Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population

Mucopolysaccharidosis type I (MPS I) was a group of rare autosomal recessive disorder caused by the deficiency of the lysosomal enzyme, alpha -L -iduronidase, and the resulting accumulation of undergraded dematan sulfate and heparan sulfate. MPS I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counseling and also impedes the selection and evaluation of patients undergoing therapy bone marrow transplantation

Effect of Oral Eliglustat on Splenomegaly in Patients With Gaucher Disease Type 1. The ENGAGE Randomized Clinical Trial

Importance Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, −32.57% to −22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, −2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of −30.03% (95% CI, −36.82% to −23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, −11.37% to −1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non–treatment related); 39 of the 40 patients transitioned to an open-label extension study. Conclusions and Relevance Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up

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

Fulminant Neonatal Liver Failure in MPV 17-Related Mitochondrial DNA Depletion Syndrome

Mitochondrial depletion syndromes are well established causes of liver failure in infants. Hepatocerebral variant related to MPV17 gene defect is characterized by infantile onset of progressive liver failure, developmental delay, neurological manifestations, lactic acidosis, hypoglycemia, and mtDNA depletion in liver tissue. We report a hepatocerebral variant of mitochondrial DNA depletion syndrome in a neonate who presented with septic shock picture, hypoglycemia, jaundice, hypotonia, and rotatory nystagmus. Family history was significant for consanguinity and a brother who died at the age of 4 months. Investigations showed mild liver function derangement contrasting with severe coagulopathy, hyperlactatemia, and generalized aminoaciduria. The brain MRI was normal. Next generation sequencing (NGS) panel identified a MPV17 gene missense homozygous pathogenic variant. The infant expired at the age of 2 weeks with refractory ascites. This case illustrates a challenging diagnosis causing liver failure and death in neonatal period. Genetic testing of mitochondrial DNA depletion syndromes should be a part of liver failure workup in addition to other treatable disorders presenting with encephalo-hepatopathy in infancy

Novel splice site IDUA gene mutation in Tunisian pedigrees with hurler syndrome

Abstract Background The mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme α-L-iduronidase (IDUA). The disease has three major clinical subtypes (severe Hurler syndrome, intermediate Hurler–Scheie syndrome and attenuated Scheie syndrome). We aim to identify the genetic variants in MPS I patients and to investigate the effect of the novel splice site mutation on splicing of IDUA- mRNA variability using bioinformatics tools. Methods The IDUA mutations were determined in four MPS I patients from four families from Northern Tunisia, by amplifying and sequencing each of the IDUA exons and intron–exon junctions. Results One novel splice site IDUA mutation, c.1650 + 1G > T in intron 11 and two previously reported mutations, p.A75T and p.R555H, were detected. The patients in families 1 and 2 who have the Hurler phenotype were homozygotes for the novel splice site mutation c.1650 + 1G > T. The patient in family 3, who also had the Hurler phenotype, was a compound heterozygote for the novel splice site mutation c.1650 + 1G > T and for the previously reported missense mutation p.A75T. The patient in family 4 who had the Hurler–Scheie phenotype was a compound heterozygote for the novel splice site mutation c.1650 + 1G > T and for the previously reported missense mutation p.R555H. In addition, four known IDUA polymorphisms were identified. Bioinformatics tools allowed us to associate the variant c.1650 + 1G > T with the severe clinical phenotype of MPS I. This variant affects the essential nucleotide + 1 (G to T) of the donor splice site of IDUA intron 11. The G > T in intron 11 leads to wild type donor site broken with minus 19.97% value compared to normal value with 0%, hence the new splice site acceptor has plus 5.59%. Conclusions The present findings indicate that the identified mutations facilitate the accurate carrier detection (genetic counseling of at-risk relatives) and the molecular prenatal diagnosis in Tunisia

A de novo large deletion of 2.8 kB produced in ABCD1 gene causing Adrenoleukodystrophy disease

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene that encodes an ATP-binding cassette transporter protein, ALDP. The disease is characterized by increased concentrations of very long-chain fatty acids (VLCFAs) in plasma, adrenal, testicular and nervous tissues. In the present study, our objective is to conduct a clinical, molecular and genetic study of a Tunisian patient with X-linked adrenoleukodystrophy. The clinical diagnosis was based on clinical symptoms, biochemical levels, typical scanner pattern and molecular biology. Whereas, the molecular analysis was based on PCR, long range PCR and sequencing. The molecular analysis by long range PCR and direct sequencing of the ABCD1 gene showed the presence of a de novo 2794 bp deletion covering the whole of exon 2. Using bioinformatics tools, we demonstrate that the large deletion is located in a region rich of Alu sequences. Furthermore, we suggest that the AluJb sequence can be the cause of the large deletion of intron 1, exon 2 and intron 2 and creation of premature stop codon within exon 3. The present report, however, is the first report in which we demonstrate the breakpoints and the size of a large deletion in an X-ALD Tunisian patient.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

RESEARCH Open Access Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population

Mucopolysaccharidosis type I (MPS I) was a group of rare autosomal recessive disorder caused by the deficiency of the lysosomal enzyme, alpha-L-iduronidase, and the resulting accumulation of undergraded dematan sulfate and heparan sulfate. MPS I patients have a wide range of clinical presentations, that makes it difficult to predict patient phenotype which is needed for genetic counseling and also impedes the selection and evaluation of patients undergoing therapy bone marrow transplantation. Aim of the study: consanguinity rates have been determined among 14 families with mucopolysaccharidosis type I, seen in the pediatric departments of different geographic areas of Tunisia (Central and Southern areas) for the period August 2004- August 2011 in order to investigate the relation between consanguinity and this disorder. Patients and methods: Clinical and molecular analyses confirmed the diagnosis for MPS type I in the studied families. Results: Most of the Tunisian MPS I patients have been identified at the homozygous status: p.P533R mutation (7 homozygous and one double heterozygous p.L578Q/p.P533R patients; 41.66 % of all the investigated MPSI patients)

Complications rénales dans la glycogénose de type 1 : quelles implications pratiques ?

International audienceAim. - To investigate risk factors of renal complications in glycogen storage disease type I, in order to identify practical implications for renal preservation. Methods. - A retrospective study of 38 patients with glycogen storage disease type I. Results. - The patients studied were 8.6 years old in average (1.5 to 22 years) and were followed during 7.4 +/- 4.5 years. Hypercalciuria was detected in 23 patients and was related to acidosis (P = 0.028), higher lactate levels (5.9 +/- 3.5 versus 3.7 +/- 1.7 mmol/L; P = 0.013) and smaller height (-2.1 +/- 1.5 SD versus -0.8 +/- 1.5 SD; P = 0.026). Urolithiasis was diagnosed in 7 cases. Glomerular disease (19/38) was more frequent in cases with severe hypertriglyceridemia (P = 0.042) and occurred at an older age (P = 0.007). Microalbuminuria occurred in 15/31 cases; ACE inhibitors were prescribed in only 8 cases. The frequency of renal complications did not differ according to the diet group (continuous enteral feeding or uncooked starch). Logistic regression concluded as risk factors: lactic acidosis for tubular disease and age > 10 years for glomerular disease. Conclusions. - Renal involvement is common in glycogen storage disease type I patients. Tubular abnormalities are precocious, related to lactic acidosis and may be detected by monitoring of urinary calcium. Glomerular hyperfiltration is the first stage of a progressive glomerular disease and is related to age. Practical implications for renal preservation are discussed based on our results and literature. (C) 2015 Association Societe de nephrologie. Published by Elsevier Masson SAS. All rights reserved

Cause of death in patients with attenuated acid sphingomyelinase deficiency: Comprehensive literature review and report of new cases

Artículo de publicación ISISin acceso a texto complet

Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases (vol 118, pg 206, 2016)

© 2017 The authors regret that the percent of deaths due to respiratory (32.1%) or liver (26.4%) disease in patients with chronic visceral ASMD stated on pages 208 and 209 are incorrect, and instead should match the data shown in Fig. 2D (30.9% and 29.1% for deaths due to respiratory or liver disease, respectively). The authors would like to apologise for any inconvenience caused.status: publishe