Leukodystrophy, Hypomyelinating, 9

A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-9 (HLD9) is caused by compound heterozygous mutation in the RARS gene (107820) on chromosome 5q34.

Description

Hypomyelinating leukodystrophy-9 is an autosomal recessive neurologic disorder characterized by onset of delayed psychomotor development, spasticity, and nystagmus in the first year of life. Additional neurologic features such as ataxia and abnormal movements may also occur. Brain imaging shows diffuse hypomyelination affecting all regions of the brain (summary by Wolf et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.

Clinical Features

Wolf et al. (2014) reported 4 patients from the Netherlands, 2 sisters and 2 unrelated patients, with severe neurologic impairment apparent in the first year of life. One of the sisters presented at age 1 year with stagnation of motor development associated with increased tone in the legs and difficulty walking; she achieved unsupported walking at age 2 years. At age 6 years, she had severe spasticity of the legs, mild intention tremor, dysmetria, dysarthria, and nystagmus. Her younger sister presented with nystagmus at age 5 months. At age 4 years, she had severe spasticity of the legs and mild ataxia. An unrelated patient presented with delayed motor development and spasticity and never achieved supported walking. At age 20 years, he had severe lower limb spasticity, pseudobulbar palsy, mild ataxia, lack of smooth pursuit, and mild mental retardation. Mild generalized atrophy with white matter volume loss was present on MRI. These 3 patients had mild mental retardation; they also had mild spasticity of the upper limbs. The other unrelated patient had a more severe phenotype, with microcephaly and delayed psychomotor development apparent at age 2 months. At age 2 years, she did not fix or follow, had axial hypotonia with poor head control, some dystonic movements, and an extrapyramidal syndrome with increased reflexes. A low level of cognition and lack of visual contact in this patient were consistent with early severe atrophy present at brain imaging. Brain imaging of all 4 patients was compatible with a severe lack of myelin affecting the supra- and infratentorial regions.

Nafisinia et al. (2017) described a sister and brother, born to unrelated Maltese parents, and a male patient, born to first-cousin Turkish parents, with a hypomyelinating disorder similar to Pelizaeus-Merzbacher disease (312080). All 3 patients had developmental delay, nystagmus, brisk deep tendon reflexes in the lower extremities, ankle clonus, and cognitive impairment. The 2 who were able to walk had an ataxic gait. One of the patients had intractable focal occipital epilepsy. Brain MRI, performed in 2 of the 3 patients, showed hypomyelination and hypoplastic corpus callosum. The sibs' father was unaffected; their mother had normal intellect, but had fluttering eye movements with rapid changes in fixation and was found to have multiple small foci of abnormal high signal intensity in the deep white matter on brain MRI. The Turkish patient had 2 aunts and an uncle in the paternal line who had severe, incompletely characterized neurologic disorders and died between 2 months and 12 years without having learned to walk or speak.

Inheritance

The transmission pattern of HLD9 in the families reported by Wolf et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 3 unrelated families from the Netherlands with hypomyelinating leukodystrophy, Wolf et al. (2014) identified compound heterozygous mutations in the RARS gene (107820.0001-107820.0005). Mutations in 2 of the families were found by whole-exome sequencing and confirmed by Sanger sequencing. All patients carried 1 missense mutation and a mutation predicted to result in the loss of a functional protein in trans; functional studies of the variants were not performed.

In a sister and brother with hypomyelinating leukodystrophy-9, who were born to unrelated Maltese parents, Nafisinia et al. (2017) identified homozygosity for one of the mutations in the RARS gene (D2G; 107820.0001) previously reported in affected sisters by Wolf et al. (2014). The mutation, found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Using Sanger sequencing of all 15 exons of the RARS gene, Nafisinia et al. (2017) screened a cohort of 45 patients with a hypomyelinating disorder who did not have a genetic diagnosis and identified a male patient, born to first-cousin Turkish parents, with compound heterozygous mutations in the RARS gene (107820.0006-107820.0007). Using patient fibroblast extracts, Nafisinia et al. (2017) found that levels of RARS protein and the multi-RNA synthetase complex into which it assembles were significantly reduced.