A number sign (#) is used with this entry because of evidence that attention deficit-hyperactivity disorder-8 (ADHD8) is caused by homozygous mutation in the CDH2 gene (114020) on chromosome 18q12. One such family has been reported.

Attention deficit-hyperactivity disorder-8 (ADHD8) is a severe early-childhood neuropsychiatric disorder characterized by a persistent pattern of hyperactive behavior and impulsivity (Halperin et al., 2021).

For a general phenotypic description and a discussion of genetic heterogeneity of attention deficit-hyperactivity disorder, see 143465.

Halperin et al. (2021) reported a consanguineous Bedouin kindred in which 3 sibs, aged 11, 7, and 6 years, had severe ADHD diagnosed in early childhood. By age 3 years, all showed severe hyperactive behavior with impulsivity. One of the 3 had mild developmental delay with autism; the other 2 patients had normal development. Brain imaging performed in 1 patient was normal. All were treated with stimulants, neuroleptics, and 3-quinuclidinyl benzilate.

The transmission pattern of ADHD8 in the family reported by Halperin et al. (2021) was consistent with autosomal recessive inheritance.

In 3 sibs, born of consanguineous Bedouin parents, with ADHD8, Halperin et al. (2021) identified a homozygous missense mutation in the CDH2 gene (H150Y; 114020.0010). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. In vitro functional expression studies showed that the mutation interfered with CDH2 protein processing, causing decreased proteolytic cleavage efficacy and defective N-cadherin protein maturation. Mutant mice with a homozygous H150Y mutation in the Cdh2 gene demonstrated motor hyperactivity, with greater traveling distance, increased velocity, and prolonged mobility time in the open-field exploratory test compared to controls (see ANIMAL MODEL).

Halperin et al. (2021) found that mutant mice homozygous for the H150Y mutation in the Cdh2 gene demonstrated hyperactive behavior. Mutant mice also showed an elevated startle amplitude in the acoustic startle reflex test (ASR) compared to controls, suggesting deficits in sensorimotor integration. Detailed analysis of the neurons from brains of mutant mice showed that homozygosity for the Cdh2 mutation was associated with a decrease in the size of the presynaptic vesicle cluster, a decrease in the readily releasable pool size of synaptic vesicles in neurons, and an attenuation of synaptic vesicle release compared to controls. The frequency of spontaneous synaptic release was also decreased compared to controls. There was reduced tyrosine hydroxylase expression and dopamine levels in the midbrain and prefrontal cortex. The authors suggested that deficits in synaptic formation due to aberrant processing of N-cadherin is the underlying mechanism for the clinical manifestations.