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LEUKODYSTROPHY, HYPOMYELINATING, 15; HLD15

LEUKODYSTROPHY, HYPOMYELINATING, 15; HLD15

Hypomyelinating leukodystrophy-15 is an autosomal recessive neurodegenerative disorder characterized by onset of motor and cognitive impairment in the first or s...

Hypomyelinating leukodystrophy-15 is an autosomal recessive neurodegenerative disorder characterized by onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum. The severity of the disorder is variable (summary by Mendes et al., 2018)

For a discussion of genetic heterogeneity of HLD, see 312080.

▼ Clinical Features
Mendes et al. (2018) reported 4 unrelated patients with HLD15. Two were born of consanguineous parents; all were Caucasian. The phenotype was somewhat heterogeneous. Two patients had onset of progressive neurologic and cognitive deterioration at ages 7 and 14 years, respectively. Additional features included optic atrophy resulting in significant visual loss with variable amblyopia, hypermetropia, nystagmus, ataxia, dysarthria, spasticity, dystonia, and intention tremor. At age 16 years, 1 patient was nearly blind, had lost ambulation, and had mild dysphagia. The other patient remained ambulatory, but she had significant cerebellar signs and developed seizures at age 23 years. The 2 other patients had a more severe disorder with earlier onset. They presented in the first months or year of life with microcephaly and delayed motor development; neither achieved unsupported walking. One developed progressive ataxia, dystonia, pyramidal signs, and dysphagia beginning around 18 months of age, but she did not have ophthalmologic abnormalities; cognitive function was not mentioned. She died at age 9 years due to pneumonia. The other patient showed motor regression with signs of upper motor neuron involvement, ataxia, dystonia, and athetoid movements around 2 years of age. She had episodic regression with febrile illnesses and later showed cognitive regression with sensorineural hearing loss, short stature, severe dysphagia necessitating a feeding tube, and optic atrophy. A similarly affected older sister had died at age 3 years. Brain MRI of all 4 patients showed hypomyelinating leukodystrophy with thinning of the corpus callosum. Supratentorial atrophy was severe in the older individuals, at ages 13 and 20 years. Cerebellar atrophy was mild. The 2 more severely affected patients also had signal abnormalities in the thalami and specific tracts in the brainstem and spinal cord.

▼ Inheritance
The transmission pattern of HLD15 in the families reported by Mendes et al. (2018) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics
In 4 unrelated patients with HLD15, Mendes et al. (2018) identified homozygous or compound heterozygous mutations in the EPRS gene (138295.0001-138295.0005). Mutations in the first 3 patients were found by whole-exome sequencing; mutation in the fourth patient was found by direct sequencing of the EPRS gene. The mutations were confirmed by Sanger sequencing and segregated with the disorder in all families. Two of the mutations were nonsense and frameshift, and 3 were missense variants affecting tRNA synthetase core domains. In vitro functional studies using patient cells or a recombinant protein model of 2 of the missense mutations showed that they resulted in decreased protein levels and impaired aminoacylation activity of EPRS. Mendes et al. (2018) concluded that reduced translation capacity and protein availability resulting from the mutations causes insufficient myelin deposition in the developing brain.

Tags: 1q41