Lab mat 2
Orpha Number: 646

Niemann-Pick disease type C (completely distinct from types A and B) is a complex lysosomal lipidosis resulting in hepatosplenomegaly and progressive neurological involvement. The estimated prevalence is approximately 1/130 000 births. The clinical picture is extremely heterogeneous, the age of onset varying between the perinatal period and the age of 50 years or more. Cases of hydrops foetalis have been described (rare). In 40% of cases, the neonatal period is marked by hepatosplenomegaly associated with prolonged cholestatic jaundice that usually regresses spontaneously but sometimes progresses to rapidly fatal liver failure. The finding of hepato- and/or splenomegaly in the child is a very frequent sign, which can remain isolated for a very variable period, before the beginning of neurological symptoms. The age of onset of these symptoms and their evolution will determine the degree of severity of the disease. In the severe infantile form (20% of cases), the onset of neurological involvement occurs before age 2 with delay in motor milestones and hypotonia, followed by pyramidal signs. In the other forms, occurring much more frequently, typical neurological signs include cerebellar ataxia and dysarthria (very frequent), cataplexy (20% of the cases), dystonia (frequent), vertical supranuclear ophtalmoplegia (almost constant), seizures (relatively frequent), and often progressive dementia, with onset between the ages of 3 and 15 (late infantile and juvenile forms, 60-70% of cases) or later (adult form, 10% of cases, with higher frequency of psychiatric disorders). The evolution is marked by a worsening of neurological signs, with the appearance of a progressive dysphagia that can ultimately require gastrotomia and often pyramidal signs. Hepatosplenomegaly may be absent (10 to 15% of cases); conversely, very few adults have been described with isolated splenomegaly only. Transmission is autosomal recessive. Two complementation groups have been described. The NPC1 gene (18q11, 57Kb, 25 exons) is mutated in 95% of families. More than 230 mutations have been identified, the most frequent being: I1061T (20% of the alleles), P1007A (« variant » phenotype). The mutation G992W is typical of the « Nova Scotia » form (formerly designated as type D). The NPC2 gene (14q24.3, 13.5 Kb, 5 exons) is only involved in few families (22 have been described). NPC1 and NPC2 proteins seem to play a synergic role in the endo-lysosomal system to facilitate the intracellular transport of cholesterol and other molecules, but their exact function has not yet been established. Whatever the mutated gene, the characteristic cellular defect consists of impaired LDL-derived exogenous cholesterol intracellular transport, causing accumulation of non-etherified cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Diagnosis is established by demonstrating these anomalies in cultured fibroblasts (especially through the cytochemical ``filipine test''). The severity of the biochemical defect varies between a ``classical phenotype'' with strongly impaired estherification reactions (85 % of cases), and a ``variant'' with moderate alteration (15 % of cases). There is no close correlation between clinics and biochemistry. Prenatal diagnostic is more easily obtained by molecular biology, but it can also be performed by cellular biology (except in ``variant'' families). There is no specific treatment available to date. Cholesterol lowering agents have been tested but they have no effect on the neurological manifestations of the disease. However, promising results have been obtained on animal models (cat and mouse) with a glycolipid synthesis inhibitor and have led to the initiation of a clinical trial (still under way). The prognosis depends on the age of onset of the neurological manifestations, with the prognosis being more severe in cases of early-onset neurological involvement.
source: Orphanet