Males with the Fragile X Syndrome
The physical features that are the clinical hallmark of the fragile X syndrome in the typical adult full mutation male are a long narrow face, prominent ears, and large testicles.212 These features are more prominent in postpubertal males, as compared to prepubertal males (Table 64-4). The long face is sometimes associated with a square chin that becomes more prominent in adulthood (Figs. 64-7 and 64-8). Several investigations discuss unusual growth patterns in fragile X syndrome, including increased birth weights, macrocephaly, increased or decreased height, and an acromegalic appearance in adults.212 Loesch et al.213 demonstrated a disturbed growth pattern in males and females with fragile X syndrome, including an increased height throughout childhood, earlier onset of puberty, and a decreased height in adulthood, compared to controls. These findings may be secondary to a proposed hypothalamic dysfunction. Two subtypes of the fragile X syndrome phenotype are also associated with overgrowth: a Soto syndrome-like phenotype with general overgrowth214 and a Prader Willi-like phenotype associated with extreme obesity with full, round face, small, broad hands/feet, and regional skin hyperpigmentation.215 Interestingly, these subtypes appear in families with males who have the typical fragile X syndrome phenotype. To date, the cause of the general growth abnormalities in the fragile X syndrome is unknown.
Facies of a single full-mutation male from 2 months of age to 22 years.
Photographs of institutionalized male patients with the fragile X syndrome. A to C, Three males, aged 11, 40, and 63. D, Individual from panel B and his three roommates in a residential home for the mentally retarded. The patients in panel D had originally chosen to room with each other because of mutual interests and compatible personalities; during a screening a number of years later, all four men were found to have the fragile X syndrome. (Courtesy of Brenda Finucane, M.S., and the Elwyn Institute.)
Table 64-4: Percentages of Males with the Full Mutation with Specific Physical Characteristics |Favorite Table|Download (.pdf) Table 64-4: Percentages of Males with the Full Mutation with Specific Physical Characteristics
| ||Prepubertal Males (%, n=97) ||Pubertal/Postpubertal Males (%, n=64) |
| Hallmark features: || || |
|Long face ||64 ||80 |
|Prominent ears ||78 ||66 |
|Macroorchidism (≥3 ml) ||54 ||92 |
| Other common features: || || |
|High arched plate ||51 ||63 |
|Hyperextensible finger joints ||81 ||49 |
|Double jointed thumbs ||58 ||48 |
|Single palmer crease ||26 ||22 |
|Hand calluses ||18 ||52 |
|Flat feet ||82 ||60 |
|Heart murmur or click ||16 ||29 |
Prominent ears are observed in the majority of affected males who are Caucasian, although prominent ears may not be as evident in other racial groups (Fig. 64-9).216 This feature is thought to be secondary to an overall connective tissue dysplasia in fragile X syndrome, first noted by Opitz et al.217 Other features consistent with a connective tissue disorder include hyperextensible finger joints, flat feet, mitral valve prolapse, and velvet-like skin. The etiology of the connective tissue dysplasia is unknown, and no hints are provided by the function of the FMRP.
Fragile X syndrome in various ethnic backgrounds. Full mutation males of (A) African-American, (B) Asian, (C) Caucasian, and (D) Hispanic background. (Modified from Jorde et al.387 Used by permission.)
Macroorchidism, the third clinical feature of the fragile X syndrome triad, occurs in approximately 80 to 95 percent of postpubertal males; the testicular volume is approximately two to three times that of normal males, with a mean volume of about 45 ml.218 Macroorchidism was noted as early as the fetal stage in one study.219 The fetal testes showed abnormalities in the ultrastructure, including an increase in glycoprotein granules. Macroorchidism may be secondary to endocrinologic abnormalities associated with fragile X syndrome, as suggested by the dramatic increase in the size of the testes in boys with fragile X syndrome between 10 and 12 years of age.218 Fryns et al.220 hypothesized hypothalamic dysfunction in fragile X syndrome males. If true, perhaps such dysfunction may cause an increase in gonadotropins in fragile X syndrome. However, observed levels of gonadotropins in fragile X syndrome are not consistent from one study to another.212 Thus, current studies are underway to identify the underlying cause of the enlarged testes. It is important to note that men with fragile X syndrome are fertile. Thus, the lack of FMRP does not inhibit spermatogenesis to a significant degree.
There are very few significant medical problems associated with the fragile X syndrome. About 30 percent of infants with fragile X syndrome have recurrent emesis in early childhood, which, in some cases, can lead to failure to thrive.212 The recurrent emesis seems to be secondary to gastroesophageal reflux. Early studies indicated that approximately 30 percent of children with fragile X syndrome had strabismus; a lower percentage of children had other vision problems.212
Other medical problems noted are recurrent otitis media infections (80 percent of children with fragile X syndrome), recurrent sinusitis (20 percent of children with fragile X syndrome), and seizures (20 percent of children with fragile X syndrome).212 Thus, although children with fragile X syndrome do not have major medical problems, each child should be evaluated for eye and ear problems, as such problems could impede a child's progress toward achieving his or her full potential.
The behavioral component of the fragile X syndrome phenotype in males includes hyperarousal, hyperactivity, anxiety, tantrums, and extreme sensitivity to sensations, and sometimes aggression.212 Some aspects of the behavioral phenotype overlap with autism, including difficulties with social interaction with peers, impaired verbal and nonverbal communication, poor eye contact, tactile defensiveness, hand flapping, hand biting, and other motor stereotypes.212,221-225 Although the exact cause of these autistic-like features is unknown, some investigators speculate that they may be related to hypersensitivity to sensory stimuli or anxiety.212,222,224,226 Miller et al.227 studied individuals with fragile X syndrome and controls using electrodermal activity as a measure of the extent to which an individual responds to stimuli. The measure of skin conductance is an indirect assessment of the sympathetic activity, as the eccrine sweat glands are innervated by the cholinergic fibers of the sympathetic nervous system. They found an enhanced electrodermal response to stimuli, and a lack of normal habituation compared with controls. These findings support a physiologic basis for the enhanced reactions to sensation, and suggest that the sympathetic nervous system is affected in the fragile X syndrome.
Adaptive development (including domains of communication, daily living skills, and socialization) does not seem to differ from that expected for mental age.221,228,229 However fragile X syndrome individuals seem to have relative strengths in daily living skills compared with the adaptive skills in communication and socialization,221,229,230 but this profile may be true only for adult fragile X syndrome males.231 Findings from longitudinal and cross-sectional studies suggest that there is significant development of adaptive skills in boys in the 1- to 10-year period. A plateau or stabilization of adaptive development subsequently occurs in late childhood and early adolescence.231,232 The decline in adaptive development seems to parallel the cognitive trajectory in fragile X syndrome males (see Cognition below).
On average, adult males with fragile X syndrome function within the moderately to severely retarded range of intelligence, although the spectrum of involvement is quite variable.233-239 Freund et al.240 found that 44 percent of a preschool fragile X syndrome group tested in the borderline to average range of IQ. There is now consistent evidence that there is a developmental decline in the IQ of males with fragile X syndrome, although the cause for this decline is unknown. This phenomenon was first shown in cross-sectional studies,233,236,241 and subsequently confirmed by longitudinal studies.242-247 It is not clear when or why the decline occurs, some results suggesting that it begins in middle childhood248 while others suggest around puberty.242
Recently, a prospective, longitudinal study has been designed to characterize the early development of males with fragile X syndrome.249 Based on 46 boys with fragile X syndrome between the ages of 24 and 72 months, preliminary results show: (a) Children varied widely in developmental status with significant differences across individuals in both mean rate and level of performance. (b) The overall development was about half the rate expected for typically developing children. (c) No differences were found in the rates of growth across the five domains including cognition, communication, adaptive, motor, and personal-social. (d) Significant differences were found in the mean levels of performance; thus at every age tested, motor and adaptive domain scores were consistently the highest, and communication and cognition were the lowest. In contrast to the study of Freund et al.,240 this study found that most children did exhibit significant delays throughout the early childhood years. Differences could be due to small numbers, sample selection, or to the type of measure used. Clearly, more work needs to be done in this area.
Most studies indicate consistent areas of weakness for males with fragile X syndrome, including deficits in short-term auditory memory, visual-spatial abilities, visual-motor coordination, and arithmetic skills.238,250-255 They also show a consistent processing style that indicates that they have problems holding information online as they solve problems (i.e., sequential processing versus simultaneous processing).234,237,239 In contrast, they seem to have relative strengths in tasks involving long-term memory, perceptual closure, and certain verbal abilities, and thus sometimes appear less affected during preschool years than others with mental retardation.256
Abnormalities in both speech production and language competence have been noted consistently for males with the fragile X syndrome. Speech production includes articulation, rate, and prosody. Articulation is consistent with mental age in fragile X syndrome males.241,257 The rate of speech has been described as rapid and dysrhythmic,233,241 and has been labeled as “cluttering” to relate a type of verbal clumsiness.258 Notably, their speech has a harsh or sometimes hoarse vocal quality.241 Lastly, males with fragile X syndrome have an increase in the repetition of parts of words or whole words.257
With respect to language competence, males with fragile X syndrome show varying degrees of impairment of syntatic257,259 and pragmatic language.260,261 More recently, two studies showed that specific aspects of the pragmatic competence among males with the fragile X syndrome is unique when compared to individuals with Down syndrome or autism.262,263 The deviant repetitive language consists of perseveration of words, phrases, and topics, and this aspect of perseveration is greater than would be expected based on mental age, and also differs from the deficits seen in other mental retardation groups. Results from Sudhalter et al.259,264 suggest that syntactic delays are unrelated to pragmatic deviance.
Memory skills in males show consistent weaknesses. Freund and Reiss238 showed that males with fragile X syndrome had weaknesses in short-term memory for sentences and a visual memory task, but did relatively well on object memory. Thus, they suggested that memory deficit is not pervasive, but depends on the type of information to be remembered. Males with fragile X syndrome have consistently shown difficulties in remembering sequences or abstract information.234,237,239 Jakala et al.265 studied specific aspects of memory in full and premutation males. They found that full-mutation males were impaired, when compared with premutation males, in visual memory, in the learning phase, and delayed recognition of the list-learning task. However, full and premutation males performed similarly in the logical memory task.
Executive functions in males with the fragile X syndrome have not been studied directly, but the preliminary evidence for a deficit comes from the pattern of impairment, as discussed by Bennetto and Pennington.256 Executive functions can be described as functions that direct behaviors that are goal-directed and future-oriented, and that involve working memory, planning, flexible strategies, and inhibition. Kaufman et al.266 found that males with fragile X syndrome were able to learn simple tasks, but showed moderate impairments on complex tasks, including delayed alternation and more significant impairments on match-to-sample tasks. These findings are consistent with a deficit in executive functions, as they suggest that tasks requiring the use of working memory or internal representations to guide behavior are difficult for males with fragile X syndrome.
Bennetto and Pennington256 also suggest that a deficit in executive functions is consistent with some of the behavioral problems observed in males with fragile X syndrome including difficulty with attention control, impulsivity, and difficulty with transitions from one environment to another.
It is now clear that variation in the degree of severity of the fragile X syndrome phenotype in males is related, in part, to characteristics of the FMR1 mutation that dictate the amount of protein translated.63,267-270 For example, there was a greater proportion of higher functioning males (IQ >70) who had incomplete or no methylation when compared with more retarded fragile X syndrome males.271 Using various methods to determine FMRP expression, it has been found that the level of FMRP expression is highly correlated with IQ in pre-/full-mutation mosaic males and partially methylated full-mutation males.128,272 There is also preliminary evidence to suggest that producing some FMRP (partially methylated full mutation or pre-/full-mutation mosaic) protects an affected male from significant IQ decline.247
Overall, females with the full mutation are significantly less affected at all levels, including physical, neuropsychological, and neuroanatomic components, than are males with the full mutation. This is due to X-inactivation of the X-linked FMR1, 273 which indicates that some cells of such females are producing FMRP. Because this is a random process, there is a greater range of severity—from essentially no phenotypic expression to profound mental retardation with characteristic physical features of the fragile X syndrome—than is seen among males. The percentage of cells that have the normal X as active, the activation ratio, has been used as a measurement to correlate with various aspects of the phenotype in females. This has been well studied in blood,268 but not in other tissues, especially not in those target tissues in the central nervous system. There is a correlation between the components of the fragile X syndrome phenotype and severity; thus, females with frank mental retardation usually have typical physical features of the fragile X syndrome, including protruding ears and long face. For example, women with the full mutation more often had a longer face, prominent ears, calluses, and double-jointed thumbs than did either women with the premutation or controls.274,275 Severity of the phenotype is negatively correlated with the activation ratio, and negatively correlated with the level of FMRP.128 In one study, the physical symptoms observed among full mutation females were correlated with the number of CGG repeats.275 The authors speculate that perhaps full mutations with fewer CGG repeat numbers have a tendency to be unmethylated in a proportion of cells in some tissues. These observations were confirmed in an extended study of the same group;274 however, it remains clear that most symptoms of the fragile X syndrome are not correlated with CGG repeat-size of full mutations.
There is considerably less information about the behavior in females with the fragile X syndrome. In general, such females seem to have abnormalities similar in quality to those in males, but which are less severe than those in males.212,241,276-278 The components that seem to be particularly important are social disability, shyness, anxiety, stereotypic behavior, and hyperactivity.278-280 These are found among females with the full mutation, irrespective of their level of mental retardation.278,281-283
A recent report by Mazzocco et al.284 examined autistic behaviors among 30 school-age girls with fragile X syndrome and 31 age- and IQ-matched controls. Girls with fragile X syndrome had significantly more autistic behaviors than did the controls. These behaviors were qualitatively similar to those reported for boys with fragile X syndrome, but were not correlated with IQ. Anxiety in girls with fragile X syndrome was positively correlated with abnormal social and communication behaviors. Severity of stereotypic/restricted behaviors was negatively correlated with the activation ratio.
In a study of 29 women with the full mutation, Sobesky et al.275 found that emotional variables were negatively correlated with neurocognitive variables (i.e., the higher the full scale IQ or more skills related to executive functioning, the lower the Lie scale and fewer schizotypal symptoms). The Lie scale assesses informant response style and, sometimes, identifies a defensive response set, which is indicated by a tendency to endorse the virtuous behaviors and to deny minor, commonly occurring problems. Thus, the Lie scale can suggest unconscious denial of psychological discomfort or a purposeful minimizing of problems. Also, the more physical symptoms present, the higher the Lie scale and schizotypal symptoms, and the lower the IQ.
The average mean IQ for all full-mutation carrier females falls in the low-average range of 80 to 90.256 This figure averages those females with no or only minor learning problems with those with frank mental retardation. Recent studies based on the DNA diagnostic methods show that mental impairment is present in 52 to 82 percent of females with the full mutation.66,285,286 The variation among studies primarily depends on the selection criteria of females and the method of measuring IQ. There is no consistent evidence of a decline in IQ in females with fragile X syndrome as seen in males.232,247
Several studies have examined the association between the size of the full mutation, the activation ratio, and the level of IQ in full-mutation females; results have varied. With respect to size of the full mutation, Abrams et al.268 and Rousseau et al.287 found an association with IQ, whereas others did not.274,286,288,289 As many have suggested, the effect of repeat size is most likely a threshold effect: after 200 repeats, methylation occurs, leading to silencing of the gene. With respect to the activation ratio, the majority of studies have found an association with IQ,66,128,268,274,275,288,289 although some found no relationship.286,287 Reiss et al.288 included the mean parental IQ in their analysis, and found that both the activation ratio and the mean parental IQ contributed about 30 percent to the overall variance of the full-mutation female's IQ. The activation ratio seems to be a better predictor of measures of performance IQ as compared to verbal IQ among fragile X syndrome females.128,289 It may be a better measure for characteristics in which females with the fragile X syndrome show the greatest impairment.268,288
There appears to be some specificity in the cognitive profile of females with fragile X syndrome. They tend to show consistent deficits in executive functioning, which is not totally accounted for by their lower IQs.253,274,275,290-293 Females with fragile X syndrome also show deficits in visual-spatial and nonverbal abilities.292,294 However, these deficits may not be specific to the fragile X syndrome phenotype, but effects of generally poor cognitive processing.256 Females with fragile X syndrome also appear to have deficits in verbal memory for rote or abstract information,238,292,295 and have relative strengths in certain types of verbal memory that impose some external structure.292,295
Neuropathology and Neuroanatomy
The relative consistency of the neuropsychologic findings among males and females with the fragile X syndrome suggests that there must be specific central nervous system abnormalities underlying the observed cognitive and behavioral abnormalities. To date, there have been few studies of the anatomic and histologic examination of the brain of an individual with fragile X syndrome.296,297 These studies showed that there were no gross neuropathologic changes. They did find abnormal dendritic spine morphology (immature, long, and tortuous) with preservation of the neuronal density in the neocortex.
In contrast to neuropathologic studies, there have been relatively more studies on full and premutation carriers that visualize the central nervous system in vivo using MRI. Studies of the structure of the temporal lobe using MRI have shown varying results depending on the age of the study individuals. Reiss et al.298 found that young males and females with the fragile X syndrome had increased volume of the hippocampus bilaterally and showed an age-related increase in the volume of the hippocampus, and an age-related decrease in volume of the superior temporal gyrus compared with controls. Jakala et al.265 examined older groups of full- and premutation males and females. They normalized hippocampal volumes by either brain area, or by coronal intracranial area. They found no statistically significant differences in hippocampal volumes normalized for either measure in full-mutation individuals when compared with premutation individuals. Furthermore, the normalized hippocampal volumes of premutation individuals tended to be smaller, not larger, than those of their age- and sex-matched controls. Furthermore, they found age correlated negatively with hippocampal raw volumes and brain areas. Lastly, the study of Jakala et al. did find nonspecific changes indicative of structural abnormalities in temporal lobe structures in greater than 50 percent of full-mutation individuals. These changes included enlargement of ventricular and perivascular spaces, focal hyperintensities in temporal pole white matter, and/or somewhat atypical hippocampal morphology. With respect to age-related changes, both studies were cross-sectional. A need for longitudinal studies is apparent.
With respect to neuropsychologic measures, Reiss et al.298 did not find any associations between cognitive, behavioral, or developmental measures and the volumes of the four temporal lobe regions studied (right and left hippocampus, right and left superior gyrus) among full-mutation individuals. Interestingly, Jakala et al.265 found positive correlations between the left normalized hippocampal volumes and performance in many delayed verbal and visual memory tests in only premutation males and females. Thus, performance was better in those with larger left-normalized hippocampal volumes. They speculated that the absence of these correlations in full-mutation males and females could be a reflection of abnormalities in the function of hippocampal circuitries in individuals with the full mutations.
Reiss et al.277 examined the involvement of the posterior fossa in males and females with fragile X syndrome. Compared with controls, the size of the posterior vermis of the cerebellum was significantly decreased and the fourth ventricle significantly increased in males with the fragile X syndrome. When compared with fragile X syndrome males and controls, the variables describing the posterior vermis and fourth ventricle were intermediate for females with fragile X syndrome. In a study of autistic behaviors among school-age girls with fragile X syndrome and 31 age- and IQ-matched controls, Mazzocco et al.284 found that the posterior cerebellar vermis area was negatively correlated with measures of communication and stereotypic/restricted behaviors.
Lastly, a study of the neuroanatomy of 51 individuals with fragile X syndrome and matched controls showed that individuals with fragile X syndrome had increased volume of the caudate nucleus and, in males, the lateral ventricle. Both were correlated with IQ. Caudate volume was also correlated with the methylation status of the FMR1 gene.131 In addition, these authors studied a pair of monozygous female twins with fragile X syndrome who were discordant for mental retardation. Neuroanatomic differences were localized to the cerebellum, lateral ventricles, and subcortical nuclei.
In summary, when compared to matched controls, males and females appear to have deviations in the size of the cerebellar vermis, fourth ventricle, hippocampus, caudate nucleus, and lateral ventricle. These findings, although not all consistent, suggest that the FMR1 mutation leads to observable changes in the neuroanatomy that, in turn, may be the cause of the neurodevelopmental disability and behavioral problems associated with the fragile X syndrome. Reiss et al.131 speculated that the FMRP may be involved in programmed cell death (apoptosis), a process crucial to normal brain development. During normal development, neurons are overproduced and are subsequently pruned back by programmed cell death within the first 2 years of life.299 It has been suggested that the lack of FMRP may cause a lack of the normal pruning process of neuronal connections early in development. This is consistent with the findings of Comery et al.300 who showed immature neuronal connections and an increase in dendritic branches in the FMR1 knockout mouse. Clearly, more studies are necessary to better define anatomic changes, particularly over time, to determine possible interventions or treatment.
Phenotype of Premutation Carriers
Only one study specifically examined the phenotype of males who carried the premutation. Loesch et al.301 compared clinical, anthropometric, and psychometric data from a sample of 10 premutation males with those from controls who were primarily married-in relatives of the family. They found that premutation males differed significantly from controls on several cognitive (decreased scores on performance and verbal IQ) and physical measurements (ear length and total facial score). Unfortunately, complete molecular and protein assessments of the premutations were not performed. Clearly, more studies are needed to confirm the phenotype among premutation males.
Jakala et al.265 studied the hippocampal volumes using MRI in adult males with the full and premutation and normal male controls (n=10 in each group). While the right and left hippocampal volumes, normalized for either brain area or coronal intracranial area, did not differ between full and premutation males, premutation males had smaller left hippocampal normalized volumes than their age- and sex-matched controls. Unfortunately, raw data on controls were not presented and, thus, it is not possible to evaluate the magnitude of this difference.
The phenotype of premutation females has been studied more intensively than that in premutation males. Intuitively, little or no phenotype is expected due to the presence of an allele with a normal repeat number. However, there is consistent evidence for a somatic phenotype and equivocal evidence for a neuropsychologic phenotype.
Several studies show that carriers with a premutation differ significantly from control individuals in various physical measurements, including overall physical index score and in ear prominence,274,302 and stature and dermatoglyphics.301 However, these features are more mild than those observed in full-mutation females.
The most impressive somatic involvement that is consistently found among only premutation carrier females, not full-mutation carriers, is premature ovarian failure (POF). This was first noted in an early study of Cronister et al.,303 in which they found that premature menopause was present in 8 of 61 normal heterozygotes and in none of the impaired heterozygotes. Later, Schwartz et al.304 confirmed this observation in a multicenter study in which 24 percent of premutation carriers had POF, whereas only 14 percent of full-mutation carriers and 6 percent of noncarriers had POF. Further studies found this phenomenon,305,306 and preliminary results from a large international collaboration indicate that among 395 premutation, 128 full-mutation, and 237 noncarrier relatives, 16 percent, 0 percent, and 0.4 percent experienced menopause prior to age 40, respectively.
A possible related phenotype is increased dizygous twinning among premutation carriers only,307 although increased rates were not confirmed in a prospective study of pregnancy outcomes of carrier females.19 However, results from a preliminary study found that among 20 pregnancies of premutation carriers with POF, two had produced twins, and that this rate was 10 times higher than that among their noncarrier relatives.308 As premutation alleles are known to express FMRP,68 this phenotype is probably caused by a gain-of-function due to increased CGG repeat numbers in the RNA transcripts, rather than by decreased protein levels. Partington et al.305 suggested that fragile X carriers may produce fewer eggs in utero, leading to premature menopause and an increased rate of dizygous twinning at an earlier age than usual. Alternatively, they suggest that excess dizygous twinning could reflect a programmed excess hypothalamic stimulation of the ovaries resulting in excess follicular usage and earlier menopause.
The neuropsychologic phenotype among premutation females is significantly more subtle, if present at all. We review only studies that used the DNA diagnostic test to classify female carriers as premutation carriers, although there is a wealth of literature on “normal obligate carriers” that includes both pre- and full-mutation carriers (e.g., Mazzocco292).
Sobesky et al. examined 92 premutation carriers for measures of emotional problems (Lie scale and schizotypal features), outer ear prominence, physical features, full-scale IQ, and executive functions. Unfortunately, no statistical comparisons were done between this group and the control group, which consisted of 35 noncarrier relatives of fragile X syndrome individuals, although the percentages of females with such problems were intermediate between full-mutation carriers and controls in all but IQ and executive functions. Clearly, the mean IQ and mean executive function variable of premutation women did not differ from controls. No relationships were found between repeat number and these variables. Similar findings related to the Lie scale and schizotypal features among premutation carriers were found in a preliminary study of Steyaert et al.309 That is, although they found no significant clinical deviation in their population on these scales, low scores on schizotypal features, social introversion, and a so-called faking good profile suggested that individuals may not be aware of some personality characteristics in these areas.
In contrast to these positive findings, Reiss et al.310 found no phenotype associated with premutation carriers in their study. They examined the neuropsychologic or psychiatric phenotype among 34 adult women with the premutation and 41 matched controls who were mothers of children with nonfragile X-related developmental disabilities. They found no differences related to cognitive abilities or profile, neuropsychologic function, psychiatric diagnoses, or symptoms and self-rated personality profile among the groups. Exploratory analyses showed no significant effect of either the size of repeat or activation ratio on any measure of neurobehavioral function. Both groups had a high lifetime prevalence of major depression, and the authors interpreted this to be related to rearing children with developmental disabilities. Franke et al.311 found the same trend: premutation carriers and mothers of autistic children had a higher frequency of affective disorders than mothers from the general population. However, they also found that the age-of-onset of psychiatric morbidity in both groups of mothers was earlier than the age when mental retardation was diagnosed in their children. Thus, they concluded that the psychosocial burden of raising a retarded child and/or feelings of guilt could not fully explain the higher frequencies of affective disorders.
Although there is no cognitive deficit among premutation carriers, there may be a specific profile. Allingham-Hawkins et al.312 studied 14 individuals and found that the mean Verbal and Performance IQs were well within the average range, as was the mean Full-Scale IQ; they observed, however, a trend toward lower Performance IQ compared with Verbal IQ. Interestingly, they also noted that while there was no significant correlation between Full-Scale IQ and CGG repeat size, there was a significant positive correlation between Full-Scale IQ and the proportion of the active X carrying the normal FMR1 allele in fibroblasts, but not in leukocytes or lymphoblasts. These data need to be confirmed, as the sample size was small.
With respect to neuroanatomic features, similar findings to those in males on normalized hippocampal volumes for full-mutation, premutation, and control females were found by Jakala et al.265 That is, premutation females had smaller right and left normalized hippocampal volumes than their age- and sex-matched controls. These findings are tantalizing, but need to be confirmed on a large number of individuals.
Phenotype of Intermediate Alleles
Evidence for a phenotypic consequence of alleles with 40 to 60 repeats (referred to as intermediate or gray-zone alleles) is not consistent. Several studies have surveyed populations with special education needs and compared the frequency of intermediate alleles with controls to the population frequency determined by other studies. For example, Murray et al.59 found a significant excess of intermediate alleles in the schoolboys in classes for intellectual needs in Wessex, England, as compared with the maternal control X chromosome (3.6 percent vs 1.9 percent; p = 0.039). The same trend was found for the increased frequency of intermediate alleles among a group of mentally retarded Brazilian males versus a set of controls (6.4 percent vs 2.8 percent; not significant).313 In contrast, a study of children in special education needs classes in Atlanta, GA, did not find an increased frequency of intermediate alleles relative to maternal X chromosome controls. Other studies have not found the increased rates of the intermediate alleles among clinically referred populations of children with academic difficulties314 or with language delay315 as compared with general population frequencies, although no control groups were studied.
Two studies examined the correlation between the full-scale IQ and FMR1 repeat number.314,316 Daniels et al.316 examined the CGG repeat number for three groups: low IQ (mean IQ = 71, n = 35), middle IQ (mean IQ = 103, n = 19), and high IQ (mean IQ = 137, n = 49). They found no difference in the number of FMR1 CGG repeats for males or females. Mazzocco et al.314 examined the association between IQ score and the number of repeats in 455 Caucasian and 462 African-American school-aged children referred to developmental pediatrics clinics and found no significant association.
In summary, no obvious cognitive deficit is observed among carriers of intermediate or premutation alleles. However, studies to examine behavioral aspects and cognitive profiles are needed to rule out subtler, but important effects of the CGG repeat.