Mental Retardation, X-Linked, Associated With Fragile Site Fraxe

A number sign (#) is used with this entry because this form of X-linked mental retardation is caused by disruption of the FMR2 gene (AFF2; 300806), either by expansion of a CCG repeat in the 5-prime untranslated region or by deletion.

Description

FRAXE mental retardation is a form of mild to moderate mental retardation associated with learning difficulties, communication deficits, attention problems, hyperactivity, and autistic behavior (summary by Bensaid et al., 2009). FRAXE is associated with a fragile site on chromosome Xq28 and is the cause of nonsyndromic X-linked mental retardation in 1 of 50,000 newborn males. The disorder can be caused either by silencing of the FMR2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene (Stettner et al., 2011).

Clinical Features

Knight et al. (1996) provided clinical details of 1 FRAXE male identified through a screening study as well as 3 other FRAXE individuals identified through previous referrals for fragile X syndrome testing. The first male had shown developmental delay and microcephaly. At the age of 10 years he showed short stature and an 'engaging' personality, which suggested William syndrome. No abnormality at the elastin locus (130160) characteristic of William syndrome was found, however. At the age of 11 years, educational psychologic assessment showed word recognition at 6.4 years and base number skills at 6.1 years. The other 3 cases, although showing developmental delay, were either of normal stature or unusually tall without microcephaly.

Mila et al. (1997) reported a boy with mosaicism for methylation in the FMR2 gene who showed mild mental retardation with psychotic behavior and no remarkable physical traits.

Russo et al. (1998) reported an Italian family with FRAXE-positive mental retardation in which all affected individuals lacked a definite phenotype and showed different degrees of mental retardation. Slight mental retardation was evident in a male with mosaic genotype.

Stettner et al. (2011) reported 2 brothers, aged 10 and 11 years, with mild to moderate mental retardation and behavioral abnormalities. Both became symptomatic in their second year of life, with mild motor and prominent language development delays, as well as marked behavioral problems including aggression, impulsivity, agitation, attention deficit, and hyperkinetic symptoms. In addition, autistic features, such as hand flapping, restricted interests, repetitive behavior, and impaired social interaction and communication, became more obvious with age. No dysmorphic features were noted.

Mapping

Using a physical mapping strategy, Knight et al. (1993) identified the fragile site FRAXE (see 300806) on chromosome Xq28 distal to the FRAXA fragile site (see 309550). Expansion and hypermethylation of the CCG repeat in FRAXE results in mental retardation.

Molecular Genetics

Fragile Site FRAXE

Sutherland and Baker (1992) thought the fragile site FRAXE was not associated with mental retardation. However, several families originally described as having the fragile X syndrome on the basis of mental impairment and cytogenetic analysis were shown by fluorescence in situ hybridization (FISH) to express FRAXE. Sutherland (1993) expressed reservations about the relationship of the FRAXE site to mental retardation because of the likelihood of bias of ascertainment. Mulley et al. (1995), however, provided data suggesting that an etiologic relationship may exist between FRAXE and nonspecific X-linked mental impairment.

Using a physical mapping strategy, Knight et al. (1993, 1994) cloned FRAXE and demonstrated that persons expressing this site possess amplification of a GCC repeat adjacent to a CpG island in Xq28. PCR analysis across the region showed that normal individuals had 6 to 25 copies of the GCC repeat, whereas mentally retarded, FRAXE-positive persons had more than 200 copies and were methylated at the CpG island.

Mulley et al. (1995) reported mental impairment and instability of the CCG repeat at FRAXE in 6 kindreds. In one of these, cosegregation of FRAXA and FRAXE was found. Cytogenetic expression of FRAXE was shown to skip a generation when associated with the reduction in size of the CCG expansion when transmitted through a male; however, in general, transmission occurred through females and copy number increased from one generation to the next. In these respects, the behavior of FRAXE paralleled that of FRAXA. After removal of index cases, Mulley et al. (1995) found that these families had more mentally impaired male and female carriers than could reasonably be expected by chance, suggesting an etiologic relationship between FRAXE and nonspecific mental impairment.

Knight et al. (1996) described the results of a UK survey designed to assess the frequency of FRAXE in a population of individuals referred for fragile X syndrome testing and found to be negative for expansion events at the FRAXA locus. No FRAXE expansion events were found in 362 cytogenetically negative males studied, and 1 expansion event was identified in a sample of 534 males for whom cytogenetic analyses were either unrecorded or not performed. Further, FRAXE expansion events were detected in 2 related females known to be cytogenetically positive for a fragile site in Xq27.3-q28. Knight et al. (1996) concluded that FRAXE is a relatively rare but significant form of mental retardation for which genetic diagnosis would be appropriate. Brown (1996) concluded that for various reasons routine FRAXE screening is not warranted. Holinski-Feder et al. (1996) concurred that routine testing for FRAXE is not indicated; follow-up testing may be useful in selected FRAXA-negative subjects.

Barnicoat et al. (1997) found that 4 of 42 families with a distal Xq fragile site did not have a FRAXA mutation. FISH and molecular analyses in 3 of these families demonstrated expansion of the CCG repeat at FRAXE and 1 at FRAXF. All the males who expressed FRAXE had a large methylated CCG repeat at FRAXE. All males with the mutation had some degree of mental handicap.

In a survey of 222 unrelated mentally retarded individuals attending Spanish special schools, Mila et al. (1997) found 11 boys with full mutations in the FMR1 gene and 1 boy with a CCG repeat expansion in the FMR2 gene. Molecular studies revealed mosaicism for methylation in the FMR2 gene.

Russo et al. (1998) reported molecular characterization in FRAXE-positive subjects with mental retardation in 2 unrelated Italian families. In 1 family, 13 subjects over 3 generations were investigated with the identification of 3 FRAXE-positive males, 1 with a fully mutated allele and 1 with a mosaic genotype. Only the propositus was investigated in family 2. All affected individuals lacked a definite phenotype and showed different degrees of mental retardation. Slight mental retardation was evident in the mosaic male, suggesting that methylation might be an important determinant of mental impairment.

The fragile X triplet repeat expansion at Xq27.3 (FMR1; 309550) is associated with mutation or instability 600 kb proximal at the FMR2 repeat locus. Ennis et al. (2001) proposed concatenated mutation as a possible explanation. Concatenated mutation is defined as the association between a mutation at one locus and a mutation, recombination, deletion, or transposition at another locus, regardless of the cause or temporal sequence of these events. By examining evidence from a sample of over 7,000 independent haplotypes from the FRAX region and using cladistic groups to define more thoroughly the properties of these haplotypes, they isolated one group of haplotypes that may be predisposed to the phenomenon of concatenated mutation. They found that distinguishing concatenated mutation from founder effects was difficult within a single population, but presented evidence for and against concatenated mutation.

Obsessive-compulsive disorder (OCD; 164230) is a chronic psychiatric disease characterized by recurrent obsessions, compulsions, or both. Wang et al. (2003) performed cytogenetic analysis of 26 patients with OCD and, in 1 male patient, identified a fragile X chromosome with 21% of cells demonstrating a fragile site at chromosome Xq27-q28. PCR and Southern blot analysis showed that the molecular basis of the fragile X chromosome was expansion of the CCG repeat at FRAXE. The number of expanded repeats was estimated to be more than 300 copies, qualifying it as a full FRAXE mutation. Another member of the family was found to have a full FRAXE mutation (630 to 1,200 copies of the CCG repeat), with speech impairment as the clinical phenotype; 2 other members of the family with normal phenotypes had no FRAXE expansion. The 2 FRAXE expansions led to complete methylation at the CCG repeat. These findings expanded the spectrum of clinical phenotypes associated with FRAXE mutations.

FMR2 Gene Deletions

Gecz et al. (1996) demonstrated that a patient with global developmental delay, speech delay, and excessive hand flapping reported by Gedeon et al. (1995) carried a 982-bp deletion in the FMR2 gene, resulting in the deletion of exons 2 and 3, a frameshift, and premature termination. A second boy reported by Gedeon et al. (1995) had less than 100-kb deletion wholly overlapped by the deletion in the first boy. The second boy had speech delay and severe difficulties in understanding speech, but showed normal development.

In 2 brothers with mild to moderate mental retardation, speech delay, and behavioral abnormalities including autistic features, Stettner et al. (2011) identified a 121- to 145-kb deletion within the FMR2 gene (300806.0002), resulting in the complete loss of exon 3. The asymptomatic mother and an affected uncle of the boys also carried the deletion. The findings indicated that deletions in FMR2 contribute to the FRAXE phenotype.

Premature Ovarian Failure

Murray et al. (1999) screened a cohort of 209 women with premature ovarian failure (POF; 311360) for FRAXA and FRAXE premutations, and found an excess of FRAXE alleles with fewer than 11 repeats. Sequence analysis of these alleles showed that the excess was caused by 3 individuals carrying cryptic deletions in FMR2. Murray et al. (1999) proposed that microdeletions in FMR2 may be a significant cause of POF, being found in 1.5% of the population with POF, but in only 0.04% of the general population.

Heterogeneity

Allingham-Hawkins and Ray (1995) examined 300 developmentally delayed males, referred for fragile X testing but negative for the FMR1 gene trinucleotide expansion, for the FRAXE expansion. The group had a wide range of intellectual or behavioral problems and included 19 who had low-level fragile site expression detected cytogenetically at Xq27-q28. None of the patients tested positive for the FRAXE expansion. These results suggested that FRAXE is not a common etiologic factor in this group of patients. The data supported the hypothesis that FRAXE is either very rare or is a benign fragile site that is not associated with any clinical phenotype, similar to the FRAXF and FRA16A sites.