Intractable seizures in malignant infantile osteopetrosis due to CLCN7 mutation: lysosomal aspects

Aims: Osteopetroses occur as a consequence of loss of function in osteoklast cells resulting in thickened and fragile bones and neurological dysfunction of varable degree dependent on the genotype. The mutated cells functioned is hampered because of disturbed acidification of the lacunae in the ruffled border membrane. Among the more severe recessive forms mutations in the chloride channel subtype 7 lead frequently to serious neuronopathy similar to lysosomal storage disorders with fatal outcome.

Case report: Two childrens of consanguineous Turkish parents were affected, both similar in early bone marrow failure, untreatable seizures, blindness and developmental arrest in early infancy. The first born girl died with 10 months, her younger brother was diagnosed aged 9 months with typical radiological findings of malignant osteopetrosis. Molecular studies revealed a homozygous mutation in CLCN7. Stem cell therapy was considered to be not effective for the advanced neurological impairment.

Lysosomal aspects: Due to homozygous ClCN7 mutation mice and men present with rapidly progredient osteopetrosis and neurodegeneration, associated with massive enlargement of the lysosome storage substance. The stored material is quite similar and also autofluorescent as the deposited pigment seen in NCL. This storage disease- like effect was observed also in men, but despite of enormous enlargement of the lysosomes no functional disturbance could be detected. Because these deleterious neurologic consequence were not seen in the more frequent mutations in TCIG1, a particular neuronal and retinal pathogenicity of some CLCN7 mutations not accessible to stem cell therapy is assumed.