Biomedical subjects

Jeanne Amiel

Publications and source records attributed to Jeanne Amiel.

25 records · Page 2Linked to original sources

PubMed2003

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.

Alanine↗

PubMed2003

Exclusion of RNX as a major gene in congenital central hypoventilation syndrome (CCHS, Ondine's curse).

Congenital central hypoventilation syndrome (CCHS) is a rare condition for which segregation analyses have suggested genetic factors. The respiratory phenotype of Rnx knock-out mice together with the Rnx expression at the brainstem level prompted us to consider the RNX gene as a candidate for CCHS in human. The screening of the RNX gene in a series of 25 patients with CCHS did not reveal any significant nucleotide variation. We therefore conclude that RNX is not a major gene for CCHS in human.

DNA↗

PubMed2003

Antenatal manifestations of mitochondrial respiratory chain deficiency.

OBJECTIVE: To review the antenatal manifestations of disorders of oxidative phosphorylation. STUDY DESIGN: A total of 300 cases of proven respiratory chain enzyme deficiency were retrospectively reviewed for fetal development, based on course and duration of pregnancy, antenatal ultrasonography and birth weight, length, and head circumference. Particular attention was given to fetal movements, oligo/hydramnios, fetal cardiac rhythm, fetal heart ultrasound, and ultrasonography/echo Doppler signs of brain, facial, trunk, limb, and organ anomalies. RESULTS: Retrospective analyses detected low birth weight (<3rd percentile for gestational age) in 22.7% of cases (68/300, P<.000001). Intrauterine growth retardation was either isolated (48/300, 16%) or associated with otherwise unexplained anomalies (20/300, 6.7%, P<.0001). Antenatal anomalies were usually multiple and involved several organs sharing no common function or embryologic origin. They included polyhydramnios (6/20), oligoamnios (2/20), arthrogryposis (1/20), decreased fetal movements (1/20), ventricular septal defects (2/20), hypertrophic cardiomyopathy (4/20), cardiac rhythm anomalies (4/20), hydronephrosis (3/20), vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula/atresia, renal agenesis and dysplasia, and limb defects (VACTERL) association (2/20), and a complex gastrointestinal malformation (1/20). CONCLUSIONS: Although a number of metabolic diseases undergo a symptom-free period, respiratory chain deficiency may have an early antenatal expression, presumably related to the time course of the disease gene expression in the embryofetal period. The mechanism triggering malformations is unknown and may include decreased ATP formation and/or an alteration of apoptotic events controlled by the mitochondria.

Birth Weight↗

PubMed2002

Facial appearance in persistent hyperinsulinemic hypoglycemia.

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.

ATP-Binding Cassette Transporters↗

PubMed2002

Segregation at three loci explains familial and population risk in Hirschsprung disease.

Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.

Alleles↗

PubMed2002

Expression of the SMADIP1 gene during early human development.

The smad binding protein 1 gene (SMADIP1, MIM 605802) has been recently identified as a disease causing gene in a polytopic embryonic defect (MIM 235730) including midline anomalies, facial dysmorphic features and enteric nervous system malformation (Hirschsprung disease). To confirm the pleiotropic role of SMADIP1 during embryogenesis and investigate its role in neural crest cell derivatives differentiation, we performed RNA in situ hybridization at early stages of human development. According to the spectrum of malformations observed in patients, expression of SMADIP1 is observed in neural crest derived cells (peripheric nervous system, enteric nervous system, facial neurectoderm and cranial nerve ganglia), central nervous system, genital tubercle, muscles and kidneys. Surprisingly, SMADIP1 expression is also found in limbs and developing eye. Although congenital heart defects are frequently observed in patients with either a SMADIP1 large scale deletion or truncating mutation, no SMADIP1 expression could be detected in the developing heart at the stages studied.

Gene Expression↗

PubMed2002

Overgrowth and trisomy 15q26.1-qter including the IGF1 receptor gene: report of two families and review of the literature.

Overgrowth is rarely associated with chromosomal imbalances. Here we report on four children from two unrelated families presenting with overgrowth and a terminal duplication of the long arm of chromosome 15 diagnosed using cytogenetic and FISH studies. In both cases, chromosome analysis of the parents showed a balanced translocation involving 15q26.1-qter. Molecular and cytogenetic studies showed three copies of the insulin-like growth factor 1 receptor (IGF1R) gene. This finding suggests that overgrowth observed in our patients might be causally related to a dosage effect of the IGF1R gene, in contrast to severe growth retardation observed in patients with terminal deletion of 15q. The present observation emphasises the importance of chromosome analysis in patients with overgrowth and mental retardation. Moreover, it further delineates a specific phenotype related to trisomy 15q26.1-qter with macrosomia at birth, overgrowth, macrocephaly and mild developmental delay being the major clinical features.

Abnormalities, Multiple↗