Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: Review of data and observations

Wisneiwski, K E; Kida, E; Patxot, O F; Connell, Fred

doi:10.1002/ajmg.1320420420

Cited by 87 publications

(29 citation statements)

References 13 publications

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“…This is because the storage material in the NCLs is nearly invisible by routine staining methods and the profound autofluorescence is easily overlooked. [Multiple attempts were necessary to demonstrate the neuronal inclusions by electron microscopy in our mice, just as in many cases of NCL in humans (22).] The macrophage infiltrate seen in the PPT2-deficient mouse does not appear as a foam cell as it does in typical lysosomal storage, but rather as a normal macrophage containing storage material that is apparent only under UV illumination.…”

Section: Discussionmentioning

confidence: 99%

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Gupta

Soyombo

Shelton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The palmitoyl protein thioesterase-2 (PPT2) gene encodes a lysosomal thioesterase homologous to PPT1, which is the enzyme defective in the human disorder called infantile neuronal ceroid lipofuscinosis. In this article, we report that PPT2 deficiency in mice causes an unusual form of neuronal ceroid lipofuscinosis with striking visceral manifestations. All PPT2-deficient mice displayed a neurodegenerative phenotype with spasticity and ataxia by 15 mo. The bone marrow was infiltrated by brightly autofluorescent macrophages and multinucleated giant cells, but interestingly, the macrophages did not have the typical appearance of foam cells commonly associated with other lysosomal storage diseases. Marked splenomegaly caused by extramedullary hematopoiesis was observed. The pancreas was grossly orange to brown as a result of massive storage of lipofuscin pigments in the exocrine (but not islet) cells. Electron microscopy showed that the storage material consisted of multilamellar membrane profiles (''zebra bodies''). In summary, PPT2 deficiency in mice manifests as a neurodegenerative disorder with visceral features. Although PPT2 deficiency has not been described in humans, manifestations would be predicted to include neurodegeneration with bone marrow histiocytosis, visceromegaly, brown pancreas, and linkage to chromosome 6p21.3 in affected families. P almitoyl protein thioesterase (PPT) 2 is a lysosomal thioesterase that is 27% identical to PPT1, a lysosomal enzyme defective in a neurodegenerative disorder called infantile neuronal ceroid lipofuscinosis, or infantile Batten disease (1). The neuronal ceroid lipofuscinosis (NCLs) are a group of neurodegenerative disorders of children characterized by the accumulation of autofluorescent storage material in the brain and other tissues, cognitive and motor deterioration, visual failure, and seizures. Notable is the absence of functionally significant manifestations outside the central nervous system (2, 3). The NCLs are caused by defects in at least eight genes (of which six have been identified), and different forms of the disease have a distinct storage ultrastructure (2). The PPT1 or CLN1 gene underlies the most severe form of the disease, and it encodes a thioesterase enzyme that removes palmitate or other fatty acids from cysteine residues in proteins (4-6). The enzyme encoded by PPT2 is a second lysosomal thioesterase with a substrate specificity that overlaps that of PPT1 (7-9).Recently, we disrupted both PPT1 and PPT2 genes in mice and showed that homozygous PPT1 knockout mice have a neurodegenerative disorder that closely parallels infantile Batten disease (10). Most PPT1 knockout mice are terminal by 10 mo of age. Preliminary analysis of homozygous PPT2 knockout mice at 10 mo had shown the development of scant autofluorescent storage material in the brain and a neurological phenotype in a proportion of the animals. In the current article, we have extended the observation of these PPT2 knockout mice throughout their natural lifespan and analyzed their behavio...

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Section: Discussionmentioning

confidence: 99%

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Gupta

Soyombo

Shelton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…A variant Finnish late infantile form is caused by a defect in a putative mapped CLN5 gene (8), and other atypical forms have been described (9). In the U.S. population, infantile, late infantile, juvenile, and adult NCL comprise 11.3%, 36.3%, 51.1%, and 1.3% of cases with NCL, respectively (10).…”

Section: Introductionmentioning

confidence: 99%

Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.

Das¹,

Becerra²,

Yi³

et al. 1998

J. Clin. Invest.

145

117

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Mutations in a newly described lysosomal enzyme, palmitoyl-protein thioesterase (PPT), were recently shown to be responsible for an autosomal recessive neurological disorder prevalent in Finland, infantile neuronal ceroid lipofuscinosis. The disease results in blindness, motor and cognitive deterioration, and seizures. Characteristic inclusion bodies (granular osmiophilic deposits [GROD]) are found in the brain and other tissues. The vast majority of Finnish cases are homozygous for a missense mutation (R122W) that severely affects PPT enzyme activity, and the clinical course in Finnish children is uniformly rapidly progressive and fatal.To define the clinical, biochemical, and molecular genetic characteristics of subjects with PPT deficiency in a broader population, we collected blood samples from U.S. and Canadian subjects representing 32 unrelated families with neuronal ceroid lipofuscinosis who had GROD documented morphologically. We measured PPT activity and screened the coding region of the PPT gene for mutations. In 29 of the families, PPT deficiency was found to be responsible for the neurodegenerative disorder, and mutations were identified in 57 out of 58 PPT alleles. One nonsense mutation (R151X) accounted for 40% of the alleles and was associated with severe disease in the homozygous state. A second mutation (T75P) accounted for 13% of the alleles and was associated with a late onset and protracted clinical course. A total of 19 different mutations were found, resulting in a broader spectrum of clinical presentations than previously seen in the Finnish population. Symptoms first appeared at ages ranging from 3 mo to 9 yr, and about half of the subjects have survived into the second or even third

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“…Cases were classified mainly on the basis of clinical manifestations, age of onset, EEG patterns and EM observations 5,11,18,[30][31][32] . The cases were grouped into INCL, 7 patients; LINCL, 5 patients; JNCL, 5 patients.…”

Section: Methodsmentioning

confidence: 99%

“…The identification of loci for infantile NCL and juvenile NCL on chromosomes 1 and 16 respectively, and the exclusion of linkage of late-infantile NCL to either one, in the early 1990's, prompted a reclassification of NCL disorders, based on molecular genetics: CLN1 for infantile NCL; CLN2 for classical late-infantile NCL; CLN3 for juvenile NCL and CLN4 for adult NCL 18,[24][25][26][27][28][29] . To date, there are eight established forms of NCL (CLN 1-8), with CLN5, 6 and 7 being variants of late-infantile NCL.…”

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confidence: 99%

Neuronal ceroid lipofuscinoses: a clinical and morphological study of 17 patients from Southern Brazil

Puga

Jardim

Chimelli

et al. 2000

Arq. Neuro-Psiquiatr.

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The neuronal ceroid lipofuscinoses (NCL) are a group of inherited progressive neurodegenerative disorders with presentation from infancy to adulthood. Three main childhood forms can be established on the basis of age of onset, clinical course, and ultrastructural morphology: infantile (INCL), late infantile (LINCL), and juvenile (JNCL). Several variant subtypes have been described. Genetic and biochemical analysis are helping to better understand, diagnose and classify these disorders. We report on clinical, neurophysiological, neuroradiological, and morphological data from 17 patients with different forms (infantile, late infantile, and juvenile ) of neuronal ceroid lipofuscinoses (NCL) evaluated at Hospital de Clínicas de Porto Alegre, Southern Brazil, during 6 years (1992-1997). Seven cases were infantile; 5 were late infantile; and 5 were juvenile NCL. Gender ratio was male:female, 11:6. Age at presentation varied from 2-24 months for INCL; 2,5 to 5 years for LINCL ; and 4-10 years for the JNCL cases. Seizures (6 patients) and psychomotor retardation (1 patient) were the initial symptoms in the INCL group. All the patients in the group of LINCL had the usual findings. JNCL patients manifested different initial symptoms, although tending to follow a similar clinical picture within familial cases. Epidemiological data on the prevalence of NCLs in Brazil are not available, we expect this series of cases to contribute to further research in our population.

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Variability in the clinical and pathological findings in the neuronal ceroid lipofuscinoses: Review of data and observations

Cited by 87 publications

References 13 publications

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Disruption ofPPT2in mice causes an unusual lysosomal storage disorder with neurovisceral features

Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.

Neuronal ceroid lipofuscinoses: a clinical and morphological study of 17 patients from Southern Brazil

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