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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 109 records · Page 6Linked to original sources
PubMed2001

A novel automated strategy for screening cryptic telomeric rearrangements in children with idiopathic mental retardation.

Cryptic unbalanced subtelomeric rearrangements are known to cause a significant proportion of idiopathic mental retardation in childhood. Because of the limited sensitivity of routine analyses, the cytogenetic detection of such rearrangements requires molecular techniques, namely FISH and comparative genomic hybridisation (CGH). An alternative approach consists in using genetic markers to detect segmental aneusomy. Here, we describe a new strategy based upon automated fluorescent genotyping to search for non mendelian segregation of telomeric microsatellites. A total of 29 individuals belonging to 24 unrelated families were screened and three abnormal patterns of segregation were detected (two rearrangements and one parental disomy). This study gives strong support to the view that cryptic telomeric rearrangements significantly contribute to idiopathic mental retardation and demonstrates that fluorescent genotyping is a very sensitive and cost-effective method to detect deletions, duplications and uniparental disomies.

Child↗
PubMed2001

TP63 gene mutation in ADULT syndrome.

TP63 gene mutations have recently been shown to be disease causing in EEC and SHFM. Two other overlapping syndromes with ectrodactyly as a major feature, have been mapped to chromosome 3q27 close by the TP63 locus, namely the LMS and ADULT syndromes. Here, we report on a missense TP63 gene mutation in an isolated ADULT syndrome case. This finding widens the spectrum of abnormalities to be ascribed to TP63 gene in human and emphasise on the variable roles of the different Tp63 isotypes.

Abnormalities, Multiple↗
PubMed2001

Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. So far, six LCA loci have been mapped but only 4 out of 6 genes have been identified. A genome-wide screen for homozygosity was conducted in seven consanguineous families unlinked to any of the six LCA loci. Evidence for homozygosity was found in two of these seven families at the 14q11 chromosomal region. Two retinal specific candidate genes were known to map to this region, namely the neural retina leucine zipper (NRL) and the retinitis pigmentosa GTPase regulator interacting protein (RPGRIP1). No mutation of the NRL gene was found in any of the two families. Thus, we determined the complete exon-intron structure of the RPGRIP1 gene. RPGRIP1 encompasses 24 coding exons, nine of which are first described here with their corresponding exon-intron boundaries. The screening of the gene in the two families consistent with linkage to chromosome 14q11 allowed the identification of a homozygous null mutation and a homozygous missense mutation, respectively. Further screening of LCA patients unlinked to any of the four already identified LCA genes (n=86) identified seven additional mutations in six of them. In total, eight distinct mutations (5 out of 8 truncating) in 8/93 patients were found. So far this gene accounts for eight out of 142 LCA cases in our series (5.6%).

Amino Acid Sequence↗
PubMed2001

Respiratory chain deficiency in Alpers syndrome.

Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on respiratory chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to respiratory chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the respiratory chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for respiratory chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.

Atrophy↗
PubMed2001

Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome.

OBJECTIVE: The objective was to determine the circadian rhythm of melatonin in the Smith-Magenis syndrome (SMS), which causes behavioral problems and sleep disturbance. STUDY DESIGN: Questionnaires, sleep consultations, and sleep diaries were obtained in 20 children with SMS (9 girls, 11 boys aged 4 to 17 years). Actigraphy, electroencephalography, and the circadian variations of plasma melatonin, cortisol, and growth hormone were recorded in 8 patients. Early sleep onset, early sleep offset, and sleep attack indicated sleep disturbance. RESULTS: All children with SMS had a phase shift of their circadian rhythm of melatonin. Time at onset of melatonin secretion was 6 AM +/- 2 (control group: 9 P.M. +/- 2). Peak time was 12 PM +/- 1 (control group: 3:30 AM +/- 1:30), and melatonin offset was at 8 PM +/- 1 (control group: 6 AM +/- 1). Behavioral problems correlated with the inverted circadian rhythm of melatonin. CONCLUSION: Considering that clock genes mediate the generation of circadian rhythms, we suggest that haploinsufficiency for a circadian system gene mapping to chromosome 17p11.2 may cause the inversion of the circadian rhythm of melatonin in SMS.

Abnormalities, Multiple↗
PubMed2001

Pierre Robin sequence: a series of 117 consecutive cases.

A series of 117 cases of Pierre Robin Sequence are classified as isolated (48%), syndromic (35%), and with associated anomalies (17%); the latter group had a poor long-term prognosis. In isolated Pierre Robin Sequence, familial cases and a high incidence of twins were noted. Among syndromic Pierre Robin Sequence, 4 syndromes represent more than 50% of the diagnoses.

Child, Preschool↗
PubMed2001

Human cultured skin fibroblasts survive profound inherited ubiquinone depletion.

Beside its role in electron transfer in the mitochondrial respiratory chain, ubiquinone is known to prevent lipid peroxidation and DNA damage by trapping cellular free radicals. Thanks to its antioxidant properties, ubiquinone may represent an important factor controlling both necrotic and apoptotic processes. We have investigated the consequences of a profound inherited ubiquinone depletion on cultured skin fibroblasts of a patient presenting with encephalomyopathy. Interestingly, cell respiration, mitochondrial oxidation of various substrates, and cell growth of ubiquinone-deficient fibroblasts were only partially decreased. Moreover, these cells did not apparently overproduce superoxide anions or lipoperoxides. Finally, apoptosis did not increase as compared to control, even after serum deprivation. These observations suggest that ubiquinone may not play a major role in the antioxidant defenses of cultured fibroblasts and that its role in controlling oxidative stress and apoptosis may greatly vary across cell types, especially as not all tissues were equally affected in the patient despite the widespread ubiquinone depletion in vivo.

Antioxidants↗
PubMed2001

Mitochondria transfection by oligonucleotides containing a signal peptide and vectorized by cationic liposomes.

The progress of research in gene therapy allows hope for treatment of mitochondrial genetic disorders provided that efficient methods for gene transfer into mitochondria can be found. In this work, we have used an oligonucleotide coupled covalently to a mitochondria-targeted peptide at one end and a cationic liposome prepared from trimethyl aminoethane carbamoyl cholesterol iodide (TMAEC-Chol) to carry it in living cells. With a fluorescent probe to label the oligonucleotide at the other end and by means of confocal microscopy, we show that such modified oligonucleotides complexed to liposomes enter into the cytoplasm of human fibroblasts in primary culture, and then, after dissociation from the complexes, they penetrate into the mitochondria. The fluorescence was still observed after 8 days, suggesting the continued presence of oligonucleotides. At the concentrations used for this study, the cationic liposomes have practically no effect on cell growth, as revealed by the MTT assay.

Amino Acid Sequence↗
PubMed2001

Single cell multiplex PCR amplification of five dystrophin gene exons combined with gender determination.

Large deletions in the dystrophin gene account for > 60% of mutations responsible for Duchenne muscular dystrophy (DMD). We have developed a genetic test that can be used directly for the preimplantation genetic diagnosis (PGD) of a majority of couples at risk of transmitting DMD. The test, a double nested multiplex polymerase chain reaction assay for the amplification of exons 8, 19, 45, 47 and 51 allows the detection of over 70% of all DMD deletions. Amelogenin sequences on the X and the Y chromosomes were also co-amplified to provide a correlation between embryo gender and deletion status. The setting up of reliable single cell assays for preimplantation genetic diagnosis is delicate and time consuming. Assays have to be validated on a large number of single cells for each specific mutation to assess efficiency and accuracy before being applied clinically. The multiplex procedure permitted the validation of all tested loci in the same series of isolated lymphocytes rather than in separate series for each exon. One hundred single lymphocytes, 50 female and 50 male cells, were analysed with an overall amplification rate of 98% and an amplification failure of 2% per exon. We suggest that this test is reliable, easy to set up and much preferable to a mere sex determination with the selective transfer of female embryos.

Dystrophin↗
PubMed2001

Hypertelorism-Microtia-Clefting syndrome (Bixler syndrome): report of two unrelated cases.

The association of Hypertelorism, Microtia and Cleft lip and palate (HMC syndrome, MIM 239800) is a rare condition of autosomal recessive inheritance. A total of seven cases of HMC syndrome in five families have been hitherto reported. Here, we report two unrelated cases and put emphasis on the possible normal psychomotor development in this syndrome.

Child, Preschool↗
PubMed2001

A novel syndrome with dwarfism, poorly muscled build, absent clavicles, humeroradial fusion, slender bones, oligodactyly and micrognathia.

We report on a 15-year-old girl with severe pre- and post-natal growth retardation, poorly muscled build, micrognathia, ulnar ray oligodactyly, absent clavicles, abnormal scapulae, humeroradial fusion, hip dislocation, small iliac wings, slender tubular bones and normal intelligence. An extensive search has failed to ascribe this association to a known condition. This child shared some clinical and radiological features with the Yunis-Varon syndrome but the normal intelligence and the ulnar ray oligodactyly of our patient does not support this diagnosis.

Abnormalities, Multiple↗
PubMed2001

Absent lacrimal ducts, distichiasis, dysmorphic features, and brachydactyly: a case report.

We report a male patient presenting with the association of absent lacrimal ducts, distichiasis, dysmorphic facial features and limb abnormalities. Extensive chromosomal studies showed normal chromosomes. We discuss differential diagnoses such as Setleis, Char and Lacrimo-Auriculo-Dento-Digital (LADD) syndromes. This may represent a novel entity for which parental consanguinity would support an autosomal recessive mode of inheritance.

Abnormalities, Multiple↗
PubMed2001

A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases.

INTRODUCTION: Congenital disorders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a new group of multisystem disorders characterised by defective glycoprotein biosynthesis, ascribed to various biochemical mechanisms. METHODS: We report the clinical, biological, and molecular analysis of 26 CDG I patients, including 20 CDG Ia, two CDG Ib, one CDG Ic, and three CDG Ix, detected by western blotting and isoelectric focusing of serum transferrin. RESULTS: Based on the clinical features, CDG Ia could be split into two subtypes: a neurological form with psychomotor retardation, strabismus, cerebellar hypoplasia, and retinitis pigmentosa (n=11), and a multivisceral form with neurological and extraneurological manifestations including liver, cardiac, renal, or gastrointestinal involvement (n=9). Interestingly, dysmorphic features, inverted nipples, cerebellar hypoplasia, and abnormal subcutaneous fat distribution were not consistently observed in CDG Ia. By contrast, the two CDG Ib patients had severe liver disease, enteropathy, and hyperinsulinaemic hypoglycaemia but no neurological involvement. Finally, the CDG Ic patient and one of the CDG Ix patients had psychomotor retardation and seizures. The other CDG Ix patients had severe proximal tubulopathy, bilateral cataract, and white matter abnormalities (one patient), or multiorgan failure and multiple birth defects (one patient). CONCLUSIONS: Owing to the remarkable clinical variability of CDG, this novel disease probably remains largely underdiagnosed. The successful treatment of CDG Ib patients with oral mannose emphasises the paramount importance of early diagnosis of PMI deficiency.

Adipose Tissue↗
PubMed2001

Acromicric dysplasia: long term outcome and evidence of autosomal dominant inheritance.

Acromicric dysplasia is a rare bone dysplasia characterised by short stature, short hands and feet, normal intelligence, mild facial dysmorphism, and characteristic x ray abnormalities of the hands. Only a very small number of children with this condition have been reported so far. Here we report on a series of 22 patients including 10 boys and 12 girls with acromicric dysplasia. Length was normal at birth and height fell progressively off the centiles postnatally. The mean adult height was 130 cm (133 cm in males, 129 cm in females). The hands, feet, and limbs were short and OFC was normal. Intelligence was normal and mild dysmorphic features were noted. Other occasional features included well developed muscles, a hoarse voice, generalised joint limitation in some patients, frequent ear, tracheal, and respiratory complication, and spine abnormalities. Long term follow up showed that facial dysmorphism was less obvious in adults and that carpal tunnel syndrome was frequent in older patients. Apart from short metacarpals and phalanges, internal notch of the second metacarpal, external notch of the fifth metacarpal, and internal notch of the femoral heads, there were no major x ray abnormalities. No major complications, such as cardiac disease or major orthopaedic problems, occurred in the course of the disease. The condition appeared to be sporadic in 16 cases but the observation of vertical transmission in three families was consistent with an autosomal dominant mode of inheritance.

Abnormalities, Multiple↗
PubMed2001

MECP2 mutation in non-fatal, non-progressive encephalopathy in a male.

To study the clinical overlap between Rett (RTT) and Angelman syndromes (AS), we screened the MECP2 gene in a cohort of 78 patients diagnosed as possible AS but who showed a normal methylation pattern at the UBE3A locus. MECP2 missense (R106W, G428S), nonsense (R255X, R270X), and frameshift mutations (803 delG) were identified in 6/78 patients including 4/6 female cases consistent with RTT, one female case with progressive encephalopathy of neonatal onset, and one isolated male case with non-fatal, non-progressive encephalopathy of neonatal onset. This study shows that MECP2 mutations can account for a broad spectrum of clinical presentations and raises the difficult issue of the screening of the MECP2 gene in severe encephalopathy in both males and females.

Angelman Syndrome↗