neuronal ceroid lipofuscinoses ( ncls ) are a group of progressive neurogenetic disorders . in 1998 ,
categorized the ncls into five major groups based primarily on age , clinical presentation , histological findings , and genetic loci ; infantile ncl ( incl ) , late infantile / early childhood ncl ( lincl ) , juvenile ncl ( jncl ) , adult ncl and variant , lincl ( vlincl ) .
this classification is still widely used . within the last decade , mutations that cause ncl have been found in 14 human genes ( cln1 , cln2 , cln3 , cln4/dnajc5 , cln5 , cln6 , cln7/mfsd8 , cln8 , cln10/ctsd , cln11/grn , cln12/atp13a2 , cln13/ctsf , cln14/kctd7 , clcn6 , and sgsh ) .
infantile ncl with cln1 mutation presents with motor disturbances ( ataxia , hypotonia , spasticity ) , visual impairment , seizures , dementia , and familial occurrence .
late infantile with cln2 mutation manifests with onset between 2 and 4 years and symptoms of epilepsy , cognitive decline , ataxia , visual failure , and death in between 9 and 18 years .
juvenile ncl , with cln3 mutation presents with progressive visual loss , speech and cognitive decline , epilepsy , behavioral disturbances and death in the 3 or 4 decade .
however , they are already reclassified on the basis of newer molecular findings , which have provided a far more overlap for the different genetic variants that have previously suggested by the clinical phenotypes .
we report three cases with atypical jncl and pertinent issues concerning diagnostic difficulties , ophthalmologic , neuroradiological , and laboratory findings are discussed .
a 9-year - old pakistani boy born to non - consanguineous parents with a normal perinatal period and early development and at 4 years , he began to show regression in motor and cognitive skills .
he was unsteady and needed support , when walking at 6 and became wheelchair bound at 7 years .
he developed progressive visual loss and was unable to follow a bright red object at 7 years .
ophthalmological examination revealed dystrophic appearance of retina , attenuation of retinal vessels with a pale disc .
serial cranial magnetic resonance imaging ( mri ) showed diffuse white matter hyperintensity in t2-weighted but not in flair at 5 years and subsequently , cerebral and cerebellar atrophy at 7 years .
electroretinogram ( erg ) was absent and visual evoked potential ( vep ) was normal .
palmitoyl protein thioesterase ( ppt ) and tripeptidyl peptidase i ( tpp 1 ) enzyme activities were within normal range .
skin and muscle biopsy for inclusion bodies were negative and blood film showed no vacuolated lymphocytes .
however , ultra structural examination of lymphocytes showed rare , membrane bound , condensed storage material with fingerprint profiles .
cln5 gene mutation was positive . at last follow - up at 11 years , he was wheelchair bound but could walk with support , had severe visual impairment and slow and slurred speech .
he was the 6-year - old brother of case 1 and his early developments were normal except for speech .
he babbled at 5 months , copied noises at 8 months and only spoke with recognizable word at 2 year 7 months ( his brother spoke at 18 months ) .
he would play football ( his eldest brother never ran or jumped ) with other children and his expressive language had never been clear and had difficulty putting words together and had developed stammer .
he was slow to learn and at 4 years , he began to have cognitive and motor regression .
cranial mri findings were very similar to that demonstrated on his brother 's scan . at last follow - up ( 8 years ) , he had drooling saliva , he was wheel chair bound with deterioration in his speech , cognition , motor skills , and fully dependent for his needs .
an 11-year-10-month - old caucasian boy with normal perinatal and neurodevelopmental history was referred to us with 3-year history of progressive visual loss and visual hallucinations .
his symptoms started with difficulty in reading , worsening handwriting , and flashes of lights in both eyes ( be ) .
he gave us a description and consistently drew figures , which he appeared to be seeing in front of his eyes .
the figures had a red border with circles and lines criss - crossing the circles .
the va at first presentation was 6/60 in be when he was 10 years . at last follow - up at 13 , va was 6/60 in right eye ( re ) and 3/60 in left eye ( le ) .
however , electron microscopy ( em ) of buffy coat showed rare , membrane bound , electron dense , granular material associated with a lipid droplet in the cytoplasm of lymphocytes .
ppt activity was low measuring 2.2 nmol / hr / mg protein and normal tpp - i .
molecular genetic analysis of exon 1 - 9 of cln1 gene showed that he was heterozygote for p.cys96tyr and p.arg151x mutations .
a diagnosis of milder form of incl ( cln1 ) was made . at his last neurology follow - up at 13 years
he had developed behavioral and cognitive problems . he had not developed seizures or motor difficulties .
a 9-year - old pakistani boy born to non - consanguineous parents with a normal perinatal period and early development and at 4 years , he began to show regression in motor and cognitive skills .
he was unsteady and needed support , when walking at 6 and became wheelchair bound at 7 years .
he developed progressive visual loss and was unable to follow a bright red object at 7 years .
ophthalmological examination revealed dystrophic appearance of retina , attenuation of retinal vessels with a pale disc .
serial cranial magnetic resonance imaging ( mri ) showed diffuse white matter hyperintensity in t2-weighted but not in flair at 5 years and subsequently , cerebral and cerebellar atrophy at 7 years .
electroretinogram ( erg ) was absent and visual evoked potential ( vep ) was normal .
palmitoyl protein thioesterase ( ppt ) and tripeptidyl peptidase i ( tpp 1 ) enzyme activities were within normal range .
skin and muscle biopsy for inclusion bodies were negative and blood film showed no vacuolated lymphocytes .
however , ultra structural examination of lymphocytes showed rare , membrane bound , condensed storage material with fingerprint profiles .
cln5 gene mutation was positive . at last follow - up at 11 years , he was wheelchair bound but could walk with support , had severe visual impairment and slow and slurred speech .
he was the 6-year - old brother of case 1 and his early developments were normal except for speech .
he babbled at 5 months , copied noises at 8 months and only spoke with recognizable word at 2 year 7 months ( his brother spoke at 18 months ) .
he would play football ( his eldest brother never ran or jumped ) with other children and his expressive language had never been clear and had difficulty putting words together and had developed stammer .
he was slow to learn and at 4 years , he began to have cognitive and motor regression .
cranial mri findings were very similar to that demonstrated on his brother 's scan . at last follow - up ( 8 years ) , he had drooling saliva , he was wheel chair bound with deterioration in his speech , cognition , motor skills , and fully dependent for his needs .
an 11-year-10-month - old caucasian boy with normal perinatal and neurodevelopmental history was referred to us with 3-year history of progressive visual loss and visual hallucinations .
his symptoms started with difficulty in reading , worsening handwriting , and flashes of lights in both eyes ( be ) .
he gave us a description and consistently drew figures , which he appeared to be seeing in front of his eyes .
the figures had a red border with circles and lines criss - crossing the circles .
the va at first presentation was 6/60 in be when he was 10 years . at last follow - up at 13 , va was 6/60 in right eye ( re ) and 3/60 in left eye ( le ) .
however , electron microscopy ( em ) of buffy coat showed rare , membrane bound , electron dense , granular material associated with a lipid droplet in the cytoplasm of lymphocytes .
ppt activity was low measuring 2.2 nmol / hr / mg protein and normal tpp - i .
molecular genetic analysis of exon 1 - 9 of cln1 gene showed that he was heterozygote for p.cys96tyr and p.arg151x mutations .
a diagnosis of milder form of incl ( cln1 ) was made . at his last neurology follow - up at 13 years
all our cases did not fit well with the typical clinicopathologic descriptions , therefore representing atypical variants of jncl or vlincl due to the late onset at 4 - 7 years and em showed fingerprints , thus , overlapping considerably with juvenile ncl . for case 1 and 2 , similarities to vlincl were age - at - onset , initial symptoms , and clinical progression .
differences from classic lincl included slower clinical progression and different inclusion profile ( revealed fingerprint , not typical curvilinear inclusion body ) .
in fact , cln2 encodes for ttp-1 enzyme , therefore , normal enzyme level excluded classic lincl ( cln2 ) . furthermore , these two cases had cln5 mutation which usually presents as vlincl and presented with typical phenotype of cln5 .
all the cases of ncl caused by mutations in cln1 are associated with granular appearance . to sum up ,
case 1 and 2 had early juvenile form of ncl ( vlincl ) due to cln5 and case 3 had atypical jncl due to cln1 mutation , reflecting phenotypical - genotypical variation .
however , delayed vep , normal erg and fundi were also unusual and were consistent with optic nerve neuropathy . visual loss in cln5 is usually due to retinal dystrophy .
ophthalmologic examination early in the course of vlincl ( cln5 ) may reveal macular changes only ; gradually typical signs of pan - retinal degeneration develop : bull 's eye maculopathy , diffuse pigmentary degeneration , arteriolar attenuation , and optic atrophy .
on contrast , case 3 ( cln1 ) showed normal erg , delayed vep and persistent normal fundi even at an advanced stage .
normal disc may still correspond to an early stage of juvenile form of cln1 but was quite unexpected at this advanced stage ( 4 years duration with va 6/60 ) .
patients with cln1 ( case 1 and 2 ) have cerebellar atrophy at the early stage , followed by brain atrophy that is more severe in the cerebellum .
in contrast , patients with typical jncl ( cln3 ) have cerebral atrophy at the early stage .
atypical jncl or vlincl should be considered in any patients who present with either psychomotor decline or progressive visual loss .
 the diagnosis of juvenile neuronal ceroid lipofuscinosis ( jncl ) is usually based on age of onset , initial clinical symptoms , clinical progression , and pathologic findings . 
 our cases manifested atypical clinical symptomatology and/or pathologic findings and therefore , represent variant forms of jncl . 
 case 1 and 2 presented with slow developmental regression from the age of 4 years and became blind and wheelchair bound at around 8 years . 
 pathologic finding of lymphocytes showed fingerprint inclusion which was consistent with jncl . 
 mutational analysis was positive for cln5 which usually presents as variant late infantile ncl ( lincl ) and more common in finnish population . 
 case 3 presented with progressive visual loss from the age of 8 years . clinical symptomatology and age of onset were similar to that of jncl but was found to have low palmitoyl protein thioesterase , granular inclusion body , and cln1 mutation , thus representing milder form of incl . 
 these three cases demonstrated phenotypic - genotypic variations . 
 pertinent issues relating diagnostic difficulties , ophthalmologic , neuroradiological , and laboratory aspects are discussed . 
Introduction
Case Reports
Case 1
Case 2
Case 3
Discussion
Conclusion