Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype-phenotype correlations
Objective Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies. Methods Clinical history and molecular de...
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| Veröffentlicht in: | Annals of neurology 2010-12, Vol.68 (6), p.876-887 |
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| container_title | Annals of neurology |
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| creator | Valstar, Marlies J. Neijs, Sanne Bruggenwirth, Hennie T. Olmer, Renske Ruijter, George J. G. Wevers, Ron A. van Diggelen, Otto P. Poorthuis, Ben J. Halley, Dicky J. Wijburg, Frits A. |
| description | Objective
Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies.
Methods
Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study.
Results
First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype.
Interpretation
We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype‐phenotype correlation was established in this cohort. Ann Neurol 2010 |
| doi_str_mv | 10.1002/ana.22092 |
| format | Article |
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Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies.
Methods
Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study.
Results
First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype.
Interpretation
We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype‐phenotype correlation was established in this cohort. Ann Neurol 2010</description><identifier>ISSN: 0364-5134</identifier><identifier>EISSN: 1531-8249</identifier><identifier>DOI: 10.1002/ana.22092</identifier><identifier>PMID: 21061399</identifier><identifier>CODEN: ANNED3</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adolescent ; Adult ; Aminoacid disorders ; Behavioral Symptoms - etiology ; Biological and medical sciences ; Cells, Cultured ; Child ; Child, Preschool ; Cohort Studies ; DNA Mutational Analysis ; Epilepsy - etiology ; Errors of metabolism ; Female ; Fibroblasts ; Genetic Association Studies ; Genotype ; Hearing Disorders - etiology ; Humans ; Hydrolases - genetics ; Kaplan-Meier Estimate ; Male ; Medical sciences ; Metabolic diseases ; Middle Aged ; Mucopolysaccharidosis III - complications ; Mucopolysaccharidosis III - enzymology ; Mucopolysaccharidosis III - genetics ; Mucopolysaccharidosis III - pathology ; Mutation - genetics ; Neurology ; Phenotype ; Pregnancy ; Regression Analysis ; Severity of Illness Index ; Skin - pathology ; Sleep Wake Disorders - etiology ; Vision Disorders - etiology ; Young Adult</subject><ispartof>Annals of neurology, 2010-12, Vol.68 (6), p.876-887</ispartof><rights>Copyright © 2010 American Neurological Association</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4242-b0a13efbca95f01e9ffc1c131b41a1ed5cb99403cba435d622940ec3e7bee7c43</citedby><cites>FETCH-LOGICAL-c4242-b0a13efbca95f01e9ffc1c131b41a1ed5cb99403cba435d622940ec3e7bee7c43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fana.22092$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fana.22092$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23725816$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21061399$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Valstar, Marlies J.</creatorcontrib><creatorcontrib>Neijs, Sanne</creatorcontrib><creatorcontrib>Bruggenwirth, Hennie T.</creatorcontrib><creatorcontrib>Olmer, Renske</creatorcontrib><creatorcontrib>Ruijter, George J. G.</creatorcontrib><creatorcontrib>Wevers, Ron A.</creatorcontrib><creatorcontrib>van Diggelen, Otto P.</creatorcontrib><creatorcontrib>Poorthuis, Ben J.</creatorcontrib><creatorcontrib>Halley, Dicky J.</creatorcontrib><creatorcontrib>Wijburg, Frits A.</creatorcontrib><title>Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype-phenotype correlations</title><title>Annals of neurology</title><addtitle>Ann Neurol</addtitle><description>Objective
Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies.
Methods
Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study.
Results
First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype.
Interpretation
We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype‐phenotype correlation was established in this cohort. Ann Neurol 2010</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aminoacid disorders</subject><subject>Behavioral Symptoms - etiology</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Cohort Studies</subject><subject>DNA Mutational Analysis</subject><subject>Epilepsy - etiology</subject><subject>Errors of metabolism</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Genetic Association Studies</subject><subject>Genotype</subject><subject>Hearing Disorders - etiology</subject><subject>Humans</subject><subject>Hydrolases - genetics</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Middle Aged</subject><subject>Mucopolysaccharidosis III - complications</subject><subject>Mucopolysaccharidosis III - enzymology</subject><subject>Mucopolysaccharidosis III - genetics</subject><subject>Mucopolysaccharidosis III - pathology</subject><subject>Mutation - genetics</subject><subject>Neurology</subject><subject>Phenotype</subject><subject>Pregnancy</subject><subject>Regression Analysis</subject><subject>Severity of Illness Index</subject><subject>Skin - pathology</subject><subject>Sleep Wake Disorders - etiology</subject><subject>Vision Disorders - etiology</subject><subject>Young Adult</subject><issn>0364-5134</issn><issn>1531-8249</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0E1v1DAQgGELUdGlcOAPoFwQ4pDWYztOzG21gu2qH1wKHC1nMqGGbBzsRLD_npTdtifEybb0zFh6GXsF_BQ4F2eud6dCcCOesAUUEvJKKPOULbjUKi9AqmP2PKXvnHOjgT9jxwK4BmnMgn25mjAModslh3jrom9C8ikbdwNlm81m-T5bdb736LosDYRjnLaZ65vsG_XhDuXD7eGWYYiROjf60KcX7Kh1XaKXh_OEff744WZ1nl9-Wm9Wy8sclVAir7kDSW2NzhQtBzJti4AgoVbggJoCa2MUl1g7JYtGCzG_CCWVNVGJSp6wt_u9Qww_J0qj3fqE1HWupzAlW1UVN6XW5v9SCFmYOecs3-0lxpBSpNYO0W9d3Fng9q63nXvbv71n-_qwdaq31DzI-8AzeHMALs0R2-h69OnRyVIUFejZne3dL9_R7t8_2uX18v7rfD_h00i_HyZc_GF1KcvCfr1e2_Pq6uJiLW-sln8A7J-mrA</recordid><startdate>201012</startdate><enddate>201012</enddate><creator>Valstar, Marlies J.</creator><creator>Neijs, Sanne</creator><creator>Bruggenwirth, Hennie T.</creator><creator>Olmer, Renske</creator><creator>Ruijter, George J. G.</creator><creator>Wevers, Ron A.</creator><creator>van Diggelen, Otto P.</creator><creator>Poorthuis, Ben J.</creator><creator>Halley, Dicky J.</creator><creator>Wijburg, Frits A.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Liss</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TK</scope></search><sort><creationdate>201012</creationdate><title>Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype-phenotype correlations</title><author>Valstar, Marlies J. ; Neijs, Sanne ; Bruggenwirth, Hennie T. ; Olmer, Renske ; Ruijter, George J. G. ; Wevers, Ron A. ; van Diggelen, Otto P. ; Poorthuis, Ben J. ; Halley, Dicky J. ; Wijburg, Frits A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4242-b0a13efbca95f01e9ffc1c131b41a1ed5cb99403cba435d622940ec3e7bee7c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aminoacid disorders</topic><topic>Behavioral Symptoms - etiology</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Cohort Studies</topic><topic>DNA Mutational Analysis</topic><topic>Epilepsy - etiology</topic><topic>Errors of metabolism</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Genetic Association Studies</topic><topic>Genotype</topic><topic>Hearing Disorders - etiology</topic><topic>Humans</topic><topic>Hydrolases - genetics</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Middle Aged</topic><topic>Mucopolysaccharidosis III - complications</topic><topic>Mucopolysaccharidosis III - enzymology</topic><topic>Mucopolysaccharidosis III - genetics</topic><topic>Mucopolysaccharidosis III - pathology</topic><topic>Mutation - genetics</topic><topic>Neurology</topic><topic>Phenotype</topic><topic>Pregnancy</topic><topic>Regression Analysis</topic><topic>Severity of Illness Index</topic><topic>Skin - pathology</topic><topic>Sleep Wake Disorders - etiology</topic><topic>Vision Disorders - etiology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Valstar, Marlies J.</creatorcontrib><creatorcontrib>Neijs, Sanne</creatorcontrib><creatorcontrib>Bruggenwirth, Hennie T.</creatorcontrib><creatorcontrib>Olmer, Renske</creatorcontrib><creatorcontrib>Ruijter, George J. G.</creatorcontrib><creatorcontrib>Wevers, Ron A.</creatorcontrib><creatorcontrib>van Diggelen, Otto P.</creatorcontrib><creatorcontrib>Poorthuis, Ben J.</creatorcontrib><creatorcontrib>Halley, Dicky J.</creatorcontrib><creatorcontrib>Wijburg, Frits A.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Annals of neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Valstar, Marlies J.</au><au>Neijs, Sanne</au><au>Bruggenwirth, Hennie T.</au><au>Olmer, Renske</au><au>Ruijter, George J. G.</au><au>Wevers, Ron A.</au><au>van Diggelen, Otto P.</au><au>Poorthuis, Ben J.</au><au>Halley, Dicky J.</au><au>Wijburg, Frits A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype-phenotype correlations</atitle><jtitle>Annals of neurology</jtitle><addtitle>Ann Neurol</addtitle><date>2010-12</date><risdate>2010</risdate><volume>68</volume><issue>6</issue><spage>876</spage><epage>887</epage><pages>876-887</pages><issn>0364-5134</issn><eissn>1531-8249</eissn><coden>ANNED3</coden><abstract>Objective
Mucopolysaccharidosis (MPS) IIIA (Sanfilippo syndrome type A) is a lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. Information on the natural course of MPS IIIA is scarce, but is much needed in view of emerging therapies.
Methods
Clinical history and molecular defects of all 110 MPS IIIA patients identified by enzymatic studies in the Netherlands were collected and included in this study.
Results
First clinical signs, mainly consisting of delayed speech development and behavioral problems, were noted between the ages of 1 and 6 years. Other symptoms included sleeping and hearing problems, recurrent upper airway infections, diarrhea, and epilepsy. The clinical course varied remarkably and could be correlated with the molecular defects. The frequent pathogenic mutations p.R245H, p.Q380R, p.S66W, and c.1080delC were associated with the classical severe phenotype. Patients compound heterozygous for the p.S298P mutation in combination with 1 of the mutations associated with the classical severe phenotype had a significantly longer preservation of psychomotor functions and a longer survival. Two patients homozygous for the p.S298P mutation, and 4 patients from 3 families heterozygous for 3 missense variants not reported previously (p.T421R, p.P180L, and p.L12Q), showed a remarkably attenuated phenotype.
Interpretation
We report the natural history and mutational analysis in a large unbiased cohort of MPS IIIA patients. We demonstrate that the clinical spectrum of MPS IIIA is much broader than previously reported. A significant genotype‐phenotype correlation was established in this cohort. Ann Neurol 2010</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>21061399</pmid><doi>10.1002/ana.22092</doi><tpages>12</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adolescent Adult Aminoacid disorders Behavioral Symptoms - etiology Biological and medical sciences Cells, Cultured Child Child, Preschool Cohort Studies DNA Mutational Analysis Epilepsy - etiology Errors of metabolism Female Fibroblasts Genetic Association Studies Genotype Hearing Disorders - etiology Humans Hydrolases - genetics Kaplan-Meier Estimate Male Medical sciences Metabolic diseases Middle Aged Mucopolysaccharidosis III - complications Mucopolysaccharidosis III - enzymology Mucopolysaccharidosis III - genetics Mucopolysaccharidosis III - pathology Mutation - genetics Neurology Phenotype Pregnancy Regression Analysis Severity of Illness Index Skin - pathology Sleep Wake Disorders - etiology Vision Disorders - etiology Young Adult |
| title | Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype-phenotype correlations |
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