Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades
Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for...
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| Veröffentlicht in: | Molecular genetics and metabolism 2020-11, Vol.131 (3), p.325-340 |
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| creator | Strauss, Kevin A. Williams, Katie B. Carson, Vincent J. Poskitt, Laura Bowser, Lauren E. Young, Millie Robinson, Donna L. Hendrickson, Christine Beiler, Keturah Taylor, Cora M. Haas-Givler, Barbara Hailey, Jennifer Chopko, Stephanie Puffenberger, Erik G. Brigatti, Karlla W. Miller, Freeman Morton, D. Holmes |
| description | Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p |
| doi_str_mv | 10.1016/j.ymgme.2020.09.007 |
| format | Article |
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Holmes</creator><creatorcontrib>Strauss, Kevin A. ; Williams, Katie B. ; Carson, Vincent J. ; Poskitt, Laura ; Bowser, Lauren E. ; Young, Millie ; Robinson, Donna L. ; Hendrickson, Christine ; Beiler, Keturah ; Taylor, Cora M. ; Haas-Givler, Barbara ; Hailey, Jennifer ; Chopko, Stephanie ; Puffenberger, Erik G. ; Brigatti, Karlla W. ; Miller, Freeman ; Morton, D. Holmes</creatorcontrib><description>Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.</description><identifier>ISSN: 1096-7192</identifier><identifier>EISSN: 1096-7206</identifier><identifier>DOI: 10.1016/j.ymgme.2020.09.007</identifier><identifier>PMID: 33069577</identifier><language>eng</language><publisher>SAN DIEGO: Elsevier Inc</publisher><subject><![CDATA[Arginine ; Carnitine ; Dystonia ; Endocrinology & Metabolism ; Genetics & Heredity ; Glutaric acidemia ; Life Sciences & Biomedicine ; Lysine ; Medical food ; Medicine, Research & Experimental ; Research & Experimental Medicine ; Science & Technology ; Striatal degeneration]]></subject><ispartof>Molecular genetics and metabolism, 2020-11, Vol.131 (3), p.325-340</ispartof><rights>2020 The Authors</rights><rights>Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>33</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000599717700006</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c404t-156909da54770cf906d727a2a34abf5ff2716d474e63c4f1304304a781c529d3</citedby><cites>FETCH-LOGICAL-c404t-156909da54770cf906d727a2a34abf5ff2716d474e63c4f1304304a781c529d3</cites><orcidid>0000-0003-0338-951X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ymgme.2020.09.007$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,28253,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33069577$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Strauss, Kevin A.</creatorcontrib><creatorcontrib>Williams, Katie B.</creatorcontrib><creatorcontrib>Carson, Vincent J.</creatorcontrib><creatorcontrib>Poskitt, Laura</creatorcontrib><creatorcontrib>Bowser, Lauren E.</creatorcontrib><creatorcontrib>Young, Millie</creatorcontrib><creatorcontrib>Robinson, Donna L.</creatorcontrib><creatorcontrib>Hendrickson, Christine</creatorcontrib><creatorcontrib>Beiler, Keturah</creatorcontrib><creatorcontrib>Taylor, Cora M.</creatorcontrib><creatorcontrib>Haas-Givler, Barbara</creatorcontrib><creatorcontrib>Hailey, Jennifer</creatorcontrib><creatorcontrib>Chopko, Stephanie</creatorcontrib><creatorcontrib>Puffenberger, Erik G.</creatorcontrib><creatorcontrib>Brigatti, Karlla W.</creatorcontrib><creatorcontrib>Miller, Freeman</creatorcontrib><creatorcontrib>Morton, D. Holmes</creatorcontrib><title>Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades</title><title>Molecular genetics and metabolism</title><addtitle>MOL GENET METAB</addtitle><addtitle>Mol Genet Metab</addtitle><description>Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.</description><subject>Arginine</subject><subject>Carnitine</subject><subject>Dystonia</subject><subject>Endocrinology & Metabolism</subject><subject>Genetics & Heredity</subject><subject>Glutaric acidemia</subject><subject>Life Sciences & Biomedicine</subject><subject>Lysine</subject><subject>Medical food</subject><subject>Medicine, Research & Experimental</subject><subject>Research & Experimental Medicine</subject><subject>Science & Technology</subject><subject>Striatal degeneration</subject><issn>1096-7192</issn><issn>1096-7206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><recordid>eNqNkF1rVDEQhg-i2Nr6CwTJpSB7OsnJx0bwoixaCwWh7H3IJhPNsudkTXIq--9N3W0vxRDIQJ53hnm67h2FngKVV9v-MP4YsWfAoAfdA6gX3TkFLReKgXz5VFPNzro3pWwBKBWav-7OhgGkFkqdd_c3u7naHB2xLnocoyX1sEdCP5F1RltHnCqxkydpri6NSFIgVC7J3tbYvgpJD5hJ_ZkRiUdnPZbL7lWwu4JvT-9Ft_76Zb36trj7fnO7ur5bOA68LqiQGrS3gisFLmiQXjFlmR243QQRAlNUeq44ysHxQAfg7Vq1pE4w7YeL7sOx7T6nXzOWasZYHO52dsI0F8O4YKC1EqyhwxF1OZWSMZh9jqPNB0PBPLo0W_PXpXl0aUCb5rKl3p8GzJsR_XPmSV4DlkfgN25SKK4JcfiMAYBo42nbrh25irUpS9MqzVNt0Y__H2305yONTedDxGxOCR8zump8iv_c5A-riqUo</recordid><startdate>202011</startdate><enddate>202011</enddate><creator>Strauss, Kevin A.</creator><creator>Williams, Katie B.</creator><creator>Carson, Vincent J.</creator><creator>Poskitt, Laura</creator><creator>Bowser, Lauren E.</creator><creator>Young, Millie</creator><creator>Robinson, Donna L.</creator><creator>Hendrickson, Christine</creator><creator>Beiler, Keturah</creator><creator>Taylor, Cora M.</creator><creator>Haas-Givler, Barbara</creator><creator>Hailey, Jennifer</creator><creator>Chopko, Stephanie</creator><creator>Puffenberger, Erik G.</creator><creator>Brigatti, Karlla W.</creator><creator>Miller, Freeman</creator><creator>Morton, D. 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Holmes</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular genetics and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Strauss, Kevin A.</au><au>Williams, Katie B.</au><au>Carson, Vincent J.</au><au>Poskitt, Laura</au><au>Bowser, Lauren E.</au><au>Young, Millie</au><au>Robinson, Donna L.</au><au>Hendrickson, Christine</au><au>Beiler, Keturah</au><au>Taylor, Cora M.</au><au>Haas-Givler, Barbara</au><au>Hailey, Jennifer</au><au>Chopko, Stephanie</au><au>Puffenberger, Erik G.</au><au>Brigatti, Karlla W.</au><au>Miller, Freeman</au><au>Morton, D. Holmes</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades</atitle><jtitle>Molecular genetics and metabolism</jtitle><stitle>MOL GENET METAB</stitle><addtitle>Mol Genet Metab</addtitle><date>2020-11</date><risdate>2020</risdate><volume>131</volume><issue>3</issue><spage>325</spage><epage>340</epage><pages>325-340</pages><issn>1096-7192</issn><eissn>1096-7206</eissn><abstract>Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.</abstract><cop>SAN DIEGO</cop><pub>Elsevier Inc</pub><pmid>33069577</pmid><doi>10.1016/j.ymgme.2020.09.007</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-0338-951X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Arginine Carnitine Dystonia Endocrinology & Metabolism Genetics & Heredity Glutaric acidemia Life Sciences & Biomedicine Lysine Medical food Medicine, Research & Experimental Research & Experimental Medicine Science & Technology Striatal degeneration |
| title | Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades |
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