Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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Fragile X syndrome is a classic neurologic disease with unique manifestations on the clinical and molecular level. It is the most common genetic cause of cognitive impairment in males and can render symptoms of speech and developmental delay. Further, it represents one of the many important inherited diseases that are caused by expansions or amplification of short DNA repeats on specific genes. This article will help elucidate the significance of the fragile X syndrome as well as fragile X tremor-ataxia syndrome (FXTAS) for both younger and older patients and will provide insight on the potential benefits of a diagnostic workup and particular situations where a screening may be beneficial. It will also point to current research that has led to possible future treatments for symptoms of fragile X syndrome.
Fragile X syndrome is the most common inherited cause of cognitive impairment in males. It is named for the folate sensitive fragile site Xq27.3 and is caused by an expansion or amplification of a CGG trinucleotide repeat in the first exon of the fragile X mental retardation gene (FMR1), located on the long arm of the X chromosome. It affects males more severely and more frequently than females. It is a paradigm of a neurologic disease with a well-recognized phenotype and a clearly defined genetic and molecular basis that explains a complex mode of inheritance and the associated phenomenon of anticipation.
Martin and Bell first described this syndrome in 1943 (59). In 1969, Lubs was the first to demonstrate a fragile site on the X chromosome (58). In 1977, Sutherland showed this to be a reliable finding in cells cultured in a folate deficient medium (83). In 1980, Turner and colleagues recognized the combination of macroorchidism and cognitive impairment in males in conjunction with a fragile site to be a distinct clinical entity (91). Verkerk and colleagues discovered the molecular basis of the condition in 1991 (94).
In 2001, Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset progressive neurologic disorder. FXTAS develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, parkinsonism, peripheral neuropathy, autonomic disorders, cognitive impairment (39), and essential tremor (32). The elevated mRNA in fragile X premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS exhibiting neuropsychiatric and neurologic symptoms (67).
The most common problems that bring a male patient with fragile X syndrome to medical attention are cognitive impairment and behavioral disturbances (69; 95), with 4% to 8% of cognitive impairment or developmental delay caused by fragile X mutation (84). The clinical severity is directly related to the number of repeats in the FMR1 gene. Attention has been directed to the increasingly recognized clinical features of the premutation expansion (55 to 200 CGG repeats). Females are less severely affected than males due to X-inactivation.
Physical features. Clinical features are variable but may include hyperkinetic or autistic spectrum behavior, macroorchidism in mature males (testicular volume greater than 30 mL in the adult), and abnormal adult craniofacial features, including macrocephaly; long, narrow face with a long, prominent jaw; high, broad forehead; prominent supraorbital ridges with puffy upper eyelids and lower epicanthal folds; and large alae nasi with mild fullness at the nasobuccal border. The ears have normal configuration but are long (greater than 60 mm in length in the adult). The philtrum is long, with a thin upper lip and a wide mouth. The palate may be high-arched and may contain a cleft. Dental malocclusion is common.
Esotropia or exotropia and errors of refraction are common, as are high myopia and hyperopia (42). Ptosis is seen in a few patients.
Fragile X patients have an underlying defect in connective tissue elastin. This results in excessive joint laxity (particularly hyperextensibility of the metacarpal-phalangeal joint of the hand), pes planus, hernias, pectus excavatum, and remarkably smooth skin. Individuals with the fragile X syndrome also appear at high risk for mitral valve prolapse and, occasionally, mild dilatation of the aortic root, but cardiac manifestations are rarely symptomatic.
Endocrine abnormalities are subtle. In childhood, patients are often bigger than their peers, but as adults they are shorter than might be expected. Severe obesity has been reported but is rare. Fertility is impaired both in affected males and in carrier females, who may have premature menopause and raised serum follicle-stimulating hormone with premature ovarian failure (62).
Neurobehavioral impairment. Cognitive impairment is the most serious and consistent manifestation of the fragile X syndrome. Affected persons may have IQs ranging from 20 to 60 (06; 52). It affects males with the full mutation and full methylation most severely. Males with partial methylation of a full mutation and patients with a mosaic premutation and mutation express variable amounts of FMRP and have IQ scores in the 60 to 80 range. Females with the full mutation are also affected to various degrees, depending on the ratio of X inactivation with 50% to 70% of full mutation heterozygote women having an IQ of 84 or less.
Mental impairment was further investigated by Annangudi and colleagues (04). Neuropeptide release was impaired in FMR1 knockout mice, specifically a reduced level Rab3A, an mRNA cargo of FMRP involved in the recruitment of vesicles. Docking and fusion abnormality of peptidergic dense-core-vesicles causes defective maturation and maintenance of synaptic connections, leading to cognitive impairment (04).
Voxel-wise gray and white matter volumes were examined over a 2-year period in a 1- to 3-year-old boy (n=41). Region-specific alterations in brain development were seen, with enlarged gray matter volume in the caudate, thalamus, and fusiform gyri and reduced gray matter volume in the cerebellar vermis in fragile X syndrome, suggesting prenatal, genetically mediated alterations in neurodevelopment of patients with fragile X syndrome. White matter volume of striatal-prefrontal regions was greater in patients with fragile X syndrome than in controls (45; 46). The same group investigated the whole-brain morphometric pattern of boys with fragile X syndrome and idiopathic autism using genotyping, cognitive measures, neuropsychiatric assessments, MRI, preprocessing procedures, and cross-site validation of imaging parameters. They found that both groups exhibit distinct neuroanatomical profiles relative to one another. Those with idiopathic autism are more likely to exhibit patterns similar to controls than those with fragile X syndrome (45; 46). Improvement in detection of fragile X syndrome is made possible by early and accurate human brain phenotype in humans affected with this disease.
Fragile X syndrome is also the most common cause of autism spectrum disorder, and reports have found that even carriers in the premutation range can have this disorder. Behavioral features in fragile X syndrome include hand flapping or biting, poor eye contact, perseverative speech and behavior, tactile defensiveness and social anxiety. These features are common in 60% to 90% of boys and 25% to 85% of girls with this disorder (36).
Hatton and colleagues (43) looked at the CARS score of patients with fragile X syndrome to determine the prevalence of autistic behaviors and found that only 21% of the 129 patients had a score at or above the cutoff for autism. Additionally, they also reported that low levels of FMRP were associated with higher mean levels of autistic behavior as measured by CARS. Hall and colleagues also found that compulsive behavior, commonly seen in individuals with fragile X syndrome, correlates with lowered levels of FMRP and cortisol (41).
Visual perceptual difficulties, dyspraxia, impaired visual-spatial abilities, and visual-motor coordination may cause the affected patient to be clumsy. Performance IQ is less than verbal IQ in most patients. Decreased attention span, hyperactivity, impaired processing of sequential information, and poor short-term memory further compromise the patient’s ability to learn. Unusual responses to sensory stimuli and stereotypic behaviors are observed in affected males.
Temporal order impairment is also seen in patients with fragile X syndrome. The CGG knock-in mouse model allowed evaluation of the nature of neurocognitive deficits in carriers of the fragile X permutation. Female knock-in mice with CGG repeat expansions between 150 and 200 at 48 weeks of age showed poor temporal order test results as compared to the wild-type mice, whereas female CGG knock-in mice with repeat expansions between 80 and 100 had similar performance with wild-type mice. Therefore, female CGG knock-in mice showed deficits in temporal ordering when the upper end of permutation range is reached (47).
Cognitive impairment is common in fragile X syndrome; it is the most common form of inherited mental impairment in patients with extensive spine dysgenesis. There is an increased density and abnormal morphology of dendritic spine, the postsynaptic sites of most excitatory synapses. Dendritic spines are found to be unstable and insensitive to modulation by sensory experience in a mouse model of fragile X syndrome. Loss of the FMR1 gene product in these patients leads to overproduction of transient spines in the primary somatosensory cortex (65). Development of neurons in fragile X patients was studied on a mouse model, wherein significant difference in terms of increased dendritic and cell-body branching of hippocampal neurons grown on fragile X astrocytes was found from the neurons grown with normal astrocytes after 7 days in vitro, but no difference was seen between the 2 groups after 21 days in culture. The study establishes the role astrocytes contribute to symptoms of delayed growth characteristics and abnormal morphological features in fragile X syndrome (48). Dysregulated actin dynamics during development and processes of synaptic plasticity have been shown to be the underlying mechanism. Regulators of actin appear to play an important role in this process (28).
The increase in density of dendritic spines is found on the cortical pyramidal neurons in affected individuals and FMR1 knockout mice. A rapid decrease in dendritic spine dynamics on the layer 2/3 neurons of wild-type mice during the first 2 postnatal weeks is then replaced by mushroom spines. Knockout mice on the other hand, show a developmental delay in the downregulation of spine turnover and in the transition from immature to mature spine subtypes. Blocking mGluR signal does not correct the instability of spines, but pharmacologic approach aimed in several other signaling pathways in the mutant mice at early postnatal ages can reverse the maturational defect in dendritic protrusions (21).
Dopamine release and uptake impairment was analyzed in FMR1 knockout mice, which model fragile X syndrome, and then was compared to wild-type control mice. Increased dopamine release was observed, uncorrected for uptake, and normalized against the predrug release peaks in FMR1 knockout mice, but not in wild-type mice. Thus, decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in FMR1 knockout mice (29).
Seizures. Although seizures are relatively common in males with fragile X syndrome (approximately 15% to 20%), the precise prevalence is unknown. Partial-complex and generalized, tonic-clonic are the most frequently described seizure types in males with fragile X syndrome. Seizures, tics, and behavioral problem exacerbation in fragile X syndrome was associated with the autoimmune disease carrier status of mothers with FMR1 premutation (17).
Berry Kravis and colleagues enrolled 1394 individuals with an FMR1 full mutation. Families completed the national fragile X survey either online or over the telephone with a trained interviewer; the survey included an additional set of questions concerned with the child’s experiences with seizures. Respondents reported that 173 (12%) had seizures--154 (14%) males and 19 (6%) females; age of onset was in young and mid-childhood, between 4 and 10 years of age (53% of males and 32% of females). Seizures were considered mild to moderate in severity; partial seizures were most common. Many of the respondents reported that medication was effective in controlling seizures (10).
A typical EEG pattern has been reported to occur in males with fragile X syndrome, including some without clinically apparent seizures (63). This pattern is described as consisting of uni- or bitemporal spikes of medium to high voltage that occur during sleep and resemble benign rolandic spikes. One study showed interictal centrotemporal spikes in children with fragile X syndrome with seizures compared to 23% in children with fragile X syndrome without seizures (08). The seizures were classified as benign focal epilepsy of childhood; the seizures were easy to treat and remission was achieved. Epilepsy in individuals with fragile X syndrome is known to follow a benign course with seizures disappearing before the age of 20 years. However, in a proportion of individuals with a history of epilepsy, the seizures continued after the age of 20 years (74). Among these, the most common abnormal EEG findings have been reported as rhythmic theta activity and a slowing of background activity.
Life expectancy for patients with fragile X syndrome is normal. These patients have been found to have decreased cancer risk due to the diminished expression of WNT7A gene, which widely relates to oncogenic processes, found on quantitative real-time PCR (73). However, cognitive impairment and behavioral problems impact an individual’s ability to function independently in society, and many patients become institutionalized.
More than 95% of males with the full mutation will function in the moderate to severe range of cognitive impairment as adults. Adult females with the full mutation show a much wider range of effects, with approximately half testing in the mentally retarded range of intellectual function, usually mild. Even when cognitive impairment is absent, females with the full mutation can show learning and psychiatric problems.
A 5-year-old boy came for evaluation by his pediatrician for developmental delay. The patient's mother reported a history of speech delay, behavior problems, and hyperactivity. The patient also displayed aversion to touch and had some hand-biting behaviors. On physical exam, the patient’s appearance was within normal limits; however, he had a long face, large ears, and a prominent jaw. The patient's mother reported that her sister's 8-year-old son had speech delays, problems with attention and learning, and was in a special education class (96).
In patients with fragile X syndrome, the CGG repeat is expanded to more than 200 CGG triplets, or so-called "full" mutation. These are inherited from the mother and arise from an unstable "premutation" of approximately 55 to 200 repeats. The risk of premutation expansion to full mutation increases with increase in number of repeats (68). The cause of cognitive impairment is the loss of FMR1 protein expression. FMR1 is an RNA binding protein that plays a role in gene expression after transcription occurs. The full-blown expansion is associated with hypermethylation of the repeat, which in turn reduces expression of FMR1. Rarely, the syndrome can occur with deletions or inactivation point mutations of FMR1, which points to the loss of FRMP function as the cause of fragile X syndrome. Of note, the premutation alleles have been associated with premature ovarian failure in women (53) and with the fragile X associated tremor ataxia syndrome in males (39). The CGG repeat expansion is found in the promoter region of the FMR1 gene and leads to the silencing and loss of gene products (80). In fragile X, the silencing of the FMR1 gene occurs at 11 weeks’ gestation and flips the “epigenetic switch” of increased methylation and modification of histone proteins (56).
Males with fragile X are hemizygous and females heterozygous for the condition. Amplification of the premutation to the full mutation occurs only in the ovum. A male who has the premutation on his only X chromosome passes the premutation to each of his daughters without significant change in the size of the repeat. A female with the premutation would pass on the affected gene to half her children, either unchanged or as a full mutation. A female with a full mutation would transmit the affected gene after further amplification to half her children. This amplification in the ovum of both premutations and full mutations is related to the phenomenon of anticipation whereby the genetic defect manifests earlier in successive generations in a family and where longer expanded repeats typically cause earlier symptom onset and more severe disease in successive generations. The stability of the premutation when transmitted by a male elucidates another observation, described as Sherman paradox, where daughters and mothers of transmitting males are unaffected, but brothers and grandsons are affected 18% and 74% of the time, respectively (79).
It is postulated that repeat expansion diseases are caused by unusual secondary structures adopted by DNA repeats that make them unstable, which may in turn cause many errors at multiple levels of DNA metabolism (ie, strand slippage during DNA replication) (68). The general principle of the type 2 trinucleotide expansion disorders is a dynamic repeat expansion that occurs outside of the coding region of a mutated gene (vs. when a mutated gene is transcribed and translated normally but produces an abnormal protein, as in type 1 repeat disorders). The repeat expansions lead to reduced expression of the affected genes, resulting in loss of gene function.
The FMRP or disease protein that causes fragile X syndrome has been linked to the regulation of microRNAs and their control of neuronal function, with FMRP defining gene expression at the synapse (52). Spinocerebellar ataxia-1, Huntington disease, myotonic dystrophy, and spinobulbar muscular atrophy (Kennedy disease) are 4 of at least 10 now recognized inherited neurologic diseases with type 2 repeat disease classification. Despite their unusual similar features related to anticipation and their typical inheritance pattern, they are clinically diverse (70).
The FMRI protein plays an important role in mediating appropriate synaptic protein synthesis in response to neuronal activity levels, although the biochemical mechanisms involved in the pathological phenotype are mostly unknown. Fragile X-associated translational dysregulation causes wide-ranging neurologic deficits, including severe impairments of biological rhythms, learning processes, and memory consolidation. Dysfunction in cytoskeletal regulation and synaptic scaffolding disrupts neuronal architecture and functional synaptic connectivity (30). In the knockout fragile X mouse, the FMR1 mRNA was most concentrated in the granular layers of the hippocampus and cerebellum. The pattern of expression in the cortex of the adult mouse brain was consistent with concentration within specific neuronal populations involved in synaptogenesis. It also has been postulated that the lack of FMR1 protein function leads to a moderate increase of the oxidative stress status in the brain that may contribute to the pathophysiology of fragile X syndrome. Higher levels of reactive oxygen species were found in the knockout fragile X mouse when compared with brains from wild-type mice (26).
Structural and functional neuroimaging studies suggest abnormal activity in the striatum of patients with fragile X syndrome, the most common form of inherited cognitive impairment in males. The absence of FMRP is associated with apparently normal striatal glutamate-mediated transmission but abnormal gamma-aminobutyric acid (GABA) transmission. This effect is likely secondary to increased transmitter release from GABAergic nerve terminals. Moreover, a small noncoding BC1 RNA associated with FMRP plays a significant role in the regulation of striatal synaptic transmission (14). Earlier studies identified a role for aberrant synaptic plasticity mediated by the metabotropic glutamate receptors (mGluRs) (16). Metabotropic glutamate receptors (mGluRs), implicated in a diverse variety of neuronal functions, showed exaggerated signaling secondary to unchecked activation in the mice model of the disease (24).
Observed symptoms in fragile X syndrome, mental impairment, and autism are derived primarily from dysfunction in the hippocampus. It has been found that surface expression of the AMPA receptor subunit, GluR1, is reduced also in the lateral amygdala of knockout mice. A lower presynaptic release is manifested by a decrease in the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), increased paired pulse ratio, and slower use-dependent block of NMDA receptor currents. Synaptic defects in the amygdala of knockout mice can be reversed by pharmacologic intervention against mGluR5 (86). Targeting the GABAergic system is a good approach to treat amygdala-based symptoms in patients with fragile X syndrome. Neuronal hyperexcitability in neurons of amygdala of mouse models in fragile X syndrome can be treated by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gabaxodal (THIP) (64). Fragile X mouse models with deleted FMR1 gene also have NMDA receptor hypofunction in the dentate gyrus, causing NMDAR-dependent electrophysiological and behavioral impairments particularly impaired performance in context discrimination tasks (25).
In the human fetal brain, the highest levels of FMR1 mRNA were detected in fetal cholinergic neurons of the nucleus basalis and in pyramidal neurons of hippocampus (01). Moreover, disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency was found to contribute to the cognitive-behavioral impairments associated with fragile X syndrome. Kesler and colleagues measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X and 9 age-matched, typically developing controls using 1(H)magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls (54).
The deficits in visual motor skills mentioned above have been attributed to impairment in the magnocellular portion of the thalamus as well as to higher cortical centers in the parietal lobe (55) and, thus, contribute to the disability and deficits in cognition in fragile X syndrome.
An MRI study showed decreased gray matter, increased white matter, increased ventricular CSF, and increased caudate volume that decreased with age. The loss of gray matter did not correlate with IQ, suggesting a defect in the structural organization in patients with the fragile X mutation. A sex difference for relative amounts of gray and white matter was noted (27).
Premutation carriers. Of note, carriers of premutation-sized fragile X repeats can develop a late-life tremor and ataxia syndrome, otherwise known as FXTAS (39; 36), possibly affecting 1 in 3000 men older than 50 years in the general population. Male carriers with 55 to 100 CGG repeats have FMR1 mRNA levels that are 2- to 4-fold higher than normal, with reduced FMR1 levels (88), suggesting possible dysregulation during the translation of mRNA. FXTAS was also seen in women who can also develop tremor, gait, ataxia, neuropsychiatric symptoms, and multisystem neurodegenerative disorder with central and peripheral nervous system involvement. Affected women with evident CGG repeat, X-chromosome inactivation, abnormal FMR1 mRNA and FMRP levels showed frontal and temporal atrophy on MRI (72). These patients had elevated FMR1 RNA with normal or borderline FRMP, suggesting that FMR1 RNA could be responsible for this neurodegenerative course (39). Typically, these patients have 70 or more CGG repeats (50). The progressive tremor of FXTAS resembles essential tremor with the compounding feature of ataxia, and affected persons may also have cognitive disturbances, parkinsonism, and findings of autonomic insufficiency, such as hypertension and impotence (Hagerman and Hagerman 2004). This is thought to be due to the excess mRNA that leads to toxicity by a variety of mechanisms, including the sequestration of proteins important for neuronal function such as DROSHA and DGCR8; dysregulation of calcium and subsequent mitochondrial dysfunction, leading to oxidative stress and the production of reactive oxygen species; and a possible role of out-of-frame, non-AUG (riboadenylate-ribouridylate-riboguanylate) translation through the CGG repeat, producing a polyglycine-containing peptide, FMRpolyG (37).
Cognitive disturbances often first include memory and executive functional impairment, which may progress to dementia that is typically subcortical or frontal. Apathy, disinhibition, and depression are additional behavioral and mental sequelae (50). Physicians evaluating patients with dementia should consider FXTAS as an etiology, especially if there is a comorbid movement disorder. In general, the progression and severity seen in FXTAS is variable, but at least 1 case report demonstrates rapid progression of dementia (1 year) as a possible clinical course (31). Imaging of the brain with MRI shows classic T2-weighted signal abnormalities in the middle cerebral peduncles (MCP sign) and cerebellar white matter, the latter has been included as a major radiologic criterion in diagnosis of "definite" FXTAS (49). Examination of CNS neurons and astrocytes reveals intranuclear inclusions, the neuropathological hallmark of FXTAS, and this is strikingly associated with the number of CGG repeats (33). The loss of whole-brain, cerebral, and cerebellar volume are also correlated with the number of CGG repeats (18).
Females are rarely affected and demonstrate a milder course of FXTAS than males. Adams and colleagues found significant radiologic differences, demonstrating less cerebellar volume loss in females and a lower incidence of the MCP sign in females (13.3%) as opposed to males (58.3%) with FXTAS (02). Furthermore, the association of brain volume with the degree of clinical disease is much more significant in affected males, likely due to the decreased radiographic findings in females. Screening for the premutation may be considered in those males older than 50 years with ataxia and tremor or those males with parkinsonism, action tremor, or dementia with a family history of cognitive impairment, premature ovarian failure, or changes on MRI described above (53).
Premutation carriers have also been shown to have social, emotional, and cognitive problems, including autism spectrum disorder as well as schizoid and obsessive-compulsive symptoms. Hessl and colleagues found this phenotype to be attributable to the impact of CGG repeats on limbic brain areas, including the amygdala and the hippocampus (due to their role in emotion and social function) (44). These psychological disturbances associated with the premutation may herald the more severe neurologic sequelae of FXTAS in later life. Among asymptomatic premutation males, a relationship between increased CGG repeat size and impairment to central executive working memory has also been observed (19).
There has been 1 case report of a female carrier of the FMR1 premutation with a positive family history of fragile X syndrome who developed severe ataxic gait with administration of chemotherapy and returned to baseline on discontinuation of therapy. This finding demonstrates the variability in those with the FXTAS gene but also indicates that environmental factors may play a role in clinical symptomology. There is no targeted treatment for FXTAS, but several medications can improve the tremor and psychiatric problems, including anxiety and depression. Studies regarding early cognitive and motor deficits prior to the onset of FXTAS, in addition to neuroimaging, demonstrate changes to the premutation brain with aging compared to controls. Neuropathological studies have shown the occasional co-occurrence of other aging problems such as Parkinson disease and even Alzheimer disease in those with FXTAS. Females progress more slowly in motor symptoms, although more rapidly in psychiatric symptoms compared to males with FXTAS (37).
Fragile X syndrome is the most common known inherited cause of cognitive impairment in males. Based on cytogenetic testing, it is thought to affect 1 in 4000 males and 1 in 8000 females. The condition is underdiagnosed, especially in females, because craniofacial abnormalities as well as neurobehavioral deficits are often subtle, and the variability in phenotype is tremendous. The prevalence for the premutation is estimated at 1 in 813 males and 1e in 259 females.
The findings of 1 study suggest that fragile X carrier screening is an acceptable option for some women seeking prenatal genetic counseling, based on reported carrier frequency, cost effectiveness, and sensitivity of the available screening test (20). To capture the behavioral phenotype of FMR1 mutations, increased FMR1 testing in individuals with intellectual disability is advised, and newborn screening methods for those with fragile X syndrome and other FMR1 mutations should be developed. This is especially helpful due to the wide range of phenotypical expression of fragile X, specifically females who may not be diagnosed at all (13).
The differential for fragile X syndrome includes other possible causes of cognitive impairment or developmental delay, including genetic and nongenetic causes (96).
A fragile site may be identified by cytogenetic techniques using folate-deficient media for culture in other X-linked genetic disorders mentioned above, including Sotos syndrome, Prader-Willi syndrome, Angelman syndrome, and Rett syndrome, whose symptoms manifest in early childhood. Other causes of developmental delay and behavioral disturbances should be considered, including fetal alcohol syndrome, cocaine exposure, lead poisoning, and hydrocephalus. The differential further includes autism, Asperger syndrome, and attention deficit disorder.
Sutherland showed that cells cultured in folate-depleted media reliably demonstrated the characteristic fragile site on the distal end of the long arm of the X chromosome (83). This test is clinically available and highly specific (99%) (76). It is also less expensive than the formerly used chromosome analysis, which is no longer used as first line test.
Detection of the CGG repeat expansion in the FMR1 gene was typically accomplished using FMR1 molecular testing on Southern blot analysis. It was found that RP PCR reduces the burden of Southern blot analysis to only those samples that require methylation information. Methylation-sensitive restriction enzymes can be used to assess FMR1 alleles, thus minimizing the need for Southern blot and contributing to the advancement toward a PCR-only workflow for FMR1 analysis (15).
The diagnosis of fragile X should be in the differential for all children with speech or developmental delay. The American College of Medical Genetics recommends consideration for testing in the following scenarios (Shaffer and American College of Medical Genetics Professional Practice and Guidelines Committee 2005):
(1) Individuals of either sex with cognitive impairment, developmental delay or autism, especially with any physical characteristic of fragile X syndrome, a family history of the disorder, or male or female relatives with cognitive impairment of unknown etiology.
(2) Individuals seeking reproductive counseling who have a family history of fragile X syndrome or a family history of cognitive impairment of unknown etiology.
(3) Fetuses of known carrier mothers.
(4) Patients who have been found to have a fragile X site on chromosome analysis done for any reason.
(5) Women with elevated levels of FSH (follicle-stimulating hormone), especially in cases with family history of premature ovarian failure, fragile X syndrome, or undiagnosed cognitive impairment.
(6) Individuals of either sex with late-onset ataxia or intention tremor, especially if there is family history of movement disorders, fragile X syndrome, or undiagnosed MR.
In addition, all patients with the full mutation should be evaluated for mitral valve prolapse. EEG should be obtained in individuals with seizures.
Brainstem auditory evoked responses should be performed in patients with fragile X syndrome suspected of hearing loss. Although fragile X syndrome patients have malformed ears, they do not have an increased incidence of hearing loss (71).
Families of patients with fragile X should be referred to the National Fragile X Foundation. This important first step will allow the family to find information in lay language and support that will empower them to act as effective advocates for the patient.
The approach to management of fragile X syndrome patients is multidisciplinary, involving medical and nonmedical personnel. The team, ideally, should be led by a pediatrician, and the anticipatory guidelines outlined by the American Academy of Pediatrics should be followed (03). Other key members of the team are educators, speech and language therapists, social workers, psychologists, counselors, and dentists. Consulting physicians should include neurologists, psychiatrists, geneticists, ophthalmologists, cardiologists, and orthopedic surgeons. Active involvement of the parents in decisions governing the lives of affected children helps ensure communication and proper implementation of treatment plans.
Referral to a genetics center with experience in the education and counseling of fragile X families is essential. When possible, a clinical geneticist should be involved antenatally for extended discussion on the prognosis of the patient as well as the implications for recurrence in future pregnancies and the evaluation of risk to other family members. There are no specific guidelines available for the transition of children or adults with fragile X syndrome (93). This can be difficult, especially when parents report worsening of aggression and self-injurious behavior during episodes of high anxiety and arousal (93).
Special education should be individually tailored, catering not only to the child’s cognitive impairment and learning disabilities but also to the behavioral problems frequently encountered. Symptomatic treatment can be provided for many problems suffered by the patient. Seizures are generally well managed with standard anticonvulsant medications. Behavioral problems can be difficult to manage and require a combination of medical and nonmedical therapies. Behavior modification may be combined with stimulant drugs for attention deficit disorder. Low doses of clonidine help control hyperactivity and aggressive behaviors. In a double-blind, placebo-controlled study, Torrioli and colleagues showed that L-acetylcarnitine (20 to 50 mg/kg daily) represents a safe alternative to the use of stimulant drugs for the treatment of ADHD in children with fragile X syndrome (89). Valproic acid can be considered an alternative to alleviate ADHD symptoms in patients with fragile X syndrome, although further research is required to clarify the issue (90). Depression may be treated with serotonin reuptake inhibitors. Intention tremor, parkinsonism, and neuropathic pain can also be managed pharmacologically with beta-blockers, levodopa, carbidopa, and gabapentin, respectively. In one case report, levetiracetam was found to be effective and well tolerated in treating intention tremor associated with fragile X syndrome (75). Folate (10 mg per day) has been utilized in the past with variable results for treatment of behavioral problems. Sleep disorders are seen in up to 77% of children with fragile X syndrome. Difficulty falling asleep and maintaining sleep are the most common problems. Melatonin at 3 mg was effective in achieving sleep (97).
Antibiotic prophylaxis may be required for patients with mitral valve prolapse during dental procedures. Malocclusion may require dental intervention. Strabismus and refractive errors are treated with prescription glasses, and in some cases surgery may be necessary. Flat feet may require orthotic intervention.
For patients with fragile X-associated tremor/ataxia syndrome (FXTAS), randomized controlled clinical trials have not been carried out, and there is currently no cure that can reverse its pathophysiology. However, symptomatic treatment may improve these patients’ quality of life. The underlying toxic RNA mechanism may be slowed down by neuroprotective agents (09). Identification of these patients is most important, and referral to appropriate specialists is very helpful.
Target for treatment. Research has indicated that receptors found on the surface of neurons called group 1 metabotropic glutamate receptors (mGluRs) may be a target for future therapy for fragile X. These receptors, which are selectively enhanced in the hippocampus of test mice lacking FMRP (Fmr1-KO or knockout mice), weaken synaptic connections in these animal models called long-term depression. This long-term depression neural plasticity is important during brain development early and later in life. The mGluR long-term depression state is exaggerated in the absence of the FMRP protein, which negatively regulate translation. Overactive group 1 MGluRs have been found to affect protein synthesis in early postnatal development, the cortex, and in long-term depression, but also in the hippocampus of mature animals, (important in memory storage, learning, and synaptic potentiation of seizure activity) and in the cerebellum (important for learning motor reflexes). These observations have coalesced into the "mGluR theory," and the suggestion has been made that many symptoms in fragile X might respond to drugs that inhibit group 1 mGluRs (07).
Research has also shown that flies missing the gene that encodes FMRP demonstrate altered courtship behavior, impaired learning and memory, and altered brain anatomy. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition (60; 61). Trials of metabotropic glutamate receptor 5 antagonists are beginning for individuals with fragile X syndrome (35); lithium is an example of this class of drugs. A small study by Berry-Kravis and colleagues showed that lithium had beneficial effects in treating the behavioral disorders associated with fragile X syndrome (11). Lower level of serine phosphorylation of glycogen synthase kinase-3 (GSK3) was found in testis and liver of FMR1 knockout mice; thus, lithium administration was found to reduce macroorchidism and reactive astrocytes in the mouse model of fragile X syndrome (98).
The toxic expanded CGG repeat FMR1 mRNA can be targeted with the use of antisense or RNA interference agents in patients with FXTAS to reduce the pathogenic RNA, but the problem with this drug is its inability to cross the blood-brain barrier (09).
The fragile X mental retardation protein (FMRP) has been associated with negative regulation of matrix metalloproteinase-9 with corresponding elevation. Minocycline is a tetracycline analogue that has been used in clinical trials for stroke, multiple sclerosis, and several neurodegenerative conditions. Studies in the Fmr1-KO, or knockout mice, show less anxiety and more strategic exploratory behavior as compared to untreated Fmr1 knockout mice. These effects of minocycline appear to relate to its inhibitory action on MMP-9 expression and activity, which is higher in the hippocampus of Fmr1 knockout mice. Its application in human clinical trials has been under investigation (12). Minocycline inhibits matrix metalloproteinases-9 (MMP-9), which is elevated in fragile X syndrome due to the lack of FRMP. Its side effect was studied using the adverse events checklist, complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA) at baseline and 8 weeks. Minocycline showed promise in treatment of behavioral abnormalities in patients with fragile X syndrome (66). Another study revealed that elevated MMP-9 is associated with immature dendritic spine morphology. Studies conducted in FMR1 knockout mice found that minocycline led to improvements in measures of anxiety, cognition, and maturation of dendritic spines (51). However, a survey conducted in 50 patients with fragile X syndrome who received minocycline for at least 2 weeks have reported gastrointestinal difficulty, including loss of appetite as the most common side effect of the drug. Additional minocycline randomized clinical trials focusing on the areas of language, attention, social communication, and anxiety are suggested by the group to furthermore establish efficacy of the drug (92). Subsequent studies in the Drosophila model of fragile X confirmed the therapeutic potential of minocycline (81). Some positive effects were noted in a placebo-controlled trial (57). Dansie and colleagues showed that minocycline treatment shows effects long after drug treatment has ended (22). This randomized control trial was complicated by an unusually wide age range in its subjects (as young as 3.5 years of age) and a mix of male and female subjects, with a corresponding variation in Fmr1 methylation status and clinical severity. However, minocycline did result in a modest but statistically significant improvement in the Clinical Global Impression Improvement Scale, and fragile X syndrome subjects showed normalization of excessive MMP-9 activation (23) and auditory evoked potentials (77), suggesting potentially useful biomarkers for future clinical trials. Overall, minocycline has had a modest success in the treatment of fragile X and has gained some acceptance in off-label use for the treatment of fragile X patients (40). Subjects with fragile X syndrome participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function (54).
An activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of fragile X syndrome in novel object recognition with improved tolerability with reduced vascular toxicity over earlier PDE4 inhibitors. The compound is being evaluated in human clinical trials at this time (34).
Pharmacologic agents targeting various neurotransmitters may also be helpful. There is some evidence that the incomplete silencing of toxic full mutation RNA may be associated with autistic features, but not intellectual functioning in fragile X males. However, decreased levels of mRNA may be more predictive of intellectual functioning than autism features (05).
Targeted oligonucleotide therapy for the treatment of tandem repeat disorders is being explored and may have implications for fragile X syndrome. However, oligonucleotide therapies in fragile X syndrome would not be as straightforward as in some other conditions due to the variant phenotype with repeat expansion (99). Treatment with noncoding RNA is in the development stages. It has potential for changes in DNA methylation. Heterochromatinization is gene therapy, which has been successful in cell lines and animal models. Concerns about being able to cross the blood brain barrier are being addressed (80).
Cannabidiol is also being explored as it appears to have a positive impact on social avoidance and anxiety, as well as improvements in sleep, feeding, motor coordination, language skills, anxiety, and sensory processing (87). More formal clinical trials are being done to explore these findings further.
Prenatal testing for the FMR1 mutation performed on either amniotic or chorionic villus sample is widely available (85). At present, it is offered to patients with a positive family history of fragile X syndrome. Population-based carrier detection is now available and is 100% sensitive and at least 99.5% specific for carriers of the mutation (82).
There are no known effects.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Robin Godshalk MS MHA LGC CGC
Dr. Godshalk of Fragile X Center at Atlantic Health System in Morristown, New Jersey has no relevant financial relationships to disclose.See Profile
Bernard L Maria MD
Dr. Maria of Thomas Jefferson University has no relevant financial relationships to disclose.See Profile
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