A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA) is caused by heterozygous mutation in the HK1 gene (142600) on chromosome 10q22.

Neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA) is characterized by global developmental delay with impaired intellectual development and speech delay, variable visual defects, including retinitis pigmentosa and optic atrophy, hypotonia or hypertonia, and variable structural brain abnormalities. Other nonspecific features may be found (summary by Okur et al., 2019).

Okur et al. (2019) reported 7 patients from 6 unrelated families with a similar neurodevelopmental disorder. The patients had global developmental delay apparent in infancy or early childhood, speech delay, and impaired intellectual development. Two sibs died of respiratory infections at 1 year of age. All had visual involvement, including 3 with retinitis pigmentosa and 5 with optic atrophy. Other visual features included cortical visual impairment, strabismus, nystagmus, and astigmatism. Brain imaging showed variable abnormalities in all but 1 patient. These included cerebral and cerebellar atrophy, thin corpus callosum, periventricular leukomalacia, brainstem abnormalities, and enlarged ventricles. Additional neurologic findings were highly variable: the deceased infant sibs had infantile spasms and limb hypertonia, whereas other patients had ataxia, hypotonia, torticollis, limb hypertonia, staring spells, and/or bulbar weakness. A few patients had scoliosis, hip dislocation, foot deformities, laryngotracheomalacia (the sibs), and/or mild nonspecific dysmorphic facial features.

The heterozygous mutations in the HK1 gene that were identified in patients with NEDVIBA by Okur et al. (2019) occurred de novo.

In 7 patients from 6 unrelated families with NEDVIBA, Okur et al. (2019) identified 4 different de novo heterozygous missense mutations in the HK1 gene (142600.0006-142600.0009). All mutations occurred at highly conserved residues in the N-terminal regulatory domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of over 100,000 exomes. Blood cells from 2 unrelated patients had normal hexokinase activity, suggesting a different pathogenic mechanism. Other functional studies of the variant and studies of patient cells were not performed, but the authors postulated a gain-of-function effect.