Leukodystrophy, Hypomyelinating, 16

A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-16 (HLD16) is caused by heterozygous mutation in the TMEM106B gene (613413) on chromosome 7p21.

Description

Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum (summary by Simons et al., 2017).

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

Clinical Features

Simons et al. (2017) reported 4 unrelated probands with hypomyelinating leukodystrophy. The patients had onset of nystagmus and hypotonia in the first days or weeks of life, but were alive at ages 19, 5, 38, and 26 years, respectively. Features apparent in early childhood included delayed motor development, mildly increased tone and reflexes, and poor feeding in some. Later examinations showed dystonia, wide-based or ataxic gait, dysarthria, dysmetria, saccadic pursuit, tremor, and mild pyramidal signs. The most severely affected individual (patient 1) achieved walking at age 13 years and was non-verbal at age 19, whereas the other 3 patients walked between 3 and 5 years. Cognitive function was variable: patient 2 had mild language delay, patient 3 had an IQ of 76 and could live on her own with support, and patient 4 had an IQ of 50. Only 1 patient had seizures with onset at age 4 months and was treated for 3 years. Brain imaging showed hypomyelination, with thin corpus callosum in the older patients. The 65-year-old father of 1 of the patients (patient 3) was mosaic for the mutation (about 25% levels in leukocytes), and had normal cognition and no obvious neurologic abnormalities as an adult, but reportedly had nystagmus and mild developmental delay in infancy. Overall, the phenotype was less severe than that observed in other forms of HLD.

Yan et al. (2018) reported a 4-year-old Chinese girl with HLD16. She presented in infancy with mixed horizontal, vertical, and rotary nystagmus and mild developmental delay affecting the gross and fine motor domains. Cognition and social interactions were spared. She had normal muscle strength, tone, hearing, and sight. Brain MRI indicated continuous and diffuse hypomyelination.

Molecular Genetics

In 4 unrelated patients with HLD16, Simons et al. (2017) identified a heterozygous missense mutation in the TMEM106B gene (D252N; 613413.0001). The mutation, which was identified by trio-based whole-exome or whole-genome sequencing, was not found in the dbSNP, ExAC, or gnomAD databases. The mutation occurred de novo in 3 patients, but the mildly affected father of 1 of the patients (patient 3) was mosaic for the mutation. The most severely affected individual (patient 1) also carried a potentially damaging de novo missense variant in the USP7 gene (602519), which may have contributed to his phenotype. Functional studies of the TMEM106B variant and studies of patient cells were not performed, but the findings suggested a link between TMEM106B and lysosomes to oligodendrocytes and myelination.

Yan et al. (2018) identified a de novo heterozygous D252N mutation in the TMEM106B gene in a 3-year-old girl of Chinese descent with HLD16. The mutation was found by trio whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but Yan et al. (2018) noted that the mutation occurred at a CpG dinucleotide, suggesting that it is a recurrent mutation due to a hotspot within the gene.