Coexisting variants in OSTM1 and MANEAL cause a complex neurodegenerative disorder with NBIA-like brain abnormalities

摘要

Coexistence of different hereditary diseases is a known phenomenon in populations with a high consanguinity rate. The resulting clinical phenotypes are extremely challenging for physicians involved in the care of these patients. Here we describe a 6-year-old boy with co-occurrence of a homozygous splice defect in OSTM1, causing infantile malignant osteopetrosis, and a loss-of-function variant in MANEAL, which has not been associated with human disease so far. The child suffered from severe infantile-onset neurodegeneration that could not be stopped by bone marrow transplantation. Magnetic resonance imaging demonstrated global brain atrophy and showed hypointensities of globus pallidus, corpora mamillaria, and cerebral peduncles, which were comparable to findings in neurodegeneration with brain iron accumulation disorders. LC-MS/MS analysis of urine and cerebrospinal fluid samples revealed a distinct metabolic profile with accumulation of mannose tetrasaccharide molecules, suggestive of an oligosaccharide storage disease. Our results demonstrate that exome sequencing is a very effective tool in dissecting complex neurological diseases. Moreover, we suggest that MANEAL is an interesting candidate gene that should be considered in the context of neurological disorders with brain iron accumulation and/or indications of an oligosaccharide storage disease.