Abstract
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.
Keywords: CLN1, CLN5, granular inclusion, juvenile neuronal ceroid lipofuscinoses, visual loss
Introduction
Neuronal ceroid lipofuscinoses (NCLs) are a group of progressive neurogenetic disorders. In 1998, Wisniewski et al. 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).[1] Approximately 160 NCL disease causing mutations have been described.
The most common forms are infantile, late infantile, and juvenile NCLs. 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 3rd or 4th 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.[1,2] We report three cases with atypical JNCL and pertinent issues concerning diagnostic difficulties, ophthalmologic, neuroradiological, and laboratory findings are discussed.
Case Reports
Case 1
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. His speech was very slow and slurred but he had good hearing. He developed progressive visual loss and was unable to follow a bright red object at 7½ years. Interestingly, he hallucinated seeing spiders. He developed seizures, which were well controlled with valproate. 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 5½ years and subsequently, cerebral and cerebellar atrophy at 7½ years. Electroencephalogram (EEG) showed bilateral synchronous generalized epileptiform discharges. 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 totally dependent for all his daily activities.
Case 2
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 was more independent and active than his brother. 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. His visual acuity (VA) was 6/18 in each eye with normal fundi. He had developed seizures, which were controlled by valproate.
Case 3
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). He was able to detect colours but could not read any letters. Visual field did not show specific defect. Optic disc and neurological examinations were unremarkable at last follow-up.
VEP of BE were delayed while ERG was normal at 12 years. MRI and EEG were normal. Blood film showed no lymphocyte vacuolation. 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, his vision remained poor. He had developed behavioral and cognitive problems. He had not developed seizures or motor difficulties.
Discussion
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.[4] 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). Therefore, we labeled them as variant of LINCL. 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.
Case 3 had a different granular inclusion body. All the cases of NCL caused by mutations in CLN1 are associated with granular appearance.[5] 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.
Case 1 and 3 developed visual hallucinations. These rare features have been described in the literature.[6,7] 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. ERG shows abnormal or absent record early in the course of the disorder. Case 1 (CLN5) manifested all these features. On contrast, case 3 (CLN1) showed normal ERG, delayed VEP and persistent normal fundi even at an advanced stage. These features were consistent with optic neuropathy, rather than retinal dystrophy. 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.[8] In contrast, patients with typical JNCL (CLN3) have cerebral atrophy at the early stage. Cerebellar atrophy usually comes later.[2,8] White matter hyperintensity on T2 appears at an early stage.[8]
Therapy is supportive and several treatments have been attempted with no success. Polyunsaturated fatty acids have been attempted in JNCL. Vitamin E and other antioxidants including selenium has been tried with no conclusive results.[9] Bone marrow and organ transplantation has been tried without success.
Conclusion
Atypical JNCL or vLINCL should be considered in any patients who present with either psychomotor decline or progressive visual loss. Early MRI may resemble leukodystrophy and ophthalmologic findings may be normal. EM of peripheral blood lymphocytes and NCL enzyme assay may facilitate early diagnosis. Children with NCL may show geno-phenotypical variations.
Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
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