Niemann-pick disease type C: new aspects in a long published family - partial manifestations in heterozygotes.

Decades ago, a family with three children with a neurovisceral lysosomal storage disease was described. The patient siblings died at ages 7, 9, and 11 years, respectively, and according to the current concept had the late-infantile neurologic form of Niemann-Pick type C1 (NPC) disease, given by the present molecular study that there were severe NPC1 gene variants: Blood samples preserved since that time from one patient sibling and his presently 55-year-old essentially healthy sister have now been studied, revealing the variants p.I1061T and p.G1162V in the NPC1 gene, the first long known, the second newly found but predicted to be pathogenic and similar to the known G1162A. Now, with the molecular diagnosis, that initial description warrants new interest for the following reasons. The mentioned sister carries only the I1061T variant. She had storage macrophages ("Niemann-Pick cells") in her bone marrow, but also displayed distinct splenomegaly with indurated consistency of the organ, proven in childhood and confirmed several times up to age 13, but disappeared at age 55 years. She shares the I1061T variant with her still healthy mother, and the bone marrow finding with both parents, her father having died at 66 years from a carcinoma. The present study is one of the first describing hematological and relevant clinical symptomatology, even in heterozygotes, of molecularly diagnosed human NPC. Feline NPC is known to model such a situation. For human diagnostic and clinical NPC management, the possibility of "heterozygous disease" should be kept in mind.