Further delineation of the clinical and pathologic features of HIKESHI-related hypomyelinating leukodystrophy

Abstract Objectives A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to be causative of a hypomyelinating leukodystrophy with high frequency in the Ashkenazi-Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi-Jewish population and provide a neuropathological study. Methods Clinical information, neuroimaging and biosamples were collected. Brain autopsy was performed for one case. Results Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth and nystagmus. Severe morbidity or death during febrile illness occurred in 5 of the 9 affected individuals. MRI of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi-Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. Conclusion We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain MRI and with the clinical features of early onset spastic/ dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi-Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.