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|Year : 2012 | Volume
| Issue : 3 | Page : 316-320
Clinico-investigative profile of infantile and late-infantile neuronal ceroid lipofuscinoses
Mahesh Kamate1, Gowda P Prashanth1, Virupaxi Hattiholi2
1 Department of Pediatrics, KLE University's JN Medical College, Belgaum, Karnataka, India
2 Department of Radiology, KLE University's JN Medical College, Belgaum, Karnataka, India
|Date of Submission||11-Apr-2012|
|Date of Decision||03-May-2012|
|Date of Acceptance||31-May-2012|
|Date of Web Publication||14-Jul-2012|
Department of Pediatrics, KLE University's JN Medical College, Belgaum -590010, Karnataka
Source of Support: None, Conflict of Interest: None
Neuronal ceroid lipofuscinosis is a group of progressive neurodegenerative disorders characterized by accumulation of ceroid lipopigment in lysosomes in neurons and other cell types. This study is a retrospective review of charts of patients with a diagnosis of infantile and late-infantile neuronal ceroid lipofuscinosis seen between January 2009 and December 2011. Of the 16 patients, 5 had infantile type and 11 had late-infantile neuronal ceroid lipofuscinosis. Diagnosis was confirmed by appropriate enzyme assay. Clinical presentation was quite varied. Common presenting features included refractory seizures, developmental delay/regression, and abnormal movements. Visual failure was not common in the present case series, and novel neuroimaging finding in the form of isolated dentate nucleus hyperintensities were noted. During follow-up, all patients had a progressive downhill course and one patient died. Prenatal diagnosis could be offered to one family. This study suggests that infantile and late-infantile neuronal ceroid lipofuscinosis is not uncommon in this region of the country and the phenotype may be different.
Keywords: Enzyme assay, India, infantile neuronal ceroid lipofuscinosis, late-infantile neuronal ceroid lipofuscinosis, neuroimaging
|How to cite this article:|
Kamate M, Prashanth GP, Hattiholi V. Clinico-investigative profile of infantile and late-infantile neuronal ceroid lipofuscinoses. Neurol India 2012;60:316-20
|How to cite this URL:|
Kamate M, Prashanth GP, Hattiholi V. Clinico-investigative profile of infantile and late-infantile neuronal ceroid lipofuscinoses. Neurol India [serial online] 2012 [cited 2019 Aug 24];60:316-20. Available from: http://www.neurologyindia.com/text.asp?2012/60/3/316/98524
| » Introduction|| |
Neuronal ceroid lipofuscinosis (NCL) is a group of childhood-onset neurodegenerative disorders characterized by lysosomal accumulation of autofluorescent material in neurons and extraneuronal tissues, with an incidence of 1 in 12,500 births. , There are at least 10 distinct loci associated with the NCL phenotypes described till date. , Though the disease group has a worldwide distribution, there are very few studies on NCL from India, especially in children, hence this report is presented. The diagnosis of NCL was based on lysosomal enzyme assays of palmitoyl protein thioesterase-1 (PPT-1) and tripeptidyl peptidase-1 (TPP- 1).
| » Materials and Methods|| |
This study was conducted at the Pediatric Neurology Clinic attached to a tertiary care hospital in North Karnataka and was a retrospective review of the case records of all patients who attended the clinic between January 2009 and December 2011, after obtaining ethics committee clearance. Among the patients with suspected neurodegenerative/neurometabolic disorders, patients with the diagnosis of NCL were included in the analysis. Diagnosis was on the basis of clinical phenotype and biochemical testing. Lysosomal enzyme study was carried out from leukocytes using 4-MU specific substrate for PPT and TPP. Demographic data including family history, neurological features at presentation, neuroimaging findings, and follow-up data were extracted to a predesigned proforma. Details of metabolic work-up including the enzyme levels were also noted. Follow-up data of some patients who lost to follow-up were obtained by telephonic interview. Descriptive statistical methods were applied for analyzing the data. Categorical variables were presented as frequency percentage. Continuous variables were presented as mean and standard deviation if normally distributed and as median and range otherwise.
| » Results|| |
Case records of 370 patients of suspected neurodegenerative/neurometabolic disorders were reviewed. Forty-eight patients, clinically suspected to have NCL, were worked up and 16 (10 males and 6 females) children with enzymatically confirmed NCL diagnosis were included in the study. The mean age at the time of evaluation was 2.9 + 2.03 years. Five patients were diagnosed to have CLN1 (ceroid lipofuscinosis, neuronal-1) palmitoylprotein thioesterase-1 (PPT- 1) deficiency and 11 patients to have CLN2 (ceroid lipofuscinosis, neuronal-2)/tripeptidyl-peptidase-1 (TPP-1) deficiency, based on specific enzyme assay.
CLN1 (PPT-1-related NCL)
The key clinical and investigative findings of these patients are summarized in [Table 1]. Common presenting features included motor delay/regression, abnormal movements, and irritability. Myoclonic seizures were present in only two patients; none had microcephaly at presentation. Parents did not have any visual concerns and fundus examination was normal in all the patients. While magnetic resonance imaging of brain of two patients showed cerebral atrophy with thalamic hypointensities three of our patients showed bilateral dentate nucleus hyperintensities only [Figure 1]. The median time for establishing the diagnosis was 18 months (range: 1-15 months). Two of the patients were siblings and death due to similar illness (no definitive diagnosis reached) was seen in three other families. The median duration of follow-up was 6 months (range: 3-24 months) and all of them had a progressive downhill course.
|Figure 1: Axial (a) and coronal (b) spin echo T2-weighted MRI image of a 15-month-old child with PPT-1– related NCL at the level of pons (TR 4050/TE 85), showing hyperintensities in the dentate nucleus (black arrows). Cerebral cortex and the deep cerebral nuclei are normal (c)|
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|Table 1: Individual patient data of CLN1/palmitoyl protein thioesterase-1 (PPT-1) deficient group|
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CLN2 (TPP-1-related NCL)
There were 11 (4 males and 7 females) patients with TPP-1-related NCL. The median age at presentation was 3 years (range: 1-7 years). Consanguinity was present in seven children and family history of similar illness was present in five patients (45.5%). The clinical findings and neuroimaging findings are summarized in [Table 2]. The most common presenting feature was seizures present in all the patients, followed by regression of milestones. Seizure types included: complex partial, myoclonic, or generalized tonic clonic (GTCS). One of the patients had presented with delayed attainment of milestones, choreoathetosis, and reflex (auditory) myoclonus. None of the patients complained or their parents had any visual concerns, and two patients had partial optic atrophy on fundus examination. All of them had cerebellar atrophy on neuroimaging, and in those who also had cerebral atrophy (two patients), cerebellar atrophy was more pronounced than the cerebral atrophy [Figure 2]. In two patients who had serial neuroimaging, cerebellar atrophy was progressive. All patients had significantly deficient activity of TPP enzyme. One patient had asymptomatic hypercholesterolemia and hypertriglyceridemia. All patients were kept on three-monthly follow-up and there was progressive worsening in seizure frequency and ataxia. One child died at the age of 5 years due to seizures complicated by aspiration pneumonia. Three of the 11 patients became non-ambulatory at 1-3 years after diagnosis (mean age 9 years 1 month; SD: 5.92). There was a delay of 6-24 months before reaching the correct diagnosis in four patients. Four patients had received a diagnosis of mitochondrial disorder and were given treatment for the same before NCL was diagnosed. Three patients were put on flupirtine without much clinical benefit. In one family, we offered prenatal diagnosis and the fetus was found to be positive for TPP-related NCL. This led to the medical termination of pregnancy.
|Figure 2: Axial T1-weighted (a) and coronal (b) spin echo T2-weighted MRI image of a 5– year- old patient with TPP-1– related NCL at the level of pons showing pancerebellar atrophy with prominent cerebellar foliae. Cerebral white matter shows subtle signal hyperintensities in the spin echo T2-weighted MRI image in the centrum semiovale (c)|
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|Table 2: Clinical manifestations in NCL-2 with tripeptidyl peptidase 1 (TPP-1) deficiency|
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| » Discussion|| |
Phenotype in different types of NCL is characterized by a progressive decline in cognitive and motor functions, progressive loss of vision, and refractory seizures. All NCLs are autosomal recessive with the exception of adult NCL (ANCL), which is either autosomal recessive or dominant.  Diagnosis of NCL is often based on estimation of enzyme activity and/or molecular genetic testing, and in some instances, electron microscopy of biopsied tissues. Low enzyme levels are taken as the definitive evidence of the mutations in the corresponding NCL genes. Treatment is largely symptomatic.
NCL has been traditionally classified based on age of onset, clinical features, and histopathologic findings into infantile, late-infantile, juvenile, and adult forms. This phenotypic classification is clinically useful for diagnosis and prognosis. However, NCLs exhibit remarkable genotype-phenotype heterogeneity. , Identical phenotypes can result from different mutations in a single gene or from different mutations in different genes. Also, the same mutation in a single gene may result in variable phenotype among individuals, and within a single family. Hence, the nomenclature based on the genetic/enzymatic defect is now preferred over/along with phenotypic classification. In the present study, we studied the infantile and late-infantile presentations of NCL.
PPT-1 related NCL
Traditional infantile form of NCL (INCL, Santavuori-Haltia disease) is caused by mutation in the CLN1 gene encoding PPT-1. This enzyme is a lysosomal thioesterase that metabolizes acyl cysteine residues in proteins. Forty-nine disease-causing mutations and six polymorphisms have been identified till date.  Characteristic granular osmiophilic deposits (GRODs) represent the lysosomal inclusions of CLN1 at the ultrastructural level. In PPT-1-related NCL, early psychomotor development is normal until the age of 6-18 months and then rapid psychomotor deterioration sets in. The children develop muscular hypotonia, microcephaly, ataxia, choreoathetosis, stereotyped hand movements, myoclonic jerks, epilepsy, irritability, and visual failure.  Clinically, CLN1 gene defects can manifest with four major phenotypes: infantile, late-infantile, juvenile, and adult form. Three CLN1/PPT-1 cases in our series had classical infantile and the other two had late-infantile presentations. Two of our CLN1/PPT-1 cases had onset of symptoms at 5 months of age. Onset before 6 months and after 2 years of age is considered unusual for CLN1/PPT-1.  Characteristic visual failure commonly described in the literature was conspicuously absent in our series. Clinical variability within the families was noticed among two kindred (one had refractory seizures and regression, whereas the other presented with developmental delay and dystonia) in our study. One child presented with predominantly speech delay and autistic features. The median time taken for diagnosis (18 months) was partly attributable to the variable presentations including lack of visual symptoms, microcephaly, and refractory seizures. The pattern of a strikingly low signal of the thalamus within cerebral white matter with high signal intensity is quite characteristic of PPT-1-related NCL. With increasing age, there is increasing atrophy. The white matter has high signal intensity on T2-weighted images in all stages of the disease, but more seriously in the later stages. The signal intensity is highest in the periventricular area.  The isolated symmetric dentate nucleus hyperintensity as an earliest sign of PPT-1-related NCL was seen in three cases. This is a novel neuroimaging finding.  This appears to be an early indicator of PPT-1-related NCL even before the diffuse cerebral and cerebellar atrophy appears. When this is the presenting feature on MRI, then the expected thalamic T2 hyperintensities may not be seen.
TPP-1 related NCL
Traditional classic late-infantile phenotype (LINCL, Jansky-Bielschowsky disease More Details) is caused by mutation in the CLN1 gene encoding TTP-1. The enzyme sequentially removes tripeptides from the unmodified N-terminus of unstructured oligopeptides. Clinically, CLN2 gene defects can manifest either with classic late-infantile (LINCL) or juvenile (JNCL) phenotype. The genetic variants of LINCL, namely, Finnish, Indian/Gypsy, and Turkish are now called CLN5, CLN6-7, and CLN8, respectively.  However, these phenotypes are not exclusive to the respective ethnic groups. Similar to the previous reports, all of our patients with CLN2/TPP-1 deficiency had refractory seizures at presentation followed by regression of milestones.  However, none of the patients had any visual complaint, which is unusual for NCL-2/TPP-1. Classically, visual impairment in CLN2 appears between ages 4 and 6 years and rapidly progresses to blindness. , One of our cases had hypercholesterolemia and hypertriglyceridemia which has not been described previously.
Very few NCL cases (n = 15) have been reported from India till date. ,, Among those, infantile and late-infantile were two cases each, and the rest were either juvenile or adult forms. This makes our study the largest series of infantile and late-infantile forms of NCL reported from India. In all three previous reports, the diagnosis was based on characteristic histopathologic and ultrastructural features. CLN1 and CLN2 in our series were diagnosed by lysosomal enzyme assays of PPT-1 and TPP-1, respectively. Out of the 12 cases reported by Sinha et al., histopathologic examination had shown curvilinear inclusions in four, and lamellar inclusions and electron dense inclusions in two cases each. 
Our study has few notable drawbacks. Visual evoked potentials (VEP) and electroretinograms (ERG) were not recorded in our series. Serial neuroimaging was possible only in two cases. Another drawback was the lack of genetic analysis to identify mutations in CLN1/2 genes to reach a definitive diagnosis. Mutational analysis is not available at our center, which could have further established the specific genotype among Indian patients. At present, no laboratories in India offer to identify NCL genes by genetic approaches. Assays of enzyme activities of the CLN1/PPT1, CLN2/TPPI, and CLN10/CTSD are available only at select centers. However, it is important to note that identification of the underlying gene may not be possible in all patients diagnosed with NCL. 
We also emphasize the feasibility of prenatal testing and genetic counseling. Prenatal diagnosis of NCLs can be made by mutation analysis, enzyme assay, or identification of typical inclusions by electron microscopy. Pre-implantation genetic diagnosis (PGD) is also possible. In our set-up, we could successfully prevent the birth of an affected offspring using enzymatic assay as a prenatal diagnostic tool.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]
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