely associated with the emergence of the quadrupedal locomotion in humans. However, no single gene has hitherto been identified that was directly responsible for the emergence of human quadrupedalism as an atavistic feature.

The concept of backward evolution, or reverse evolution, or atavism, caused an interesting debate among scientists, asking if evolution may be reversible or not. In fact, probably due to incomplete definitions, reverse evolution has nothing to do with the direction of evolution, which may not have a direction due to randomness in its origins. Evolution in reverse as another variation of evolution may easily be accounted for if the Darwinian medicine of phylogenetic diseases is taken into consideration instead of using the misleading terms for reverse evolution. Among these, atavism would better describe the situation. Studying the mechanisms of atavism as a reappearance of ancestral features would be more reasonable than struggling around phylogenetic ideas. Whatever may be, the theory of reverse evolution was seriously taken into consideration by many notable laboratories. For instance, Bridgham et al. (2009) recently found that resurrecting ancient proteins constrains the direction of receptor evolution, consistent with the notion of irreversibility of evolution. However, these authors did not report the behavioral correlates of the resurrected ancient proteins within their laboratory conditions. In this context, it must always be kept in mind that the atavism or reverse evolution both describe the behavioral or structural traits.

Consistent with the theory of reverse evolution, there are experimental studies suggesting it is plausible and testable (Teotonio & Rose, 2000, 2001, 2002), and there are indeed studies supporting the theory of evolution in reverse. For instance, Bekpen et al. (2009) reported a gene associated with Crohn's disease deleted about 50 MYA in primates could have been resurrected during human evolution. Harris et al. (2006) have succeeded in breeding a mutant strain of chicken with teeth, formerly only seen in their ancestors. This suggests modern chickens without teeth would still have ancestral genes available to be switched back on. Similarly, mutations in the Ubx gene produced four-winged flies, reflecting their ancestral species from more than 200 MYA (Lewis, 2006). Moreover, Tvrdik & Capecchi (2006) also demonstrated the reconstruction of a 530-million-year old gene in the modern mouse. Interestingly, VLDLR,, the gene associated with quadrupedalism in the affected cases of the Antep and Canakkale families, playing a role in neuroblast migration as a part of the reeling signaling pathway, is also conserved from stem amniotes (stem reptiles) to mammals (Bar et al., 2000) and even to avian species (Bujo et al., 1994), within a time span of about 350-400 MYA.

In addition to these examples for the process of reverse evolution, it was suggested some apes may have human ancestors, suggesting also backwards evolution (Filler, 2010). These results, however, contradict Dollo's Law (1893), which states that "*an organism is unable to return, even partially, to a previous stage already realized in the ranks of its ancestors."* However, this law was not entirely supported by researchers after Dollo's time. Human

Üner Tan Syndrome: Review and Emergence of

rain, wind, and temperature fluctuations.

*state without any selection process whatsoever."*

Oudeyer (2006, p.1) also suggested:

*the motion of all the parts."*

Human Quadrupedalism in Self-Organization, Attractors and Evolutionary Perspectives 25

selection, being entirely the art of nature with self-organizing properties within dynamical complex systems, following the principle: "*the sum of the parts is greater than the parts taken independently,"* contrary to Sir Isaac Newton who argued: "*the motion of the whole is the sum of*

Fig. 15. Examples of self-organized nature: left and center, travertines, terraces

spontaneously made of carbonate minerals left by the flowing warm water in Pamukkale ("cotton castle"), Turkey: right, "Fairy Chimneys" (roof-like formations) in Cappadocia, Turkey, spontaneously formed from the solidified lava streams, ash, and tuff stone, through

The above exemplified natural complex systems, with a strong tendency to self-organize, may also be applied to biological systems. For instance, insects can spontaneously build nests or hives, hunt in groups, and explore the food resources of their environment (Camazine et al., 2002), like the formation of the colored patterns of many creatures such as butterflies, zebras, jaguars, etc (Ball, 2001). The self-organization, *i.e.*, "*the spontaneous formation of patterns and pattern change in open nonequilibrium systems"* (Kelso, 1995, preface), is essentially the quintessence of all living systems. The evolution of the biological forms and structures may also be associated with self-organization. In this context, some authors have questioned the centrality of natural selection in evolution, since Darwinism essentially

ignores the principles of self-organization. Accordingly, Waldrop (1990) suggested:

*"Complex dynamic systems can sometimes go spontaneously from randomness to order; it is a driving force in evolution? Have we missed something about evolution—some key principle that has shaped the development of life in ways quite different from natural selection, genetic drift, and all the other mechanisms biologists have evoked over years?... Yes! And the missing element… is spontaneous self-organization: the tendency of complex dynamical systems to fall into an ordered*

*"Thus, the explanation of the origins of forms and structures in the living can not only rely on the principle of natural selection, which should be complemented by the understanding of physical*

The process of self-organization is closely coupled with "emergence," a fundamental property of complex systems: *"a new property or behavior, which appears due to non-linear interactions within the system; emergence may be considered the product or by-product of the system… It is the product of interconnections and the interaction makes it dynamic and*

*unpredictable; entities, interactions, their environment and time are key contributors to emergence, even though there is no simple relationship between them"* (Dobrescu & Purcarea, 2011).

*mechanisms of form generation in which self-organization plays a central role."*

quadrupedalism for instance, is the most impressive contradictory example of this law. Accordingly, Siler and Brown (2011) stated that "*Dollo's law came into question recently with the advent of phylogenetic methods and new tools for ancestral character state reconstruction… The results of our study join a nascent body of literature showing strong statistical support for character loss, followed by evolutionarily reacquisition of complex structures…"*

Actually, atavism was first demonstrated more than a hundred years ago by Castle (1906; cited by Wright, 1978) who succeeded in obtaining guinea-pigs with well-developed little toes after selective breeding these animals, which normally have three toes. This phenomenon was later explained as "*atavistic polydactyly"* (Wright, 1978). Tomic and Meyer-Rochow (2011) provided more convincing examples for the atavistic features in their review article about atavism, such as whales with rudimentary hind limbs (Hall, 1984), coccygeal projections as truly atavistic human tails (Dubrow et al., 1988), a mutant mouse without tail formation due to down-regulated signaling in the Wnt-3a gene (Chan et al., 2002). These are structural throwbacks, in contrast to human quadrupedalism, which is an example of a functional throwback, which may also be defined as "*evolution in reverse character."* These apparently violate Dollo's law, and, since 1893—Dollo's time—there have been numerous studies demonstrating violations of this law (Galis et al., 2010; Wiens., 2011), such as Wiens (2011), who reported the re-evolution of mandibular teeth lost 230 MYA in the frog *Gastrotheca,* which reappeared in the last 5-17 million years. Moreover, the lost wings in stick insects were re-evolved, suggesting that "*living developmental pathways are conserved in wingless phasmids"* (Whiting et al., 2003); lost digits were re-evolved in lizards (Galis et al., 2010), etc. These studies, concerning the process of re-evolution, are consistent with the concept of evolution in reverse, both involving the conserved patterns of the ancestral characters or structures acquired millions of years ago, and emerging much later during the developmental constraints.

#### **8. Complex systems and self-organization**

A dictionary definition of the word "complex" is: *"consisting of interconnected or interwoven parts"* (Bar-Yam, 1997, p. 1). Examples for complex systems are governments, families, the human body in its physiological perspective, an individual in psychological perspective, the brain, weather, the ecosystem of the world, and sub-world ecosystems such as desert, rainforest, ocean, etc. The complex systems involve parts, which are interconnected or interwoven, contrary to simple systems. Single independent disciplines diverge as specific knowledge increases in simple systems, but the behavior of the parts must be considered as a whole consisting of converging disciplines with interacting elements creating the behavior of the whole.

Many complex systems in physics have the tendency to spontaneously generate novel and organized forms, such as ice crystals, galactic spirals, cloud formations, or lightning flashes in the sky, or polygonal impressions in the earth. Fig. 15 illustrates self-organized landscapes in Turkey: on the left, terraces, travertines in Pamukkale (cotton castle) spontaneously made of carbonate minerals left by the flowing warm water. The other pictures are "fairy chimneys" rock formations in Cappadocia, which were also spontaneously formed through volcanic activity (some three million years ago), wind, water, and temperature fluctuations. Residents believed the region was inhabited by fairies. These formations are in no way designed by anyone or anything, not even by natural

quadrupedalism for instance, is the most impressive contradictory example of this law. Accordingly, Siler and Brown (2011) stated that "*Dollo's law came into question recently with the advent of phylogenetic methods and new tools for ancestral character state reconstruction… The results of our study join a nascent body of literature showing strong statistical support for character*

Actually, atavism was first demonstrated more than a hundred years ago by Castle (1906; cited by Wright, 1978) who succeeded in obtaining guinea-pigs with well-developed little toes after selective breeding these animals, which normally have three toes. This phenomenon was later explained as "*atavistic polydactyly"* (Wright, 1978). Tomic and Meyer-Rochow (2011) provided more convincing examples for the atavistic features in their review article about atavism, such as whales with rudimentary hind limbs (Hall, 1984), coccygeal projections as truly atavistic human tails (Dubrow et al., 1988), a mutant mouse without tail formation due to down-regulated signaling in the Wnt-3a gene (Chan et al., 2002). These are structural throwbacks, in contrast to human quadrupedalism, which is an example of a functional throwback, which may also be defined as "*evolution in reverse character."* These apparently violate Dollo's law, and, since 1893—Dollo's time—there have been numerous studies demonstrating violations of this law (Galis et al., 2010; Wiens., 2011), such as Wiens (2011), who reported the re-evolution of mandibular teeth lost 230 MYA in the frog *Gastrotheca,* which reappeared in the last 5-17 million years. Moreover, the lost wings in stick insects were re-evolved, suggesting that "*living developmental pathways are conserved in wingless phasmids"* (Whiting et al., 2003); lost digits were re-evolved in lizards (Galis et al., 2010), etc. These studies, concerning the process of re-evolution, are consistent with the concept of evolution in reverse, both involving the conserved patterns of the ancestral characters or structures acquired millions of years ago, and emerging much later during the

A dictionary definition of the word "complex" is: *"consisting of interconnected or interwoven parts"* (Bar-Yam, 1997, p. 1). Examples for complex systems are governments, families, the human body in its physiological perspective, an individual in psychological perspective, the brain, weather, the ecosystem of the world, and sub-world ecosystems such as desert, rainforest, ocean, etc. The complex systems involve parts, which are interconnected or interwoven, contrary to simple systems. Single independent disciplines diverge as specific knowledge increases in simple systems, but the behavior of the parts must be considered as a whole consisting of converging disciplines with interacting elements creating the behavior

Many complex systems in physics have the tendency to spontaneously generate novel and organized forms, such as ice crystals, galactic spirals, cloud formations, or lightning flashes in the sky, or polygonal impressions in the earth. Fig. 15 illustrates self-organized landscapes in Turkey: on the left, terraces, travertines in Pamukkale (cotton castle) spontaneously made of carbonate minerals left by the flowing warm water. The other pictures are "fairy chimneys" rock formations in Cappadocia, which were also spontaneously formed through volcanic activity (some three million years ago), wind, water, and temperature fluctuations. Residents believed the region was inhabited by fairies. These formations are in no way designed by anyone or anything, not even by natural

*loss, followed by evolutionarily reacquisition of complex structures…"*

developmental constraints.

of the whole.

**8. Complex systems and self-organization**

selection, being entirely the art of nature with self-organizing properties within dynamical complex systems, following the principle: "*the sum of the parts is greater than the parts taken independently,"* contrary to Sir Isaac Newton who argued: "*the motion of the whole is the sum of the motion of all the parts."*

Fig. 15. Examples of self-organized nature: left and center, travertines, terraces spontaneously made of carbonate minerals left by the flowing warm water in Pamukkale ("cotton castle"), Turkey: right, "Fairy Chimneys" (roof-like formations) in Cappadocia, Turkey, spontaneously formed from the solidified lava streams, ash, and tuff stone, through rain, wind, and temperature fluctuations.

The above exemplified natural complex systems, with a strong tendency to self-organize, may also be applied to biological systems. For instance, insects can spontaneously build nests or hives, hunt in groups, and explore the food resources of their environment (Camazine et al., 2002), like the formation of the colored patterns of many creatures such as butterflies, zebras, jaguars, etc (Ball, 2001). The self-organization, *i.e.*, "*the spontaneous formation of patterns and pattern change in open nonequilibrium systems"* (Kelso, 1995, preface), is essentially the quintessence of all living systems. The evolution of the biological forms and structures may also be associated with self-organization. In this context, some authors have questioned the centrality of natural selection in evolution, since Darwinism essentially ignores the principles of self-organization. Accordingly, Waldrop (1990) suggested:

*"Complex dynamic systems can sometimes go spontaneously from randomness to order; it is a driving force in evolution? Have we missed something about evolution—some key principle that has shaped the development of life in ways quite different from natural selection, genetic drift, and all the other mechanisms biologists have evoked over years?... Yes! And the missing element… is spontaneous self-organization: the tendency of complex dynamical systems to fall into an ordered state without any selection process whatsoever."*

#### Oudeyer (2006, p.1) also suggested:

*"Thus, the explanation of the origins of forms and structures in the living can not only rely on the principle of natural selection, which should be complemented by the understanding of physical mechanisms of form generation in which self-organization plays a central role."*

The process of self-organization is closely coupled with "emergence," a fundamental property of complex systems: *"a new property or behavior, which appears due to non-linear interactions within the system; emergence may be considered the product or by-product of the system… It is the product of interconnections and the interaction makes it dynamic and unpredictable; entities, interactions, their environment and time are key contributors to emergence, even though there is no simple relationship between them"* (Dobrescu & Purcarea, 2011).

Üner Tan Syndrome: Review and Emergence of

Fig. 17. Types of attractors.

Human Quadrupedalism in Self-Organization, Attractors and Evolutionary Perspectives 27

The emergence of unpredictable outcomes within a complex system such as the human body is closely related to neural networks in the brain exhibiting "*self-organized criticality*" (Tetzlaff et al., 2010), which may play a role in the developmental processes with emergent outcomes as exemplified above for the emergence of new locomotor patterns. Although the self -organization remains an enigma in many respects, "*it is realized that no discipline on its own will be able to solve the enigma"* (Skar, 2003). By definition, however, "*organization arises through the interaction of its components (endogenously) or by some environmental influence (exogenously). Self-organization is neither and the curious thing is that no external force can be identified as the organizer… self-organization seems to be characterized by the almost spontaneous creation of global or semi-global patterns developed from local interactions among independent and autonomous components or agents. Creation and patterns are two basic components of selforganization. Patterns are often visible and transient, while creation is less visible and mysterious. Creation of self-organization is, as a special case, believed to be triggered by 'strange attractors'"*  (Skar, 2003). An attractor can be defined as a kind of steady state in a dynamical system, or, "*a set of states of a dynamical physical system toward which that system tends to evolve, regardless of the starting conditions of the system."* There are three kinds of attractor: point attractor, periodic attractor, and strange attractor. "*A strange (or chaotic) attractor is an attractor for which the evolution through the set of possible physical states is nonperiodic (chaotic), resulting in an evolution through a set of states defining a fractal set. Most real physical systems (including the actual orbits of planets) involve strange attractors"*  (http://science.yourdictionary.com/attractor. Fig. 17 shows different types of attractors.

The brain itself has strange attractors, which are involved in each particular activity.

For instance, the EEG plots showing the brain activity may exhibit one type of strange attractor while a person is at rest, but another type of strange attractor during, for instance, mathematical thinking. The unpredictability of consciousness may also be considered a strange attractor, or what we call "personality," as the consciousness itself is also a strange attractor. The brain, as a dynamic system with many strange attractors, may show state transitions, thereby creating novel and unpredictable patterns, such as during the postnatal development of children. For instance, various locomotion patterns or locomotor strange attractors may emerge during postnatal motor development in children and even in adult individuals. The common property of strange attractors is their unpredictability, which is one of the main constraints for the applicability of the physical concept of self-organization

As mentioned above, different genes are found associated with a clinical condition. For UTS, we already know three genes which may be associated with the human quadrupedalism. However, considering the dynamical system theory, and the principles of self-organization, no genetic or neural code may be the causative factor for the human quadrupedalism. There are also rarely occurring cases of patients who had childhood poliomyelitis, and who have normal brains, speech, intelligence etc., and who also prefer walking on all four extremities, rejecting all measures to assist them to walk upright, such as using crutches. The first case noted of walking on all fours following childhood poliomyelitis was photographed by Eadweard Muybridge (1887, 1901), with photographs taken in rapid succession to create a movie using his zoopraxiscope (see Fig. 16). Despite his paralyzed leg the boy exhibited diagonal-sequence quadrupedal locomotion.

Fig. 16. Child with a paralyzed leg walking on all fours (Muybridge, 1901). Notice the diagonal-sequence quadrupedal locomotion with interference between the left foot and left hand.

This kind of adaptation to locomotor constraints occurs as a polio sequel in only a few individuals among millions of cases, as an emergent property of a complex system consisting of the mind-brain-body triad in human beings (Tan, 2007b). Much later, an adult man with a paralyzed leg as a polio sequel was reported (Tan, 2007a), who had an entirely normal brain and cognition, but who preferred quadrupedal locomotion, even though his father forced him to walk upright using crutches. Interestingly, these cases used diagonalsequence quadrupedal locomotion.

There are millions of individuals with paralyzed legs as a result of polio, but the walking patterns these few cases exhibited are extremely rare. This suggests that the creation of an extremely rarely occurring motor pattern would occur randomly without any influence of a previously established genetic or neural code. This hypothesis may also be reasonably applied to the UTS cases for the emergence of a well-developed, easily performed quadrupedalism (habitual walking on all four extremities). UTS is also a rarely occurring condition, suggesting randomly occurring events in the emergence of human quadrupedalism. As mentioned above, the unpredictable outcomes of a complex system are related to the principles of the self-organizing processes.

The emergence of unpredictable outcomes within a complex system such as the human body is closely related to neural networks in the brain exhibiting "*self-organized criticality*" (Tetzlaff et al., 2010), which may play a role in the developmental processes with emergent outcomes as exemplified above for the emergence of new locomotor patterns. Although the self -organization remains an enigma in many respects, "*it is realized that no discipline on its own will be able to solve the enigma"* (Skar, 2003). By definition, however, "*organization arises through the interaction of its components (endogenously) or by some environmental influence (exogenously). Self-organization is neither and the curious thing is that no external force can be identified as the organizer… self-organization seems to be characterized by the almost spontaneous creation of global or semi-global patterns developed from local interactions among independent and autonomous components or agents. Creation and patterns are two basic components of selforganization. Patterns are often visible and transient, while creation is less visible and mysterious. Creation of self-organization is, as a special case, believed to be triggered by 'strange attractors'"*  (Skar, 2003). An attractor can be defined as a kind of steady state in a dynamical system, or, "*a set of states of a dynamical physical system toward which that system tends to evolve, regardless of the starting conditions of the system."* There are three kinds of attractor: point attractor, periodic attractor, and strange attractor. "*A strange (or chaotic) attractor is an attractor for which the evolution through the set of possible physical states is nonperiodic (chaotic), resulting in an evolution through a set of states defining a fractal set. Most real physical systems (including the actual orbits of planets) involve strange attractors"*  (http://science.yourdictionary.com/attractor. Fig. 17 shows different types of attractors. The brain itself has strange attractors, which are involved in each particular activity.

Fig. 17. Types of attractors.

26 Latest Findings in Intellectual and Developmental Disabilities Research

As mentioned above, different genes are found associated with a clinical condition. For UTS, we already know three genes which may be associated with the human quadrupedalism. However, considering the dynamical system theory, and the principles of self-organization, no genetic or neural code may be the causative factor for the human quadrupedalism. There are also rarely occurring cases of patients who had childhood poliomyelitis, and who have normal brains, speech, intelligence etc., and who also prefer walking on all four extremities, rejecting all measures to assist them to walk upright, such as using crutches. The first case noted of walking on all fours following childhood poliomyelitis was photographed by Eadweard Muybridge (1887, 1901), with photographs taken in rapid succession to create a movie using his zoopraxiscope (see Fig. 16). Despite his paralyzed leg the boy exhibited

Fig. 16. Child with a paralyzed leg walking on all fours (Muybridge, 1901). Notice the diagonal-sequence quadrupedal locomotion with interference between the left foot and left

This kind of adaptation to locomotor constraints occurs as a polio sequel in only a few individuals among millions of cases, as an emergent property of a complex system consisting of the mind-brain-body triad in human beings (Tan, 2007b). Much later, an adult man with a paralyzed leg as a polio sequel was reported (Tan, 2007a), who had an entirely normal brain and cognition, but who preferred quadrupedal locomotion, even though his father forced him to walk upright using crutches. Interestingly, these cases used diagonal-

There are millions of individuals with paralyzed legs as a result of polio, but the walking patterns these few cases exhibited are extremely rare. This suggests that the creation of an extremely rarely occurring motor pattern would occur randomly without any influence of a previously established genetic or neural code. This hypothesis may also be reasonably applied to the UTS cases for the emergence of a well-developed, easily performed quadrupedalism (habitual walking on all four extremities). UTS is also a rarely occurring condition, suggesting randomly occurring events in the emergence of human quadrupedalism. As mentioned above, the unpredictable outcomes of a complex system are

diagonal-sequence quadrupedal locomotion.

hand.

sequence quadrupedal locomotion.

related to the principles of the self-organizing processes.

For instance, the EEG plots showing the brain activity may exhibit one type of strange attractor while a person is at rest, but another type of strange attractor during, for instance, mathematical thinking. The unpredictability of consciousness may also be considered a strange attractor, or what we call "personality," as the consciousness itself is also a strange attractor. The brain, as a dynamic system with many strange attractors, may show state transitions, thereby creating novel and unpredictable patterns, such as during the postnatal development of children. For instance, various locomotion patterns or locomotor strange attractors may emerge during postnatal motor development in children and even in adult individuals. The common property of strange attractors is their unpredictability, which is one of the main constraints for the applicability of the physical concept of self-organization

Üner Tan Syndrome: Review and Emergence of

jerking legs (palmigrade saltatoric locomotion).

man (right).

poliomyelitis.

constraints.

adaptive behavior (Tschacher et al., 2003).

Human Quadrupedalism in Self-Organization, Attractors and Evolutionary Perspectives 29

Fig. 19 illustrates further locomotor strange attractors in a paraplegic woman (left) and a

Both of them had had childhood poliomyelitis, and could not ambulate at all as a result. The woman always rejected crutches to help her to walk upright, but instead she spontaneously created an entirely novel walking style to ambulate around without assistance, by holding her ankles with her hands to travel forward and backward. The locomotion of the woman with a childhood polio sequel also occurs extremely rarely, there being one individual in Adana and another one in Istanbul, nearly 1000 km away from each other. The woman is now in her fifties, and she has managed using this type of locomotion since she was eight years old, after years of effort. The man in Fig. 19 also rejected crutches to help him to walk upright on two legs. Instead he developed another strange attractor: palm walking with

Fig. 19. Examples of strange attractors: walking patterns of a paraplegic woman (left) and a

The couple shown in Fig. 20 may also illustrate strange attractors. The father and mother were both paraplegic individuals due to childhood polio sequels, but when she was 10 years old the woman had learned to ambulate after long periods of exercise, and had learned to use palm walking with jerking legs with the help of her hip muscles, i.e., she exhibited saltatoric palm-walking. Her husband, despite having the same clinical picture, could not ambulate, but rather remained sitting without assistance. These two cases were also good examples of the emergence of strange attractors triggered by severe locomotor

As mentioned above, these adaptive self-organization phenomena may provide basic explanations for the emergence of the locomotor strange attractors, such as walking on all four extremities (face-down), inverse quadrupedalism (face-up), saltatoric palm-walking, and grasping-foot walking. In essence, the dynamical systems tend to control the outcome pattern of the system to find a compromise between "*which patterns can possibly be built from the systems components to begin with, and the structural constraints of the environmental situation*," and a synergetic pattern formation—with possible strange attractors—may be "intentional," with the self-organization phenomena being basic explanations for the

man (right) both having emerged at about eight years of age, following childhood

to biological systems. However, new insights have been gained through increasing cooperation between biological sciences and computer modeling. For instance, biocomputational models of the primary visual cortex have revealed new and unpredictable lateral connectivities among neural networks emerging through input-driven selforganization (Skar, 2003). So there may be some inputs or common factors triggering the self-organizing process in a complex system. The common factor for individuals with UTS to trigger (input) a locomotor strange attractor, i.e., diagonal-sequence quadrupedal locomotion like the non-human primates, was their disability or difficulty in achieving upright walking. The rarely occurring locomotor pattern in UTS cases may be related to the unpredictability of the strange attractors.

An entirely different locomotor strange attractor emerged in a man from Tanzania, who exhibited all the symptoms of UTS, including no upright ambulation, quadrupedal locomotion, no speech, and impaired intelligence. However, an entirely new and unpredictable locomotor posture emerged in this man, as a strange attractor. Namely, the Tanzania man (Fig. 18) exhibited the same phenotype as UTS (Type-I) with truncal ataxia, inability to stand up and walk upright without assistance, mental retardation, no speech, no conscious experience, and walking on all four extremities, without early hypotonia. However, his quadrupedal locomotion was upside down, i.e., in face-up position. He used his hands and feet for locomotion, but used palms and heels instead of the soles. This is the first case reported in the scientific literature exhibiting UTS with quadrupedal locomotion but in reverse posture with face-up position.

Fig. 18. Tanzania man with UTS, walking on all fours but with inverse quadrupedal locomotion.

to biological systems. However, new insights have been gained through increasing cooperation between biological sciences and computer modeling. For instance, biocomputational models of the primary visual cortex have revealed new and unpredictable lateral connectivities among neural networks emerging through input-driven selforganization (Skar, 2003). So there may be some inputs or common factors triggering the self-organizing process in a complex system. The common factor for individuals with UTS to trigger (input) a locomotor strange attractor, i.e., diagonal-sequence quadrupedal locomotion like the non-human primates, was their disability or difficulty in achieving upright walking. The rarely occurring locomotor pattern in UTS cases may be related to the

An entirely different locomotor strange attractor emerged in a man from Tanzania, who exhibited all the symptoms of UTS, including no upright ambulation, quadrupedal locomotion, no speech, and impaired intelligence. However, an entirely new and unpredictable locomotor posture emerged in this man, as a strange attractor. Namely, the Tanzania man (Fig. 18) exhibited the same phenotype as UTS (Type-I) with truncal ataxia, inability to stand up and walk upright without assistance, mental retardation, no speech, no conscious experience, and walking on all four extremities, without early hypotonia. However, his quadrupedal locomotion was upside down, i.e., in face-up position. He used his hands and feet for locomotion, but used palms and heels instead of the soles. This is the first case reported in the scientific literature exhibiting UTS with quadrupedal locomotion

Fig. 18. Tanzania man with UTS, walking on all fours but with inverse quadrupedal

unpredictability of the strange attractors.

but in reverse posture with face-up position.

locomotion.

Fig. 19 illustrates further locomotor strange attractors in a paraplegic woman (left) and a man (right).

Both of them had had childhood poliomyelitis, and could not ambulate at all as a result. The woman always rejected crutches to help her to walk upright, but instead she spontaneously created an entirely novel walking style to ambulate around without assistance, by holding her ankles with her hands to travel forward and backward. The locomotion of the woman with a childhood polio sequel also occurs extremely rarely, there being one individual in Adana and another one in Istanbul, nearly 1000 km away from each other. The woman is now in her fifties, and she has managed using this type of locomotion since she was eight years old, after years of effort. The man in Fig. 19 also rejected crutches to help him to walk upright on two legs. Instead he developed another strange attractor: palm walking with jerking legs (palmigrade saltatoric locomotion).

Fig. 19. Examples of strange attractors: walking patterns of a paraplegic woman (left) and a man (right) both having emerged at about eight years of age, following childhood poliomyelitis.

The couple shown in Fig. 20 may also illustrate strange attractors. The father and mother were both paraplegic individuals due to childhood polio sequels, but when she was 10 years old the woman had learned to ambulate after long periods of exercise, and had learned to use palm walking with jerking legs with the help of her hip muscles, i.e., she exhibited saltatoric palm-walking. Her husband, despite having the same clinical picture, could not ambulate, but rather remained sitting without assistance. These two cases were also good examples of the emergence of strange attractors triggered by severe locomotor constraints.

As mentioned above, these adaptive self-organization phenomena may provide basic explanations for the emergence of the locomotor strange attractors, such as walking on all four extremities (face-down), inverse quadrupedalism (face-up), saltatoric palm-walking, and grasping-foot walking. In essence, the dynamical systems tend to control the outcome pattern of the system to find a compromise between "*which patterns can possibly be built from the systems components to begin with, and the structural constraints of the environmental situation*," and a synergetic pattern formation—with possible strange attractors—may be "intentional," with the self-organization phenomena being basic explanations for the adaptive behavior (Tschacher et al., 2003).

Üner Tan Syndrome: Review and Emergence of

beings.

walking, trotting, and galloping (Shik et al., 1966).

*fictive locomotion, has no direct equivalent in humans."*

Human Quadrupedalism in Self-Organization, Attractors and Evolutionary Perspectives 31

electrical stimulation of this region induced different patterns of quadrupedal locomotion:

CPGs were also demonstrated in animals other than cats, including a wide variety of invertebrates and vertebrates (see Rossignol & Dubue, 1994, for a review).The presence of the CPGs in primates, including human beings, would be interesting, since the primate locomotion may not be related to the spontaneous or induced activity of the previously established spinal circuits because of the strong supraspinal control of the lower motor neurons. In accord with this, no stepping in hind limbs occurred in the macaque monkeys following spinalization (Eidelberg, 1981). This could be due to the increased role of the tractus corticospinals in primates, in suppressing the locomotor circuitry within the spinal cord by increased corticospinal control on the lower motoneuronal system for the relatively rough walking movements, and in facilitating skilled hand movements, especially in human

In this context, Duysens et al. (1998) argued that, *"For Old World monkeys and higher primates the evidence is much less convincing."* In humans, newborn infants may exhibit primitive steplike movements with external assistance (Forssberg, 1985). These stereotyped movements of newborns may be the basis for the adult locomotor patterns. The prenatal stepping movements were also considered to be further evidence for the hard-wired intraspinal circuits for locomotion. However, these prenatal and postnatal observations may not show the existence of the spontaneously active intraspinal CPGs in human beings. As Duysens et al. (1998) concluded: *"In contrast to the abundance of data in cats… there is relatively little known about spinal networks acting like CPGs in humans. The most convincing evidence for a CPG, i.e.,*

In light of the dynamical systems theory, the concept of CPGs formerly invoked much interest among motor neurophysiologists studying the origins of quadrupedal locomotion, but did not find supporters among system theoreticians. For instance, Cohen (1992) suggested that, *"it is not possible to speak of the command neurons driving the CPG since they are both driving each other. As a consequence of the mutual interaction within the system, each portion of the system contributes its own peculiar properties and constraints to the final output."* Moreover, Thelen & Smith (1996) argued, *"the notion of the CPGs as the essence of locomotion does not fit the data… They simply do not account for what we really observe in developing organisms… The fact of development is not explained by a list of innate ideas. Just as the assumption of a built-in CPG does not explain the development of walking."* The CPG was considered to be a "motor program" by some experimental psychologists. Rosenbaum & Saltzman (1984) explained the motor program as, *"before the execution of a sequence of voluntary movements, a memory representation for instructions for the entire sequence is thought to be established in the central nervous system … (p.51). The motor program construct has not successively accounted for the hallmark of human intentional actions: their functional adaptability (p.74). …both the CPG and the motor program… consider movement to be generated by 'pure' neural commands" (p.75).* In this context, Thelen and Smith (1994) stated that, *"Real data from real frogs, chicks, cats, and humans render the construct of the CPG illusory… the motor program construct has not successively accounted for the hallmark of human intentional actions: their functional adaptability. If the motor program contains the instructions for the entire sequence of behaviors ahead of time, how can novel and adapted forms be generated?"* (p.74). On the other hand, the CPGs are not static, previously hard-wired, firmly organized systems, but instead are rather loosely organized systems under the influence of

Fig. 20. Family with paraplegic mother and father. The mother was able to walk on her palms with jerking legs (saltatoric palm walking), but the father could not ambulate, despite having the same polio sequel as the mother

#### **9. Central pattern generators; motor programs**

A central pattern generator (CPG) for locomotion is a set of motoneurons responsible for creating a motor pattern (Grillner, 1985). Human quadrupedalism might be associated with CPGs, which are embedded in the spinal cord, spontaneously producing rhythmic locomotor activity (Hooper, 2000) without being controlled by the supraspinal centers above the brain stem (Hiebert et al., 2006). The spinal motor system seems to be similar in all quadrupeds and humans (Dietz, 2002). Individuals with or without UTS all use the same neural networks associated with diagonal-sequence quadrupedal locomotion as the nonhuman primates, probably because they all are using the common neuronal control mechanisms for locomotion (Shapiro & Jungers, 1994).

Until the discovery of CPGs, the dominant idea about the mechanisms of locomotion was based on the proprioceptive information and intact descending control from supraspinal centers, considering the results on spinal reflexes and the clinical observation of flaccid paralysis following spinal cord injury (Clarac, 2008). However, it was found in different laboratories that deafferented crayfish sometimes continued to produce spontaneous rhythmic bursts in motor axons innervating the leg muscles (Hughes & Wiersma, 1960). In accord with these findings, Wilson (1961) suggested *"it seems not too early to conclude that central oscillators in anthropods are of such fundamental importance that they are used even when other mechanisms might suffice."* These neural oscillators are characteristic of cyclic activities in many species. *"For locomotion, one usually refers to the term central pattern generator (CPG) to indicate a set of neurons responsible for creating a motor pattern. It should be emphasized indeed that 'pattern' is used here in a broad sense to indicate alternating activity in groups of flexors and extensors. Hence it is not implied that an overground walking animal would use the same pattern of muscle activation as the one seen."* (Duysens et al., 1998). These centrally generated spontaneous motoneuronal bursts, are, however, not the origin of normal locomotion in intact animals. Moreover, the CPGs do not reflect the coordinated walking pattern in intact animals, since it was shown that there are separate CPGs for each leg in the cat (Duysens et al., 1998). On the other hand, it was originally shown that spinalized cats with cut dorsal roots exhibited alternating contractions in ankle extensor and flexor muscles (Brown, 1911, 1912). The coordinated locomotor activity inducing quadrupedal locomotor movements was, however, produced by electrical stimulation of a specific region in the brainstem located below the intercollicular transection of decerebrate cats (the mesencephalic locomotor region) (Shik & Orlovsky, 1976). Depending on the stimulus strengths, the

Fig. 20. Family with paraplegic mother and father. The mother was able to walk on her palms with jerking legs (saltatoric palm walking), but the father could not ambulate, despite

A central pattern generator (CPG) for locomotion is a set of motoneurons responsible for creating a motor pattern (Grillner, 1985). Human quadrupedalism might be associated with CPGs, which are embedded in the spinal cord, spontaneously producing rhythmic locomotor activity (Hooper, 2000) without being controlled by the supraspinal centers above the brain stem (Hiebert et al., 2006). The spinal motor system seems to be similar in all quadrupeds and humans (Dietz, 2002). Individuals with or without UTS all use the same neural networks associated with diagonal-sequence quadrupedal locomotion as the nonhuman primates, probably because they all are using the common neuronal control

Until the discovery of CPGs, the dominant idea about the mechanisms of locomotion was based on the proprioceptive information and intact descending control from supraspinal centers, considering the results on spinal reflexes and the clinical observation of flaccid paralysis following spinal cord injury (Clarac, 2008). However, it was found in different laboratories that deafferented crayfish sometimes continued to produce spontaneous rhythmic bursts in motor axons innervating the leg muscles (Hughes & Wiersma, 1960). In accord with these findings, Wilson (1961) suggested *"it seems not too early to conclude that central oscillators in anthropods are of such fundamental importance that they are used even when other mechanisms might suffice."* These neural oscillators are characteristic of cyclic activities in many species. *"For locomotion, one usually refers to the term central pattern generator (CPG) to indicate a set of neurons responsible for creating a motor pattern. It should be emphasized indeed that 'pattern' is used here in a broad sense to indicate alternating activity in groups of flexors and extensors. Hence it is not implied that an overground walking animal would use the same pattern of muscle activation as the one seen."* (Duysens et al., 1998). These centrally generated spontaneous motoneuronal bursts, are, however, not the origin of normal locomotion in intact animals. Moreover, the CPGs do not reflect the coordinated walking pattern in intact animals, since it was shown that there are separate CPGs for each leg in the cat (Duysens et al., 1998). On the other hand, it was originally shown that spinalized cats with cut dorsal roots exhibited alternating contractions in ankle extensor and flexor muscles (Brown, 1911, 1912). The coordinated locomotor activity inducing quadrupedal locomotor movements was, however, produced by electrical stimulation of a specific region in the brainstem located below the intercollicular transection of decerebrate cats (the mesencephalic locomotor region) (Shik & Orlovsky, 1976). Depending on the stimulus strengths, the

having the same polio sequel as the mother

**9. Central pattern generators; motor programs**

mechanisms for locomotion (Shapiro & Jungers, 1994).

electrical stimulation of this region induced different patterns of quadrupedal locomotion: walking, trotting, and galloping (Shik et al., 1966).

CPGs were also demonstrated in animals other than cats, including a wide variety of invertebrates and vertebrates (see Rossignol & Dubue, 1994, for a review).The presence of the CPGs in primates, including human beings, would be interesting, since the primate locomotion may not be related to the spontaneous or induced activity of the previously established spinal circuits because of the strong supraspinal control of the lower motor neurons. In accord with this, no stepping in hind limbs occurred in the macaque monkeys following spinalization (Eidelberg, 1981). This could be due to the increased role of the tractus corticospinals in primates, in suppressing the locomotor circuitry within the spinal cord by increased corticospinal control on the lower motoneuronal system for the relatively rough walking movements, and in facilitating skilled hand movements, especially in human beings.

In this context, Duysens et al. (1998) argued that, *"For Old World monkeys and higher primates the evidence is much less convincing."* In humans, newborn infants may exhibit primitive steplike movements with external assistance (Forssberg, 1985). These stereotyped movements of newborns may be the basis for the adult locomotor patterns. The prenatal stepping movements were also considered to be further evidence for the hard-wired intraspinal circuits for locomotion. However, these prenatal and postnatal observations may not show the existence of the spontaneously active intraspinal CPGs in human beings. As Duysens et al. (1998) concluded: *"In contrast to the abundance of data in cats… there is relatively little known about spinal networks acting like CPGs in humans. The most convincing evidence for a CPG, i.e., fictive locomotion, has no direct equivalent in humans."*

In light of the dynamical systems theory, the concept of CPGs formerly invoked much interest among motor neurophysiologists studying the origins of quadrupedal locomotion, but did not find supporters among system theoreticians. For instance, Cohen (1992) suggested that, *"it is not possible to speak of the command neurons driving the CPG since they are both driving each other. As a consequence of the mutual interaction within the system, each portion of the system contributes its own peculiar properties and constraints to the final output."* Moreover, Thelen & Smith (1996) argued, *"the notion of the CPGs as the essence of locomotion does not fit the data… They simply do not account for what we really observe in developing organisms… The fact of development is not explained by a list of innate ideas. Just as the assumption of a built-in CPG does not explain the development of walking."* The CPG was considered to be a "motor program" by some experimental psychologists. Rosenbaum & Saltzman (1984) explained the motor program as, *"before the execution of a sequence of voluntary movements, a memory representation for instructions for the entire sequence is thought to be established in the central nervous system … (p.51). The motor program construct has not successively accounted for the hallmark of human intentional actions: their functional adaptability (p.74). …both the CPG and the motor program… consider movement to be generated by 'pure' neural commands" (p.75).* In this context, Thelen and Smith (1994) stated that, *"Real data from real frogs, chicks, cats, and humans render the construct of the CPG illusory… the motor program construct has not successively accounted for the hallmark of human intentional actions: their functional adaptability. If the motor program contains the instructions for the entire sequence of behaviors ahead of time, how can novel and adapted forms be generated?"* (p.74). On the other hand, the CPGs are not static, previously hard-wired, firmly organized systems, but instead are rather loosely organized systems under the influence of

Üner Tan Syndrome: Review and Emergence of

million years since the Devonian tetrapod-like fishes.

non-human primates walking on all four extremities.

and environmental subsystems.

cerebellar ataxias.

Human Quadrupedalism in Self-Organization, Attractors and Evolutionary Perspectives 33

process, consisting of many decentralized and local interactions among neuronal, genetic,

UTS was divided into two subgroups: Type-I and Type-II, the former exhibiting no hypotonia, and the latter being associated with early hypotonia. The comparison with other closely related syndromes, such as DES, Cayman ataxia, and Joubert syndrome, indicated that UTS may be distinguished from these syndromes by habitual locomotion on all four extremities, normal stature, and normal muscle tone in Type-I cases, but early hypotonia in Type-II cases. For these reasons, UTS may be considered a distinct entity among the

The most remarkable characteristic of UTS is diagonal-sequence quadrupedal locomotion, similar to the non-human primates and contrary to non-primate species. The evolutionary advantage of diagonal-sequence quadrupedal locomotion is not known. However, interestingly, there seems to be an evolutionary advantage of this type of locomotion for primate evolution, with regard to the emergence of complex neural circuits with related highly complex structures. Namely, only primates with diagonal-sequence quadrupedal locomotion followed an evolution favoring larger brains, highly developed cognitive abilities, highly developed hand skills, and language, with erect posture and bipedal locomotion, creating the unity of human beings. The non-primate mammals using lateralsequence quadrupedal locomotion did not show a similar phylogenetic progress compared to those with diagonal-sequence quadrupedal locomotion, which, in essence, was the phylogenetically oldest type of locomotion since it was a characteristic of the first tetrapods during the Devonian period. This suggests that the ancestral neural networks responsible for the diagonal-sequence quadrupedal locomotion were reserved for at least nearly 400

The human quadrupedal locomotion seen in UTS showed some similarities with nonhuman primates. For instance, the human quadrupeds supported their body weight more on the feet than on the hands during quadrupedal locomotion, in a similar way to the weight distribution during location in most non-human primates. In contrast, non-primate quadrupedal mammals usually support their body weight more on the forelimbs than their hind limbs. The body weight support patterns in non-human and human primates suggests that the reduced body weight on hands than feet would be beneficial for the development of fine hand skills in primates. The complete freeing of hands in human beings during upright walking would be entirely associated with highly developed hand skills compared to the

It was suggested that UTS may be considered a further example for Darwinian diseases, which may be associated with an evolutionary understanding of the disorders using evolutionary principles, such as natural selection. In this context, UTS may also be considered a disease with phylogenetic regression. In some UTS cases, the supraorbital tori were remarkably prominent, and were more or less similar to those in non-human primates. This was taken to be an ancestral feature, in addition to the diagonal-sequence quadrupedal

Human quadrupedalism was proposed to be a phenotypic example of evolution in reverse, i.e., the reacquisition by derived populations of the same character states as those of ancestor

locomotion, and the body weight being supported predominantly by the hind legs.

the steadily changing chemical or sensory control, with newly emerged functional circuits (Selverston, 1988, cited by Kelso, 1995, p.243). Consequently, they exhibit one of the principles of biological self-organization, i.e., different neural networks can induce similar outcomes (tasks), while similar neural networks can produce different outcomes (tasks) (Marder, 1988, cited by Kelso, 1995, p.243). *"Still others are ready to give up, or at least expand the (no longer recognizable) CPG concept to that of a motor pattern network" (Kelso, 1995, p. 243).* A neuronal network such as a CPG can change itself according to current conditions and exhibit transitions between functional states, resulting from dynamic instabilities in the system with dynamic interactions at neuronal, synaptic and network levels. *"At such transitions, self-organization becomes apparent: new and different patterns arise as cooperative states of the coupling among neural elements"* (Kelso, 1995, p.243).

#### **10. Concluding remarks**

Uner Tan syndrome (UTS), discovered in 2005 in Southern Turkey, mainly consists of habitual quadrupedal locomotion, mental retardation, and dysarthric or no speech, with or without cerebello-vermial hypoplasia and mildly simplified cortical gyri. A man walking on all four extremities, probably exhibiting the symptoms of the UTS, was first discovered and reported in 1917, nearly a hundred years ago, by a British traveler on the Middle Black Sea coast, near Samsun, on the famous Baghdad road, during the time of the Ottoman Empire. Between 2005 and 2010, 10 families with 33 cases—13 women (42.4%) and 19 men (57.6%) were discovered in Turkey (see Table 1). In addition, there were two male children (4 and 12 years old) resident in Adana and Istanbul, who were normal in cognitive abilities, with no neurological signs and symptoms, and normal brain MRIs, but with facultative quadrupedal locomotion. Including the cases from Brazil, Iraq, Mexico, and Chile, there were 25 men (64.1%) and 14 women (35.9%) around the world. Statistics showed that the number of men significantly exceeded the number of women (p<.05), suggesting a male preponderance in UTS. Genealogical analysis suggested autosomal recessive transmission linked to chromosome 17p<IP_ADDRESS> with a missense mutation in the WDR81 gene in the affected members of the first described Iskenderun family. Homozygocity was found in two families resident in remote villages of Southern and Northern Turkey, and was mapped to a region on chromosome 9p24 that included the very low density lipoprotein receptor gene, VLDLR. These results suggested that UTS may be a genetically heterogeneous syndrome. Interestingly, the mother of the affected siblings in the Iskenderun family had Type-I diabetes, which may be associated with congenital malformations such as caudal regression in mice, suggesting that the maternal diabetes in some cases with UTS could be associated with neuronal damage, resulting in impaired balance.

UTS can be considered within the framework of the non-progressive autosomal recessive cerebellar ataxias, which are associated with various genetic mutations. Among these conditions, such as disequilibrium syndrome (DES), Cayman ataxia, and Joubert syndrome, there are overlapping symptoms, like truncal ataxia, psychomotor delay, and dysarthric speech. All of these syndromes show genetic heterogeneity, which is characteristic for many diseases. Thus, genetics alone do not seem to be informative for the origins of many syndromes, including UTS. From the viewpoint of dynamical systems theory, there may not be a single factor including a genetic code that predetermines the emergence of human quadrupedalism, seen, for instance, in UTS. Rather, it may involve a self-organization

the steadily changing chemical or sensory control, with newly emerged functional circuits (Selverston, 1988, cited by Kelso, 1995, p.243). Consequently, they exhibit one of the principles of biological self-organization, i.e., different neural networks can induce similar outcomes (tasks), while similar neural networks can produce different outcomes (tasks) (Marder, 1988, cited by Kelso, 1995, p.243). *"Still others are ready to give up, or at least expand the (no longer recognizable) CPG concept to that of a motor pattern network" (Kelso, 1995, p. 243).* A neuronal network such as a CPG can change itself according to current conditions and exhibit transitions between functional states, resulting from dynamic instabilities in the system with dynamic interactions at neuronal, synaptic and network levels. *"At such transitions, self-organization becomes apparent: new and different patterns arise as cooperative states*

Uner Tan syndrome (UTS), discovered in 2005 in Southern Turkey, mainly consists of habitual quadrupedal locomotion, mental retardation, and dysarthric or no speech, with or without cerebello-vermial hypoplasia and mildly simplified cortical gyri. A man walking on all four extremities, probably exhibiting the symptoms of the UTS, was first discovered and reported in 1917, nearly a hundred years ago, by a British traveler on the Middle Black Sea coast, near Samsun, on the famous Baghdad road, during the time of the Ottoman Empire. Between 2005 and 2010, 10 families with 33 cases—13 women (42.4%) and 19 men (57.6%) were discovered in Turkey (see Table 1). In addition, there were two male children (4 and 12 years old) resident in Adana and Istanbul, who were normal in cognitive abilities, with no neurological signs and symptoms, and normal brain MRIs, but with facultative quadrupedal locomotion. Including the cases from Brazil, Iraq, Mexico, and Chile, there were 25 men (64.1%) and 14 women (35.9%) around the world. Statistics showed that the number of men significantly exceeded the number of women (p<.05), suggesting a male preponderance in UTS. Genealogical analysis suggested autosomal recessive transmission linked to chromosome 17p<IP_ADDRESS> with a missense mutation in the WDR81 gene in the affected members of the first described Iskenderun family. Homozygocity was found in two families resident in remote villages of Southern and Northern Turkey, and was mapped to a region on chromosome 9p24 that included the very low density lipoprotein receptor gene, VLDLR. These results suggested that UTS may be a genetically heterogeneous syndrome. Interestingly, the mother of the affected siblings in the Iskenderun family had Type-I diabetes, which may be associated with congenital malformations such as caudal regression in mice, suggesting that the maternal diabetes in some cases with UTS could be associated

UTS can be considered within the framework of the non-progressive autosomal recessive cerebellar ataxias, which are associated with various genetic mutations. Among these conditions, such as disequilibrium syndrome (DES), Cayman ataxia, and Joubert syndrome, there are overlapping symptoms, like truncal ataxia, psychomotor delay, and dysarthric speech. All of these syndromes show genetic heterogeneity, which is characteristic for many diseases. Thus, genetics alone do not seem to be informative for the origins of many syndromes, including UTS. From the viewpoint of dynamical systems theory, there may not be a single factor including a genetic code that predetermines the emergence of human quadrupedalism, seen, for instance, in UTS. Rather, it may involve a self-organization

*of the coupling among neural elements"* (Kelso, 1995, p.243).

with neuronal damage, resulting in impaired balance.

**10. Concluding remarks**

process, consisting of many decentralized and local interactions among neuronal, genetic, and environmental subsystems.

UTS was divided into two subgroups: Type-I and Type-II, the former exhibiting no hypotonia, and the latter being associated with early hypotonia. The comparison with other closely related syndromes, such as DES, Cayman ataxia, and Joubert syndrome, indicated that UTS may be distinguished from these syndromes by habitual locomotion on all four extremities, normal stature, and normal muscle tone in Type-I cases, but early hypotonia in Type-II cases. For these reasons, UTS may be considered a distinct entity among the cerebellar ataxias.

The most remarkable characteristic of UTS is diagonal-sequence quadrupedal locomotion, similar to the non-human primates and contrary to non-primate species. The evolutionary advantage of diagonal-sequence quadrupedal locomotion is not known. However, interestingly, there seems to be an evolutionary advantage of this type of locomotion for primate evolution, with regard to the emergence of complex neural circuits with related highly complex structures. Namely, only primates with diagonal-sequence quadrupedal locomotion followed an evolution favoring larger brains, highly developed cognitive abilities, highly developed hand skills, and language, with erect posture and bipedal locomotion, creating the unity of human beings. The non-primate mammals using lateralsequence quadrupedal locomotion did not show a similar phylogenetic progress compared to those with diagonal-sequence quadrupedal locomotion, which, in essence, was the phylogenetically oldest type of locomotion since it was a characteristic of the first tetrapods during the Devonian period. This suggests that the ancestral neural networks responsible for the diagonal-sequence quadrupedal locomotion were reserved for at least nearly 400 million years since the Devonian tetrapod-like fishes.

The human quadrupedal locomotion seen in UTS showed some similarities with nonhuman primates. For instance, the human quadrupeds supported their body weight more on the feet than on the hands during quadrupedal locomotion, in a similar way to the weight distribution during location in most non-human primates. In contrast, non-primate quadrupedal mammals usually support their body weight more on the forelimbs than their hind limbs. The body weight support patterns in non-human and human primates suggests that the reduced body weight on hands than feet would be beneficial for the development of fine hand skills in primates. The complete freeing of hands in human beings during upright walking would be entirely associated with highly developed hand skills compared to the non-human primates walking on all four extremities.

It was suggested that UTS may be considered a further example for Darwinian diseases, which may be associated with an evolutionary understanding of the disorders using evolutionary principles, such as natural selection. In this context, UTS may also be considered a disease with phylogenetic regression. In some UTS cases, the supraorbital tori were remarkably prominent, and were more or less similar to those in non-human primates. This was taken to be an ancestral feature, in addition to the diagonal-sequence quadrupedal locomotion, and the body weight being supported predominantly by the hind legs.

Human quadrupedalism was proposed to be a phenotypic example of evolution in reverse, i.e., the reacquisition by derived populations of the same character states as those of ancestor

Üner Tan Syndrome: Review and Emergence of

walking. *Med Hypothesis,* Vol. 73, pp. 169-176.

*biological Nature of Cancer.* Lexington, KY, USA.

gene. *PLoS Genet,* Vol. 5 : e1000403.

*Nonlin Soft Matter Phys,* Vol. 67, pp. 066118.

*Child Neurol,* Vol. 24(10), pp. 1310-1315.

Island. *Neurology,* Vol. 34, pp. 271-273.

Africa. *Nature,* Vol. 18(6894), pp. 145-151.

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**12. References**

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Abed, R.T., & Pauw, K.W. (1998). An evolutionary hypothesis for obsessive compulsive disorder : a-psychological immune system. *Behav Neurol,* Vol. 11(4), pp. 245-250. Akpinar S. (2009). In restless legs syndrome, the neural substrates of the sensorimotor

Andermann, F., Andermann, E. et. al. (1999). History of Joubert syndrome and a 30-year follow-up of the original proband. *J Child Neurol,* Vol. 14, pp. 565-569. Arguello, F. (2011). *Atavistic Metamorphosis A New and Logical Explanation for the origin and*

Baala, L., Romano, S., et al. (2007). The Meckel-Gruber syndrome gene, MKS3, is mutated in

Bailey K.G. (1978). The concept of phylogenetic regression. *J Am Acad Psychoanal,* Vol. 6, pp.

Bal, P. (2001). *The self-made tapestry : pattern formation in nature,* Oxford: Oxford University

Bar, I., et al. (2000). The evolution of cortical development. An hypothesis based on the role of the reelin signaling pathway. *Trends Neurosci,* Vol. 23, pp. 633-638. Bar-Yam, Y. (1997). *Dynamics of complex systems. Perseus* Books, Reading Massachusetts,

Bekpen, C., Marques-Bonet, T., et al. (2009). Death and resurrection of the human IRGM

Bomar, J.M., Benke, P.J., et al. (2003). Mutations in a novel gene encoding a CRAL-TRIO

Bornholdt, S., & Rohl, T. (2003)ç Self-organized critical neural networks. *Phys Rev E Stat*

Boycott, K.M., Bonnemann, C., et al. (2009). Mutations in VLDLR as a cause for autosomal

Boycott, K.M., Flavelle, S., et al. (2005). Homozygous deletion of the very low density

Braddock, B.A. (2006). Oromotor and communication findings in Joubert syndrome: further

Braddock, S.R., Henley, K.M., et al. (2007). The face of Joubert syndrome: a study of dysmorphology and anthropometry. *Am J Med Genet,* Vol. 143A, pp. 3235-3242. Brown, T.G. (1911). The intrinsic factors in the cat of progression in the mammal. *Proc R Soc*

Brown, T.G. (1912). The factors in rhythmic activity of the nervous system. *Proc R Soc London*

Brown, L., Mueller, M., et al. (1984). A non-progressive cerebellar ataxia on Grand Cayman

Brunet, M., Guy, F., et al. (2002). A new hominid from the upper Miocene of Chad, central

cerebral gyral simplification. *Am J Genet,* Vol. 77(3), pp. 477-483.

evidence of multisystem apraxia. *J Child Neurol,* Vol. 21, pp. 1-3.

domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse. *Nat*

recessive cerebellar ataxia with mental retardation (disequilibrium syndrome). *J*

lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with

symptoms are also normally involved in upright standing posture and bipedal

populations. On the other hand, UTS may be considered within the framework of phylogenetic diseases (phylogenetic regression), which may be related to the phenotypic backward evolutionary atavism (the reappearance of a lost character (either morphological or behavioral) that was typical of remote ancestors). The habitual diagonal-sequence quadrupedal locomotion, standing with bent knees and bent trunk (flexor posture contrary to the extensor posture in modern human beings), prominent supraorbital tori, fist walking with bent fingers, and non-opposable thumb, may be related to ancestral characteristics in the UTS cases. The diagonal-sequence quadrupedal locomotion (habitual or facultative) was also the preferred gait of some individuals with entirely normal brains, probably as a result of the neural networks preserved during nearly 400 million years of evolution.

The emergence of human quadrupedalism was related to the self-organizing processes occurring in complex systems, which selects or attracts one preferred behavioral state or locomotor trait out of many possible attractor states. Since this is a spontaneous and unpredictable event, behavioral variability being a common precursor, the dynamic systems provide enormous flexibilities. According to the interactions of the internal components with their sensitivities to external conditions, the complex dynamical systems prefer a behavioral mode or modes. Concerning the locomotor patterns, the dynamical systems (brain and body) of the developing child may prefer or create some kind of locomotion, according to interactions of the internal components and environmental conditions, without a direct role of any causative factor(s), such as genetic or neural codes. This self-organization occurs through the interactions of its components, endogenously (within the brain), and/or exogenously through some environmental influence, but without any external force.

The emergence of human locomotion is a developmental event in which the selforganization processes play the major role, suggesting no innate or previously prescribed codes are essential for the emergence of walking during locomotor development. The developing skeleto-motor system of the individuals with impaired balance may selforganize, which is itself triggered by the exogenous environmental constraints, and they will then find the most suitable and most comfortable, and hence preferred, mode of locomotion, spontaneously generating novel and organized forms and attractor states. In UTS, these spontaneous, unpredictable strange attractors may include diagonal-sequence quadrupedal locomotion, as also seen in the non-human primates, or an entirely unpredictable novel quadrupedal locomotion may emerge, such as the inverse (face-up) quadrupedal locomotion. More examples of the unpredictable, self-organized, and emergent strange attractors were presented in this article. The contribution of the single factors such as the genetic and/or neural codes (central pattern generators) to the emergence of the locomotor patterns during locomotor development were rejected, considering the current scientific research in these fields, consistent with the concept of self-organization, suggesting no single element has causal priority.

#### **11. Acknowledgments**

This study was partly supported by the Turkish Academy of Sciences (Ankara, Turkey).

Special thanks to Derya Deniz Elalmş (PhD) for generously supplying the pictures of the healthy individuals during bipedal and quadrupedal locomotion (Fig. 5).

#### **12. References**

34 Latest Findings in Intellectual and Developmental Disabilities Research

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The emergence of human quadrupedalism was related to the self-organizing processes occurring in complex systems, which selects or attracts one preferred behavioral state or locomotor trait out of many possible attractor states. Since this is a spontaneous and unpredictable event, behavioral variability being a common precursor, the dynamic systems provide enormous flexibilities. According to the interactions of the internal components with their sensitivities to external conditions, the complex dynamical systems prefer a behavioral mode or modes. Concerning the locomotor patterns, the dynamical systems (brain and body) of the developing child may prefer or create some kind of locomotion, according to interactions of the internal components and environmental conditions, without a direct role of any causative factor(s), such as genetic or neural codes. This self-organization occurs through the interactions of its components, endogenously (within the brain), and/or exogenously through some environmental influence, but

The emergence of human locomotion is a developmental event in which the selforganization processes play the major role, suggesting no innate or previously prescribed codes are essential for the emergence of walking during locomotor development. The developing skeleto-motor system of the individuals with impaired balance may selforganize, which is itself triggered by the exogenous environmental constraints, and they will then find the most suitable and most comfortable, and hence preferred, mode of locomotion, spontaneously generating novel and organized forms and attractor states. In UTS, these spontaneous, unpredictable strange attractors may include diagonal-sequence quadrupedal locomotion, as also seen in the non-human primates, or an entirely unpredictable novel quadrupedal locomotion may emerge, such as the inverse (face-up) quadrupedal locomotion. More examples of the unpredictable, self-organized, and emergent strange attractors were presented in this article. The contribution of the single factors such as the genetic and/or neural codes (central pattern generators) to the emergence of the locomotor patterns during locomotor development were rejected, considering the current scientific research in these fields, consistent with the concept of self-organization, suggesting no

This study was partly supported by the Turkish Academy of Sciences (Ankara, Turkey).

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Special thanks to Derya Deniz Elalmş (PhD) for generously supplying the pictures of the

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**Management of Children with Intellectual and**

**Developmental Disability in an African Setting**

Disability is an umbrella term, covering impairments, activity limitations, and participation restrictions. Impairment is a problem in body function or structure; an activity limitation is a difficulty encountered by an individual in executing a task or action; while a participation restriction is a problem experienced by an individual in involvement in life situations. Thus disability is a complex phenomenon, reflecting an interaction between features of a person's body and features of the society in which he or she lives (WHO, 2011). This issue is so important that World Health Organization (WHO) and World Bank Group command a report on it (WHO, 2011). People who experience mental health conditions or intellectual impairments appear to be more disadvantaged in many settings than those who experience physical or sensory impairments. Prevalence of children with disabilities vary substantially depending on the definition and measure of disability. Available data suggests that 93 million (5.1%) children aged 0–14 years have moderate or severe disability" (WHO, 2011). This matter is poorly addressed in Africa especially in sub Sahara region. We present here childhood intellectual and developmental disability management in an African setting. We will cover in this prospective survey, diagnosis tools regarding the clinical practices (clinical examination, psychomotor evaluation) with contribution from pediatricians, specialists of psychiatrics and neurologists; laboratory investigations with insight on South-North collaboration in medical genetics sector (cytogenetics and molecular biology); main etiologies; management; social considerations and perspectives in intellectual and developmental disability management in

The present survey was conducted in the Pediatrics and Medical Genetics Service of the National Teaching Hospital of Cotonou in Benin. Cotonou is the main city of Benin, a low income country in West Africa located between Nigeria and Togo. Health services are still poor and the under 5 morbidity and mortality are related to malaria, pneumonia and diarrhea (Black et al., 2010). Health conditions such as birth asphyxia and congenital abnormalities exist (Black et al., 2010). Birth asphyxia and birth defects are known to cause neurodevelopmental impairment with intellectual and developmental disability (Wright et al., 2009). But some efforts were made to cover these matters with the implementation of medical genetics services in the Pediatric ward (Alao et al., 2008; Alao et al., 2010). It was the

**1. Introduction**

Benin and in West African sub region.

**2. Patient and methods**

*1Univeristé d'Abomey Calavi, Faculté des Sciences de la Santé de Cotonou, Benin,*

Maroufou Jules Alao1, Blaise Ayivi1 and Didier Lacombe2

### **Management of Children with Intellectual and Developmental Disability in an African Setting**

Maroufou Jules Alao1, Blaise Ayivi1 and Didier Lacombe2 *1Univeristé d'Abomey Calavi, Faculté des Sciences de la Santé de Cotonou, Benin, 2Université de Bordeaux 2, France*

#### **1. Introduction**

44 Latest Findings in Intellectual and Developmental Disabilities Research

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Disability is an umbrella term, covering impairments, activity limitations, and participation restrictions. Impairment is a problem in body function or structure; an activity limitation is a difficulty encountered by an individual in executing a task or action; while a participation restriction is a problem experienced by an individual in involvement in life situations. Thus disability is a complex phenomenon, reflecting an interaction between features of a person's body and features of the society in which he or she lives (WHO, 2011). This issue is so important that World Health Organization (WHO) and World Bank Group command a report on it (WHO, 2011). People who experience mental health conditions or intellectual impairments appear to be more disadvantaged in many settings than those who experience physical or sensory impairments. Prevalence of children with disabilities vary substantially depending on the definition and measure of disability. Available data suggests that 93 million (5.1%) children aged 0–14 years have moderate or severe disability" (WHO, 2011). This matter is poorly addressed in Africa especially in sub Sahara region. We present here childhood intellectual and developmental disability management in an African setting. We will cover in this prospective survey, diagnosis tools regarding the clinical practices (clinical examination, psychomotor evaluation) with contribution from pediatricians, specialists of psychiatrics and neurologists; laboratory investigations with insight on South-North collaboration in medical genetics sector (cytogenetics and molecular biology); main etiologies; management; social considerations and perspectives in intellectual and developmental disability management in Benin and in West African sub region.

#### **2. Patient and methods**

The present survey was conducted in the Pediatrics and Medical Genetics Service of the National Teaching Hospital of Cotonou in Benin. Cotonou is the main city of Benin, a low income country in West Africa located between Nigeria and Togo. Health services are still poor and the under 5 morbidity and mortality are related to malaria, pneumonia and diarrhea (Black et al., 2010). Health conditions such as birth asphyxia and congenital abnormalities exist (Black et al., 2010). Birth asphyxia and birth defects are known to cause neurodevelopmental impairment with intellectual and developmental disability (Wright et al., 2009). But some efforts were made to cover these matters with the implementation of medical genetics services in the Pediatric ward (Alao et al., 2008; Alao et al., 2010). It was the

Management of Children with Intellectual and Developmental Disability in an African Setting 47

synostosis, brachycephaly from premature closure of the coronal sutures or plagiocephaly from closure of only one coronal or lamboid suture and scalp defects. Face examination could lead to discover abnormalities such as facial cleft, asymmetry, coarse face, small/narrow/elongated/ broad face, round-shaped, square-shaped, triangular-shaped, flat, hypoplastic malae, midface hypoplasia, full cheeks. Hands and feet could showed single transverse palmar crease, deep palmar and plantar creases, polydactyly, syndactyly, oligodactyly, ectrodactyly, camptodactyly, arachnodactyly, absent or hypoplastic nails, and terminal transverse defects of the fingers and toes. Ulnar ray and radial ray defects could be seen in some patients. The neck findings that one should specifically be looked for include short webbed neck, torticollis, branchial pits or sinuses and thyromegaly (Suri, 2005; Mercks et al., 2003). Skin anomalies and neurological status with tonus and reflexes testing were also done. General physical examination was done to detect problems which could be found in the other systems or organs such as locomotors, digestive, cardiologic, respirator, urologic, genital and ear, nose and throat. The examination was terminated by hypotheses' evocation. Pictures were taken with patient's permission and signed consent form in which it was stated that iconography and data could be used for scientific communications and publications in the respect of strict anonymous. Laboratory investigations generally encompassed karyotype and deoxyribonucleic acid extraction when single gene disorder was suspected. These genetic investigations were carried out in Cotonou in the Cytogenetics Laboratory of the Faculty of Health Sciences (Gangbo et al., 2010). Karyotype was done on whole blood which was collected in tube with heparin sodium. If needed, molecular tests were performed abroad through scientific cooperation with some genetics centers in Europe such as Human genetics centre of Leuven, Belgium; Institut of Pathology and Genetics of Liege, Belgium; Biochemistry and molecular genetics laboratory, Hôpital Cochin, Paris, France; Functional cardiogenetics and molecular and cellular myogenetics Unit, Hôpital Pitié Salpêtrière, Paris, France and Human genetics laboratory, Université Victor Segalen, Bordeaux, France. Extract deoxyribonucleic acid was sent to them either by postmail or by a person that was travelling to the dedicated laboratory place. Deoxyribonucleic acid was extracted with phenol/chloroform method on whole blood (Adeli and Ogbona, 1990). Patients were reviewed monthly until the suspected diagnosis was confirmed (or refuted). Follow up was established for individual assistance. This included a medical component which help preventing and detecting known complications regarding each disorder. A supportive care was planned for each patient with referral to physiotherapist, psychologist and speech therapist if appropriate. Prenatal diagnosis was also proposed if it was thought to be relevant especially in chromosomal aberration situations. Data upon socio demographic and clinical patients' characteristics (referral reasons, origin of referral, psychometric performance, etiologies, external birth defects, outcome and bad prognosis factors), contributions from specialists (medical and supportive) and school attending rate were collected. There were treated and analyzed with Epi info software package version3.5.3. Proportions were compared with chi square, Pearson's correlation test and

difference was thought to be statistically valuable when p< 0.05.

A total of 206 patients were received for intellectual and developmental disability during these two years of survey. They were categorized having intellectual and developmental disability since they failed to achieve the WHO labeled six gross motor development milestones.  Six cases of autism spectrum disorders were suspected in children

**3. Results**

unique place where people can receive genetics services in Benin. Medical genetics consultation was carried out by a pediatrician who specialized in clinical genetics assisted by two nurses. This consultation took place once a week and three persons were checked per session. This prospective and descriptive study was conducted from January 1st 2009 through December 31rst 2010. The recruitment was systematic with the fulfillment of a questionnaire by the medical crew. Each consultation took 45 to 60 minutes with four steps that were medical history record, psychomotor evaluation, dysmorphological examination and a general physical examination. Medical history record is a very important moment because it helps collecting any information that could lead to genetic disease or environmental factor. The previous birth of a similarly affected child suggests that the condition is likely to be genetic in origin. It is, however, important to consider the possibility of the mother taking a teratogenic drug in successive pregnancies or that the mother is alcoholic, which could result in more than one child being born with fetal alcohol syndrome. Parental consanguinity may suggest that the patient had an autosomal recessive disorder. Maternal drug/alcohol intake or any other teratogenic agent must be revealed. Maternal illnesses such as viral infections in the antenatal period were run out since they could result in the birth of a baby with mental retardation (suri, 2007). We also collected data regarding delivery, neonatal period, infant period and childhood. Informations were obtained on onset age and progression, the quality of sleeping, nutrition, social behavior and status regarding being clean by day and night. This record ended by family's tree drawing (Goldenberg and Saugier-Veber, 2010). Psychomotor evaluation was based on gross motor milestone checking. We controlled if the patient had achieved on time the expected milestone according to his or her age which was expressed in months. The six milestones studied were sitting without support, standing with assistance, hands-and-knees crawling, walking with assistance, standing alone and walking alone. Concern was expressed only if the child has not performed one or more milestones that he or she should have achieve on expected time (WHO, 2006). This psychomotor evaluation were completed by primitive reflexes and hypotonia monitoring in the young infant which were not supposed to start sitting according to their age. This stage was said to be less than 4 months. Normally these primitives reflexes were known to disappear before three months and at that time infant must be able to control his or her neck. So the persistence of primitive reflexes or failing in controlling neck position was categorized in psychomotor delay. Autism spectrum was suspected in children if the onset story was before the age of three years and these three impairments were present: social interaction disability, communication disability and restricted repetitive behavior. Social interaction disability regards lack of response to other people's emotions and deficient of inappropriate use of social signals; communication disability is related to the lack of social usage of whatever language skills are present, impaired imagination, a "mechanical" style of expression, with little flexibility or variation and lack of accompanying gesture to add meaning to communication. Restricted repetitive behavior seems to an apparent preference for rigidity and routine in a wide range of aspects of daily living such as insistence to perform routines in nonfunctional rituals, motor stereotypies, stereo typed interests, resistance to change in personal environment (WHO, 1996). When communication was poor without the full spectrum, patient was considered having autistic trait. The third time of this examination was reserved to the detection of any minor or major physical abnormalities regarding dysmorphology. The principles that were used were conformed to the Jones smith book (Jones, 1997). This took into account particular parts of the body. Craniofacial abnormalities could be found at the head, face, hand and feet, neck, chest, abdomen, skin, external genitalia and spine. Head examination could disclosed microcephaly, macrocephaly, craniosynostosis with scaphocephaly, due to sagittal synostosis, brachycephaly from premature closure of the coronal sutures or plagiocephaly from closure of only one coronal or lamboid suture and scalp defects. Face examination could lead to discover abnormalities such as facial cleft, asymmetry, coarse face, small/narrow/elongated/ broad face, round-shaped, square-shaped, triangular-shaped, flat, hypoplastic malae, midface hypoplasia, full cheeks. Hands and feet could showed single transverse palmar crease, deep palmar and plantar creases, polydactyly, syndactyly, oligodactyly, ectrodactyly, camptodactyly, arachnodactyly, absent or hypoplastic nails, and terminal transverse defects of the fingers and toes. Ulnar ray and radial ray defects could be seen in some patients. The neck findings that one should specifically be looked for include short webbed neck, torticollis, branchial pits or sinuses and thyromegaly (Suri, 2005; Mercks et al., 2003). Skin anomalies and neurological status with tonus and reflexes testing were also done. General physical examination was done to detect problems which could be found in the other systems or organs such as locomotors, digestive, cardiologic, respirator, urologic, genital and ear, nose and throat. The examination was terminated by hypotheses' evocation. Pictures were taken with patient's permission and signed consent form in which it was stated that iconography and data could be used for scientific communications and publications in the respect of strict anonymous. Laboratory investigations generally encompassed karyotype and deoxyribonucleic acid extraction when single gene disorder was suspected. These genetic investigations were carried out in Cotonou in the Cytogenetics Laboratory of the Faculty of Health Sciences (Gangbo et al., 2010). Karyotype was done on whole blood which was collected in tube with heparin sodium. If needed, molecular tests were performed abroad through scientific cooperation with some genetics centers in Europe such as Human genetics centre of Leuven, Belgium; Institut of Pathology and Genetics of Liege, Belgium; Biochemistry and molecular genetics laboratory, Hôpital Cochin, Paris, France; Functional cardiogenetics and molecular and cellular myogenetics Unit, Hôpital Pitié Salpêtrière, Paris, France and Human genetics laboratory, Université Victor Segalen, Bordeaux, France. Extract deoxyribonucleic acid was sent to them either by postmail or by a person that was travelling to the dedicated laboratory place. Deoxyribonucleic acid was extracted with phenol/chloroform method on whole blood (Adeli and Ogbona, 1990). Patients were reviewed monthly until the suspected diagnosis was confirmed (or refuted). Follow up was established for individual assistance. This included a medical component which help preventing and detecting known complications regarding each disorder. A supportive care was planned for each patient with referral to physiotherapist, psychologist and speech therapist if appropriate. Prenatal diagnosis was also proposed if it was thought to be relevant especially in chromosomal aberration situations. Data upon socio demographic and clinical patients' characteristics (referral reasons, origin of referral, psychometric performance, etiologies, external birth defects, outcome and bad prognosis factors), contributions from specialists (medical and supportive) and school attending rate were collected. There were treated and analyzed with Epi info software package version3.5.3. Proportions were compared with chi square, Pearson's correlation test and difference was thought to be statistically valuable when p< 0.05.

#### **3. Results**

46 Latest Findings in Intellectual and Developmental Disabilities Research