Mental Retardation, Autosomal Recessive 1

A number sign (#) is used with this entry because autosomal recessive nonsyndromic mental retardation-1 (MRT1) is caused by homozygous mutation in the gene encoding neurotrypsin (PRSS12; 606709) on chromosome 4q25.

Clinical Features

Mental retardation is a leading feature of many mendelian syndromes. In addition, studies in mental institutions such as those of Priest et al. (1961) and of Wright et al. (1959) show that mental retardation of unclassified type occurs in multiple sibs in a considerable number of cases. Some of these doubtless represent rare recessive disorders. Breg (1962) has in his classification of mental defect a wastebasket group, 'hereditary cerebral maldevelopment, not clinically classifiable.' Most of these cases are, he thinks, autosomal recessive disorders. Two or more sibs show intellectual impairment, usually in the low or middle grade range without other clinical or laboratory manifestations that permit further classification. Among 3,500 admissions to an institution for persons with mental retardation, he found 53 cases he so classified. In the same group 25 cases of phenylketonuria, 3 of goitrous cretinism, 39 of cerebral degenerative diseases (including the lipidoses and scleroses), and 20 of primary microcephaly were observed.

The study of Carson and Neill (1962) is illustrative of the type of chemical investigations that can be used to detect metabolic errors in an inbred population and specifically in cases of mental retardation. McMurray (1962) also reviewed the biochemical defects that have been identified in patients with mental retardation. Maternal phenylketonuria (261600) can result in mental retardation in multiple sibs and the mother may appear normal. Morton (1960) arrived at the conclusion that homozygosity at any 1 of 69 loci may result in low-grade mental defect, that about 8% of such cases are recessive, and that about a third of normal persons are heterozygous for a gene for low-grade mental defect. An estimate of 114 loci was arrived at by Dewey et al. (1965). Karlsson et al. (1961) used the approach of studying families with multiple affected sibs. In the family reported by Friedman and Roy (1944) all 6 children of parents who were first cousins once removed but of normal intelligence were severely retarded with internal strabismus, hyperactive tendon reflexes, and positive Babinski reflexes. The mother was said to have an abnormal electroencephalogram, nystagmus, and external strabismus. Dekaban (1958) described a family in which both parents had undifferentiated mental retardation, as did all 3 of their children. A brother of the father was also retarded. All 4 grandparents were of normal intelligence. He suggested that an accumulation of pedigrees in which both parents are affected would help elucidate the category of undifferentiated mental retardation.

Molecular Genetics

In a family of 8 children born to first-cousin Algerian parents, Molinari et al. (2002) identified 3 girls and 1 boy who were moderately to severely mentally retarded with IQs below 50. All children reportedly had normal milestones in the first 1 to 2 years and were identified as retarded thereafter. All 4 affected children were homozygous for a 4-bp deletion in exon 7 of the PRSS12 gene (606709.0001). The mutation was not identified in 200 unrelated control individuals (100 from Maghrebian and 100 from various ethnic origins). By screening 17 other nonsyndromic inbred mental retardation families and 23 isolated mentally retarded children, Molinari et al. (2002) identified 1 child, born to first-cousin Algerian parents, who carried the same deletion. Whereas this child was thought to be unrelated, he had the same haplotype across the PRSS12 locus, suggesting either distant consanguinity or a founder effect in the Algerian population.

Molinari et al. (2003) reviewed the molecular pathogenesis of autosomal recessive mental retardation caused by mutation in neurotrypsin.