Mental Retardation, X-Linked, Syndromic, Hedera Type

A number sign (#) is used with this entry because of evidence that this form of X-linked mental retardation (MRXSH) is caused by mutation in the ATP6AP2 gene (300556) on chromosome Xp11. Mutation in the ATP6AP2 gene can also cause X-linked parkinsonism with spasticity (XPDS; 300911), which has overlapping features.

Clinical Features

Hedera et al. (2002) reported a kindred in which 7 males were affected with mild to moderate mental retardation and epilepsy, transmitted as a monogenic X-linked recessive trait. Affected subjects demonstrated delays in motor milestones and speech acquisition in infancy. Generalized tonic-clonic seizures developed in all subjects between 4 and 14 months of age. Four patients had additional drop attacks consisting of brief atonic or myoclonic seizures with loss of posture. All seizure patterns were inconsistent with infantile spasms. Cognitive impairment was first evident between ages 24 and 36 months, with IQs in the 50 range. Two affected subjects had scoliosis, progressive gait disturbance, and pes planovalgus. Genetic linkage analysis using microsatellite polymorphisms mapped the disorder to Xp21.1-p11.4. Further analysis excluded linkage to West syndrome (308350), an X-linked syndrome with mental retardation and infantile spasms.

Gupta et al. (2015) reported 2 brothers with a syndromic form of X-linked mental retardation. Both had global developmental delay since infancy, and 1 had onset of generalized tonic-clonic seizures at 1 year of age. At age 18 years, the first sib developed features of parkinsonism, including tremor, instability, bradykinesia, rigidity, festinating gait, hypomimia, drooling, slurred speech, and illegible writing. He did not have resting tremor, but had action tremor and extensor plantar responses. His 31-year-old brother showed bradykinesia without rigidity, resting tremor, or postural instability. Other features in both sibs included hyporeflexia, ideomotor apraxia, agraphesthesia, astereognosis, and cerebellar atrophy on brain imaging. The patient with early-onset seizures also had global cerebral atrophy and thinning of the corpus callosum. Gupta et al. (2015) noted that the additional motor abnormalities in these patients resembled that observed in XPDS, suggesting variable expressivity.

Inheritance

The transmission pattern of MRXSH in the family reported by Gupta et al. (2015) was consistent with X-linked recessive inheritance.

Molecular Genetics

In the family described by Hedera et al. (2002), Ramser et al. (2005) detected a silent mutation in the ATP6AP2 gene (300556.0001) residing in a putative exonic splicing enhancer site. Quantitative RT-PCR showed that the mutation resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA. The authors proposed a novel specific role for the renin receptor in cognitive functions and brain development. Apparently the consequences of the mutation did not affect the downstream angiotensin system (see 106150).

In 2 brothers with MRXSH, Gupta et al. (2015) identified a hemizygous mutation in the ATP6AP2 gene (300556.0003) that was predicted to result in a splice site alteration. Functional studies of the variant and studies of patient cells were not performed.