 therapy (ISIS- SM NRx) that allows the nucleotides to bind to the mRNA se- quence in the SMN2gene. Then exon 7 of the SMN2gene is able to be included in the sequencing instead of being repressed; thus, a full length and more functional SMN protein is created (Castro and Iannaccone 2014; Zanetta et al. 2014a,b). In mice and non- human primates, the use of ISIS-SMNRx, a 2 ′-O-Methoxyethyl- modified antisense drug, has shown the ability to increase the production of fully functional SMN protein (Rigo et al. 2014). In the ISIS clinical trial phase I study, patients with types II and III SMA were injected with an ASO into their intrathecal space, thus allowing for a bypass of the blood brain barrier and ensuring the drug can have an effect in the central nervous system (Castro and Iannaccone 2014). A phase II study is currently underway de- signed to examine the safety, tole rability and pharmacokinetics of multiple dose administration (Zanetta et al. 2014a). Braun ( 2013) describes a possible limitation of ASO use in treating patients with SMA. He notes re-administration of the ASO would be necessary due to the limited half-life of the compound. Viral vector mediated gene therapy in animal trials involves injection of a viral vector carrying SMNinto mice with SMA. Glascock et al. ( 2011) found when injecting a viral vector with SMN intracerebroventricularly into SMA mice, they gained more weight and displayed fewer early deaths than mice injected intravenously thus demonstrating route of delivery of vector mediated gene replacement is crucial in gene therapy treatment for SMA. In 2014, a phase I clinical trial began at Nationwide Children ’s Hospital in Ohio. The study is investi- gating the ability of an adenovirus vector, AAV9, to cross the blood brain barrier and replace the missing SMN1gene in patients with SMA (Castro and Iannaccone 2014; Zanetta et al. 2014b ). Viral gene therapy has shown an advantage of having a long survival time in preclinical studies with the need for only one delivery (Braun 2013). Another new SMNdependent therapy being evaluated is the idea of neuroprotection. Trophos, a French pharmaceutical company, recently conducted a phase II study concerning the ability of olesoxime to provide protection for motor neurons. The therapy was found to be effective in keeping motor neu- rons alive in culture (Zanetta et al. 2014a). Olesoxime was provided orally to patients with SMA II or III. The goal was to determine if the medication, a cholesterol-like molecule, could also aid the survival of motor neurons in human sub- jects. At this time, no results of the phase II study are available for review (Castro and Iannaccone 2014; Zanetta et al. 2014a). SMN independent potential therapies include but are not limited to myotrophic effects, axonal dynamics, and stem cells. Investigation of albuterol is an example of a potential therapy involving myotrophic effects. A trial with 23 type II SMA patients showed better Hammersmith motor functional 38 Carré and Empey scores after daily treatment for 6 or 12 months (Pane et al. 2008). With reference to axonal dynamics, treatment of SMA model mice with Rho-kinase inhibitor Y-27632 led to signif- icant prolonged survival and improvement in the integrity of neuromuscular junctions (Bowerman et al. 2012; Tsai 2012). Stem cell therapy includes neural stem cells, embryonic stem cells and induced pluripotent stem cells. Kerr et al. ( 2003 ) researched the ability to use stem cell therapy to estab- lish motor neurons to replace those which degenerated due to the disease. Corti et al. ( 2008) used intrathecal injection of neural stem cells derived from mouse spinal cord into a severe type of SMA mouse model. This therapy showed promoted motor neuron survival, improved motor function and prolonged lifespan. There is much still to be accomplished in cell therapy before clinical application is possible (Tsai 2012). For more intensive reviews of current and future medical therapies for SMA, please refer to the 2013 article BGene- based therapies of neuromuscular disorders: an update and the pivotal role of patient organizations in their discovery and implementation (Serge Braun, The Journal of Gene Medicine), ^Chiara Zanetta ’s2014article BMolecular thera- peutic strategies for spinal muscular atrophies: current and future clinical trials (Clinical Therapeutics journal), ^and the 2014 article from Journal of Cellular and Molecular Medicine by C. Zanetta BMolecular, genetic, and stem cell-mediated therapeutic strategies for spinal muscular atrophy. ^Through ongoing research, treatments may soon be designed to signif- icantly reduce the severity of symptoms associated with SMA. For patients wishing to participate in research, an up-to-date list of ongoing trials for spinal muscular atrophy can be found at www.clinicaltrials.gov. At the time of the writing of this paper, there were 160 studies registered for SMA testing. Other Types of Spinal Muscular Atrophies When an individual with symptoms suggestive for SMA pre- sents for clinical examination with no confirmed genetic di- agnosis, numerous genetic disorders may be considered in the differential diagnosis. Some of these genetic disorders may include forms of SMA unrelated to changes in the SMN1gene. The following is a short review of a number of different spinal muscular atrophies included in the differential diagnosis list. This list is not all inclusive. SMA with respiratory distress type 1 (SMARD) is another autosomal recessive condition. It is linked to the IGHMBP2 gene at 11q13.2-q13.4. Affected individuals present in the first 3 months of life with eventration of the right or both hemidiaphragms plus finger and feet abnormalities (Wang et al. 2007). X-linked infantile SMA with arthrogryposis is also associ- ated with loss of anterior horn cells in the spinal cord (Baumbach-Reardon et al. 2012). X-linked infantile SMA, however, has been linked to a change at Xp11.3-q11.2. For affected children, death can occur at less than 2 years of age (Wang et al. 2007). The disorder is associated prenatally with polyhydramnios and poor fetal movement, which can lead to bone fractures. After delivery, these children face restrictive lung disease (Baumbach-Reardon et al. 2012). X-linked spinal and bulbar muscular atrophy is a disorder seen in men, with an onset between 20 and 50 years of age. These affected individuals show muscle weakness, muscle atrophy, fasciculations, gynecomastia, testicular atrophy, and reduced fertility (La Spada 2011; Russman 2007). Carrier fe- males for X-linked spinal and bulbar muscular atrophy may experience muscle cramps or tremors (Mariotti et al. 2000). Autosomal dominant SMA typically has an onset after 20 years of age; however, there are a few cases of adolescents with autosomal dominant SMA. This slowly progressing disor- der comprises up to 30 % of adult onset SMA (Pearn 1978 ; R ietscheletal. 1992). As a specific example of an autosomal dominant SMA, individuals with scapuloperoneal spinal muscu- lar atrophies experience a loss of ambulation occurring in the fifth decade or later. A linkage analysis of one large affected family suggests a change in the area of 12q24.1 –24.31 to be the causa- tive factor (Isozumi et al. 1996). These disorders are diagnosed through the presence of large motor units on electromyography with normal sensory potentials and normal nerve conduction velocities (Russman 2007). They clinically present with progres- sive weakness of scapuloperoneal and laryngeal muscles (Wang et al. 2007). Distal spinal muscular atrophies, unlike SMN1-associated SMA which starts in the proximal muscles, are classified as such due to the wasting of the distal muscles with slow pro- gression to the proximal muscles (Russman 2007). There are currently ten subtypes of distal spinal muscular atrophy, with both autosomal dominant and autosomal recessive methods of inheritance noted (Irobi et al. 2004). Individuals with later-onset autosomal recessive hexosa- minidase A, or G M2 -gangliosidoses, deficiencies have been incorrectly identified as affected by SMA. Case reports have discussed how affected individuals were found to meet the clinical diagnosis of SMA –difficulty in ambulation, progres- sive decline in muscle strength, SMA electromyography find- ings, and SMA muscle biopsy findings. However, when fur- ther tested for hexosaminidase A activity levels, the patients were found to be lacking normal levels of hexosaminidase A and were thus diagnosed with hexosaminidase A deficiencies (Johnson et al. 1982; Karni et al. 1988). Pontocerebellar hypoplasia with SMA is an autosomal reces- sive condition, caused by a mutation in the VRK1gene, present- ing with cerebellar and brainstem hypoplasia and neuronal loss in the basal ganglia (Renbaum et al. 2009;Wangetal. 2007). Fazio-londe disease affects the lower cranial nerves and symptoms become apparent in the second decade of life. Death usually occurs within 1 to 5 years of the diag- nosis (Russman 2007). Review of SMA for Prenatal and Pediatric Genetic Counselors 39 Summary There is substantial variability in the natural history of SMA as