Rett syndrome in a boy with a 47,XXY karyotype confirmed by a rare mutation in the MECP2 gene

Rett syndrome (RTT) is an X-linked condition which affects almost exclusively females. Here we report the first case of RTT syndrome in a boy with an XXY chromosomal constitution. Mutation analysis of the MECP2 gene in the affected patient revealed a 423 C-->G substitution in exon 4, resulting in a new stop codon (Y141 X). This change was not present in both his parents or in his older sister. Taking into account the incidence of both RTT syndrome as well as of Klinefelter syndrome, the probability for the simultaneous occurrence of these two events is very low (about approximately 1 in 10 to 15,000,000 births). However, the recent identification of mutations in the MECP2 gene in affected males indicates that screening of the MECP2 gene should be considered also in males with severe mental retardation (MR) in whom the most common forms of MR have been excluded.     

MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother

Rett syndrome is a severe neurodevelopmental disorder affecting principally females and characterized by a normal postnatal development followed by stagnation and regression of acquired skills. We report a 4-year-old boy with a Rett syndrome phenotype and his unaffected mother both carrying a 44 bp truncating deletion mutation (c.1158del44 or p.388X) in the MECP2 gene. The presence of a skewed X inactivation in the mother provides a possible explanation for the absence of penetrance. The finding of a MECP2 mutation in an unaffected female complicates genetic counseling and further confirms that it is essential to look for mutations in the mothers of all patients with MECP2 mutations.     

MECP2 mutation screening in Swedish classical Rett syndrome females

Rett syndrome (RS) is a neurodevelopmental disorder almost exclusively affecting females. We have studied the mutation spectrum of the responsible gene MECP2, encoding methyl-CpG-binding protein 2 (MeCP2), in 16 sporadic classical RS females from Sweden. In 13 of 16 patients (81%) we detected nonsense or missense mutations in the coding parts of MECP2. This mutation rate is in agreement with other reports (65-80%). In all, 12 different mutations and one polymorphism were found; three of the mutations have not been reported previously. The missense mutations were restricted to highly conserved regions of the gene. None of the mutations was detected in parents; thus, they had probably arisen de novo. In contrast, two normal variants, one intron deletion and one silent mutation, were seen singly only in two patients' mothers; neither has been reported previously. One patient showed two different mutations closely located, i.e. 802C > T (R268W) together with 808C > T (R270X). Another patient had a mutation in the stop codon 1459T > C (X487R), leading to a gene product prolonged with 27 amino acids. In conclusion, our results indicate that the majority of Swedish RS patients (81%) have mutations in MECP2 that are sporadic cases with de novo mutations. Moreover, both missense and nonsense mutations occur, but in different parts of the gene, probably reflecting the function of the domains in MeCP2. This study has improved our ability to offer these families an early confirmation of Rett diagnoses.     

Another patient with MECP2 mutation without classic Rett syndrome phenotype

Rett syndrome and Angelman syndrome are two neurodevelopmental disorders characterized by partial overlapping features. Rett syndrome is frequently caused by a mutation in methyl-CpG-binding protein (MECP2) gene, localized on chromosome Xq28, whereas Angelman syndrome is frequently caused by different genetic anomalies at chromosome 15q11-q13 (deletions, uniparental disomy, imprinting center mutations, ubiquitin E3 ligase [UBE3A] gene mutations). Recently, some patients with a clinical diagnosis of Angelman syndrome were found to have a mutation in MECP2 gene. This report describes another patient with an Angelman-like phenotype and with an MECP2 mutation.     

MECP2 mutation in a boy with severe apnea and sick sinus syndrome

Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene, which encodes methyl-CpG-binding protein 2 (MECP2). It almost exclusively affects the female sex and is considered lethal in the male sex. However, an increasing number of male patients with MECP2 mutations have been reported, including patients who suddenly died of unknown causes. We report a case of MECP2 mutation in a male patient who exhibited neonatal encephalopathy. He developed severe apnea, epilepsy, and psychomotor developmental delay and died suddenly of sick sinus syndrome at 17?months of age. Severe bradycardia had been noticed since 16?months of age. His older brother followed a similar clinical course and died at 30?months of age. The brother had also experienced severe bradycardia. This familial case might help to clarify the causes of sudden death in cases of MECP2 mutations.     

Anti-MOG antibody encephalitis mimicking neurological deterioration in a case of Rett syndrome with MECP2 mutation

Background

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, resulting in developmental regression after normal development during infancy. Transient presentation of many autistic features is also commonly seen in RTT. Anti-myelin oligodendrocyte glycoprotein (MOG)-antibody encephalitis is an acquired relapsing demyelinating syndrome characterized by a variety of neuroinflammatory symptoms. Here, we report a case of anti-MOG antibody encephalitis in a patient with genetically confirmed RTT, which mimicked many of the features of RTT.

A Rett syndrome MECP2 mutation that causes mental retardation in men.

OBJECTIVE: To characterize the clinical features of a new type of X-linked mental retardation associated with MECP2 mutation in the index family. BACKGROUND: MECP2 mutations, originally described in a high percentage of patients with classic Rett syndrome, were considered lethal in men. The authors recently described a novel A140V MECP2 missense mutation in an Italian family with X-linked semidominant mental retardation. METHODS: The neurologic features of six symptomatic relatives (two women and four men) carrying the mutation were compiled. Laboratory investigations included EEG, EMG, conduction velocity (CV) of peripheral nerves, brain MRI, and (1)H-MR spectroscopy. RESULTS: Mental retardation and signs of neurologic impairment were present in all the affected members, but more pronounced in men. Neurologic features included slowly progressive spastic paraparesis/pyramidal signs (6/6), distal atrophy of the legs (6/6), ataxia (2/6), and postural tremor of the hands (3/6). Speech was preserved (6/6) but was dysarthric in the oldest brothers (2/6). Mild dysmorphic features were present in all cases. CONCLUSION: The neurologic disorder associated with A140V MECP2 mutation is not necessarily lethal in men, but they are more severely affected than women of the same family.     

Spectrum of MECP2 mutations in Rett syndrome

Mutations in the methyl-CpG-binding protein 2 gene (MECP2) are identified in the majority of females with Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder. We searched for mutations by sequencing the MECP2 coding region in 45 sporadic cases (35 with classic RTT, eight with variant forms and two males) and in seven families with two or more affected females. Following our previous report of mutations in two families and eight sporadic cases [1], we here present 18 additional mutations. We found 13 single nucleotide substitutions, all of which are C→T transitions at CpG hot spots. Frameshift mutations, leading to premature termination of translation, include two single guanine (G) nucleotide deletions from a stretch of contiguous Gs, a novel four nucleotide deletion, a novel 32 nucleotide deletion in the C-terminal domain and a novel complex duplication/deletion rearrangement in the same region. When X-chromosome inactivation patterns were compared in 16 MECP2 mutation-positive and 23 mutation-negative samples, no significant differences were observed. The mutational spectrum in our subject population is similar to studies from around the world. Of over 300 MECP2 mutations reported, two-thirds are truncating mutations and one-third are missense mutations, mostly in the methyl-binding domain. Nearly 70% of all identified mutations are C→T transitions at one of eight CpG hot spots, and about 10% are intragenic deletions or complex rearrangements that lead to frameshifts in the C-terminal region. The rate of mutation detection in the MECP2 coding region ranges from 70 to 85% in clinically diagnosed RTT and is much lower in diagnostic variants.     

Widened clinical spectrum of the Q128P MECP2 mutation in Rett syndrome

Case report We describe a female patient with Arnold Chiari type I malformation, atypical Rett syndrome characterized by postnatal onset microcephaly, stereotypic hand movements, ataxia, severe developmental delay, intractable tonic–clonic seizures, and a MECP2 mutation with a unique set of clinical findings. Implementation of a ketogenic diet resulted in decreased seizure activity and an improvement in the patients degree of social relatedness with her family members.Discussion An early diagnosis of Rett syndrome allows families to maximize utilization of existing treatment modalities and seek appropriate genetic counseling and prenatal diagnoses. This case also provides further evidence for the treatment benefit of ketogenic diets for seizures in patients with Rett syndrome.     

A FOXG1 mutation in a boy with congenital variant of Rett syndrome

Mutations in the FOXG1 gene have been shown to cause congenital variant of Rett syndrome. To date, point mutations have been reported only in female patients. We screened the entire coding region of the gene for mutations in 50 boys with congenital encephalopathy, postnatal microcephaly, and complex movement disorders, a clinical picture very similar to that described in girls with FOXG1 mutations. We found one boy carrying the de novo c.256_257dupC frameshift mutation. He presented the association of postnatal microcephaly, severe axial dystonia with severe feeding difficulties with protruding tongue movements during the first year of life that subsequently evolved into dyskinetic movement disorders with hand stereotypies. In contrast to his severe motor impairment, he developed nonverbal communication skills and relative good eye contact. Brain MRI showed frontal gyral simplification with dramatic myelination delay most prominent in both frontal lobes. Altogether the presentation in this male patient is highly reminiscent of that observed in FOXG1-mutated females with the congenital variant of Rett syndrome. This new case confirms the prediction that congenital variant of Rett syndrome should be found also in males, with the characteristic hallmarks consisting of postnatal microcephaly, dyskinetic movement disorder with Rett-like features, i.e., hand stereotypies, and frontal gyral simplification with myelination delay. FOXG1 screening should be considered in individuals with these clinical features.     

Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation

The authors report the unusual clinical and neurophysiologic features of a sporadic case of a boy carrying an 806delG mutation on the MECP2 gene. A 28-month-old boy was examined for severe developmental delay, seizures, microcephaly, breathing dysfunction, and spontaneous and evoked myoclonic jerks of upper limbs. Neurophysiologic study proved the cortical origin of myoclonus; however, it was not associated with signs of cortical hyperexcitability. 3-Methoxy-4-hydroxy-phenylethylene glycol and valine concentrations were low in CSF.     

R133C and R168X mutations in Japanese Rett syndrome patients: a caution for misdiagnosis

Rett syndrome is a neurodevelopmental disorder characterized by regression of motor and mental abilities in females after a period of normal development. The gene, MECP2, has been reported to be responsible for Rett syndrome. Here, we report the cases who were at first misdiagnosed as having homozygous mutations, and later corrected as heterozygous ones. We analyzed the MECP2 gene in three sporadic Japanese patients with Rett syndrome. Direct sequencing by using a primer set that was originally used in the first report of MECP2 mutation suggested two types of homozygous mutations (R133C and R168X). Previous reports of these mutations with heterozygous status, as well as the general nature of dominant inheritance in Rett syndrome females and lethality in hemizygous males, urged us to confirm the homozygosity of these mutations. By using a newly designed PCR primer, we found that these mutations actually occurred heterozygously in these patients. Sequence analyses of PCR products suggested that a C/T polymorphism found upstream of these mutations caused the preferential PCR amplification of the mutated alleles. These results recommend paying attention to biased PCR amplification that may lead to misjudgment of the result for mutational analysis of the MECP2 gene.     

Movement disorders in Rett syndrome: An analysis of 60 patients with detected MECP2 mutation and correlation with mutation type

Rett syndrome (RS) is one of the best human models to study movement disorders. Patients evolve from a hyperkinetic to a hypokinetic state, and a large series of abnormal movements may be observed along their lives such as stereotypies, tremor, chorea, myoclonus, ataxia, dystonia, and rigidity. The aim of this work was to analyze movement disorders in RS patients with a detected MECP2 mutation, as well as their correlation with genotype, in a clinically and genetically well‐characterized sample of patients, and thus contribute to redefine the clinical profile of this disease. In this study, we included 60 patients with detected MECP2 mutations. These were categorized and grouped for analysis, according to (1) type of change (missense or truncating, including nonsense and frameshift but also large deletions) and (2) location of the mutation. Differences were found concerning the frequency of independent gait, dystonia, type of tremor, and global score severity when comparing the group of patients with missense and truncating mutations. We also found differences in the presence, distribution, severity, or type of movement disorders in the two groups of patients according to the median duration of the disease (less than 60 months; 60 months or more). We conclude that movement disorders seem to reflect the severity and rate of progression of Rett disorder, patients with truncating mutations presenting a higher rate and more severe dystonia and rigid‐akinetic syndrome, when comparing groups with similar time of disease evolution. © 2008 Movement Disorder Society     

MECP2 and beyond: phenotype-genotype correlations in Rett syndrome

The association of Rett syndrome with pathogenic mutations of the methyl-CpG binding protein 2 (MECP2) gene was first made in 1999. Since that time, it has been found that the clinical phenotype can, at least in part, be explained in terms of the type and location of the MECP2 mutation and epigenetic factors such as skewing of X-chromosome inactivation. In addition, MECP2 mutations may be associated with non-Rett syndrome clinical phenotypes, including nonsyndromic and syndromic X-linked mental retardation and Angelman-like phenotypes. Intense research efforts are currently focused on understanding the pathogenesis of Rett syndrome, using sophisticated techniques such as microarray analysis, and the development of mouse models, with an ultimate aim being the development of targeted therapies that could ameliorate or even prevent the devastating consequences of this enigmatic neurodevelopmental disorder.