Intellectual Developmental Disorder, Autosomal Recessive 71

A number sign (#) is used with this entry because of evidence that autosomal recessive intellectual developmental disorder-71 (MRT71) is caused by homozygous mutation in the ALKBH8 gene (613306) on chromosome 11q22.

Clinical Features

Monies et al. (2019) reported 7 patients from 2 unrelated large consanguineous Saudi kindreds with intellectual developmental disorder. The patients, who ranged in age from 5 to 28 years, presented in the first years of life with global developmental delay, mildly delayed walking, impaired intellectual development (IQ of 1 patient was 52 at age 12 years), and very poor language. Six of the 7 patients developed seizures in the first years of life, but the seizures were well controlled and even showed spontaneous remission in some patients. Many patients had behavioral abnormalities, including hyperactivity, poor attention span, and stereotypic behavior. The proband from family 1 had an overbite, small penis, and undescended testes. Four sibs from family 2 showed some similar dysmorphic features, including macrocephaly, large ears, long face, deep-set eyes, and prune belly syndrome; 1 patient in this family had a congenital ventricular septal defect and thickened aortic valve, 1 had a solitary kidney, and another had cryptorchidism. Brain imaging was essentially normal.

Inheritance

The transmission pattern of MRT71 in the families reported by Monies et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 patients from 2 unrelated large consanguineous Saudi kindreds with MRT71, Monies et al. (2019) identified homozygous loss-of-function mutations in the ALKBH8 gene (613306.0001-613306.0002). The mutations, which were found by exome sequencing and confirmed by linkage analysis, segregated with the disorder in the families. Analysis of patient-derived lymphoblastoid cell lines showed that various types of mcm(5)U and mchm(5)U wobble modifications were absent or dramatically decreased compared to controls. The ribose-methylated form mcm(5)Um was completely absent in all affected individuals from both families, indicating aberrant modification of the selenocysteine-specific tRNA(Sec) that is required for the specific expression of certain stress-related selenoproteins. There was also abnormal accumulation of the precursor cm(5)U in patient cells, which was not observed in controls. The findings were consistent with an emerging role of abnormal tRNA modification in the pathogenesis of developmental brain disorders.