Genetic heterogeneity in hypokalemic periodic paralysis

Abstract Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disorder belonging to a group of muscle diseases known to involve an abnormal function of ion channels. The latter includes hypokalemic and hyperkalemic periodic paralyses, and non-dystrophic myotonias. We recently showed genetic linkage of hypoPP to loci on chromosome lq31-32, co-localized with the DHP-sensitive calcium channel CACNL1A3. We propose to term this locus hypoPP-1. Using extended haplotypes with new markers located on chromosome lq31-32, we now report the detailed mapping of hypoPP-1 within a 7 cM interval. Two recombinants between hypoPP-1 and the flanking markers D1S413 and D1S510 should help to reduce further the hypoPP-1 interval. We used this new information to demonstrate that a large family of French origin displaying hypoPP is not genetically linked to hypoPP-1. We excluded genetic linkage over the entire hypoPP-1 interval showing for the first time genetic heterogeneity in hypoPE E. Plassart -A. Elbaz. J. V. Santos 9 J. Reboul 9 P. Lapie B. Fontaine ([5~) INSERM U134, H6pital de la Salp~tri6re

Intérêt de l'urée urinaire et du rapport molaire urée / AMM urinaire dans la surveillance métabolique des enfants atteints d'acidurie méthylmalonique

TOULOUSE3-BU Santé-Centrale (315552105) / SudocTOULOUSE3-BU Santé-Allées (315552109) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

The phenotype of adult versus pediatric patients with inborn errors of metabolism

International audienceUntil recently, inborn errors of metabolism (IEM) were considered a pediatric specialty, as emphasized by the term "inborn," and the concept of adult onset IEM has only very recently reached the adult medical community. Still, an increasing number of adult onset IEM have now been recognized, as new metabolomics and molecular diagnostic techniques have become available. Here, we discuss possible mechanisms underlying phenotypic variability in adult versus children with IEM. Specifically, phenotypic severity and age of onset are expected to be modulated by differences in residual protein activity possibly driven by various genetic factors. Phenotypic variability may also occur in the context of similar protein expression, which suggests the intervention of environmental, ontogenic, and aging factors

Peroxisomal disorders

Peroxisomes are subcellular organelles catalyzing a number of indispensable functions in cellular metabolism. The importance of peroxisomes is stressed by the existence of an expanding number of genetic diseases in which there is an impairment of one or more peroxisomal functions. The prototype of this group of diseases is the cerebro-hepato-renal syndrome of Zellweger (ZS), first described as a familial syndrome of multiple congenital defects in 1964. ZS is characterized by the presence of dysmorphias and polymalformative syndrome, severe neurologic abnormalities including neurosensory defects and hepato-intestinal dysfunction with failure to thrive and usually early death. Other peroxisomal disorders share some of these symptoms, but with varying degrees of organ involvement, severity of dysfunction and duration of survival. This paper provides an overview of the peroxisomal disorders including their clinical, biochemical and molecular characteristics with particular emphasis on the clinical presentation in neonates

METABOLISME DU GLUCOSE APRES PANCREATECTOMIE POUR HYPERINSULINISME PERSISTANT DE L'ENFANT

ST QUENTIN EN YVELINES-BU (782972101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview

International audienceOver one hundred diseases related to inherited defects of complex lipids synthesis and remodeling are now reported. Most of them were described within the last 5 years. New descriptions and phenotypes are expanding rapidly. While the associated clinical phenotype is currently difficult to outline, with only a few patients identified, it appears that all organs and systems may be affected. The main clinical presentations can be divided into (1) Diseases affecting the central and peripheral nervous system. Complex lipid synthesis disorders produce prominent motor manifestations due to upper and/or lower motoneuron degeneration. Motor signs are often complex, associated with other neurological and extra-neurological signs. Three neurological phenotypes, spastic paraparesis, neurodegeneration with brain iron accumulation and peripheral neuropathies, deserve special attention. Many apparently well clinically defined syndromes are not distinct entities, but rather clusters on a continuous spectrum, like for the PNPLA6-associated diseases, extending from Boucher-Neuhauser syndrome via Gordon Holmes syndrome to spastic ataxia and pure hereditary spastic paraplegia; (2) Muscular/cardiac presentations; (3) Skin symptoms mostly represented by syndromic (neurocutaneous) and non syndromic ichthyosis; (4) Retinal dystrophies with syndromic and non syndromic retinitis pigmentosa, Leber congenital amaurosis, cone rod dystrophy, Stargardt disease; (5) Congenital bone dysplasia and segmental overgrowth disorders with congenital lipomatosis; (6) Liver presentations characterized mainly by transient neonatal cholestatic jaundice and non alcoholic liver steatosis with hypertriglyceridemia; and (7) Renal and immune presentations. Lipidomics and molecular functional studies could help to elucidate the mechanism(s) of dominant versus recessive inheritance observed for the same gene in a growing number of these disorders

Neonatal hypoglycaemia: aetiologies

International audienceDiagnosis of glucose status requires knowledge of the homeostatic mechanisms that maintain the blood glucose concentration between the narrow range of 2.5 and 7.5 mmol/l during periods of eating or fasting. Hypoglycaemia occurring within the first few hours after eating is suggestive of hyperinsulinism. Most glucose is subsequently converted into glycogen in the liver, and hypoglycaemia occurring during this phase is suggestive of glycogenosis. During fasting, gluconeogenesis progressively replaces glycogen as the major source of blood glucose, and hypoglycaemia occurring during this period is suggestive of impaired gluconeogenesis or fatty acid disorders. Growth hormone, glucagon, cortisol and insulin-like growth factor 1 deficiencies may also play a role. Other causes of hypoglycaemia have also been identified recently, namely glucose transporter disorders, respiratory chain disorders and congenital disorders of glycosylation