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Synonyme(s)clinical polymorphism ;clinical variability ;hétérogénéité clinique ;polymorphisme clinique ;variation clinique ;clinical variations clinical heterogeneity
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van Dijkhuizen EP, Deakin CT, Wedderburn LR, et al.
Statistical methods in medical research, 2019, 28, 1, p 35
Revue : Statistical methods in medical research, 28, 1 Titre : Modelling disease activity in juvenile dermatomyositis: A Bayesian approach Type de document : Article Auteurs : van Dijkhuizen EP, Auteur ; Deakin CT ; Wedderburn LR ; De Iorio M Année de publication : 2019 Pages : p 35 Langues : Anglais (eng) Mots-clés : dermatomyosite juvénile ; étude longitudinale ; étude observationnelle ; évolution de la maladie ; modélisation ; pronostic ; variabilité clinique Pubmed / DOI : DOI : 10.1177/0962280217713233 / Pubmed : 28589751 En ligne : http://www.ncbi.nlm.nih.gov/pubmed/28589751
Phosphorylase Kinase Deficiency : Synonyms: Glycogen Storage Disease Type IX, GSDIX, PhK Deficiency, Phosphorylase b Kinase DeficiencyHerbert M, Goldstein JL, Rehder C, et al.
GeneReviews® [Internet], 2018
Revue : GeneReviews® [Internet] Titre : Phosphorylase Kinase Deficiency : Synonyms: Glycogen Storage Disease Type IX, GSDIX, PhK Deficiency, Phosphorylase b Kinase Deficiency Type de document : Article Auteurs : Herbert M ; Goldstein JL ; Rehder C ; Austin S ; Kishnani PS ; Bali DS Année de publication : 01/11/2018 Langues : Anglais (eng) Mots-clés : activité enzymatique ; article de synthèse ; classification des maladies ; conseil génétique ; corrélation génotype-phénotype ; déficit en phosphorylase kinase ; description de la maladie ; diagnostic biochimique ; diagnostic différentiel ; diagnostic moléculaire ; foie ; génétique moléculaire ; grossesse ; hypoglycémie ; muscle squelettique ; pénétrance ; prévention des complications ; prise en charge thérapeutique ; suivi du malade ; variabilité clinique Résumé : Initial Posting: May 31, 2011; Last Update: November 1, 2018.
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that patients need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
The enzyme PhK comprises four copies each of four subunits (alpha, beta, gamma, and delta).
Pathogenic variants in:
PHKA1, encoding subunit alpha, cause the rare X-linked disorder muscle PhK deficiency;
PHKA2, also encoding subunit alpha, cause the most common form, liver PhK deficiency (X-linked liver glycogenosis);
PHKB, encoding subunit beta, cause autosomal recessive PhK deficiency in both liver and muscle;
PHKG2, encoding subunit gamma, cause autosomal recessive liver PhK deficiency.
The diagnosis of PhK deficiency is established in a proband with the characteristic clinical findings, a family history of suspected storage disease, and/or a hemizygous pathogenic variant in PHKA1 or PHKA2 or biallelic pathogenic variants in PHKB or PHKG2 identified by molecular genetic testing.
Treatment of manifestations:
Liver PhK deficiency. Hypoglycemia can be prevented with frequent daytime feedings that are high in complex carbohydrates and protein. When hypoglycemia or ketosis is present, Polycose® or fruit juice is given orally as tolerated or glucose by IV. Liver manifestations (e.g., cirrhosis, liver failure, portal hypertension) are managed symptomatically.
Muscle PhK deficiency. Physical therapy based on physical status and function; optimization of blood glucose concentrations by a metabolic nutritionist based on activity.
Liver PhK deficiency. Regular evaluation by a metabolic physician and a metabolic nutritionist. Monitoring of blood glucose concentration and blood ketones routinely as well as during times of stress (e.g., illness, intense activity, rapid growth, puberty) and reduced food intake. In children younger than age 18 years, liver ultrasound examination should be performed every 12 to 24 months. With increasing age, CT or MRI using intravenous contrast should be considered to evaluate for complications of liver disease. Echocardiogram should be performed at least every two years.
Muscle PhK deficiency. Regular evaluation by a metabolic physician, a metabolic nutritionist, and a physical therapist.
Agents/circumstances to avoid:
Liver PhK deficiency. Large amounts of simple sugars as they will increase liver storage of glycogen; prolonged fasting; high-impact contact sports if significant hepatomegaly is present; drugs known to cause hypoglycemia such as insulin and insulin secretogogues (the sulfonylureas) or drugs known to mask symptoms of hypoglycemia such as beta blockers; alcohol (which may predispose to hypoglycemia).
Muscle PhK deficiency. Vigorous exercise; medications like succinylcholine and statins that can cause rhabdomyolysis.
Evaluation of relatives at risk: Molecular genetic testing (if the family-specific pathogenic variant[s] are known) and/or evaluation by a metabolic physician (if the family-specific pathogenic variant[s] are not known) allows early diagnosis and treatment for sibs at increased risk for GSD IX.
Pregnancy management: Individualized dietary management is necessary to maintain euglycemia throughout pregnancy.
PHKA2-related liver PhK deficiency and PHKA1-related muscle PhK deficiency are inherited in an X-linked manner. PHKB-related liver and muscle PhK deficiency and PHKG2-related liver PhK deficiency are inherited in an autosomal recessive manner.
X-linked inheritance. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers); the development of symptoms in individuals depends on the pattern of X-chromosome inactivation. Affected males pass the pathogenic variant to all of their daughters and none of their sons.
Autosomal recessive inheritance. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Carrier testing for at-risk relatives, prenatal testing for pregnancies at risk, and preimplantation genetic testing are possible if the pathogenic variant(s) in the family have been identified.
Lien associé : Texte complet disponible en accès libre sur Bookshelf GeneReviews® Pubmed / DOI : Pubmed : 21634085Wolfe L, Jethva R, Oglesbee D, et al.
GeneReviews® [Internet], 2018
Revue : GeneReviews® [Internet] Titre : Short-Chain Acyl-CoA Dehydrogenase Deficiency : Synonyms: SCADD, SCAD Deficiency Type de document : Article Auteurs : Wolfe L ; Jethva R ; Oglesbee D ; Vockley J Année de publication : 09/08/2018 Langues : Anglais (eng) Mots-clés : acyl-CoA déshydrogénase ; article de synthèse ; conseil génétique ; corrélation génotype-phénotype ; déficit en acyl-CoA déshydrogénase ; diagnostic biochimique ; diagnostic différentiel ; diagnostic moléculaire ; examen clinique ; génétique moléculaire ; prévalence ; prise en charge thérapeutique ; régime alimentaire ; taux urinaire ; trouble du développement ; variabilité clinique ; vitamine B2 Résumé : Initial Posting: September 22, 2011; Last Update: August 9, 2018.
Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.
SCADD has been defined as the presence of:
Increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions);
Biallelic ACADS pathogenic variants.
Treatment of manifestations: As most individuals with SCADD are asymptomatic, there is no need for treatment. There are no generally accepted recommendations for dietary manipulation or use of carnitine and/or riboflavin supplementation.
Prevention of primary manifestations: No preventive measures are necessary.
Surveillance: Longitudinal follow up of persons with SCADD on a research basis may be helpful in order to more clearly define the natural history over the life span, including annual visits to a metabolic clinic to assess growth and development as well as nutritional status (protein and iron stores, concentration of RBC or plasma essential fatty acids, and plasma carnitine concentration).
SCADD is inherited in an autosomal recessive manner. At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic ACADS pathogenic or susceptibility variants and possibly developing clinical findings associated with SCADD, a 50% chance of being a carrier of an ACADS pathogenic variant, and a 25% chance of not being a carrier. If the pathogenic variants in the family have been identified, carrier testing for at-risk family members is possible, and prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible but not necessary and not recommended.
Lien associé : Texte complet disponible en accès libre sur Bookshelf GeneReviews® Pubmed / DOI : Pubmed : 21938826
A 22-year follow-up reveals a variable disease severity in early-onset facioscapulohumeral dystrophyGoselink RJM, van Kernebeek CR, Mul K, et al.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2018
Revue : European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society Titre : A 22-year follow-up reveals a variable disease severity in early-onset facioscapulohumeral dystrophy Type de document : Article Auteurs : Goselink RJM, Auteur ; van Kernebeek CR ; Mul K ; Lemmers RJLF ; van der Maarel SM ; Brouwer OF ; Voermans N ; Padberg GW ; Erasmus CE ; van Engelen BGM Année de publication : 03/05/2018 Langues : Anglais (eng) Mots-clés : début précoce de la maladie ; degré de sévérité ; dystrophie musculaire facio-scapulo-humérale ; évolution de la maladie ; examen clinique ; histoire naturelle de la maladie ; variabilité clinique Résumé : Comment in:
Genotype-phenotype correlation: The ultimate challenge in facioscapolohumeral muscular dystrophy. [Eur J Paediatr Neurol. 2018]
Pubmed / DOI : DOI : 10.1016/j.ejpn.2018.04.013 / Pubmed : 29753614 N° Profil MNM : 2018051 En ligne : http://www.ncbi.nlm.nih.gov/pubmed/29753614
Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literatureIvanov I, Atkinson D, Litvinenko I, et al.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 2018
Garone C, Taylor RW, Nascimento A, et al.
Journal of medical genetics, 2018
Characteristics of Japanese Patients with Becker Muscular Dystrophy and Intermediate Muscular Dystrophy in a Japanese National Registry of Muscular Dystrophy (Remudy): Heterogeneity and Clinical VariationMori-Yoshimura M, Mitsuhashi S, Nakamura H, et al.
Journal of Neuromuscular Diseases, 2018
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Flow Cytometry-Defined CD49d Expression in Circulating T-Lymphocytes Is a Biomarker for Disease Progression in Duchenne Muscular DystrophySavino W, Pinto-Mariz F, Mouly V
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Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patientsBest M, Jachiet M, Molinari N, et al.
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Variable clinical presentation of glycogen storage disease type IV: from severe hepatosplenomegaly to cardiac insufficiency. Some discrepancies in genetic and biochemical abnormalitiesSzymaiska E, Szymaiska S, Truszkowska G, et al.
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