The ABCA4 gene in autosomal recessive cone-rod dystrophies.
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ATP-Binding Cassette Transporters↗
Biomedical subjects
Arnold Munnich
Publications and source records attributed to Arnold Munnich.
The place of 'social sexing' in medicine and science.
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Ethics, Medical↗
Birth of healthy female twins after preimplantation genetic diagnosis of cystic fibrosis combined with gender determination.
Two healthy sisters with a familial history of mental retardation were referred to our centre for preimplantation genetic diagnosis (PGD). Their two brothers showed severe mental retardation. The molecular basis for their disorder could not be identified, but one of the sisters and the mother presented a highly skewed pattern of X-inactivation reinforcing the likelihood of an X-linked mode of inheritance. Both sisters requested PGD to avoid the abortion of potentially affected male fetuses. PGD for sex by fluorescent in-situ hybridization was carried out for the first sister and resulted in the birth of a female child. The second sister and her partner, whose niece had cystic fibrosis (CF), were tested for CF mutations, and were both found to be deltaF508 heterozygous. We developed an efficient single cell PCR protocol for the simultaneous amplification of the CF (deltadeltaF508) locus as well as the X-linked amelogenin gene and its highly homologous pseudogene on the Y chromosome. Two PGD cycles were carried out to screen against male and deltaF508 homozygous deleted embryos. In each case several embryos could be selected for transfer and the second cycle resulted in a twin pregnancy followed by the birth of two healthy female infants.
Cystic Fibrosis↗
Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother.
A child with X-linked osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID) was recently reported. We report the clinical features of a second boy with this novel syndrome and his mother, who presented with signs of incontinentia pigmenti (IP). The child had mild osteopetrosis without neurosensory complications, unilateral lymphedema of the left leg, and characteristic features of anhidrotic ectodermal dysplasia with sparse hair, facial dysmorphy, delayed eruption of teeth, and sweat gland abnormalities. He died at 18 months of severe immunodeficiency with multiple infections caused by Gram-negative (Salmonella enteritidis) and Gram-positive (Streptococcus pneumoniae) bacteria, nontuberculous mycobacteria (Mycobacterium kansasii), and fungi (Pneumocystis carinii). His 30-year-old mother's medical history, together with residual cutaneous lesions, was highly suggestive of IP without neurologic impairment. In this patient with OL-EDA-ID, we detected the same NF-kappaB essential modulator stop codon hypomorphic mutation identified in the previous patient. The occurrence of the same clinical features in 2 unrelated patients with the same genotype demonstrates that OL-EDA-ID is a genuine clinical syndrome. The clinical and biological descriptions of the proband and his mother further corroborate the relationship between IP and EDA. Both syndromes are allelic and are associated with mutations in NF-kappaB essential modulator, with a genotype-phenotype correlation in hemizygous males. In contrast, loss-of-function mutations and hypomorphic mutations may cause IP in females.
Abnormalities, Multiple↗
[Preimplantation genetic diagnosis: update of the Parisian group].
To report the birth of the first fourteen infants conceived after preimplantation genetic diagnosis (PGD) in our unit. Fifty-nine couples were enrolled between January 2000 and July 2001. They had a total of 71 oocyte pick-up cycles. The collected oocytes were inseminated by intracytoplasmic sperm injection. The resulting embryos were biopsied on the third day of development and the genetic analysis was performed on the same day. Most of the embryo transfers were carried out on the fourth day. The 71 oocyte pick-up cycles yielded 872 oocytes of which 731 were suitable for intracytoplasmic sperm injection. Among the 505 embryos obtained, 421 embryos were biopsied and genetic diagnosis was performed for 312 (74%) of these 127 embryos were transferred during the course of 58 transfer procedures. There were 18 biochemical and 12 ongoing (7 singles, 4 twins and 1 triple) pregnancies. Sixteen infants have been born and 2 are expected. PGD has gained a place among the choices offered to couples at risk of transmission of a serious and incurable genetic disease.
Adult↗
Another observation with VATER association and a complex IV respiratory chain deficiency.
The VATER association of vertebral anomalies (V), anal atresia (A), esophageal atresia and/or tracheo-esophageal fistula (TE), radial and renal anomalies (R) is a common congenital association of unknown origin with probably heterogeneous causes. Here, we report on a girl presenting with pre- and postnatal growth retardation, esophageal atresia, vertebral and costal anomalies and a unilateral radial defect, consistent with the diagnosis of VATER association. In the first month of life, she presented with failure to thrive, severe episodes of hypoglycemia, liver dysfunction and high levels of lactate, which prompted us to perform metabolic screening. A complex IV respiratory chain deficiency (RCD) was diagnosed on a liver biopsy. The respiratory chain defect was not observed in skin fibroblasts. No mtDNA point mutation or deletion was identified. The girl is now 9 years old and has a normal mental development but persistent feeding difficulties and moderate hyperlactatemia. To our knowledge, this is the second report of VATER association with mitochondrial disorder. In a previous report, a VACTERL association was observed in a girl with the mitochondrial A3243G point mutation. The association of VATER phenotype with a mitochondrial disorder may be coincidental but could also suggest that the presence of multiple malformations is the result of the antenatal expression of RCD.
Abnormalities, Multiple↗
Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects.
Carnitine palmitoyltransferase (CPT) deficiencies are common disorders of mitochondrial fatty acid oxidation. The CPT system is made up of two separate proteins located in the outer (CPT1) and inner (CPT2) mitochondrial membranes. While CPT2 is an ubiquitous protein, three tissue-specific CPT1 isoforms--the so-called "liver" (CPT1-A), "muscle" (CPT1B) and < > (CPT1-C) CPT1s--have been shown to exist. Amino acid and cDNA nucleotide sequences have been identified for all of these proteins. CPT1-A deficiency presents as recurrent attacks of fasting hypoketotic hypoglycemia. Twenty four CPT1A mutations have been reported to date. CPT1-B and -C deficiencies have not been hitherto identified. CPT2 deficiency has several clinical presentations. The "benign" adult form (more than 200 families reported) is characterized by episodes of rhabdomyolysis triggered by prolonged exercise. The prevalent S113L mutation is found in about 50% of mutant alleles. The infantile-type CPT2 presents as severe attacks of hypoketotic hypoglycemia, occasionally associated with cardiac damage commonly responsible for sudden death before 1 year of age. In addition to these symptoms, features of brain and kidney dysorganogenesis are frequently seen in the neonatal-onset CPT2 deficiency, almost always lethal during the first month of life. Around 40 CPT2 mutations (private missense or truncating mutations) have hitherto been detected. Treatment is based upon avoidance of fasting and/or exercise, a low fat diet enriched with medium chain triglycerides and carnitine. Prenatal diagnosis may be offered for pregnancies at a 1/4 risk of infantile/severe-type CPT2 deficiency.
Animals↗
Recent advances in Dyggve-Melchior-Clausen syndrome.
Dyggve-Melchior-Clausen (DMC) is a rare autosomal-recessive disorder characterized by the association of a progressive spondylo-epi-metaphyseal dysplasia and mental retardation ranging from mild to severe. Electron microscopy studies of both DMC chondrocytes and fibroblasts reveal an enlarged endoplasmic reticulum network and a large number of intracytoplasmic membranous vesicles, suggesting that DMC syndrome may be a storage disorder. Indeed, DMC phenotype is often compared to that of type IV mucopolysaccharidosis (Morquio disease), a lysosomal disorder due to either N-acetylgalactosamine-6-sulphatase or beta-galactosidase deficiency. To date, however, the lysosomal pathway appears normal in DMC patients and biochemical analyses failed to reveal any enzymatic deficiency or accumulated substrate. Linkage studies using homozygosity mapping have led to the localization of the disease-causing gene on chromosome 18q21.1. The gene was recently identified as a novel transcript (Dym) encoding a 669-amino acid product (Dymeclin) with no known domains or function. Sixteen different Dym mutations have now been described in 21 unrelated families with at least five founder effects in Morocco, Lebanon, and Guam Island. Smith-MacCort syndrome (SMC), a rare variant of DMC syndrome without mental retardation, was shown to be allelic of DMC syndrome and to result from mutations in Dym that would be less deleterious to the brain. The present review focuses on clinical, radiological, and cellular features and evolution of DMC/SMC syndromes and discusses them with regard to identified Dym mutations and possible roles of the Dym gene product.
Abnormalities, Multiple↗
Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits.
While there have been major advances in both the identification of the molecular basis and our understanding of mitochondrial pathology, the clinical management of patients with mitochondrial respiratory chain disease is still essentially supportive. Quinones are the only pharmacological agents that have proven some efficacy when, and only when, given to patients presenting with quite specific respiratory chain defects. In this article, after a short presentation of the coenzyme Q(10) molecule, its origin and distribution in human body, we summarize our present knowledge on its several physiological functions. We next discuss the rational that justifies using different types of quinones in the therapy of mitochondrial disorders. We finally briefly review the available data obtained in the therapy of mitochondrial disorders by using quinones as either substitutive electron carriers or antioxidant compounds.
Antioxidants↗