Mental Retardation, X-Linked 63

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-63 can be caused by mutation in the ACSL4 (300157) gene.

Clinical Features

Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation. Affected males showed nonprogressive mental retardation ranging from severe to moderate, without seizures, whereas carrier females showed highly variable cognitive capacities, ranging from moderate mental retardation to normal intelligence.

Mapping

Raynaud et al. (2000) reported a 4-generation family with nonspecific nonsyndromic X-linked mental retardation mapped between DXS990 and DXS1227 (Xq21.33-q27.1) with a maximum lod at theta = 0.0 of 2.14 at DXS1001.

Molecular Genetics

In the proband of the family reported by Raynaud et al. (2000) as MRX63, Meloni et al. (2002) identified a mutation in the ACSL4 gene (300157.0001). The proband of a second affected family carried a mutation in the 3-prime splice site of intron 10 of the ACSL4 gene (300157.0002). Mental retardation was severe. Six of 6 informative carrier females in family MRX63 showed completely skewed X inactivation in leukocytes. Similarly, 3 of 3 carrier females from 2 different families with ATS-MR (300194) showed completely skewed X inactivation in leukocytes, as did the carrier mother of the proband of the second family.

In a family with nonsyndromic X-linked mental retardation (MRX68), Longo et al. (2003) identified a mutation in the ACSL4 gene (300157.0003). Neurocognitive levels ranged from mild to moderate in affected males and were borderline in female carriers. X-inactivation studies in the female carriers showed 100% skewed inactivation in all of them.

Animal Model

Zhang et al. (2009) demonstrated that the Drosophila ACSL-like protein, Acsl, and ACSL4 are highly conserved, allowing ACSL4 to substitute for Acsl in organismal viability, lipid storage, and the neural wiring in the visual center. In neurodevelopment, production of decapentaplegic (Dpp), a BMP-like protein in Drosophila, diminished specifically in the larval brain of Drosophila Acsl mutants. Consistent with the Dpp reduction, the number of glial cells and neurons dramatically decreased and the retinal axons mistargeted in the visual cortex. All of these defects in Drosophila brain were rescued by the wildtype ACSL4 but not by the mutant products found in nonsyndromic X-linked mental retardation patients. Expression of an MRX63-associated ACSL4 mutant form in a wildtype background led to lesions in the visual center, suggesting a dominant-negative effect. Zhang et al. (2009) proposed a connection between ACSL4 and the BMP pathway in neurodevelopment.