Juvenile dystonic lipidosis (variant of Niemann-Pick disease type C)

Martin, Jean‐Jacques; Lowenthal, A.; Ceuterick, C.; Vanier, Marie T.

doi:10.1016/0022-510x(84)90139-4

Cited by 36 publications

(19 citation statements)

References 21 publications

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“…Of note, fibroblasts from patients with an adult-onset of neurological symptoms may show either a severe cholesterol trafficking defect or only minimal alterations (biochemical variant) [35,69,70]. Conversely, in two "variant" siblings who had died from a juvenile form, the liver showed no lipid accumulation (spleen did), but the brain showed typical accumulation of GM2 and GM3 gangliosides [79]. …”

Section: Etiologymentioning

confidence: 99%

Niemann-Pick disease type C

Vanier

2010

Orphanet J Rare Dis

982

1,127

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Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

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Section: Etiologymentioning

confidence: 99%

Niemann-Pick disease type C

Vanier

2010

Orphanet J Rare Dis

982

1,127

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“…--W W \o modifications of the liver lipids were quite discrete, and diagnosis remained difficult even by this criterion. Cases 20 and 29, in whom definitive assessment of the lipid storage profile awaited a study of the spleen tissue (Martin et al 1984), are a good illustration of this atypical pattern.…”

Section: Assessment Of the Storage Process (Tables 1 And 2)mentioning

confidence: 99%

Niemann‐Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification: A collaborative study on 70 patients

Vanier¹,

Wenger²,

Comly³

et al. 1988

Clinical Genetics

173

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Seventy patients were selected to cover the range of variability in clinical expression of Niemann‐Pick disease group C (NP‐C). Their individual main clinical features and course of the disease (age at discovery and type of visceromegaly, age at onset and first neurological manifestation, later neurological symptoms) are schematically described. In cultured skin fibroblasts from these patients, sphingomyelinase activities measured in vitro showed decreased values only in approximately half of the cases, and when the metabolic fate of [14C]‐sphingomyelin was studied in living cell cultures, still 20% of the cases had a normal hydrolysis rate. Esterification of exogenous cholesterol was investigated in cell lines from these and 5 additional patients and in 21 of their parents. Using a non‐lipoprotein [3H]cholesterol source, very low esterification rates were obtained in more than 90% of the cases. All the numerous other pathological conditions studied, including Niemann‐Pick disease types A and B, gave normal results. A more sensitive method was elaborated, in which the cells were challenged with pure human low density lipoproteins (LDL) and the early rate of esterification studied. With the latter procedure, a pronounced deficiency could also be demonstrated in the few cases which had shown a milder impairment using a [3H]cholesterol source, and intermediate rates of esterification were obtained in heterozygotes. Discrimination of these difficult cases and of heterozygotes could also be achieved replacing LDL with total unfrozen human serum. Correlations were established between given clinical phenotypes and the severity of the biochemical lesion. Defective intracellular cholesterol esterification is further established as an intrinsic feature of NP‐C, and demonstration of this metabolic alteration appears as a major advance in diagnosing the condition.

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“…A typical cerebellar ataxia with incoordination and inten tional tremor is a prominent early feature in most pa tients. Cerebellar ataxia is often found in neurolipidoses, but its association to extrapyramidal manifestations is characteristic of Niemann-Pick type C. The principal symptom is a dystonia which is implied in the name of 'juvenile dystonic lipidosis' [10,13,16] but mental dete rioration is always present. Other extrapyramidal move ments have been described such as choreic movements, or athetosis.…”

Section: A Taxia-dystoniamentioning

confidence: 99%

Clinical Aspects of Niemann-Pick Type C Disease in the Adult

1991

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Niemann-Pick type C disease diagnosed in adult neurology departments may be infantile or juvenile forms with prolonged life span or forms starting at adolescence or adulthood. The evolution is generally slower compared to the infantile cases. Psychomotor retardation is practically constant. Cerebellar ataxia and extrapyramidal manifestations are often found in opposition to pyramidal symptoms. Supranuclear ophthalmoplegia with a down-gaze failure is nearly constant. Cataplexy and other types of seizures may be found during the evolution of the disease. In some cases a psychosis may be the only manifestation for several years; the treatment by psychotropic drugs raises the question of a superimposition of a drug-induced lipidosis. Hepatosplenomegaly is often discrete, contrary to infantile cases. Foam cells or sea-blue histiocytes are a general feature of the disease. Although the primary defect is unknown, diagnosis must be confirmed by the defect in cholesterol esterification from exogenous cholesterol.

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Juvenile dystonic lipidosis (variant of Niemann-Pick disease type C)

Cited by 36 publications

References 21 publications

Niemann-Pick disease type C

Niemann-Pick disease type C

Niemann‐Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification: A collaborative study on 70 patients

Clinical Aspects of Niemann-Pick Type C Disease in the Adult

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