Rett Syndrome

A number sign (#) is used with this entry because Rett syndrome (RTT) is caused by mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2; 300005) on chromosome Xq28.

See also the congenital variant of Rett syndrome (613454), which is caused by mutation in the FOXG1 gene (164874) on chromosome 14q13.

Description

Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. It is characterized by arrested development between 6 and 18 months of age, regression of acquired skills, loss of speech, stereotypic movements (classically of the hands), microcephaly, seizures, and mental retardation. Rarely, classically affected males with somatic mosaicism or an extra X chromosome have been described (Moog et al., 2003).

Clinical Features

Rett (1966, 1977), a Viennese pediatrician, first described Rett syndrome after observing 2 girls who exhibited the same unusual behavior who happened to be seated next to each other in the waiting room.

Hagberg et al. (1983) described 35 patients, all girls from 3 countries (France, Portugal, and Sweden), with a uniform and striking, progressive encephalopathy. After normal development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of high brain functions. Within 1.5 years, this deterioration progressed to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and 'acquired' microcephaly. Thereafter, a period of apparent stability lasted for decades. Additional neurologic abnormalities intervened insidiously, mainly spastic paraparesis, vasomotor disturbances of the lower limbs, and epilepsy.

Bruck et al. (1991) described a set of monozygotic female twins with Rett syndrome. The authors noted that normal early development has generally been insisted on as an essential criterion for the diagnosis; however, twin 1 was considered to be abnormal from birth, while delay was not suspected in twin 2 until she was about 1 year old. Some regression occurred during the second year in both twins, who at age 4 years were clinically indistinguishable.

A striking deceleration of growth has been found across all measurements in 85 to 94% of girls with Rett syndrome and may provide the earliest clinical indication of this disorder. Motil et al. (1994) studied dietary intake and energy production in 9 Rett syndrome girls, comparing them to 7 healthy controls. Metabolic rate while sleeping was 23% lower in Rett syndrome girls than in controls, while metabolic rates during waking hours did not differ between the 2 groups. Dietary intake and fecal fat loss were also the same. The energy balance in girls with Rett syndrome was 55 +/- 43 kcal/kg lean body mass daily; in controls, the balance was 58 +/- 22 kcal/kg lean body mass per day. Motil et al. (1994) speculated that a small difference in energy balance would be sufficient to account for the growth failure in Rett syndrome girls and may explain the greater time that the Rett syndrome girls spent in involuntary motor activity.

Hagberg (1995) reviewed a Swedish series of 170 affected females, aged 2 to 52 years. The well-recognized classic phenotype was found in 75% of cases. Atypical variant forms, mainly more mildly affected mentally retarded girls and adolescent women, were still in a minority, but constituted an expanding cohort.

The presence of metatarsal and metacarpal abnormalities in some patients with Rett syndrome prompted Leonard et al. (1995) to conduct radiologic studies of 17 cases. Short fourth and/or fifth metatarsals were identified in 11 (65%), short fourth and/or fifth metacarpals in 8 of 14 (57%), and reduced bone density in the hands was found in 12 of 14 cases (86%). Leonard et al. (1999) examined hand radiographs of 100 girls with Rett syndrome, representing 73% of the known Australian population of girls with Rett syndrome, aged 20 and under. A metacarpophalangeal pattern profile was established, revealing that the shortest bone was the second metacarpal. Short distal phalanx of the thumb was seen in all age groups and in classic and atypical cases. In girls less than 15 years old, bone age was more advanced in Rett syndrome patients compared with controls (left hand p = 0.03, right hand p = 0.004), but was most advanced in the younger group. Bone age normalized with chronological age.

Miyamoto et al. (1997) described 2 Japanese sisters with classic RTT. The youngest sister, aged 6 years and 6 months, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly, developed sleep-wake rhythm disturbance from age 4, and seizures from age 5 years. The elder, 7 years and 9 months old at the time of report, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm, and no seizures. The variability in the sisters stood in contrast to that in monozygotic twins with RTT who usually show little clinical difference.

Sirianni et al. (1998) reported 3 affected sisters of a Brazilian family who showed rapid deceleration of head growth with subsequent progressive mental deterioration. Two surviving affected daughters, examined at ages 9 and 5.5 years, showed no purposeful hand movements, but had persistent hand stereotypes and rubbing of the torso. They had significant muscle wasting and inability to walk, and showed spontaneous episodes of hyperventilation while awake. They had a severe attention deficit and no language development, with intellectual and adaptive behavior at the 1- to 6-month level. Although the younger daughter was still able to reach for food, she was without other purposeful hand use. Leonard and Bower (1998) retrospectively studied the neonatal characteristics and early development of Australian girls with Rett syndrome. The mean weight and head circumference of newborn girls later identified as Rett patients was lower than that of the reference Australian population. Girls who had learned to walk had larger heads at birth than those who had not; girls who had never been ambulant had the smallest heads at birth. In 46.5% of girls, parents reported unusual development or behavior in the first 6 months. The authors stated that these results provided evidence that girls with Rett syndrome may not be normal at birth. They further suggested that using normal development in the first 6 months and normal neonatal head circumference as diagnostic criteria may cause missed or delayed diagnoses.

Neuropathologic Findings

Papadimitriou et al. (1988) reported light-microscopic evidence of white matter disease in the brain biopsy of a patient with Rett syndrome. Ultrastructurally, many neurons and oligodendroglia contained membrane-bound electron-dense inclusions with a distinct lamellar and granular substructure. Armstrong et al. (1995) systematically studied brains of 16 girls with Rett syndrome who ranged in age from 2 to 35 years. They found no evidence that the pyramidal neurons in Rett syndrome degenerate progressively with increasing age. Instead, they found a striking decrease in the dendritic trees of selected cortical areas, chiefly projection neurons of the motor, association, and limbic cortices. They suggested that this may result in abnormalities of trophic factors.

Neuroradiographic Findings

Horska et al. (2009) performed proton magnetic resonance spectroscopy (MRS) on 40 girls with Rett syndrome with a mean age of 6.1 years. Compared to 12 controls, Rett syndrome patients had a decreased N-acetylaspartate (NAA)/creatinine (Cr) ratio and increased myoinositol/Cr ratio with age (p = 0.03), suggestive of progressive axonal damage and astrocytosis. The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared with those without seizures (p = 0.017), and NAA/Cr ratios decreased with increasing clinical severity score (p = 0.031). The mean glutamate and glutamine/Cr ratio was 36% greater in RTT patients than in controls (p = 0.043), which may have been secondary to increasing glutamate/glutamine cycling at the synaptic level. The findings indicated that Rett syndrome is associated with mild white matter pathology, and suggested that MRS can provide a noninvasive measure of cerebral involvement in RTT.

Cardiac Abnormalities

Kerr et al. (1997) found an annual mortality rate in Rett syndrome of 1.2%; a high proportion (26%) of these deaths were sudden and unexplained. Sekul et al. (1994) reported prolonged QT interval in patients with Rett syndrome.

Guideri et al. (1999) studied the heart rate variability and corrected QT interval in 54 females (mean age, 10 +/- 5.5 years) in various clinical stages of Rett syndrome, using continuous 12-lead ECG monitoring for 10 minutes in the supine position. The total power spectrum of heart rate variability (from 0.03 to 0.4 Hz), mainly its low frequency (LF) and high frequency (HF) components, was significantly lower in children with Rett syndrome compared with that in controls. The sympathovagal balance, expressed by the ratio LF/HF, was significantly higher in patients, reflecting the prevalence of sympathetic activity. The RR interval was significantly shorter and the corrected QT interval longer in the patient group than in the control group. The authors suggested that in children with Rett syndrome, loss of physiologic heart rate variability associated with an increase of adrenergic tone, represents the electrophysiologic basis of cardiac instability and sudden death. Ellaway et al. (1999) determined the prevalence of QT prolongation in a cohort of 34 Australian patients. Nine patients had significantly longer corrected QT values than a group of healthy, age-matched controls. There was no apparent correlation between the presence of QT prolongation and phenotypic severity. The authors concluded that QT prolongation should be considered in all patients with Rett syndrome.

Zappella Variant

De Bona et al. (2000) stated that preserved speech variant (PSV) Rett syndrome shares with classic Rett syndrome the same course and the stereotypic hand-washing activities, but differs in that patients typically recover some degree of speech and hand use, and usually do not show growth failure. Progressive scoliosis, epilepsy, and other minor handicaps, usually present in Rett syndrome, are rare in the preserved speech variant. The authors reported mutations in the MECP2 gene in both classic and PSV Rett syndrome (see 300005.0012), establishing that the 2 forms are allelic disorders.

Zappella et al. (2001) reported clinical and mutation analysis findings in 18 patients with preserved speech variant Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared.

Renieri et al. (2009) presented a detailed evaluation of 29 patients with Zappella variant, also known as preserved speech variant, Rett syndrome. All 29 patients had mutation in the MECP2 gene, of which 28 were missense (see, e.g., R133C; 312750.0001) or late truncating mutations. There was great variability with respect to language, manual abilities, and somatic features, allowing for further statistical subdivision into low, intermediate, and high functioning. In general, patients with Zappella variant Rett syndrome had less microcephaly, later onset of regression, a tendency to be overweight, better hand use, and better speech acquisition compared to patients with classic Rett syndrome. The majority (76%) of patients with Zappella variant had autistic features. Diagnostic criteria was presented. Renieri et al. (2009) proposed the term 'Zappella variant' rather than 'preserved speech variant' to described milder forms of Rett syndrome because other aspects besides speech are involved.

Adegbola et al. (2009) reported a 10-year-old girl who had slowing of motor skills and hypotonia at age 12 months. She had purposeful hand movements with occasional hand-wringing stereotypes, was morbidly obese, was prone to aggressive outbursts, and had mild autistic features. EEG showed multifocal spike and wave discharges without overt seizures. Full-scale IQ was 70 at age 6 years and 58 at age 8 years. Her father had an IQ of 85, had special schooling, and showed behavioral dyscontrol and hyperactivity in childhood and adolescence. His behavioral difficulties improved with age. Both father and daughter were found to have a mutation in the MECP2 gene (300005.0036), that resulted in decreased, but not absent MECP2 function. The findings were consistent with a hypomorphic MECP2 allele contributing to a neuropsychiatric phenotype in this family.

Affected Males

Coleman (1990) reported a possible case of Rett syndrome in a male, and Philippart (1990) reported 2 such cases.

Schwartzman et al. (1999) described a male patient with Rett syndrome and the 47,XXY karyotype of Klinefelter syndrome. The propositus showed normal development until age 8 months. At that time, he sat without support, played normally, and was able to grasp objects and to put food into his mouth. He had started to say some words comprehensibly. At age 11 months, it was noted that he had lost purposeful hand movements and language skills. He also began to show regression in social contact. At age 1 year, he began to show stereotypic hand movements, bruxism, and constipation. At age 28 months, he presented severe global retardation and slight diffuse hypotonia. At the time of the last observation, at age 37 months, loss of purposeful hand movements, manual apraxia, and slight global hypotonia were persistent. The clinical and laboratory findings did not overlap with any described for Klinefelter syndrome. DNA studies indicated that the additional sex chromosome was paternal in origin, i.e., that the nondisjunction occurred in the paternal first meiotic division.

Clayton-Smith et al. (2000) presented a male with somatic mosaicism for an MECP2 mutation (300005.0010) leading to a progressive but nonfatal neurodevelopmental disorder. The patient was a normal-sized product of a full-term gestation. He was a placid baby who never crawled, but walked at 15 months and learned to say some single words in the second year of life. At around 2 years of age, he lost interest in his surroundings and lost his speech. At age 3 years, he began to have generalized seizures, and magnetic resonance imaging (MRI) revealed atrophy of the brainstem and frontal and temporal lobes. Electroencephalography (EEG) showed excessive slow-wave activity during sleep and a relative poverty of rhythmic activity while awake. At 6 years of age, he had a thoracic scoliosis and poor lower-limb musculature, and he walked with an ataxic gait. He had abnormal muscle tone with rigidity of the limbs and truncal hypotonia. His feet were small, blue, and puffy. His hand use was very limited, but there were no obvious hand-wringing movements.

Maiwald et al. (2002) reported a 46,XX male with Rett syndrome caused by mutation in the MECP2 gene (300005.0026). Upon amniocentesis performed because of advanced maternal age, a female karyotype was detected in a sonographically male fetus. Both the phenotype and the karyotype were confirmed after birth, and the absence of mullerian structures was demonstrated by ultrasonography. Motor development was delayed; he was able to sit only at 14 months of age. He was still not able to walk and there was no speech at the age of 24 months. At the age of 2 years, he showed truncal muscular hypotonia, microcephaly, spasticity, and convergent strabismus of the left eye. There was a loss of purposeful hand skills at approximately 6 months of age, and a deceleration of head growth at approximately 7 months. The clinical appearance of the boy resembled female Rett cases, which was explained by the karyotype. In addition, preferential expression of the normal allele may have contributed to the rather mild phenotype. The authors noted that similar features had been described in male patients with MECP2 mutations and a Klinefelter karyotype (46,XXY).

Topcu et al. (2002) reported a boy with features of classic Rett syndrome who was a somatic mosaic for a mutation in the MECP2 gene (300005.0005). He had normal psychomotor development through the first 6 months. Loss of acquired purposeful hand skills began around 11 months, and stereotypic hand movements became apparent at 15 months. He never crawled or walked and had never spoken. On examination at 12 years of age he was microcephalic with stereotypic hand movements, tremors, and apraxia. He had a thoracic scoliosis and poor lower limb musculature, small and cold hands and feet, hypospadias, and cryptorchidism. Electroencephalography showed an excess of slow wave activity and paroxysmal sharp theta wave activity prominent on wake recordings of frontal regions.

Atypical Rett Syndrome

Molecular analysis has allowed the broadening of the phenotype of MECP2 mutations beyond RTT to include girls who have mild mental retardation, autism, and a phenotype resembling Angelman syndrome (105830), as well as males with severe encephalopathy. Heilstedt et al. (2002) reported a girl with a phenotype of atypical RTT who had a heterozygous mutation in the MECP2 gene (300005.0016). She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports of RTT. The mother did not carry an MECP2 mutation.

Watson et al. (2001) identified MECP2 mutations in 5 of 47 patients with a clinical diagnosis of Angelman-like phenotype and no cytogenetic or molecular abnormality of chromosome 15q11-q13. Four of these patients were female and 1 male. By the time of diagnosis, 3 of the patients were showing signs of regression and had features suggestive of Rett syndrome; in the remaining 2, the clinical phenotype was still considered to be Angelman-like.

Imessaoudene et al. (2001) identified MECP2 mutations in 6 of 78 patients with possible Angelman syndrome but with normal methylation pattern at the UBE3A locus (601623). Of these, 4 were females with a phenotype consistent with Rett syndrome, one was a female with progressive encephalopathy of neonatal onset, and one was a male with a nonprogressive encephalopathy of neonatal onset. This boy had a gly428-to-ser mutation (300005.0023).

Diagnosis

Hagberg and Skjeldal (1994) suggested a model of inclusion and exclusion criteria for the diagnosis of Rett syndrome that relaxed the international criteria originally drawn up in Vienna in September 1984. The new model permitted the diagnosis of forme frustes, cases with late regression, and congenital variants. Hagberg et al. (2002) provided an updated diagnostic criteria.

Neul et al. (2010) provided revised diagnostic criteria for Rett syndrome and emphasized that it remains a clinical diagnosis, since not all Rett patients have MECP2 mutations and not all patients with MECP2 mutations have Rett syndrome. The most important feature for classic Rett syndrome is a period of clear developmental regression followed by limited recovery or stabilization. Other main criteria include loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements. Although deceleration of head growth is a supportive feature, it is no longer necessary for diagnosis. Exclusion criteria include other primary causes of neurologic dysfunction and abnormal psychomotor development in the first 6 months of life. Criteria for variant or atypical forms of Rett syndrome were also presented.

Percy et al. (2010) validated the revised diagnostic criteria provided by Neul et al. (2010) in an analysis of 819 patients enrolled in a natural history study of Rett syndrome. Of the 819 patients, 765 females fulfilled 2002 criteria (Hagberg et al., 2002) for classic (85.4%) or variant (14.6%) Rett syndrome. All those classified as having classic Rett syndrome fulfilled the revised main criteria, and all those with variant Rett syndrome met 3 of 6 main criteria in the 2002 classification, 2 or 4 main criteria in the revised system, and 5 of 11 supportive criteria in both.

See early infantile epileptic encephalopathy-2 (EIEE2; 300672) for discussion of a Rett syndrome-like phenotype caused by mutation in the CDKL5 gene (300203).

Prenatal Diagnosis

As pointed out by Amir et al. (1999), the discovery of MECP2 as the gene responsible for Rett syndrome enabled testing for early diagnosis and prenatal detection. In addition, the finding that epigenetic regulation has a role in the pathogenesis of RTT opened possible opportunities for therapy. Amir et al. (1999) suggested that partial loss of function of MECP2 may decrease transcriptional repression of some genes. The relatively normal development during the first 6 to 18 months of life may allow for presymptomatic therapeutic intervention, especially if newborn screening programs can identify affected females.

Inheritance

Schanen et al. (1997) stated that familial recurrences of Rett syndrome comprise only approximately 1% of the total reported cases; the vast majority of cases are sporadic. However, it is the familial cases that are key for understanding the genetic basis of the disorder.

Hagberg et al. (1983) suggested that the exclusive involvement of females is best explained by X-linked dominant inheritance with lethality in the hemizygous males.

Tariverdian et al. (1987) and Tariverdian (1990) reported 5-year-old monozygotic Turkish female twins concordant for Rett syndrome, suggesting a genetic cause of RTT. Partington (1988) described affected monozygotic twin sisters. Buhler et al. (1990) pointed to the existence of about 10 familial cases of Rett syndrome and to an elevated parental consanguinity rate of 2.4%. They suggested a model involving autosomal modifying genes that function as a suppressor in relation to an X-chromosomal mutation causing Rett syndrome. Zoghbi et al. (1990) reviewed familial instances including 6 pairs of concordantly affected monozygotic twins; 4 families with 2 affected sisters; and 2 families with 2 affected half sisters. The affected half sisters had the same mother. Anvret et al. (1990) described Rett syndrome in 2 generations of a family. The index case was a 12-year-old girl with classic Rett syndrome; her maternal aunt, aged 44 years, had mild Rett syndrome. Studies with X-linked DNA markers detected no deletions.

Martinho et al. (1990), in agreement with others, found no increase in parental age or in spontaneous abortion rates among the mothers of affected children and found a normal sex ratio among sibs. They found no chromosome rearrangements and no correlation between the fragile site at Xp22 and Rett syndrome. In 2 isolated cases of RTT, Benedetti et al. (1992) excluded both maternal uniparental heterodisomy and isodisomy. Webb et al. (1993) likewise excluded unilateral parental disomy through study of the locus DXS255 using the probe M27-beta; all informative probands had inherited an allele from each of their parents.

Akesson et al. (1992) presented genealogic data on 77 Swedish females with Rett syndrome suggesting that there is a genetic component in transmission of the disorder. In most cases, ancestry was traced back to 1720-1750. Common ancestry was seen in 2 pairs of females with Rett syndrome. In 39 of the 77 cases, it was possible to trace ancestry to 9 small and separate rural areas, and 17 pairs even originated from the same farm or small group of dwellings. The common origin was found equally often among descendants of the father as of the mother, and there was a raised rate of consanguineous marriages. In what they referred to as 'an a priori test of the first study,' Akesson et al. (1995) examined an additional 20 Rett syndrome females who were consecutively traced. Of these, 10 of 19 (53%) originated from the earlier defined 'Rett areas,' and 11 of 19 (58%) could be traced to the same homestead. In 2 clusters, each consisting of 3 Rett syndrome females, all 6 subjects were descendants of the same 2 couples several generations ago. Consanguineous marriages among grandparents on both sides were found to have occurred in 11% (4 of 37), compared to 1% in the general Swedish population. The authors considered the findings a confirmation of the first study, and postulated that transmission starting with a premutation may result in a full mutation over generations, most likely if the parents have the premutation in homozygous form. A genealogic study of 32 Swedish patients with atypical Rett syndrome led Akesson et al. (1996) to conclude that most atypical cases are variants of classic Rett syndrome. Eleven persons (34%) were traced to a small number of parishes in areas in which classic patients had been found. In 4 cases, typical and atypical Rett syndrome patients were found in the same pedigree. The authors proposed a 2-gene model, including one autosomal and one X-linked gene, to explain the genetics of this disorder. In a follow-up study looking for mutations of the MECP2 gene in 3 clusters and 2 pedigrees chosen at random in Sweden, Xiang et al. (2002) could not demonstrate that patients with Rett syndrome from the same cluster area share a common genetic defect. All of the identified mutations in the MECP2 gene were de novo and not premutations such as trinucleotide expansion. Recurrence of cases with the syndrome present in Rett clusters appeared to be the result of independent mutational events.

Thomas (1996) suggested that the exclusive occurrence of RTT in females, without evidence of male lethality, can be explained by de novo X-linked mutations occurring exclusively in male germ cells that result in affected daughters. Thus, he suggested that it is the high male:female de novo germline mutation rate that explains the absence of affected males in Rett syndrome.

Villard et al. (2001) identified a mutation in the MECP2 gene in only 1 of 5 families with RTT, suggesting an alternative molecular basis for the phenotype in the other 4 familial cases. X-chromosome inactivation studies showed that all the mothers and 6 of 8 affected girls had a totally skewed pattern of X inactivation, whereas only 9% of 43 sporadic RTT females had a skewed pattern of X inactivation, and all of their mothers had random X inactivation. In the familial cases, it was the paternal X chromosome that was active. Genotype analysis suggested that the skewed X-inactivation phenotype was due to a locus in the region between markers at DXS1068 and DXS1024, although the lod score for this analysis was not significant. The results suggested that the 2 traits, completely skewed X inactivation and RTT, are not linked. Villard et al. (2001) proposed that familial Rett syndrome transmission is due to 2 traits being inherited: an X-linked locus abnormally escaping X inactivation, and the presence of a skewed X inactivation in carrier women.

Rosenberg et al. (2001) reported a female patient with Rett syndrome and 46,X,r(X) karyotype. The X-derived marker was about one-tenth the size of a normal X chromosome, with FISH analysis showing that the breakpoint on Xq was proximal to the MECP2 gene. X-inactivation studies demonstrated that the normal X chromosome was active and the ring X chromosome inactive in all cells examined. Methylation studies showed that the ring X was of paternal origin. No mutation was found in the MECP2 gene after sequencing of the whole coding region. The authors proposed a model invoking a second X-linked gene for RTT. Given the model, the second putative RTT gene could account for the minority of sporadic and the majority of familial cases that are negative for MECP2 mutations. To manifest as RTT, the disease allele would have to be expressed in a majority of cells, i.e., be associated with skewing of X inactivation as in cases of X-chromosome rearrangements.

Gill et al. (2003) studied 11 families in each of which 2 females were thought to have Rett syndrome. In 1 family, an identical MECP2 mutation was found in 2 affected sisters and their healthy mother. In 5 families, an MECP2 mutation was found in 1 affected female but not in the other, possibly affected female. In 5 families, no MECP2 mutation was found. Gill et al. (2003) concluded that Rett syndrome is only rarely familial and that if girls with Rett syndrome who have MECP2 mutations have sisters with developmental difficulties, the disorder in the sisters is more likely to have a separate cause.

Evans et al. (2006) reported a family in which 2 half sisters with the same father were found to have Rett syndrome caused by the same mutation in the MECP2 gene. Genetic analysis detected the mutation in approximately 5% of the father's sperm, but not in his buccal or lymphocyte DNA, indicating paternal germline mosaicism.

Venancio et al. (2007) reported a rare familial case of Rett syndrome due to maternal germline mosaicism. A mutation in the MECP2 gene was identified in a girl with classic Rett syndrome and in her brother, who had severe congenital encephalopathy. The mutation was absent in DNA extracted from the blood of both parents.

X-Inactivation Studies

In the unaffected mother of 2 affected half sisters, Zoghbi et al. (1990) found nonrandom X-chromosome inactivation in leukocyte DNA. They also found an increased incidence of nonrandom X inactivation in sporadic RTT patients (36%), as compared to healthy controls (8%). Kormann-Bortolotto et al. (1992) found no abnormality of the X chromosome in 9 girls with Rett syndrome or the 6 mothers who were studied. X-inactivation studies suggested that there 'may be an alteration in the timing of the X-inactivation process in the region Xp11.3 or 4-Xp21' in patients with RTT.

Camus et al. (1996) studied X-chromosome inactivation in 30 girls with Rett syndrome, in 30 control girls, 8 sisters, and their mothers. There was a significant increased frequency of partial paternal X inactivation (more than 65%) in lymphocytes from 16 of 30 RTT patients compared with 4 of 30 controls (P = 0.001). These results did not support the hypothesis of a monogenic X-linked mutation, but the authors suggested that there may be a complex secondary role played by X-inactivation in this disorder.

In a family with recurrence of Rett syndrome in a maternal aunt and niece, Schanen et al. (1997) and Schanen and Francke (1998) found skewing of the X-chromosome inactivation pattern in the obligatory carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the X-inactivation pattern in the mother of affected half sisters showed random X-inactivation, suggesting germline mosaicism as the cause of repeated transmission in that family. There was an affected male in the family, who was a maternal half brother of the affected niece, also suggesting germline mosaicism in the mother.

Brown (1997) noted that males who carry a Rett mutation may survive. The identification of such cases in sibships with diagnosed RTT females requires a carrier mother who either is a germline mosaic or has a favorably skewed X-inactivation pattern.

Mapping

On the basis of a girl with Rett syndrome and a translocation t(X;22)(p11.22;p11), Journel et al. (1990) suggested that the gene for this disorder may be located on the short arm of the X chromosome. The same translocation was present in her unaffected mother and in her sister, who was affected with a neurologic disorder compatible with a forme fruste of Rett syndrome. In the course of a systematic high-resolution chromosome analysis on 28 patients with Rett syndrome, Zoghbi et al. (1990) found a patient with a de novo balanced translocation t(X;3)(p22.1;q13.31). Zoghbi et al. (1990) noted, however, that the Rett syndrome locus may map to a different location on the X chromosome than the breakpoint, as has occurred in incontinentia pigmenti (308300). Archidiacono et al. (1991) studied the unaffected mother of 2 half sisters with Rett syndrome for evidence of germinal mosaicism. The analysis of 34 X-linked RFLPs in these 2 affected females and in their unaffected mother and half brother, together with the reconstruction of phase for 15 informative RFLPs in somatic cell hybrids retaining a single X chromosome from each female, made it possible to exclude some regions of the X chromosome as sites of the mutation causing the disorder. The 2 regions with X chromosome breakpoints found in RTT patients with X-autosome translocations, Xp22.11 (Zoghbi et al., 1990) and Xp11.22 (Journel et al., 1990), were not excluded as the localization of the RTT gene. In 2 families with maternally related, affected half sisters, Ellison et al. (1992) performed genotypic analysis using 63 DNA markers from the X chromosome. In at least 1 of the 2 families, 36 markers were informative, and 25 markers were informative in both families. On the basis of discordance for maternal alleles in the half sisters, they excluded 20 loci as candidates for the Rett syndrome gene. Using the exclusion criterion of a lod score less than -2, they excluded the region from Xp21.2 to Xq21-q23. Curtis et al. (1993) did linkage studies in 4 families, each with 2 individuals affected by Rett syndrome. In 2 of the families, X-linked dominant inheritance of the RTT defect from a germinally mosaic mother could be assumed. Using maternal X chromosome markers showing discordant inheritance they excluded much of Xp, including 3 candidate genes, OTC (311250), synapsin I (SYN1; 313440), and synaptophysin (313475). Although most of the long arm was inherited in common, it was possible to exclude a centromeric region. Curtis et al. (1993) also presented information on 2 families with affected aunt-niece pairs. To determine which regions of the X chromosome were inherited concordantly and discordantly in an affected maternal aunt and niece, Schanen et al. (1997) genotyped the individuals in the aunt-niece family and 2 previously reported pairs of half sisters. The combined exclusion mapping data allowed exclusion of the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. In a family with 3 affected individuals, including a male, Schanen and Francke (1998) compared haplotypes to narrow the RTT candidate region to a small interval on Xp and the distal long arm. The authors noted that identification of a severely affected male in a family with recurrent classic Rett syndrome strengthened the hypothesis that RTT is caused by an X-linked gene.

Xiang et al. (1998) presented haplotype analysis of 9 families with at least 2 closely related females affected by classic Rett syndrome. They concluded that the Rett syndrome locus is likely to lie within Xq28, close to marker DXS15. Xiang et al. (1998) suggested that the GABRE (300093) and GABRA3 (305660) genes are candidate genes for Rett syndrome. Webb et al. (1998) presented a study of 6 families with more than 1 female affected with Rett syndrome. They showed weak linkage to loci in Xq28, with a maximum lod score of 1.935 at theta = 0.0 at DXYS154. Webb et al. (1998) also noted the presence of the candidate genes GABRA3 and L1CAM (308840) in this region, but cautioned that their lod scores did not quite reach significance. Sirianni et al. (1998) presented information that they interpreted as confirming X-linked dominant inheritance of Rett syndrome. They described a family with the largest number (3) of female sibs affected with Rett syndrome identified to that time, and used data from this family, as well as from families previously described, to demonstrate the mode of inheritance and to localize the gene to Xq28. Concordance analysis with DNA markers showed that only Xq28 was shared among the 3 affected girls, whereas the same region was not shared with the unaffected sisters. The data complemented the exclusion-mapping data described by Xiang et al. (1998) who could not exclude the distal region of the long arm of the X chromosome. In a Brazilian family, Sirianni et al. (1998) found that the mother had extreme skewing of X inactivation with the unaffected X active in 95% of cells. Thus, the finding of highly skewed X inactivation in the mother, with preferential use of the unaffected X chromosome, strongly suggested that she was a nonpenetrant carrier of Rett syndrome. An unaffected daughter and an affected daughter did not show the skewed X inactivation.

Molecular Genetics

Exclusion of Linked Genes

Ferlini et al. (1990) excluded the synapsin I gene as the cause of RTT. Narayanan et al. (1998) excluded the M6b gene (300051), Wan and Francke (1998) excluded glutamate dehydrogenase-2 (GLUD2; 300144) and Rab GDP-dissociation inhibitor GDI1 (300104), which were chosen because of their location in the nonexcluded region of Xq. Heidary et al. (1998) excluded the gastrin-releasing peptide receptor gene (GRPR; 305670), Cummings et al. (1998) excluded the glycine receptor alpha-2 subunit gene (GLRA2; 305990), and Van den Veyver et al. (1998) excluded the holocytochrome c-type synthetase gene (HCCS; 300056), all of which had been candidate genes for Rett syndrome because they mapped to a region on Xp.

Mutations in the MECP2 Gene

In 5 of 21 sporadic patients with RTT, Amir et al. (1999) identified 3 de novo missense mutations in the MECP2 gene (300005.0001, 300005.0002, 300005.0007). Among 8 cases of familial Rett syndrome, Amir et al. (1999) found an additional missense mutation (300005.0008) in a family with 2 affected half sisters. The mutation was not detected in their obligate carrier mother, suggesting that the mother was a germline mosaic for the mutation. The authors suggested that abnormal epigenetic regulation may be a mechanism underlying the pathogenesis of Rett syndrome. Wan et al. (1999) identified 5 additional mutations in the MECP2 gene (see, e.g., 300005.0003) in patients with RTT. They found that the mutations were de novo, and that female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement.

Villard et al. (2000) reported a family in which a daughter had classic Rett syndrome and her 2 brothers died in infancy from severe encephalopathy. The affected girl and one brother tested showed a mutation in the MECP2 gene (300005.0007). The unaffected carrier mother had a completely biased pattern of X-chromosome inactivation that favored expression of the normal allele. One of the affected boys showed severe mental retardation and hypotonia soon after birth and died at age 11 months.

Zappella et al. (2001) reported clinical and mutation analysis findings in 18 patients with the preserved speech variant form of Rett syndrome. Ten (55%) had an MECP2 mutation. All had slow recovery of verbal and praxic abilities, evident autistic behavior, and normal head circumference. Six were overweight, often obese, had kyphosis, coarse face, and mental age of 2 to 3 years, and were able to speak in sentences; 4 had normal weight, mental age not beyond 1 to 2 years, and spoke in single words and 2-word phrases. The course of the disorder was in stages as in classic Rett syndrome. Hand washing was present in the first years of life but often subsequently disappeared.

Clayton-Smith et al. (2000) presented a male with somatic mosaicism for an MECP2 mutation (300005.0010), leading to a progressive but nonfatal neurodevelopmental disorder. In an affected boy, Topcu et al. (2002) identified an R270X mutation (300005.0005) along with the wildtype allele. The authors speculated that the somatic mosaicism could be the result of an early postzygotic mutation or chimerism.

Bourdon et al. (2001) reported somatic mosaicism for deletions of the MECP2 gene in 2 girls, 1 with a classic Rett phenotype and 1 with an atypical Rett phenotype without a period of regression. The deletions in these girls were detected not by sequence analysis but by CSGE or DGGE. Bourdon et al. (2001) suggested that this had implications for diagnostic methods used in Rett cases and cases of possible Rett syndrome.

Mnatzakanian et al. (2004) identified a theretofore unknown isoform of MECP2 that they called MECP2B, which utilizes exon 1 and exons 3 and 4, skipping exon 2. They screened 19 girls with typical Rett syndrome in whom no mutations had been found in exons 2, 3, or 4. In 1 affected individual, they identified a deletion of 11 basepairs in exon 1 (300005.0028). Ravn et al. (2005) identified a mutation in exon 1 of the MECP2 gene (300005.0029) in a patient with typical Rett syndrome. Ravn et al. (2005) emphasized the importance of mutation screening of MECP2 exon 1. Bartholdi et al. (2006) reported 2 unrelated girls with Rett syndrome caused by 2 different mutations affecting exon 1 of the MECP2 gene (see, e.g., 300005.0031).

Using multiplex ligation-dependent probe amplification (MLPA), Hardwick et al. (2007) identified multiexonic deletions in the MECP2 gene in 12 (8.1%) of 149 apparently mutation-negative patients with Rett syndrome. All of the deletions involved exon 3, exon 4, or both. There was no correlation between phenotypic severity and deletion size.

Saunders et al. (2009) identified 4 patients with classic Rett syndrome associated with mutations in exon 1 of the MECP2 gene, affecting the MeCP2_e1 isoform. Three of the mutations were predicted to result in absent translation of the isoform. Three of the mutations were proven to be de novo; the fourth was likely de novo, but the unaffected father was not available for DNA analysis. Two of the patients had previously tested negative for MECP2 mutation, which at the time only included sequencing of exons 2 to 4 of the gene (MeCP2_e2 isoform). The findings suggested that mutations affecting exon 1 of MECP2 are important in the etiology of RTT.

Disruption of the NTNG1 Gene

Borg et al. (2005) reported a girl with characteristic features of Rett syndrome who had no mutations in MECP2 or CDKL5 but carried a de novo balanced translocation, t(1;7)(p13.3;q31.3). No known gene was disrupted by the chromosome 7 breakpoint, but the chromosome 1 breakpoint was located within intron 6 of the NTNG1 gene (608818) and affected alternatively spliced transcripts. Borg et al. (2005) suggested that NTNG1 is a candidate disease gene for RTT. Archer et al. (2006) failed to identify any pathogenic mutations in coding exons of the NTNG1 gene among 115 patients with Rett syndrome.

Associations Pending Confirmation

For a discussion of a possible association between Rett syndrome and variation in the JMJD1C gene, see 604503.0001.

Genotype/Phenotype Correlations

Zappella et al. (2001) noted that all MECP2 mutations found in PSV patients have been either missense or late truncating mutations. In particular, the 4 early truncating hotspot mutations, R168X (300005.0020), R255X (300005.0021), R270X (300005.0005), and R294X (300005.0011), have not been found in PSV patients. These results suggested that early truncating mutations lead to a poor prognosis (classic Rett), whereas late truncating missense mutations lead either to classic Rett or to PSV.

Smeets et al. (2003) reported on 30 adolescent and adult females with classic or atypical Rett syndrome, of whom 24 had an MECP2 mutation. Mutations were found in all of the classic cases and in 64% of the variant cases. No correlation was found between skewing and milder phenotype. Early truncating mutations were associated with a more severe course of the disorder. A deletion hotspot in the C-terminal segment was predominantly characterized by rapid progressive neurogenic scoliosis. The R133C mutation (300005.0001) was associated with a predominantly autistic presentation, whereas the R306C mutation (300005.0016) was associated with a slower disease progression.

Smeets et al. (2005) described the long-term history of 10 females with a deletion in the C terminus of the MECP2 gene. Although their disease appeared 'classic' at an older age, in the beginning their symptoms resembled the forme fruste described by Hagberg and Skjeldal (1994). All had a more slowly progressive course with better-preserved cognitive functions in adolescence and adulthood. Their primary clinical problems were a gradual decline in gross motor ability despite preventive measures and a rapidly progressive spine deformation due to marked dystonia present from childhood.

Hammer et al. (2003) reported a 5-year-old girl with a 47,XXX karyotype who had relatively mild atypical Rett syndrome leading initially to a diagnosis of infantile autism with regression. Mutation analysis identified a de novo MECP2 mutation (L100V; 300005.0027). The supernumerary X chromosome was maternally derived. X-inactivation patterns indicated preferential inactivation of the paternal allele. Hammer et al. (2003) suggested that the patient illustrated the importance of allele dosage on phenotypic presentation.

Weaving et al. (2003) reported a large MECP2 screening project in patients diagnosed with Rett syndrome. Composite phenotype severity scores did not correlate with mutation type, domain affected, or X inactivation. Other correlations, including head circumference, height, presence of speech, and age at development of hand stereotypies, suggested that truncating mutations and mutations affecting the methyl-CpG-binding domain (MBD) tend to lead to a more severe phenotype. Skewed X inactivation was found in 31 (43%) of 72 patients tested, primarily in those with truncating mutations and mutations affecting the MBD. Weaving et al. (2003) concluded that it is likely that X inactivation modulates the phenotype