Germline mosaicism for a MECP2 mutation in a man with two Rett daughters.

Rett syndrome is a severe neurodevelopmental disorder that is caused by mutations in the X-linked gene, methyl-CpG binding protein 2 (MECP2). The majority of cases are sporadic, but rarely germline mosaicism can lead to familial cases. Here, we report the first case where germline mosaicism for a MECP2 mutation has been shown in a man. He has two affected daughters who are half sisters, and both have the c.808delC mutation. We show that this mutation is present at a low level in DNA extracted from the patient's semen. This case has implications for genetic counseling, and pre-natal testing should be offered for the partners of men who have a daughter with Rett syndrome.

CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients.

OBJECTIVE: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. METHODS: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. RESULTS: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. CONCLUSIONS: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.

People with MECP2 mutation-positive Rett disorder who converse.

BACKGROUND: People with useful speech after regression constitute a distinct group of those with mutation-positive Rett disorder, 6% (20/331) reported among mutation-positive people in the British Survey. We aimed to determine the physical, mental and genetic characteristics of this group and to gain insight into their experience of Rett syndrome. METHODS: Clinical and molecular data for people with Rett, aged 10 or more years at follow-up (the study group, n = 13), with the ability to converse and a MECP2 mutation are presented. They were compared with an age-matched control group (n = 110), who could not converse and had a pathogenic MECP2 mutation. RESULTS: The study group differed significantly from the control group with regard to their disease severity (P < 0.001); feeding difficulty scores (P < 0.001); health scores (P < 0.001); epilepsy (P < 0.001); head circumference (P < 0.004); age at onset of the regression period (P < 0.001) (six in the study group did not regress) and mutation frequency (C-terminal deletions P = 0.014, R133C P < 0.006). The results indicate that favourable skewing of X-inactivation is only present in a small proportion of mild cases. Speech was fragmented with a soft, breathless quality, and all but two had obviously irregular breathing. One person with an R168X mutation preferred signing to speech. All enjoyed interpersonal contact, showing affection and preferring people to objects, clearly distinguishing the condition from autism. Most were habitually anxious. Music was a source of pleasure and relaxation also providing a valuable educational asset. Even in these most able cases, understanding was severely restricted in most and little initiative was shown. CONCLUSIONS: While the Rett profile is present in these people they are commonly not classic, and the presence of speech, good head growth and lack of regression may lead to missed diagnoses. A strong association was demonstrated between this milder form of the disease and R133C and C-terminal deletions.

Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Distinct phenotype associated with a cryptic subtelomeric deletion of 19p13.3-pter.

Telomeres are gene rich regions with a high recombination rate. Cryptic subtelomeric rearrangements are estimated to account for 5% of mental retardation/malformation syndromes. Here we present the first patient with a deletion of 19p13.3, identified by subtelomeric FISH analysis. His features included a distinctive facial appearance, cleft palate, hearing impairment, congenital heart malformation, keloid scarring, immune dysregulation, and mild learning difficulties. Subtelomeric FISH analysis identified a deletion of 19p13.3-pter. The deletion size was determined to be 1.2 Mb by FISH analysis. It extended from within the chromosomal region covered by BAC RP11-50C6 to 19pter. The deleted area encompassed approximately 60 genes. Fifteen possible candidate genes were considered with respect to the phenotype, including follistatin-related precursor 3 (FSTL3) and serine-threonine kinase 11 (STK-11).