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Padres de Lillie
Rett syndrome (RTT)
¿Que es Rett syndrome (RTT)?
Rett síndrome es una enfermedad genética rara que afecta principalmente a las niñas. Es un neurologico síndrome que se diagnostica en bebés de entre 6-18 meses.
Es una condición progresiva y una de las primeras síntomas es una regresión en desarrollo. Afecta a alrededor de 1 de 10,000 niñas.
Esta rara afección neurológica afecta todas las áreas del desarrollo de un individuo afectado, incluida su capacidad para caminar, comer, hablar y respirar.
Autismo, demencia, ataxia y pérdida del uso intencionado de las manos
¿Qué causan los cambios genéticos Rett syndrome (RTT)?
Las mutaciones en el gen MECP2 son responsables del síndrome. 99% de las mutaciones son mutaciones nuevas.
El síndrome está presente casi exclusivamente en niñas y los bebés varones con una mutación en MECP2 rara vez sobreviven a la infancia.
En algunos casos, un síndrome genético puede ser el resultado de una mutación de novo y el primer caso en una familia. En este caso, se trata de una nueva mutación genética que se produce durante el proceso reproductivo.
¿Cuales son los principales síntomas de Rett syndrome (RTT)?
El síntomas del síndrome Por lo general, aparecen entre los 6-18 meses de edad en las niñas que parecen desarrollarse normalmente desde el nacimiento.
El desarrollo lento y regresivo es uno de los primeros síntomas del síndrome. La mayor síntoma son movimientos de manos constantes y repetitivos.
Otro síntomas incluyen arranque intenso, parpadeo excesivo, manos y pies fríos, problemas para dormir y comportamientos autistas.
El síndrome eventualmente afecta la capacidad del habla, caminar, alimentarse y respirar.
Posibles rasgos / características clínicas:
Corea, Bruxismo, Atetosis, Apraxia, Anormalidad del EEG, Patrón de circunvolución simplificado, Estreñimiento, Discinesia, Babeo, Distonía, Retraso motor, Convulsiones, Paquigiria, Mal contacto visual, Pes plano, Cifosis, Hipoplasia del cuerpo calloso, Reflujo gastroesofágico, Discapacidad intelectual , grave, hipotonía neonatal, microcefalia progresiva, mielinización tardía, empuje de la lengua, escoliosis, talipes equinovarus, espasticidad
¿Cómo se hace la prueba a alguien? Rett syndrome (RTT)?
La prueba inicial para el síndrome de Rett puede comenzar con la detección del análisis facial, a través de la plataforma de telegenética FDNA Telehealth, que puede identificar los marcadores clave del síndrome y describir la necesidad de más pruebas. Seguirá una consulta con un asesor genético y luego con un genetista.
Con base en esta consulta clínica con un genetista, se compartirán las diferentes opciones para las pruebas genéticas y se buscará el consentimiento para realizar más pruebas.
Información médica sobre Rett Síndrome
The criteria for diagnosing this syndrome are a female patient with a normal pre and perinatal history, normal development and head circumference up to 6 months of age (and often up to 12-18 months), subsequent regression of social and motor skills, hand-wringing or clapping with frequent mouthing, and truncal and gait ataxia (Hagberg 1997). Epilepsy may be a feature and the respiratory pattern is characteristic with periods of rapid breathing and hyperventilation followed by reactive apnoea. After the stage of regression there is a ""pseudo-stationary period"" where walking is preserved, there may be some improvement in communication and any overall regression is slow. Later on in the disease the patient becomes chair-bound with spasticity, joint contractures and a staring gaze. It should be noted that in the third phase of the illness patients can continue to maintain or acquire skills and this seems to occur over a period of at least 3 years (Hyman and Naidu, 1994). The frequency in Norway is 2.17 per 10,000 girls (Skjeldal et al., 1997) and in France it is 0.55 per 10,000 females aged between 4-15 years (Bienvenu et al., 2006). Braddock et al., (1993) and Clarke (1996) provide good clinical reviews.
Leonard et al., (1995) suggest that adolescent cases tend to have short metacarpals and metatarsals. Sekul et al., (1994) reported ECG abnormalities, including long QT intervals and T-wave abnormalities. They suggested that this could provide an explanation for unexpected death in Rett syndrome. Haas et al., (1997) provide data suggesting osteopenia might be a feature.
Ellaway et al., (2001) reported a mutation proven (see below) case with a congenital inter-arytenoid web, mild subglottic stenosis, a small larynx and laryngomalacia. She required a permanent trachoeostomy. Later on in the disease the patient becomes chair-bound with spasticity, joint contractures and a staring gaze. Falsaperla et al., (2012) reported a male with severe hypotonia, apneic episodes and respiratory failure.
The vast majority of cases are sporadic, but familial cases have been reported. Anvret and Wahlstrom (1992) reviewed the genetics of the condition - to that date there was one report of classical Rett syndrome in a 12-year-old girl and her more mildly affected maternal aunt (Anvret et al., 1990), 3 full sister pairs, 2 half-sister pairs, and cousins. Engerstrom and Forslund (1992) reported a convincingly affected mother and daughter. It is difficult to assess the reports of common ancestry (Pini et al., 1996). Schanen et al., (1997) reported a niece and her maternal aunt. The intervening mother showed skewed X-inactivation supporting X-linked inheritance. Schanen et al., (1998) reported two families (one being the same as that quoted above) in which besides the 2 affected girls, there were males with a neonatal encephalopathy. Both were severely affected, but would not have been thought to have Rett were it not for their sisters. Further evidence of abnormal X-inactivation in Rett syndrome was suggested by Krepischi et al., (1998) and Knudsen et al., (2006). Miyamoto et al., (1997) reported two apparently affected sisters. However one sister was much more mildly affected and could walk, had mild spasticity, no growth retardation, and no seizures. Schwartzman et al., (1999) reported a male case with an XXY karyotype. Schwartzman et al., (1999) and Leonard et al., (2001) reported male cases with an XXY karyotype. The father of 2 affected daughters reorted by Evans et al., (2006) was found to be mosaic for the MECP2 mutation.
Gillberg et al., (1985) studied 15 children with Rett syndrome by cytogenetic techniques and found that 40% of cases showed a fragile site at Xp22. Telvi et al., (1994) noted an increased frequency of chromosome breakage in girls with Rett syndrome. Migeon et al., (1995) found no evidence for uniparental disomy for the X chromosome, nor a correlation between non-random X-inactivation and the disease in three sets of MZ twins, two of which were concordant. They concluded that the gene for the condition might not be on the X chromosome. Zoghbi et al (1990) reported a case with a de novo X;3 translocation with breakpoints at Xp22 (later interpreted to be Xp21.3, Ellison et al., (1992).
Beekman et al., (1994) reported a case with medium-chain acyl-CoA dehydrogenase deficiency. Alembik et al., (1995) reported a girl with apparently classical features of Rett syndrome in a fragile X pedigree. She was shown to carry the full FMR1 mutation and to express fragile X chromosomes in 12% of her lymphocytes. The cases (14/15) reported by Tang et al., (1998), had mtDNA mutations not found in the control group. However these associations are likely to be spurious in view of the MECP2 mutations reviewed below.
Xiang et al., (1998), Webb et al., (1998) and Sirianni et al., (1998) provided linkage data suggesting Xq28 as a possible location for the gene. Amir et al., (1999) demonstrated mutations in the MECP2 gene which codes for a methyl-CpG-binding protein 2 (MECP2). This protein binds CpG dinucleotides and mediates transcriptional repression through interaction with histone deacetylase and the co-repressor SIN3A. Cheadle et al., (2000) reported further mutations in the MECP2 gene in Rett syndrome patients. In females with classical sporadic or familial Rett syndrome, they found mutations in 44 out 55 patients (80%). Obata et al., (2000) found mutations in 36 out of 40 (90%) patients with the Rett phenotype. Hampson et al., (2000) found mutations in 15 out of 40 patients. Vacca et al., (2001) studied 62 patients from Britain and Italy and found mutations in about 70%. Wan et al., (1999) explored genotype/phenotype correlations in patients with MECP2 mutations. They reported a woman with mild learning disability, and motor co-ordination problems who had a sister and a daughter with classical Rett syndrome and also had a son who died from congenital encephalopathy. This woman was found to have skewed X-inactivation. In the male case reported by Dayer et al., (2007), the normal mother was found to have the same mutation. Huppke et al., (2000) studied the MECP2 gene in 31 cases and found mutations in 24. Most mutations were truncating and only a few were missense mutations. There were four mutation hotspots (T158M, R168X, R255X and R270X). Several patients with the same mutation had varying phenotypes. Bienvenu et al., (2000) studied 46 patients and found mutations in 65%. Xiang et al., (2000) studied 9 familial cases and 59 sporadic cases and found mutations in the MECP2 gene in 27 sporadic cases (50%) but in none of the familial cases. Amir et al., (2000) found MECP2 mutations in 76% of sporadic cases and 29% of familial cases. Bourdon et al., (2001) found very similar figures. Amano et al., (2000) reported mutations in 19 out of 26 Japanese patients. Ravn et al., (2005) reported mutations in exon1 of MECP2.
Huppke et al., (2003) developed a 10-item checklist with a score ranging from 0 to 12. If only girls with a score of 8 or more were tested, 46% of a group of girls without mutations would have been excluded from testing without missing a single girl with a MECP2-positive result.
Orrico et al., (2000) reported an A140V mutation in a mildly affected female. Adult males in the same pedigree had severe mental retardation. Further details of this family were provided by Dotti et al., (2002). Neurological features included slowly progressive spastic paraparesis, distal atrophy of the legs, ataxia and postural tremor of the hands. Moog et al., (2003) reported a similarly affected 21-year-old male. Couvert et al., (2001) reported two males with the same nucleotide change with non-specific mental retardation. However Laccone et al., (2002) argue that this nucleotide change could be a polymorphism. Meloni et al., (2000) studied the pedigree first reported by Claes et al., (1997) where two affected males had severe mental retardation and progressive spasticity. A mutation in the MECP2 gene was demonstrated. The mutation caused a substitution of glutamine 406 with a stop codon. Two affected males, the brothers of a classically affected female were reported by Villard et al., (2000). They had severe hypotonia and developmental delay and died before the age of 1 year from apnoea. They both had unusual silvery-grey hair. Ravn et al., (2003) reported and eleven year old boy with classical Rett syndrome with a truncating mutation of the MECP2 gene and no evidence of mosaicism.
Leonard et al., (2003) suggested that the phenotype of a patient with an R133C mutation is milder overall with better ambulation and hand use and a greater likelihood of being able to use speech. Mutations in the nuclear localisation signal region (NLS) tend to be more severe (Colvin et al., 2004). Other mild cases are due to skewed X inactivation (Huppke et al., 2006).
Nielsen et al., (2001) detected MECP2 mutations in 26 out of 30 Danish Rett syndrome patients. There was no consistent correlation between the type of mutation and the clinical presentation. Girard et al., (2001) showed that in 5 cases out of 7 the mutation was paternal origin (71%). Further mutations were reported by Buyse et al., (2000). Bienvenu et al., (2001) reported frameshift mutations in 5 cases. Trappe et al., (2001) showed that sporadic mutations were almost exclusively paternal (26 out of 27 cases). Bourdon et al., (2001) found two cases with a mosaic MECP2 mutation out of 102 putative Rett cases. Dragich et al., (2000) provide a good review of the molecular story.
It is now apparent that some children with possible clinical features of Angelman syndrome can have mutations in the MECP2 (Rett) gene. Features that are atypical for Angelman syndrome are growth failure, small cold feet, subtle but repetitive hand movements, excess bruxism, tremors and absence of the typical EEG findings. Turner et al., (2003) studied 66 children referred with a diagnosis of Angelman syndrome and found mutations in the MECP2 gene in 6 (3 out of 38 girls and 2 out of 28 males). The males had relatively mild developmental delay with head circumference less than third centile. Imessaoudene et al., (2001) studied 78 patients diagnosed as possible Angelman syndrome, looking for mutations of the MECP2 (Rett) gene. Missense, nonsense, and frameshift mutations were identified in six patients including one isolated male case with non-fatal, non-progressive encephalopathy of neonatal onset who had a G1282A nucleotide change. However this change was also carried by his mother and two healthy sisters and Laccone et al., (2002) suggest this is a polymorphism. They reported a similar family where a boy with very severe encephalopathy and seizures carried the change, as did his healthy mother and paternal grandfather. Watson et al., (2001) reported five further cases with this phenotype, including a male with possible mosaicism for a MECP2 mutation (see also Clayton-Smith et al., 2000). Topcu et al., (2002) reported a further male case with mosaicism for a MECP2 mutation. Further males with possible MECP2 mutations were reported by Moncla et al., (2002). Yntema et al., (2002) performed MECP2 mutation analysis in 475 mentally retarded males who were negative for FRAXA investigation. Only one definite MECP2 mutation was found. Three other changes were found in normal males in the pedigree although not in a control population. Lynch et al., (2002) reported a a male infant with neonatal encephalopathy and a de novo MECP2 mutation is reported. The presenting phenotype of decelerating head growth, spasticity, scoliosis, and central respiratory disturbance. This picture was also found in 4 boys reported by Kankirawatana et al., (2006). A boy, with features of Rett syndrome, including severe retardation, stereotopy and regression was found by Meins et al., (2005) to have an Xq28 duplication. A male reported by Piersa et al., (2011), was a somatic mosaic for a Y120X mutation. The clinical picture was atypical, but he did have stereopathy, lack of purposeful hand movements and intense eye contact.
Couvert et al., (2001) studied 185 patients with mental retardation but negative for expansion across the FRAXA gene and found 4 mutations in the MECP2 gene. They suggested that the frequency of mutations in the MECP2 gene in the mental retarded population is comparable to the frequency of FRAXA mutations. However, see the comments by Laconne et al., (2002) on some of the 'mutations' reported by Couvert et al., (2001) in males which might be polymorphisms. Yntema et al., (2002) studied one member from 176 families segregating for X-linked mental retardation (13 mapped to the Xq28 region). One in-frame deletion in the MECP2 gene was found. Moog et al., (2006) confirm the rarity of mutations in males with MR and neurological features. Villard (2007), describes the wide clinical phenotype in males. The picture included central hypoxia, reduced neuronal dendritic processes and clinically an encephalopathy (Schule et al., 2008).
Mutations have also been found in the preserved speech variety (PSV) by Auranen et al., (2001). These same authors found mutations in 100% of their classical patients. Zappella et al., (2001) also reported mutations in the preserved speech variety of the condition. These tended to be missense or late truncating mutations in contrast to early truncating mutations seen in classical Rett syndrome. Lam et al., (2000) studied 21 patients with autism and mental retardation and found a MECP2 mutation in one of these. However detailed clinical information about this girl was not available. Carney et al., (2003) studied 69 females with autistic features and found convincing de novo Rett mutations in two. They had severe delay but not all the classical features of Rett syndrome. The patient reported by Oexle et al., (2005), was macrocephalic.
Orrico et al., (2001) reported a brother and sister with features of the condition. From the facial photographs the brother's appearance was less marked. There were seizures from the first two years of life. The halluces were short. The girl had ptosis. A MRI scan showed slight cortical cerebellar hypoplasia with enlargement pericerebellar ventricles but with a normal vermis. There were also episodes of over breathing, more severe in the girl than the boy.
Villlard et al., (2001) studied 5 families where 2 sisters had Rett syndrome. A mutation in the MECP2 gene was found in only one family. In the four families without a MECP2 mutation, totally skewed X inactivation was found in the mothers and 6 out of the 8 affected girls. The paternally inherited X chromosome was active in the affected girls. A possible locus on the short arm of the X chromosome, responsible for the skewed X inactivation, was identified by linkage analysis. Weaving et al., (2003) presented data suggesting that truncating mutations and mutations affecting the methyl-CpG-binding (MBD) domain tend to lead to a more severe phenotype. Skewed X-inactivation was found in a large proportion (43%) of patients, particularly in those with truncating mutations and mutations affecting the MBD. The authors conclude that it is likely that X-inactivation modulates the phenotype in RTT.
Gill et al., (2003) studied 11 families with more than one female with features of the condition. In one family, there were MECP2 mutations in the two affected sisters and their healthy mother. In five families, a MECP2 mutation was found in one affected female but not in the other, possibly affected female. In five families, no MECP2 mutation was found.
Amir and Zoghbi (2000) and Webb and Latif (2001) provide good reviews of the clinical and molecular features up to 2000 and Weaving et al (2005) up to 2005. A new isoform of MECP2 was reported by Mnatzakanian et al., (2004), with mutations, which may well account for some of the 20% of those girls without mutations. Three Rett patients (Longo et al., 2004) with MECP2 mutations, also had 15q11-q13 rearrangements (as seen in autism). Those females with C-terminus deletions might be recognisable, in that they develop severe scoliosis despite all peventative measures and have better preserved cognitive functions (they can recognize and learn about new persons and situations in their dayly life) in adolescence and adulthood (Smeets et al., 2005). At least 85% of individuals with Rett have exon 3 or 4 mutations, but exon 1 mutations are a rare cause (Amir et al., 2005, Chunshu et al., 2006). Clinicians beware! Germline mosaicism can cause couselling problems. Mari et al., (2005) decided to offer parents who had had a previous child with Rett, prenatal diagnosis, and in their first 9 cases found 1 positive.
Borg et al., (2005) report on a girl with Rett syndrome with a 1;7 translocation, by which the gene Netrin G1 on chromosome 1 was disrupted. They suggest this gene to be involved in the pathogenesis of Rett syndrome. Archer et al., (2006) looked at 110 patients with phenotypic Rett in whom no MECP2 mutations could be found. They performed a dosage analysis of MECP2 and large deletions were found in 14/37 with classic Rett and 4/53 with atypical Rett. They conclude that quantitative analysis should be included in the molecular diagnosis. The same conclusion was reached by Hardwick et al., (2007) who found 12/149 cases without point mutations to have large deletions and by Scala et al., (2007). Homozygosity for a MECP2in a girl with classical Rett was reported by Karall et al., (2007). There was mosaicsm.
Note that FOXG1 mutations not only lead to the severe phenotype (see Rett syndrome - 2nd locus), but can give rise to the classical phenotype (Philippe et al., 2010).
Additional genes to look for in Rett-like syndrmes are STXBP1, SCN8A and IQSEC2 (Olson et al., 2015).
Roene et al. (2016) described two unrelated families with males affected with atypical features of Rett syndrome and carrier mothers with cognitive abnormalities. The disorder was caused by C-terminal mutations in MECP2. Features observed in males included hypotonia, global developmental delay, seizures (myoclonic and atonic), and motor regression. Additional neurological abnormalities included intention and myoclonic tremor, choreiform movements, myoclonus, ataxia and spasticity. EEG showed multifocal spike slow-waves and bitemporal spike slow-waves. Brain MRI revealed enlarged frontal subarachnoid space, periventricular white matter changes and vermis atrophy. One male patient had macrocephaly, large prominent teeth, gingival hyperplasia, and lumbar lordosis. In addition, he was diagnosed with pancreatitis due to gallstones, recurrent pneumonia and bone fractures. Affected females showed learning disabilities, depression, gastrointestinal problems, fatty liver, and syncopal-like episodes.
* This information is courtesy of the L M D.
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