A number sign (#) is used with this entry because of evidence that intellectual disability and myopathy syndrome (IDMYS) is caused by homozygous mutation in the ABCC9 gene (601439) on chromosome 12p12.

Intellectual disability and myopathy syndrome (IDMYS) is an autosomal recessive developmental disorder characterized by global developmental delay with mildly impaired intellectual development, hypotonia, muscle weakness and fatigue, and white matter abnormalities on brain imaging. Variable additional features may include sensorineural hearing loss, dysmorphic facies, and progressive heart disease (summary by Smeland et al., 2019).

Smeland et al. (2019) reported 6 patients from 2 unrelated families from Northern Norway with probable Finnish origin with a syndromic neurodevelopmental disorder. Four patients in family 1 ranged between 11 and 21 years of age, whereas the sibs in family 2 were 29 and 33 years of age, respectively. The patients presented in the first years of life with global developmental delay, hypotonia, lower limb muscle weakness, and mildly impaired intellectual development. A few had feeding difficulties and poor overall growth. Common features included toe-walking, lumbar lordosis, hyperreflexia of the lower limbs, and Achilles hyperreflexia or subclonus. Poor balance, muscle pain, muscle stiffness, and fatigue were also reported. Three sibs in family 1 had onset of mild bilateral sensorineural hearing loss in the first decade. All patients had focal, periventricular, or widespread white matter hyperintensities on brain imaging, which were progressive in the patients from family 2. The patients had mild intellectual disability and anxiety. At age 21, the oldest sib in family 1 lived independently, but required supervision and help. One of the sibs in family 2 lived in a supervised sheltered home, and the other lived independently but had assistance. Five of the 6 patients had food intolerance, such as lactose intolerance, or food allergies. Variable dysmorphic features were noted, including strabismus, prominent supraorbital ridges, hypotelorism, broad nasal tip, dental malocclusion, flat face, thin upper lip vermilion, dental malocclusion, and widely-spaced upper incisors. All patients showed skin marmoration, and the 2 sibs in family 2 had depigmented patches and atopic dermatitis. Both sibs in the second family, who were older than the other patients, developed progressive cardiac biventricular systolic dysfunction; one had dilated ventricles and hypertension. Smeland et al. (2019) termed the disorder 'ABCC9-related intellectual disability myopathy syndrome (AIMS).'

The transmission pattern of IDMYS in the families reported by Smeland et al. (2019) was consistent with autosomal recessive inheritance.

In 6 patients from 2 unrelated families from the same region of Northern Norway with probable Finnish ancestry with IDMYS, Smeland et al. (2019) identified a homozygous splice site mutation in the ABCC9 gene (601439.0012). The mutation, which was found by targeted next-generation sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro functional expression assays in cells expressing the mutation showed about a 50% decrease in protein expression compared to controls, and complete loss of K(ATP) channel function, consistent with a loss of function. There was no evidence for a dominant-negative effect. The authors postulated that some of the phenotypic features may be due to disrupted function of the gene in striated muscle, smooth muscle, and the cerebral vasculature.

Smeland et al. (2019) found that homozygous mice with a nonsense mutation in exon 8 of the Abcc9 gene showed progressively decreased motor performance due to fatigability, although sensorimotor function was normal. Older mutant mice developed cardiac abnormalities, including impaired left ventricular function, dilated cardiomyopathy, and hypertension. No abnormalities were observed in cognitive and behavioral tests. CRISPR/Cas9-mediated knockdown of the abcc9 gene in zebrafish resulted in decreased overall movements and decreased total swimming distance compared to controls, but they moved for a similar time period. Mutant zebrafish developed systolic dysfunction, reduced cardiac output, enlarged heart size, and increased velocity of red blood cells (possible hypertension) compared to controls. They also showed hypotelorism as an isolated dysmorphic feature; hypotelorism was not observed in the mutant mice.