Clinical and cellular manifestations of OSTM1-related infantile osteopetrosis.

Infantile ARO is a genetic disorder characterized by osteoclast dysfunction that leads to osteopetrosis. We describe a novel mutation affecting the OSTM1 locus responsible for ARO. In addition to common clinical features of osteopetrosis, the patient developed a unique neuronal pathology that provided evidence for an essential role of OSTM1 in normal neuronal cell development. Infantile autosomal recessive osteopetrosis (ARO) is a genetic disorder characterized by osteoclast dysfunction that leads to osteopetrosis. We describe a novel mutation affecting the OSTM1 locus responsible for ARO. In addition to common clinical features of osteopetrosis, the patient developed a unique neuronal pathology that provided evidence for an essential role of OSTM1 in normal neuronal cell development. We report a new case of ARO caused by an homozygous mutation in OSTM1. In addition to osteopetrosis and bone marrow failure, this patient also had neurological impairment not related to bone entrapment. Retinal dystrophy with absent evoked visual potentials and sensorineural deafness were documented, as well as cerebral atrophy and bilateral atrial subependymal heterotopias. The patient developed generalized seizures and had a profound developmental delay. Nerve biopsy failed to show inclusion material suggestive of neuroaxonal dystrophy. Bone marrow transplantation was declined considering the severe neurological compromise. The patient died at 1 yr of age. Osteoclasts derived from peripheral blood were mature and multinucleated. Expression analysis showed that the amount of OSTM1 cDNA transcript was significantly lowered but not absent. These results support the role of OSTM1 in osteoclast function and activation. However, they also suggest that OSTM1 has a primary role in neural development not related to lysosomal dysfunction.