Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

beta S haplotypes, alpha-globin gene status, and hematological data of sickle cell disease patients in Guadeloupe (F.W.I.).

The beta gene cluster haplotypes, alpha gene status, Hb F level and hematological parameters have been characterized in 154 unrelated Guadeloupe patients with sickle cell disease: 112 with sickle cell anemia, 26 with SC disease, 15 with Hb S-beta-thalassemia, and one patient with Hb S in association with the hereditary persistence of fetal hemoglobin. Fourteen haplotypes in 16 combinations were found, the three major African haplotypes were present on 92% of all chromosomes: 73% Benin, 11% Bantu, 8% Senegal. Among SS patients, 57% were Benin homozygotes, one patient was a Senegal homozygote, one patient was a Bantu homozygote, and all the others were heterozygous. The A gamma T chain was observed on seven chromosomes and about 5% of the analyzed beta S chromosomes exhibited atypical haplotypes. The common haplotype beta C was found in all patients with SC disease. An interesting feature was the high frequency (44%) of deletional alpha-thalassemia among SS patients. Two patients have an alpha-gene globin triplication. The DNA haplotypes and alpha-gene status have been correlated with hematological parameters in these patients. The anthropological aspect of these data is interesting as the haplotypes of the beta-globin gene throw light on the slave trade from the various parts of Africa to the Caribbean Islands in particular, and North America in general.

Haplotype of ás chromosomes, A gene status, haematological data from patients with sickle-cell disease in Guadeloupe, F.W.I. - abstract

The á gene cluster haplotypes and O gene status, Hb F and æ chain composition have been characterized in 154 unrelated patients with sickle-cell disease: 112 with sickle-cell anaemia (SS), 26 with SC disease: 112 with sickle-cell anaemia patient SHPFH. Fourteen haplotypes in 16 combinations were found, and three major African haplotypes were present on 92 percent of all chromosomes: 73 percent Benin, 11 percent Bantu (CAR), 8 percent Senegal. Among SS patinets, 57 percent were Benin homozygotes, one patient was Senegal homozygote, one patient was Bantu homozygote, while all the others were heterozygote. The AçT chain was observed on 7 chromosomes and about 5 percent of the analyzed ás chromosomes exhibited a typical haplotypes. The common haplotype ác was found in all patients with SC disease. An interesting feature was the high frequency of deletional O-thalassaemia: 50 percent. Two patients had the O gene globin triplication. The DNA haplotypes have been correlated with HbF and Gç levels in these patients. The anthropological aspect of this data is interesting as the haplotypes of the á globin gene throw light on the slave trade from the various parts of Africa to the Caribbean islands in particular, and North America (AU)

[Natural history of sickle cell anemia]. / Histoire naturelle de la drépanocytose.

Sickle-cell anaemia is characterized by three categories of clinical signs: anaemia, vaso-occlusive phenomena and infective complications, which are described here according to age. The natural history of the disease can be divided into four periods: the neonatal period which is asymptomatic but important to organize an effective protection; the first 5 years of life are characterized by a high risk of mortality, a high level of morbidity due to severe infections, episodes of acute anaemia and painful crises typical of that age-group; the life of older children and adolescents is dotted with painful crises; it is in this period that degenerative tissue pathology begins; in adulthood, the acute episodes are less frequent, but multiple complications develop. Some of them (cerebral vascular accidents or lung diseases) may be fatal, while others are the source of chronic and disabling lesions, notably ocular, orthopaedic and renal lesions, which affect the functional prognosis. Pregnancy remains a high risk. There is, therefore, a striking contrast between the basic physiopathological mechanism (polymerization of haemoglobin S) and the various clinical manifestations which depend on the type of haemoglobin, on the social and sanitary conditions in each country and on other reasons which remain to be elucidated.

Post-perinatal infant mortality and cot deaths in Guadeloupe, FWI - abstract

A retrospective study of cot death was carried out in Guadeloupe, FWI over the two-year period 1989 - 1990 by analysis of data from post-perinatal infant mortality (PPIM). Information was obtained from death certificates, hospital records and telephone calls to general practitioners. The PPIM. rate 5.2 percent per 1,000 live births (LB) forms an important part of infant mortality. The 82 deaths (PPIM) were divided into four main categories: perinatal disease (42 percent), congenital disorders (18 percent), acquired disease or accidents (17 percent), cot death or unknown cause of death at home (22 percent). Cot deaths were subdivided into known causes, possible causes and unexplained death with or without necropsy. Of the 12 cot deaths no necropsy was obtained but a satisfactory explanation was found in half of the cases. This study showed a low sudden death rate between 0.8 and 1.2/1,000 LB. One-half of deaths occurred in babies who remained in hospital from birth. A quarter of deaths (among acquired diseases and cot deaths) could have been avoided if these babies had received adequate management (AU)

Haploptyes of ás chromosomes and O gene status among patients with sickle-cell disease in Guadeloupe - abstract

A sample of 42 unrelated sickle cell (SS) patients were randomly selected from regular attenders at the paediatric services of the Pointe-a-Pitre Hospital. á gene cluster and O gene haplotypes were determined by Southern blotting. Twelve á haplotypes in 12 combinations were found for the 84 ás chromosomes studied. The most common were Benin (63 per cent), Bantu (12 per cent) and Senegal (11 per cent) types which accounted for 87 per cent of all chromosomes. About 13 per cent of the ás chromosomes analysed had atypical haplotypes. Much the same diversity was observed for the ás gene in Jamaicans and Black patients in the USA. An interesting feature was the high (46 per cent) gene frequency of deletional O thalassemia. One patient had the O gene globin triplication. The frequency of (-O) was 0.24, and there is no evidence that this frequency differs from one á-haplotype to another. No clear correlations could be made between the haemoglobin level, haematological parameters and á haplotype status in this study because of the large number of variables and small sample size. From the anthropological aspect, haplotyping may shed light on the slave trade from various parts of Africa to the Caribbean (AU)

[Accidents caused by poisons in children in Guadeloupe. A 3-1/2 year study in Pointe-à-Pitre CHRU]. / Accidents par toxiques chez l'enfant en Guadeloupe. Etude sur 3 ans et demi au CHRU de Pointe-à-Pitre.

We report the results of a study on poisoning by ingestion of toxic products in children performed in the Pointe-à-Pitre hospital from January 1986 to June 1989. We found a high frequency of domestic poisoning, a balanced sex ratio, a prevalence among the 1-5 years old children and a high annual cost of hospitalization. This underlines the need for intensified preventive measures.