Mutations affecting pigmentation in man: I. Neuroectodermal melanolysosomal disease

We describe a syndrome identified in three consanguineous families who had two and probably four common ancestors five generations ago. The syndrome is characterized by profound dysfunction of the central nervous system, silver‐leaden colored hair, abnormal melanosomes and melanocytes, and abnormal inclusion bodies in fibroblasts, bone marrow histiocytes and lymphocytes which appear to represent abnormal lysosomal bodies. Because of the biochemical relationships between melanin‐melanosomes and neuromelanin, we think that all the manifestations of the condition are related to and represent pleiotropic effects of a newly identified gene in man in its homozygous state. Biochemical reactions of the cells of these patients indicate presence of tyrosinase in the melanosomes and show that the substance accumulated in cultured fibroblasts and in the bone marrow histiocytes is a PAS and Oil‐red‐O positive material but is Oil‐red‐O negative after extraction; it has the typical reactions of melanin with the Masson and Fontana stain, but cannot be considered typical melanin, since without stain it is colorless. The ultrastructural studies showed round granules with variable matrix, similar in fibroblast and bone marrow, and with variable intensity of reaction to osmium. This mutation principally affects the neuroectoderm, but also the mesoderm.