Iqbal et al. (2019) reported 4 patients from 2 unrelated families with a similar neurodevelopmental disorder. The first family was a consanguineous Syrian family...
Iqbal et al. (2019) reported 4 patients from 2 unrelated families with a similar neurodevelopmental disorder. The first family was a consanguineous Syrian family with 2 sibs aged 5 years and 13 months, and the second family was a consanguineous Pakistani family with 2 sibs aged 32 and 29 years. All had hypotonia, moderately to severely impaired intellectual development, short stature (range -2 to -3.9 SD), and microcephaly (-2.63 to -6.43 SD). The 3 patients who could walk had mildly delayed walking by age 3 and an ataxic gait. More variable features included abnormal chest shape and aggressive behavior (in the adult patients).
Pagnamenta et al. (2019) reported 8 patients from 3 unrelated consanguineous families with NEDAHM. The patients presented in infancy or early childhood with global developmental delay, delayed walking, impaired intellectual development, and significant speech delay with poor expressive language. Some had behavioral abnormalities, including autistic features and short temper. Most had microcephaly (about 0.4 percentile or less) and coarse facial features. The patients had lower limb spasticity with brisk reflexes, ankle clonus, or extensor plantar responses and hypertonia, causing an unsteady gait. Three patients had seizures: 2 had seizures in the first years of life that resolved by the teenage years, and the third had seizures at 13 to 14 years of age. Brain imaging results, available for 4 patients, showed thin corpus callosum, dilated ventricles, and reduced periventricular white matter. Additional findings included mirror hand movements (4 patients) and short metacarpals or thumbs and atrophy of the intrinsic hand muscles (3 patients).
The transmission pattern of NEDAHM in the families reported by Iqbal et al. (2019) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 4 patients from 2 unrelated highly consanguineous families with NEDAHM, Iqbal et al. (2019) identified a homozygous nonsense mutation in the SVBP gene (Q28X; 617853.0001). The mutation, which was found by a combination of linkage analysis and exome or next generation sequencing of candidate genes and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not found in the 1000 Genomes Project or gnomAD database, or in in-house ethnically matched controls. One family was of Syrian descent and the other of Pakistani descent; haplotype analysis indicated a founder effect. Analysis of patient cells showed no significant reduction in SVBP mRNA, but transfection of the mutation into HEK293 cells showed no evidence of a truncated protein by Western blot analysis, suggesting that the mutant mRNA or protein is rapidly degraded and results in a loss of function. Knockdown of about 50% Svbp expression using shRNA in rat hippocampal neurons impaired the formation of excitatory synapses compared to controls. The authors concluded that SVBP plays a role in proper synapse formation and that loss of this function may contribute to neurodevelopmental abnormalities.
In 8 patients from 3 unrelated consanguineous families with NEDAHM, Pagnamenta et al. (2019) identified homozygous loss-of-function mutations in the SVBP gene: Q28X and a frameshift (617853.0002). The mutation in the first family was found by a combination of linkage analysis and whole-exome sequencing; the other families were subsequently identified through genetic databases of patients who had undergone whole-genome or whole-exome sequencing. The mutations segregated with the disorder in all families. In vitro functional cellular expression studies showed that protein levels of the SVBP mutants were barely detectable, suggesting instability, and that the mutant proteins had lost VASH/SVBP catalytic detyrosination activity toward tubulin.
▼ Animal Model
Pagnamenta et al. (2019) found that Svbp-null mice had a significant reduction in whole brain volume, with a particular decrease in white matter. Neurons isolated from Svbp-null mice showed a large decrease in the amount of detyrosinated tubulin, accumulation of tyrosinated tubulin, delayed axonal differentiation, and morphologically disturbed dendritic branching compared to controls. Mutant mice showed behavioral abnormalities, including increased activity and reduced social investigation compared to controls, although they did not appear to have severe memory deficits.