Molecular analysis of iduronate -2- sulfatase gene in Tunisian patients with mucopolysaccharidosis type II

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is X-linked recessive lysosomal storage disorder resulting from the defective activity of the enzyme iduronate-2-sulfatase (IDS). Hunter disease can vary from mild to severe, depending on the level of enzyme deficiency. We report the IDS mutation and polymorphisms causing the Hunter syndrome in patients from one family in Tunisi

Molecular analysis of mucopolysaccharidosis type I in Tunisia: identification of novel mutation and eight Novel polymorphisms

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in alpha-L-iduronidase (IDUA) which is involved in the degradation of dermatan and heparan sulfates. The disease has severe and milder phenotypic subtypes. The aim of this study was the detection of mutations in the IDUA gene from 12 additional MPS I patients with various clinical phenotypes (severe, 8 cases; intermediate, 3 cases; mild, 1 case)

Glucose-6-phosphatase deficiency

Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span

Glucose-6-phosphatase deficiency

Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span

Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia?

<p>Abstract</p> <p>Background</p> <p>Hyperammonemia in patients with methylmalonic aciduria (MMA) and propionic aciduria (PA) is caused by accumulation of propionyl-CoA which decreases the synthesis of N-acetyl-glutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetyl-glutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises.</p> <p>Case presentation</p> <p>We described two patients (one with MMA and one with PA) with hyperammonemia at diagnosis. Carglumic acid, when associated with standard treatment of organic acidurias, may be helpful in normalizing the ammonia level.</p> <p>Conclusion</p> <p>Even though the usual treatment which decreases toxic metabolites remains the standard, carglumic acid could be helpful in lowering plasma ammonia levels over 400 micromol/L more rapidly.</p

Mucopolysaccharidosis type I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients

<p>Abstract</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is an autosomal storage disease resulting from defective activity of the enzyme α-L-iduronidase (IDUA). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. MPS I has severe and milder phenotypic subtypes.</p> <p>Aim of study: This study was carried out on six newly collected MPS I patients recruited from many regions of Tunisia.</p> <p>Patients and methods: Mutational analysis of the IDUA gene in unrelated MPS I families was performed by sequencing the exons and intron-exon junctions of IDUA gene.</p> <p>Results</p> <p>Two novel IDUA mutations, p.L530fs (1587_1588 insGC) in exon 11 and p.F177S in exon 5 and two previously reported mutations p.P533R and p.Y581X were detected. The patient in family 1 who has the Hurler phenotype was homozygous for the previously described nonsense mutation p.Y581X.</p> <p>The patient in family 2 who also has the Hurler phenotype was homozygous for the novel missense mutation p.F177S. The three patients in families 3, 5 and 6 were homozygous for the p.P533R mutation. The patient in family 4 was homozygous for the novel small insertion 1587_1588 insGC. In addition, eighteen known and one unknown IDUA polymorphisms were identified.</p> <p>Conclusion</p> <p>The identification of these mutations should facilitate prenatal diagnosis and counseling for MPS I in Tunisia.</p> <p>Background</p> <p>Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by the deficient activity of the enzyme of α-L-iduronidase (IDUA, EC 3.2.1.76). This glycosidase is involved in the degradation of heparan sulfate and dermatan sulfate. The clinical phenotype of MPS I ranges from the very severe in Hurler syndrome (MPS IH) to the relatively benign in Scheie syndrome (MPS IS), with an intermediate phenotype designated Hurler/Scheie (MPS IH/S) <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Isolation of complementary and genomic DNAs encoding human α -L- iduronidase <abbrgrp><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp> have enable the identification of mutations underlying the enzyme defect and resulting in MPS I clinical phenotype. More than 100 mutations have been reported in patients with the MPS I subtypes (Human Gene Mutation Database; <url>http://www.hgmd.org</url>). High prevalence of the common mutations p.W402X and p.Q70X has been described; both of them in the severe clinical forms <abbrgrp><abbr bid="B4">4</abbr><abbr bid="B5">5</abbr></abbrgrp>. A high prevalence of common mutation p.P533R has also been described in MPS I patients with various phenotypes <abbrgrp><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr></abbrgrp>. In addition, rare mutations including single base substitution, deletion, insertion and splicing site mutation have been identified <abbrgrp><abbr bid="B7">7</abbr></abbrgrp>, indicating a high degree of allelic heterogeneity in IDUA gene.</p> <p>Here, we described two novel IDUA mutations in MPS I Tunisian patients. These lesions were homoallelic in all the patients of the six families investigated as consanguineous marriages are still frequent in Tunisia <abbrgrp><abbr bid="B8">8</abbr></abbrgrp>.</p

"Les Confluences" SSIEM 2015 Annual Symposium in Lyon

International audienc

Development of a Tandem Mass Spectrometry Method for Rapid Measurement of Medium- and Very-Long-Chain Acyl-CoA Dehydrogenase Activity in Fibroblasts

International audienceMitochondrial fatty acid oxidation is a vital biochemical process for energy metabolism. Among the known fatty-acid metabolism disorders, very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency count among the most frequent. Both are potentially very serious diseases as they carry a risk of severe neurological post-crisis sequelae, and even sudden death. Diagnosis relies on plasma acylcarnitine profile analysis and urine organic acid analysis, followed by genetic testing to confirm diagnosis. However, in some cases, it is crucial to run a specific diagnostic assay for enzyme activity, which is generally performed in leukocytes or fibroblasts. The aim of this study was to address this need, first by developing a MCAD and VLCAD enzyme activity-specific diagnostic assay in fibroblasts (by measuring the reaction products, i.e. enoyl-CoA) via a rapid LC-MS/MS-based technique, and then by testing MCAD-deficient patients (n = 6), VLCAD-deficient patients (n = 10), and control patients (n = 12). MCAD activity was significantly different in the MCAD-deficiency (MCADD) group (mean = 0.07 nmol C8:1 formed/min/mg protein) compared to the control group (mean = 0.36 nmol C8:1 formed/min/mg protein). All MCADD patients showed less than 35% residual MCAD activity. VLCAD activity was significantly decreased in the VLCADD group (mean = 0.06 nmol C16:1 formed/min/mg protein) compared to the control group (mean = 0.86 nmol C16:1 formed/min/mg protein, respectively). All VLCADD patients showed less than 35% residual VLCAD activity. This technique allowed also to confirm that a novel ACADVL gene mutation (c.1400T\textgreaterC) is responsible for a defective VLCAD activity (residual activity at 10%)

Acidurie L-2-hydroxyglutarique : à propos de 2 cas

International audienceL-2-hydroxyglutaric aciduria is a rare genetic neurometabolic disease. It occurs in childhood with mental retardation, cerebellar ataxia, and epilepsy. Macrocephaly is present in half of the cases. Diagnosis is based on clinical symptoms, biological and radiological findings, and molecular testing. Specific treatments can improve the spontaneous progression of the disease. We examined two independent patients who presented with L-2-hydroxyglutaric aciduria. Clinical presentation led to cerebral MRI and urinary organic acid chromatography. The genetic analysis confirmed the diagnosis. Under specific treatment, the progression of the disease was subsequently stopped. L-2-hydroxyglutaric aciduria shares common symptoms with other genetic and metabolic diseases. However, the association of a distinct phenotype and typical MRI abnormalities (such as a high signal in the subcortical white matter, pallidum, and dentate nuclei) should draw the clinician's attention to this diagnosis. It can easily be suspected with a simple urinary analysis and can then be confirmed by genetic testing. With this case report, we show the importance of genetic identification to begin treatment with riboflavin. Early detection of L-2-hydroxyglutaric aciduria based on MRI abnormalities can enable rapid initiation of treatment and prevent disease progression