A Novel Homozygous ADCY5 Variant is Associated with a Neurodevelopmental Disorder and Movement Abnormalities

Abstract

The genetic and clinical spectrum of adenylyl cyclase 5 (ADCY5)related disease has considerably been expanding in recent years. To date, from over 70 ADCY5-related disease reports, only three have been associated with an autosomal recessive (AR) inheritance, while the rest of the reports were linked to an autosomal dominant (AD) inheritance. Clinical comparison of the cases with different modes of inheritance in ADCY5-related disease is currently challenging due to the paucity of reports on the AR form and broad phenotype of the AD form. Herein, we report a family with an AR ADCY5-related disease. Three affected siblings, including two females and one male, were born to the non-consanguineous parents originating from the same Egyptian village (Fig. 1A). The elder affected sibling (III-2) died at the age of 4 years old, and the younger affected siblings are currently aged 8 (III-5) and 2 (III-6) years old. All were the products of an uneventful full-term pregnancy and delivery with normal postnatal measurements. The disease started with global developmental delay, axial hypotonia, and appendicular spasticity. By the ages of 7 and 9 months, all affected siblings developed intermittent limb dyskinesia and dystonia (Tables S1 and S2 for detailed clinical information). Slightly later, they had started displaying abnormal eye movements and facial twitches. Limb spasticity and dystonia had a progressive course with dystonia gradually becoming constant and severe, as could be seen in the older sibling (III-5) aged 8 years old (Fig. 1D and Video 1 for III-5 and III-6). The hyperkinetic movements persisted with no alleviation from sleep and tended to exacerbate in a paroxysmal manner. Occasionally, there had been motor exacerbations in arousal. Episodes of obsessive–compulsive behavior with anxiety, phobias, and grinding movements were commonly displayed behavioral signs. Two siblings (III-2 and III-5) developed bouts of laughing and crying leading to apneic spells. Upon the last follow-up examinations at the ages of 4, 8, and 2 years, the siblings had globally unachieved milestones with head circumferences, weights, and heights below the 5th percentile. They were non-verbal with severe intellectual disability and were not able to understand simple instructions. Limb dystonia and spasticity leading to joint contractures were more prominent in the older siblings. The youngest sibling (III-6) had subtle twitching of the perioral muscles, dyskinetic limb movements, and mild superimposed myoclonic jerks in the upper limbs. He also displayed intermittent upward tonic eye deviations. Tremor, persisting axial hypotonia, and brisk tendon reflexes were present in all affected siblings. (Fig. 1D, Video 1 III-5, III-6). Cardiomyopathy was found only in the elder sister (III-2) who succumbed to recurrent chest infections at 4 years old. A trial of clonazepam, levodopa, biperiden, amantadine, and cyclobenzaprine failed to adequately control hyperkinetic movements and spasticity in all three siblings. The results of comprehensive metabolic panel testing including alpha-fetoprotein (III-5, III-6), lactic acid (all siblings), ceruloplasmin (III-2, III-5), 24-hour urinary copper (III-2, III-5) were unremarkable and the possibility of Wilson’s disease was ruled out. The eye fundi appeared normal in all affected cases and brain magnetic resonance imaging (MRI) was suggestive of the thin corpus callosum in sibling III-6 (Fig. 1E). The parents of the affected cases and their unaffected siblings have remained asymptomatic upon the most recent follow-up. To identify the genetic cause of the disease in the affected children, exome sequencing (ES) on DNA extracted from proband’s blood (III-5) was performed as previously described. In accordance with the recessive mode of inheritance, priority was given to rare biallelic functional variants with allele frequency <0.001% in public databases, including 1000 Genomes project, NHLBI