The diagnosis and frequency of X‐linked conditions in a cohort of moderately retarded males with affected brothers

Abstract

An epidemiological study was carried out on the group of moderately retarded brothers (IQ, 30-55) identified by Turner and Turner [1974]. Of the original 58 sets of brothers, 54 sets (now 17 to 32 years old) were traced; another four sets (missed in the earlier survey) were added. Forty-five of the 58 pairs were diagnosed as having nonspecific X-linked mental retardation (MR) giving an overall frequency of 5.57 moderately retarded males/10,000 male births. In 12 of the 45 families, affected males had the fragile(X) and macroorchidism; six had macroorchidism alone, giving a frequency of 2.8 moderately retarded males with X-linked MR and macroorchidism +/- the fragile(X) per 10,000 males. Corresponding heterozygote frequencies are 7.34 and 3.65/10,000 females respectively. A new subgrouping of nonspecific X-linked mental retardation is described in six families: X-linked MR, macroorchidism without the fragile(X). Three other X-linked conditions were identified: in one family, the Coffin-Lowry syndrome, in another, Duchenne muscular dystrophy, and in two families X-linked MR and muscle atrophy. Half (56%) of the obligatory carriers of fra(X)-MR in this study were dull to mildly retarded. The mildly retarded heterozygotes had a significantly higher percentage of fra(X) expressing lymphocytes as compared to the intellectually normal heterozygotes. When the three types of nonspecific X-linked MR for which population frequencies were calculated were considered together, half of the obligatory carriers (46%) were dull or mildly retarded, thus confirming that this condition is a significant cause of mild intellectual handicap in females.

Monogenic X-linked mental retardation: Is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations

“…These pooled data suggest that the proportion of monogenic XLMR in sporadic MR males would be at best 10% (Table 1). Indeed, this would fit with the data on affected male sibpairs of Fishburn et al, 3 as the proportion of non-fragile X to fragile X sibpairs was about 3 to 1, and, given the incidence of fragile X mutation (2 -2.5% of MR males), this would suggest an incidence of 6 -8% for nonfragile X XLMR in nonsyndromic (or at least nonclearly syndromic) patients.…”

Genetics and pathophysiology of mental retardation

“…Epidemiological studies repeatedly showed a sex bias, with 30 -50% excess of males over females, and led to the assumption that much of the excess of male MR may be due to X-linked genes. 7,10,11 If monogenic XLMR was to account for an excess of 30% of mentally retarded males over females, one would expect that 20 -25% of genetically based MR in males, including sporadic MR cases, are caused by XLMR genes (see also Supplementary information S2 in Ropers and Hamel 5 ). However, recent molecular studies, 12,13 in combination with clinical follow-up of a large cohort of patients, 7 are suggesting that the proportion of monogenic XLMR in sporadic MR males would account at best for 8 -10% of the genetic causes of MR. More generally, this new revision of estimates downwards and the recent progress in genetic counseling and prenatal diagnosis of specific MR conditions such as fragile X syndrome, as well as the lack of data concerning the prevalence of autosomal causes justify achievement of further epidemiological studies on MR.…”

Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium

“…Patients with MRX only have reduced mental capacities, whereas patients with MRXS have additional clinically recognizable features, such as neuromuscular abnormalities, dysmorphisms and congenital malformations. On average one in every 600 males has XLMR [Herbst and Miller, 1980;Roeleveld et al, 1997;Leonard and Wen, 2002] and about two thirds of these patients are thought to be nonsyndromic [Fishburn et al, 1983]. Currently, 25 genes are known to be involved in MRX and 42 genes in MRXS (http://xlmr.interfree.it/home.htm).…”