Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth.

OBJECTIVE: Barth Syndrome (BTHS) is an X-linked multisystem disorder (OMIM 302060) usually diagnosed in infancy and characterized by cardiac problems [dilated cardiomyopathy (DCM) ± endocardial fibroelastosis (EFE) ± left ventricular non-compaction (LVNC)], proximal myopathy, feeding problems, growth retardation, neutropenia, organic aciduria and variable respiratory chain abnormalities. We wished to determine whether BTHS had a significant impact on fetal and perinatal health in a large cohort of family groups originating from a defined region. METHOD: Case note review on 19 families originating from the UK and known to the Barth Syndrome Service of the Bristol Royal Hospital for Children. RESULTS: Details are presented on six kindreds (32%) with genetically and biochemically proven BTHS that demonstrate a wider phenotype including male fetal loss, stillbirth and severe neonatal illness or death. In these families, 9 males were stillborn and 14 died as neonates or infants but there were no losses of females. BTHS was definitively proven in five males with fetal onset of DCM ± hydrops/EFE/LVNC. CONCLUSION: These findings stress the importance of considering BTHS in the differential diagnosis of unexplained male hydrops, DCM, EFE, LVNC or pregnancy loss, as well as in neonates with hypoglycemia, lactic acidosis and idiopathic mitochondrial disease.

The personal experience of juvenile Huntington's disease: an interpretative phenomenological analysis of parents' accounts of the primary features of a rare genetic condition.

There has been a paucity of research into the psychosocial impact of juvenile Huntington's disease (JHD) on the child and the family. The study reported here is part of larger project that aimed to address this and investigate the social and health care needs of those affected by JHD. Ten semistructured interviews with the main caregiver(s) were carried out and were analyzed using the qualitative methodology interpretative phenomenological analysis. The main themes arising from the analysis are reported here: first becoming aware something is wrong; physical symptoms; speech and communication difficulties; behavioral problems; a slow but relentless process. These are discussed in relation to extant literature. We hope the article will be helpful to clinicians working with families where a child is affected by JHD and also contribute to the general literature on understanding symptoms in childhood illness.

Familial visceral neuropathy: a defined entity?

Familial visceral neuropathy (FVN) is a heterogeneous group of disorders due to abnormalities of the myenteric plexus. FVN with neuronal intranuclear inclusions is one particular form of FVN with a variable phenotype that includes achalasia, gastro-esophageal reflux, intestinal dysmotility and pseudo-obstruction, dysarthria, peripheral neuropathy and pupillary defects, and the presence of intranuclear inclusions within the neurons of the enteric nervous system. We present a four-generation family in which 10 individuals (7 of whom have been examined) are affected with FVN. The family was previously reported as familial esophageal achalasia, an autosomal recessive condition (MIM200400). At that time, several individuals in a single sibship were affected and there were no manifestations in either parent. Since that report, two individuals have had affected children and the mother has developed symptoms and has abnormalities on electromyography, thus enabling us to reclassify the family. This family provides further evidence of autosomal dominant inheritance, with marked variation in expression.

The neurogenetics of mucolipidosis type IV.

BACKGROUND: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. OBJECTIVE: To comprehensively characterize the clinical and genetic abnormalities of MLIV. METHODS: Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. RESULTS: All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. CONCLUSIONS: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS).

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS) is in progress. The study design, accrual to date, and related research projects are described. Revised accrual rates and expected recruitment are given. 15 cancers have been detected to date, from a total of 1236 screening measurements. This event rate and the tumour grades reported are compared with recent reports from other studies in women at high risk of breast cancer.

An epidemiological study of Wolf-Hirschhorn syndrome: life expectancy and cause of mortality.

OBJECTIVE: Early research into Wolf-Hirschhorn syndrome (WHS) described a high mortality and no relationship between deletion size and phenotype. This may need to be revised in the light of improved cytogenetic resolution and medical care. We have collected epidemiological data to allow the calculation of birth incidence and mortality figures. In addition, we have investigated the possibility of a relationship between deletion size and mortality. METHOD: Information relating to past and present cases diagnosed in the UK was collected by multiple ascertainment. RESULTS: A total of 159 cases were collected. The status (alive or dead) was determined for 146, of whom 96 are alive, 37 had died, and 13 were detected on prenatal diagnostic tests. A minimum birth incidence of 1 in 95 896 was calculated. The crude infant mortality rate was 17% (23/132) and in the first two years of life the mortality rate was 21% (28/132). Cases with large de novo deletions (proximal to and including p15.2) were more likely to have died than those with smaller deletions (odds ratio=5.7, 95% CI=1.7-19.9) after adjusting for age. A comparison of survival curves for de novo deletions and translocations did not show a statistically significant difference (p=0.11). The median survival time for de novo deletions was 34+ years while for translocation cases it was 18+ years. CONCLUSIONS: The mortality rate is lower than previously reported. There is a statistically significant relationship between deletion size and overall risk of death in de novo deletion cases. The difference in survival curves between de novo deletions and translocations is not statistically significant.

Clinical studies on submicroscopic subtelomeric rearrangements: a checklist.

BACKGROUND: Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions. METHODS: We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities. RESULTS: Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50% v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the "chromosomal phenotype", the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects. CONCLUSIONS: Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.

Schinzel-Giedion syndrome: evidence for a neurodegenerative process.

We report on a case of Schinzel-Giedion syndrome in which serial magnetic resonance (MR) brain-imaging studies demonstrated a progressive neurodegenerative process. These findings in addition to "coarse" facial appearance and skeletal abnormality suggest that a progressive metabolic defect underlies this syndrome. However, results of detailed investigations for metabolic disorder were all normal.

No change in striatal glutamate in Huntington's disease measured by proton magnetic resonance spectroscopy.

The combined caudate head and anterior putamen of six patients with Huntington's disease (HD) was studied by quantitative magnetic resonance spectroscopy (MRS) and the spectra compared with those from a group of six age-matched normal subjects. The concentrations of the three major metabolites, choline, creatine and N-acetylaspartate (NAA), were quantified using tissue water as an internal concentration reference. Glutamate concentration was assessed as the (glutamate+glutamine)/creatine peak area ratio (Glx/Cre). In normal subjects the mean (+/-SD) concentrations of the three metabolites were 1.8+/-0.4mumol/g wet weight for choline, 11.9+/-1.4 for creatine and 14.1+/-2.4 for NAA. The ratio Glx/Cre was 1.3+/-0.3. The concentrations of both creatine and NAA were significantly lower in the striatum of patients with HD, 8.9+/-1.5 and 12.1+/-1.5 respectively. There was, however, no difference in choline concentration or in the Glx/Cre ratio, 1.7+/-0.4 and 1.6+/-0.5 respectively. The results are discussed in relation to the mechanism of neuronal loss in HD.

ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.

A distinct syndrome of familial cleft lip and palate with prominent eyes and characteristic facies in two unrelated families.

A variable degree of facial and oral clefting segregating with the characteristic facies, wide set prominent eyes, a broad nasal tip, and protruding external ears is described in several individuals spread over four generations in a British family and over two generations in a Spanish family. None of the affected individuals have any other developmental anomaly. The occurrence of oral and facial clefting associated with prominent eyes and characteristic facies probably indicates the existence of a distinct autosomal dominant syndrome.

Evidence for possible Mendelian inheritance of septo-optic dysplasia.

We describe two siblings from a highly consanguineous pedigree with absent mid-line brain structures and hypopituitarism. This raises the possibility of a heritable basis for at least some forms of the septo-optic dysplasia sequence.

Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome.

Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.

Detecting deletions in the critical region for lissencephaly on 17p13.3 using fluorescent in situ hybridisation and a PCR assay identifying a dinucleotide repeat polymorphism.

During a study of lissencephaly in England and Wales, 23 children were identified with this diagnosis. They were classified as follows: three children had Miller-Dieker syndrome (MDS), 13 had isolated lissencephaly sequence (ILS), two had type II lissencephaly, and five children were reclassified as focal or diffuse cortical dysplasia. Microdeletions of chromosome 17p13.3, also known as the Miller-Dieker critical region, have been associated with both MDS and ILS. We used the commercially available Oncor probe for fluorescent in situ hybridisation (FISH) studies on 14 patients and a further four were studied elsewhere. Deletions were identified in all three MDS patients and two of the ILS patients. These results are consistent with previously reported data. No deletions were found in those patients with focal or diffuse cortical dysplasia. In addition, a CA repeat polymorphism which maps to the Miller-Dieker critical region was studied in 12 families and was informative in nine; the results were consistent with the FISH data. We conclude that FISH is a reliable method to detect deletions in patients with MDS and ILS and also useful to identify chromosome rearrangements in their parents which are not detected by conventional cytogenetic analysis. The PCR assay, if informative, is also reliable and a useful alternative if only DNA is available. None of the five children with atypical radiological features had a deletion. We therefore suggest that as well as looking for other aetiologies a careful review of the diagnosis should be made of the MDS or ILS cases in whom a deletion is not found.

Mitochondrial mutation commonly associated with Leber's hereditary optic neuropathy observed in a patient with Wolfram syndrome (DIDMOAD).

DIDMOAD is usually considered an autosomal recessive condition, with wide phenotypic variation, but the possibility of mitochondrial mutations occurring in this condition has been considered. A 19 year old man presented with long standing diabetes mellitus, optic atrophy, and grand mal seizures. Further investigations showed unilateral sensorineural hearing loss and the most common mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy, which was inherited from his mother. This suggests the DIDMOAD phenotype is a mitochondrial disorder in some cases and is likely to have a heterogeneous aetiology.

Liver histology in the arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC) syndrome: report of three new cases and review.

We report three cases from two unrelated families of infants with arthrogryposis multiplex congenita, cholestatic jaundice, and renal Fanconi's syndrome. In both families the parents were consanguineous. All three children died by 7 months of age. This association was first reported in 1973 by Lutz-Richner and Landolt and again in another family by Nezelof et al in 1979. However, because of differing liver histology the two sibships were considered to have two separate conditions. Based on the histological findings in one of our cases we propose that all cases described so far represent variation within a single syndrome.