Leukodystrophy, Hypomyelinating, 10

A number sign (#) is used with this entry because of evidence that hypomyelinating leukodystrophy-10 (HLD10) is caused by homozygous mutation in the PYCR2 gene (616406) on chromosome 1q42.

Description

Hypomyelinating leukodystrophy-10 is an autosomal recessive neurologic disorder characterized by postnatal progressive microcephaly, severely delayed psychomotor development, and hypomyelination on brain imaging (summary by Nakayama et al., 2015).

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

Clinical Features

Nakayama et al. (2015) reported 4 children, ranging in age from 7 to 11 years, with progressive postnatal microcephaly and hypomyelination. The patients were born of 2 unrelated consanguineous families of Omani and Palestinian origin, respectively. All presented with severely delayed psychomotor development soon after birth or within the first months of life. All had poor overall growth and progressive microcephaly (up to -7.7 SD). Other features included truncal hypotonia, appendicular hypertonia, hyperreflexia, and severe muscle wasting. Two were bedridden, 1 could not roll over or sit unsupported, and 1 could roll over and sit with support; all were nonverbal. Two patients has hyperextensibility of the wrists and ankles. Abnormal facial features included down- or upslanting palpebral fissures and thin vermilion borders as well as other abnormalities, but there was no consistent facial gestalt. Brain imaging showed hypomyelination, decreased white matter volume, and thin corpus callosum and brainstem.

Zaki et al. (2016) reported 14 patients from 11 unrelated families with HLD10. Ten of the families were consanguineous, and 10 were of Egyptian origin; 2 families had deceased children affected with the same disorder. The patients had overall failure to thrive, microcephaly (up to -6.6 SD), and profound psychomotor disability with poor fine motor skills and inability to speak or stand. Dysmorphic facial features included triangular facies, bitemporal narrowing, malar hypoplasia, large malformed ears with overfolded helices, upturned bulbous nose, and a long smooth philtrum. Neurologic features included truncal hypotonia, variable limb spasticity, and hearing loss; about half of the patients had seizures, including focal myoclonic and generalized tonic-clonic seizures. Some patients had variable skeletal abnormalities, including arachnodactyly, long toes, and pectus carinatum. Brain imaging showed global brain atrophy, thin corpus callosum, hypomyelination with reduced white matter volume, and white matter hyperintensities. The disorder was progressive, and none of the patients survived beyond the first decade of life. Zaki et al. (2016) concluded that the features of intellectual disability, microcephaly, epilepsy, and brain atrophy suggested primary neuronal dysfunction with a secondary defect in myelination.

Inheritance

The transmission pattern of HLD10 in the families reported by Nakayama et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 children from 2 unrelated consanguineous families with HLD10, Nakayama et al. (2015) identified 2 homozygous missense mutations in the PYCR2 gene (R119C, 616406.0001 and R251C, 616406.0002, respectively). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. In vitro studies showed that the mutations resulted in decreased protein expression. Mutant cells and cells transfected with an engineered truncated PYCR2 variant showed decreased staining for a mitochondrial membrane-potential-dependent marker, suggesting that the gene plays a role in maintaining mitochondrial membrane potential. Loss of PYCR2 resulted in increased susceptibility to apoptosis under oxidative stress. Pathogenic variants in the PYCR2 gene were not found in the exomes from 82 additional individuals with microcephaly.

In 14 patients from 11 families, 10 of which were consanguineous, with HLD10, Zaki et al. (2016) identified 6 different homozygous mutations in the PYCR2 gene (see, e.g., 616406.0003-616406.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 4 missense mutations, 1 truncating mutation, and 1 splice site mutation. In vitro functional studies of selected mutations showed that they impaired protein dimerization, putatively resulting in a loss of function.

Animal Model

Nakayama et al. (2015) found that morpholino knockdown of 1 of the 2 PYCR2 zebrafish orthologs, pycr1b, resulted in a small head and eyes, short body, down-tilted tail, and hypomotility. The effects were dose-dependent. The phenotype could be rescued by wildtype PYCR2 transcripts.