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R Newbury-Ecob

Publications and source records attributed to R Newbury-Ecob.

15 recordsLinked to original sources
PubMed2006

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.

Adolescent↗
PubMed2005

Inherited pericentric inversion (X)(p11.4q11.2) associated with delayed puberty and obesity in two brothers.

We report two brothers with hypogonadotropic hypogonadism (HH), obesity and short stature associated with a maternally inherited pericentric inversion (X)(p11.4q11.2). On the basis that either breakpoint might disrupt a gene whose function is critical to normal sexual development we mapped the chromosomal breakpoints using two-colour fluorescent in situ hybridisation (FISH). The position of both the Xp11.4 and Xq11.2 breakpoints was refined using a panel of ordered BAC clones. No known genes were shown to map to the breakpoint regions. While we cannot entirely exclude the possibility that association between the clinical and cytogenetic phenotypes in the family is coincidental, it is possible that the inversion is responsible for HH through alternative molecular mechanisms such as position effects.

Adolescent↗
PubMed2003

Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy.

We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of "thalidomide embryopathy" might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.

Abnormalities, Multiple↗
PubMed2001

3-Hydroxyisobutyric aciduria: phenotypic heterogeneity within a single family.

3-Hydroxyisobutyric aciduria is a rare biochemical finding associated with a variable clinical phenotype in the literature. We report two siblings excreting abnormal levels of this metabolite from a consanguineous family who manifested distinct phenotypic variation. We speculate as to whether this biochemical anomaly may simply be an incidental finding and suggest that pre-natal counselling on the basis of metabolite identification may be unwarranted.

Child↗
PubMed2001

The role of comparative genomic hybridisation in prenatal diagnosis.

The aims of this study were to assess the feasibility of using comparative genomic hybridisation instead of conventional cytogenetics in prenatal diagnosis and to determine the size of DNA loss that can be detected. Using comparative genomic hybridisation, six cases with standard aneuploidies were diagnosed correctly. This technique clearly identified a partial duplication of the long arm of chromosome 1 but was not capable of detecting the associated inversion. A small interstitial deletion on short arm of chromosome 10 also was detected precisely. Although the current comparative genomic hybridisation resolution is similar to the sensitivity of the highest resolution G banding, the latter is not a routine strategy in prenatal diagnosis. Comparative genomic hybridisation can allow full chromosome assessment equal to the highest resolution cytogenetic studies without the need for cell culture.

Cytogenetic Analysis↗
PubMed2001

Pancreatic dysfunction in severe obesity.

AIMS: To investigate pancreatic function in children attending an obesity clinic. METHODS: Thirty six children (of which 34 were white) with severe obesity of prepubertal onset (body mass index more than +2 SDS) were reviewed clinically and dysmorphologically, with assessment of pancreatic function. RESULTS: Eight had dysmorphic features and 13 had learning difficulties. Four of 17 prepubertal children had hyperinsulinaemia and seven had hyperproinsulinaemia. All 19 pubertal children had hyperinsulinaemia, 14 had hyperproinsulinaemia, and one had type II diabetes. CONCLUSIONS: Metabolic abnormalities predictive of type II diabetes occur in severely obese white children.

Adolescent↗
PubMed2000

Mesenteric angina complicating a mesodermal anomaly.

A child with macrocephaly-cutis marmorata developed severe abdominal pain thought to represent mesenteric angina. There were abnormalities of the aortic and mesenteric vasculature not previously reported in this condition. Angina therapy afforded amelioration of his symptoms. Mesenteric angina should be considered as a cause for abdominal pain in children with mesodermal anomalies.

Abdominal Pain↗
PubMed1999

Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.

EEC syndrome is an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts. We have mapped the genetic defect in several EEC syndrome families to a region of chromosome 3q27 previously implicated in the EEC-like disorder, limb mammary syndrome (LMS). Analysis of the p63 gene, a homolog of p53 located in the critical LMS/EEC interval, revealed heterozygous mutations in nine unrelated EEC families. Eight mutations result in amino acid substitutions that are predicted to abolish the DNA binding capacity of p63. The ninth is a frameshift mutation that affects the p63alpha, but not p63beta and p63gamma isotypes. Transactivation studies with these mutant p63 isotypes provide a molecular explanation for the dominant character of p63 mutations in EEC syndrome.

Abnormalities, Multiple↗
PubMed1998

Atelosteogenesis type 2.

Atelosteogenesis type 2 (AO2) (MIM 256050) is a neonatally lethal chondrodysplasia characterised by severe limb shortening and deficient ossification of parts of the skeleton. Other features include facial dysmorphism, cleft palate, talipes, and abducted thumbs and toes. Phenotypic overlap with non-lethal diastrophic dysplasia (DTD) suggested a common aetiology and it has recently been confirmed that both syndromes result from mutations in the DTDST (diastrophic dysplasia sulphate transporter) gene.

Abnormalities, Multiple↗
PubMed1996

A translocation at 12q2 refines the interval containing the Holt-Oram syndrome 1 gene.

A gene for Holt-Oram syndrome (HOS) has been previously mapped to chromosome 12q2 and designated HOS1. We have identified a HOS patient with a de novo chromosomal rearrangement involving 12q. Detailed cytogenetic analysis of this case reveals three breaks on 12q, and two of these are within the HOS1 interval. By using a combination of chromosome painting and FISH with YACs and cosmids, it has been possible to map these breakpoints within the critical HOS1 interval and thus provide a focus for HOS gene-identification efforts.

Arm↗
PubMed1994

Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q.

Holt-Oram syndrome (HOS) is an autosomal dominant condition affecting the heart and upper limbs. We have sought to identify the location of this gene using microsatellite DNA markers in a linkage study. Of seven families analysed, five show linkage between HOS and markers on chromosome 12q. But the two remaining families, phenotypically indistinguishable from the others, do not show this linkage. Analysis with the computer program HOMOG indicates that HOS is a heterogeneous disease. Our analysis places one HOS locus in a 21 cM interval in the distal region of chromosome 12q. The localization of a gene for HOS, reported here, represents an important step towards a better understanding of limb and cardiac development.

Abnormalities, Multiple↗