In some series, fully 10 percent of developmentally delayed males have this fragile X chromosomal abnormality, although 2 to 4 percent is more accurate according to other series. Females are sometimes affected, but their cognitive function is only slightly reduced. Affected males have only mild dysmorphic features (large ears, broad forehead, elongated face, and enlarged testes) that may not become obvious until puberty. Others are somatically normal. Behavioral problems of one sort or another are almost universal. Pulsifer, whose review of the neuropsychologic aspects of developmental delay is recommended, lists self-injurious, hyperactive, and impulsive behaviors as the most common. The hand-flapping that is more characteristic of autism may be seen.
Fragile X premutation syndrome of adults As discussed in Chap. 5, a curious form of progressive adult onset ataxia and tremor, previously thought to be of a degenerative type, has been discovered to be caused by a “premutation” of the fragile X gene (50 to 200 trinucleotide repeats). Some of these patients have characteristic symmetrical MRI signal changes in the middle cerebellar peduncles in the T2 sequence. Other unusual late presentations have been described, including a spastic paraparesis without ataxia or tremor (Cellini et al). A report by Grigsby and coworkers suggests that cognitive function may be diminished in these men, but only when adjusted for their level of education and not compared to normative data; the observation requires confirmation and any suggestions that a fragile X premutation is responsible for dementia in adults should be accepted cautiously. The permutation expansion may be manifest in women as premature ovarian failure. In contrast to the mutation that causes developmental delay, this disorder is thought to be related in some way to an excess of messenger RNA. Several papers suggest that the premutation may also be the cause of some cases of mild retardation and autistic-like behavior.
This is yet another hereditary form of developmental delay, but one that affects girls. None of the cases in the extensive studies of Hagberg and coworkers (1983) was male. The responsible spontaneous mutation was shown to relate to a defect at chromosomal site Xq28, making it one of the X-linked developmental delays. A fatal outcome in boys because of a severe neonatal encephalopathy explains the expression of the disease only in girls, who are mosaics for the mutation. The involved gene, MECP2, is responsible for suppressing various other genes at critical stages of development (see Dunn and MacLeod). It has this effect by binding to methylated DNA. Defective function of the gene leads to an alteration in synaptogenesis and neural connectivity (Neul and Zoghbi). Severe inactivation of gene expression causes classic Rett syndrome, but it has become apparent that incomplete expression and mosaicism lead to a number of partial syndromes, including nonspecific developmental delay, tremor, psychiatric disturbances, and autism-like presentations.
Prevalence studies from Sweden indicate an occurrence of 1 per 10,000 girls; thus Rett syndrome is more common than phenylketonuria. Although most cases appear to be sporadic, there is a high familial incidence and concordance in monozygotic twins.
The syndrome is usually marked by withdrawn behavior that simulates autism, dementia, ataxia, loss of purposeful hand movements, and respiratory irregularities. Highly characteristic is a period of 6 to 18 months of normal development followed by the rapid appearance and progression of all these signs, and then by relative stability for decades. Spasticity, muscle wasting, scoliosis, and lower limb deformities may become evident in the late stages of the illness. Handwringing and similar stereotypes are very typical features (and are different in subtle ways from the hand-flapping of autistic children).