Neurodevelopmental Disorder With Impaired Intellectual Development, Hypotonia, And Ataxia

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia (NEDIDHA) is caused by homozygous or compound heterozygous mutation in the DOCK3 gene (603123) on chromosome 3p21.

Clinical Features

Helbig et al. (2017) reported 2 sibs, born of unrelated parents of Ashkenazi and Yemeni Jewish descent, with a similar neurodevelopmental disorder. The patients, aged 11 and 12 years, presented in the first months of life with global developmental delay. They had delayed walking between 2.5 and 5 years, ataxic gait, hypotonia, hyporeflexia, and poor or absent speech. Mild and variable dysmorphic features included pointed chin, downslanting palpebral fissures, high-arched palate, long face, and long fingers. Neither had seizures, and brain imaging in 1 patient was normal.

Iwata-Otsubo et al. (2018) reported a 28-month-old boy, born of consanguineous parents, with global developmental delay, hypotonia, and speech/language delay with only a few words. He walked at age 22 months, but had an ataxic gait. He also had mild short stature, breath-holding spells, and dysmorphic features, such as epicanthal folds, upturned nares, anteverted nares, prominent cheeks, and small joint laxity. Intelligence testing yielded scores of 98 and 108 on the Bayley II Mental Scale at age 26 and 32 months, respectively. Brain imaging was essentially normal, although the corpus callosum was slightly dysmorphic. The child was adopted and there was no family history available.

Inheritance

The transmission pattern of NEDIDHA in the family reported by Helbig et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of unrelated parents of Ashkenazi and Yemeni Jewish descent, with NEDIDHA, Helbig et al. (2017) identified a heterozygous nonsense mutation in the DOCK3 gene (Q128X; 603123.0001) and a heterozygous 458-kb deletion on chromosome 3p21.2, including part of the DOCK3 gene. The deletion and mutation, which were found by a combination of microarray analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to result in a complete loss of DOCK3 function.

In a 24-month-old boy, born of consanguineous parents, with NEDIDHA, Iwata-Otsubo et al. (2018) identified a homozygous 170-kb deletion on chromosome 3p21.2 including exons 6-12 of the DOCK3 gene (603123.0002). The intragenic deletion was found by SNP microarray analysis, but familial segregation studies could not be performed because the patient was adopted. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a frameshift and premature termination, and the transcript was likely subjected to nonsense-mediated mRNA decay, consistent with a complete loss of function.

Animal Model

Chen et al. (2009) found that Dock3-null mice developed limb weakness, gait abnormalities, ataxia, and impaired ability to swim compared to controls. The findings were consistent with a loss of sensorimotor function. Spinal cord sections from mutant mice showed abnormal neurofilament accumulation with increased numbers of autophagic vacuoles and degenerative axonal changes consistent with axonal dystrophy. There was also evidence of impaired axonal transport and disruption of the axonal cytoskeleton, which was associated with defects in actin dynamics.