A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD) is caused by homozygous mutation in the ADCY5 gene (600293) on chromosome 3q21.

Biallelic mutation in the ADCY5 gene can cause a less severe autosomal recessive hyperkinetic disorder (DSKOR; 619647), and heterozygous mutation can cause an autosomal dominant hyperkinetic disorder with overlapping features (DSKOD; 606703).

Neurodevelopmental disorder with hyperkinetic movements and dyskinesia (NEDHYD) is an autosomal recessive complex neurologic disorder characterized by severe global developmental delay with axial hypotonia, impaired intellectual development, poor overall growth, and abnormal involuntary hyperkinetic movements, including dystonia, myoclonus, spasticity, and orofacial dyskinesia. It is the most severe manifestation of ADCY5-related dyskinetic disorders (summary by Okamoto et al., 2021 and Kaiyrzhanov et al., 2021).

Okamoto et al. (2021) reported 2 sibs, born of unrelated Japanese parents, with NEDHYD. The patients presented in infancy with feeding difficulties, poor growth, and global developmental delay. At 3 and 1.5 years of age, the patients had severe intellectual disability with speech delay, axial hypotonia with inability to control the head or roll over, poor eye contact, hyperreflexia, and dystonic posturing. The patients became agitated in response to sounds and touch, and showed sudden movements when surprised. Brain imaging in 1 patient showed mild brainstem hypoplasia. The parents were clinically unaffected. The authors noted that these sibs had the most severe manifestations of ADCY5-related dyskinetic disorders.

Kaiyrzhanov et al. (2021) reported 3 sibs, born of consanguineous Egyptian parents, with a complex severe neurologic disorder. They had poor overall growth, global developmental delay apparent in infancy, axial hypotonia, and appendicular spasticity. They all developed intermittent dystonia, limb dyskinesia, poor eye contact with abnormal eye movements, facial twitching, myoclonus, and tremor. The hyperkinetic movements persisted during sleep and tended to worsen in a paroxysmal manner; the movements became more constant with time. The patients were nonverbal, unable to walk or speak, developed contractures, and demonstrated behavioral abnormalities, including anxiety, phobia, grinding movements, and obsessive-compulsive features. Brain imaging showed thin corpus callosum, mildly enlarged ventricles, and deep white matter signals. One patient had cardiomyopathy; she died at 4.5 years of age. The parents were clinically unaffected.

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

In 2 sibs, born of unrelated Japanese parents, with NEDHYD, Okamoto et al. (2021) identified a homozygous missense mutation affecting the C terminus of the ADCY5 gene (R1238W; 600293.0010). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

In 3 sibs, born of consanguineous Egyptian parents, with NEDHYD, Kaiyrzhanov et al. (2021) identified a homozygous splice site mutation in the ADCY5 gene (600293.0011). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro minigene constructs confirmed that the mutation resulted in splicing defects of ADCY5. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.