A Child Presenting with Mucopolysaccharidosis

The lysosomal storage disorders are a group of diseases that are typified by an accumulation of waste products in the lysosomes. Mucopolysaccharidoses are lysosomal storage disorders due to diverse lysosomal enzyme deficiencies. Ms HT was 2 years and 5 months old when she presented to our metabolic bone clinic with clinical features that were suggestive of a genetic syndrome that was associated with a metabolic bone disease. The urine GAG spot test was positive. The MPS screen identified a reduction in arylsulfatase B activity and sequencing of the ARSB gene detected a pathogenic variant, in keeping with Maroteaux-Lamy syndrome. The diagnosis of MPS is confirmed by urine GAG, enzyme activity analysis and genetic testing. The available treatments include hematopoietic stem cell transplantation, enzyme replacement therapy and surgery. MPSs are heterogeneous, progressive, multisystem diseases for which diagnosis is often delayed. Greater awareness of MPS will enable early diagnosis and treatment. Treatment is however costly and is frequently unavailable to patients in the public sector.

Growth patterns in children with mucopolysaccharidosis Ⅰ and Ⅱ

Background:Mucopolysaccharidosis(MPS)diseases lead to a profound disruption in normal mechanisms of growth and development.This study was undertaken to determine the general growth of children with MPS I and II.Methods:The anthropometric data of patients with MPS I and II(n=76)were retrospectively analyzed.The growth patterns of these patients were analyzed and then plotted onto Polish reference charts.Longitudinal analyses were performed to estimate age-related changes.Results:At the time of birth,the body length was greater than reference charts for all MPS groups(Hurler syndrome,P=0.006;attenuated MPS II,P=0.011;severe MPS II,P<0.001).The mean z-score values for every MPS group showed that until the 30th month of life,the growth patterns for all patients were similar.Afterwards,these growth patterns start to differ for individual groups.The body height below the 3rd percentile was achieved around the 30th month for boys with Hurler syndrome,between the 4th and 5th year for patients with severe MPS H and between the 7th and 8th year for patients with attenuated MPS H.Conclusions:The growth pattern differs between patients with MPS I and H.It reflects the clinical severity of MPS and may assist in the evaluation of clinical efficacy of available therapies.

Successful spinal anesthesia in a patient with mucopolysaccharidosis type I under femoral fracture reduction and external fixation

Introduction:Mucopolysaccharidosis(MPS)is an inherited lysosomal storage disorders with glycosaminoglycans accumulation in tissues.MPS patients undergoing intratracheal intubation anesthesia show high mortality,with serious anesthetic complications associated with airway thickness and narrow.The regional anesthesia is a useful alternative to general anesthesia,however performing spinal anesthesia in MPS patients are rarely documented.Case presentation:We report a case of a boy with MPS type I undergoing femoral reduction and external fixation under spinal anesthesia in combination with sevoflurane inhalational induction,getting rid of difficulties associated with intubation.Conclusion:Sevoflurane inhalational induction with spinal anesthesia without tracheal intubation is a safe choice for MPS I patient.

A boy with mucopolysaccharidosis type Ⅱ accompanied with a novel variation in heparan-N-sulfatase

To the Editor:The mucopolysaccharidosis (MPS) disorders are a group of rare,inherited lysosomal storage disorders in which progressive cellular accumulation of glycosaminoglycans (GAGs) caused by lysosomal enzyme deficiency,leads to multi-organ dysfunction.Each kind of MPS disorder (I-IX) is caused by deficiency of a specific lysosomal enzyme and subsequent degraded GAGs fragments increase in urine,blood,and cerebral spinal fluid.

A new mutation (1062 del 16) of iduronate-2-sulfatase gene from a Chinese patient with Hunter syndrome

Objective: To identify the mutations of iduronate-2-sulfatase (IDS) gene, to reveal its mutation features, and to establish a basis for genetic counseling and prenatal gene diagnosis of Hunter syndrome. Methods: Urine glycosaminoglycans (GAGs) assay, PCR and DNA sequencing were performed to detect mutation of IDS gene of the patient and his parents. Results: The result showed that the patient was: DS(++), HS(++), KS(-), CS(-), and that both of his parents were negative. A frame-shift deletion mutation (1062 del 16) was identified in exon 7 of the patient's IDS gene. His parents' genotypes were normal. Conclusion:The patient's mutation was not inherited by his parents but a novel one. The mutation probably altered the primary structure and tertiary structure of IDS enzyme protein remarkably and lowered the activity of IDS enzyme greatly. Therefore it is supposed to be the direct cause of the disorder.

Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism

Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two genetic disorders of hyaluronan metabolism have been reported in humans: HYAL1 deficiency(Mucopolysaccharidosis IX) in four individuals with joint pathology as the predominant phenotypic finding and HAS2 deficiency in a single person having cardiac pathology. However, inherited disorders and induced mutations affecting hyaluronan metabolism have been characterized in other species. Overproduction of hyaluronan by HAS2 results in skin folding and thickening in shar-pei dogs and the naked mole rat, whereas a complete deficiency of HAS2 causes embryonic lethality in mice due to cardiac defects. Deficiencies of murine HAS1 and HAS3 result in a predisposition to seizures. Like humans, mice with HYAL1 deficiency exhibit joint pathology. Mice lacking HYAL2 have variably penetrant developmental defects, including skeletal and cardiac anomalies. Thus, based on mutant animal models, a partial deficiency of HAS2 or HYAL2 might be compatible with survival in humans, while complete deficiencies of HAS1, HAS3, and HYAL3 may yet be recognized.

Cardiac Complications in Maroteaux-Lamy Syndrome： Case Report

MLS （Maroteaux-Lamy syndrome） or MPS VI （mucopolysaccharidosis VI） is an autosomal recessive pathology in which there is absence or low activity of the enzyme N-Acetylgalactosamine-4-Sulfatase, which hydrolyzes GAGs （glycosaminoglycans） in the body （mainly dermatan sulfate）. Consequently, there occurs lysosomal deposition of GAGs in connective tissue multisystemic. Myocardium and heart valves are frequently affected structures, presenting a direct correlation with the reports of complications and deaths. Case report： RGS, male, 3 years and 2 months, diagnosed with MPS VI from the first month of life, in weekly ERT （enzyme replacement therapy） since 4 months of age （inconstant）. At physical examination： normotensive, with holosystolic heart murmur 3＋/6＋ in mitral focus. Complementary tests： normal electrocardiogram, echocardiogram with pronounced mitral regurgitation, concentric left ventricular hypertrophy of moderate degree and mild aortic insufficiency. Discussion： Mitral valve disease is common in patients with MLS. Conditions such as cardiomyopathy, fibroelastosis, aneurysm and pulmonary hypertension may occur in these patients, indicative of morbidity and mortality. Early and constant ERT may be useful in slowing a progression of heart disease. Conclusions： follow-up with a cardiologist is important to evaluate the progression of cardiac complications in MPS VI. Constant and early ERT provides better prognosis for these patients.

Genetic Analysis of 17 Children with Hunter Syndrome:Identification and Functional Characterization of Four Novel Mutations in the Iduronate-2-Sulfatase Gene

Mucopolysaccharidosis type II （MPS II） is a rare X-linked disorder caused by alterations in the iduronate-2-sulfatase （IDS） gene. In this study, IDS activity in peripheral mononuclear blood monocytes （PMBCs） was measured with a fluorimetric enzyme assay. Urinary glycosaminoglycans （GAGs） were quantified using a colorimetric assay. All IDS exons and intronic flanks were bidirectionally sequenced. A total of 15 mutations （all exonic region） were found in 17 MPS II patients. In this cohort of MPS II patients, all alterations in the IDS gene were caused by point nucleotide substitutions or small deletions. Mutations p.Arg88His and p.Arg172＊ occurred twice. All mu- tations were inherited except for p.Gly489Alafs＊7, a germline mutation. We found four new mutations （p.Ser142Phe, p.Arg233Gly, p.Glu430＊, and p.Ile360Tyrfs＊31）. In Epstein-Barr virus （EBV）-immortalized PMBCs derived from the MPS II patients, no IDS protein was detected in case of the p.Ser142Phe and p.Ile360Tyrfs＊31 mutants. For p.Arg233Gly and p.Glu430＊, we observed a residual expression of IDS. The p.Arg233Gly and p.Glu430＊ mutants had a residuary enzymatic activity that was lowered by 14.3 and 76-fold, respectively, compared with healthy controls. This observation may help explain the mild disease phenotype in MPS II patients who had these two mutations whereas the p.Ser142Phe and p.Ile360Tyrfs＊31 mutations caused the severe disease manifestation.

Update of the spectrum of mucopolysaccharidoses type Ⅲ in Tunisia: identification of three novel mutations and in silico structural analysis of the missense mutations

Background:Mucopolysaccharidoses type Ⅲ (MPS Ⅲ) are a group of autosomai recessive lysosomal storage diseases,caused by mutations in genes that code for enzymes involved in the lysosomal degradation of heparan sulphate:heparan sulfate sulfamidase (SGSH),a-N-acetylglucosaminidase (NAGLU),heparan sulfate acetyl-CoA:a-glucosaminide N-acetyltransferase (HGSNAT),and N-acetylglucosamine-6-sulfatase (GNS).Methods:In this study,we have performed the molecular analysis of the SGSH,NAGLU and HGSNAT genes in 10 patients from 6 different MPS Ⅲ Tunisian families.Results:In the SGSH gene,two mutations were identified:one novel (p.D477N) and one already described (p.Q365X).In the NAGLU gene,two novel mutations were discovered (p.L550P and p.E153X).For the novel missense mutations found in these two genes we performed an in silico structural analysis and the results were consistent with the clinical course of the patients harboring those mutations.Finally,in HGSNAT gene,we found the splicesite mutation c.234+1G>A that had already been reported as relatively frequent in MPS ⅢC patients from countries surrounding the basin of the Mediterranean sea.Its presence in two Tunisian MPS ⅢC families points to the hypothesis of its peri Mediterranean origin.With the exception of the c.234+1G>A mutation,that was identified in two unrelated MPS ⅢC families,the other identified mutations were family-specific and were always found in homozygosity in the patients studied,thus reflecting the existence of consanguinity in MPS Ⅲ Tunisian families.Conclusions:Three novel mutations are reported here,further contributing to the knowledge of the molecular basis of these diseases.The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis,leading to an improvement in genetic counseling.

Detection of a new mutation(T1140C)in a patient with Hunter syndrome from Guangdong,China

This study identified mutations of the idurnate-2-sulfatase(IDS)gene in a patient with Hunter syndrome,and established a basis for the diagnosis of the prenatal gene of Hunter syndrome.Urine glyeosaminoglycan(GAG)assay was used to make the preliminary diagnosis of mucopolysac-charidosis type II.Polymerase chain reaction(PCR)from dried blood spots and DNA sequencing were applied to analyze hotspot mutations in exons 9,3 and 8 of the IDS gene in the proband and his parents.A new missense mutation(T1140C)in exon 8 of the IDS gene was found by using DNA sequencing.This mutation caused a substitution of codon 339 from CTA(leucine)to CCA(praline).The patient is a hemi-zygote,and his mother is a heterozygote.The new missense mutation results in a change in the primary and tertiary struc-ture of the IDS protein.It is possible that this mutation severely impairs enzymatic activity and is the underlying basis for the pathology seen in this patient with Hunter syndrome.