Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort
Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene ( MMACHC ) c.482G > A mutation in 195 Chinese cases with CblC disease. Methods We carried out a national, retrospective multi...
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| creator | Wu, Sheng-Nan E, Hui-Shu Yu, Yue Ling, Shi-Ying Liang, Li-Li Qiu, Wen-Juan Zhang, Hui-Wen Shuai, Rui-Xue Wei, Hai-Yan Yang, Chi-Ju Xu, Peng Chen, Xi-Gui Zou, Hui Feng, Ji-Zhen Niu, Ting-Ting Hu, Hai-Li Zhang, Kai-Chuang Lu, De-Yun Gong, Zhu-Wen Zhan, Xia Ji, Wen-Jun Gu, Xue-Fan Chen, Yong-Xing Han, Lian-Shu |
| description | Background
The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (
MMACHC
) c.482G > A mutation in 195 Chinese cases with CblC disease.
Methods
We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the
MMACHC
c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months.
Results
Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (
P
A group, while the concentration of urinary methylmalonic acid was slightly lower (
P
> 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (
P
|
| doi_str_mv | 10.1007/s12519-023-00770-2 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11402842</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>38070096</sourcerecordid><originalsourceid>FETCH-LOGICAL-c398t-8bf30a195714fec5c8f12c3a4aadcccf65e157204c50e1c7913bb56cfcbcf18d3</originalsourceid><addsrcrecordid>eNp9Uctu1TAQtRCIlsIPsED-AZex87DDAnQVlRapVTeFreVM7BtXuXFkO1RdIHXLb_Il5HKhgg2L0czRmXNGmkPIaw6nHEC-TVxUvGEgCrZCCUw8Icdc1ZJBreTTdZagmKrq5oi8SOkWoBa8hufkqFAgAZr6mHz7YqI33WjpPNgp5PvZJmqmnoYlY9jtQUoBvcm2p3c-DzQPll5dbdqLluJpqcT5j4fv79fa0N2STfZhekddGMdwx5aZ-okaOpq4tbTtxpb2PlmTLMUwhJhfkmfOjMm--t1PyOePZzftBbu8Pv_Ubi4ZFo3KTHWuAMObSvLSWaxQOS6wMKUxPSK6urK8kgJKrMBylA0vuq6q0WGHjqu-OCEfDr7z0u1sj3bK0Yx6jn5n4r0Oxut_mckPehu-as5LEKoUq4M4OGAMKUXrHsUc9D4NfUhDr2noX2novejN32cfJX_evy4Uh4W0UtPWRn0bljitr_if7U-TxJl3</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Wu, Sheng-Nan ; E, Hui-Shu ; Yu, Yue ; Ling, Shi-Ying ; Liang, Li-Li ; Qiu, Wen-Juan ; Zhang, Hui-Wen ; Shuai, Rui-Xue ; Wei, Hai-Yan ; Yang, Chi-Ju ; Xu, Peng ; Chen, Xi-Gui ; Zou, Hui ; Feng, Ji-Zhen ; Niu, Ting-Ting ; Hu, Hai-Li ; Zhang, Kai-Chuang ; Lu, De-Yun ; Gong, Zhu-Wen ; Zhan, Xia ; Ji, Wen-Jun ; Gu, Xue-Fan ; Chen, Yong-Xing ; Han, Lian-Shu</creator><creatorcontrib>Wu, Sheng-Nan ; E, Hui-Shu ; Yu, Yue ; Ling, Shi-Ying ; Liang, Li-Li ; Qiu, Wen-Juan ; Zhang, Hui-Wen ; Shuai, Rui-Xue ; Wei, Hai-Yan ; Yang, Chi-Ju ; Xu, Peng ; Chen, Xi-Gui ; Zou, Hui ; Feng, Ji-Zhen ; Niu, Ting-Ting ; Hu, Hai-Li ; Zhang, Kai-Chuang ; Lu, De-Yun ; Gong, Zhu-Wen ; Zhan, Xia ; Ji, Wen-Jun ; Gu, Xue-Fan ; Chen, Yong-Xing ; Han, Lian-Shu</creatorcontrib><description>Background
The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (
MMACHC
) c.482G > A mutation in 195 Chinese cases with CblC disease.
Methods
We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the
MMACHC
c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months.
Results
Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (
P
< 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (
P
> 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (
P
< 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group).
Conclusions
The c.482G > A variant in
MMACHC
is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes.
CNU96JjhPhuCQHh9ViZTVJ
Video Abstract (MP4 136794 kb)</description><identifier>ISSN: 1708-8569</identifier><identifier>EISSN: 1867-0687</identifier><identifier>DOI: 10.1007/s12519-023-00770-2</identifier><identifier>PMID: 38070096</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Adolescent ; Amino Acid Metabolism, Inborn Errors - genetics ; Carrier Proteins - genetics ; Child ; Child, Preschool ; China - epidemiology ; Cohort Studies ; Critical Care Medicine ; Female ; Follow-Up Studies ; Homocystinuria ; Humans ; Imaging ; Infant ; Infant, Newborn ; Intensive ; Male ; Maternal and Child Health ; Medicine ; Medicine & Public Health ; Mutation ; Neonatal Screening ; Original ; Original Article ; Oxidoreductases - genetics ; Pediatric Surgery ; Pediatrics ; Phenotype ; Radiology ; Retrospective Studies ; Surgery ; Vitamin B 12 Deficiency - congenital</subject><ispartof>World journal of pediatrics : WJP, 2024-08, Vol.20 (8), p.848-858</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c398t-8bf30a195714fec5c8f12c3a4aadcccf65e157204c50e1c7913bb56cfcbcf18d3</cites><orcidid>0000-0003-4209-5119</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12519-023-00770-2$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12519-023-00770-2$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38070096$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Sheng-Nan</creatorcontrib><creatorcontrib>E, Hui-Shu</creatorcontrib><creatorcontrib>Yu, Yue</creatorcontrib><creatorcontrib>Ling, Shi-Ying</creatorcontrib><creatorcontrib>Liang, Li-Li</creatorcontrib><creatorcontrib>Qiu, Wen-Juan</creatorcontrib><creatorcontrib>Zhang, Hui-Wen</creatorcontrib><creatorcontrib>Shuai, Rui-Xue</creatorcontrib><creatorcontrib>Wei, Hai-Yan</creatorcontrib><creatorcontrib>Yang, Chi-Ju</creatorcontrib><creatorcontrib>Xu, Peng</creatorcontrib><creatorcontrib>Chen, Xi-Gui</creatorcontrib><creatorcontrib>Zou, Hui</creatorcontrib><creatorcontrib>Feng, Ji-Zhen</creatorcontrib><creatorcontrib>Niu, Ting-Ting</creatorcontrib><creatorcontrib>Hu, Hai-Li</creatorcontrib><creatorcontrib>Zhang, Kai-Chuang</creatorcontrib><creatorcontrib>Lu, De-Yun</creatorcontrib><creatorcontrib>Gong, Zhu-Wen</creatorcontrib><creatorcontrib>Zhan, Xia</creatorcontrib><creatorcontrib>Ji, Wen-Jun</creatorcontrib><creatorcontrib>Gu, Xue-Fan</creatorcontrib><creatorcontrib>Chen, Yong-Xing</creatorcontrib><creatorcontrib>Han, Lian-Shu</creatorcontrib><title>Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort</title><title>World journal of pediatrics : WJP</title><addtitle>World J Pediatr</addtitle><addtitle>World J Pediatr</addtitle><description>Background
The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (
MMACHC
) c.482G > A mutation in 195 Chinese cases with CblC disease.
Methods
We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the
MMACHC
c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months.
Results
Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (
P
< 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (
P
> 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (
P
< 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group).
Conclusions
The c.482G > A variant in
MMACHC
is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes.
CNU96JjhPhuCQHh9ViZTVJ
Video Abstract (MP4 136794 kb)</description><subject>Adolescent</subject><subject>Amino Acid Metabolism, Inborn Errors - genetics</subject><subject>Carrier Proteins - genetics</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>China - epidemiology</subject><subject>Cohort Studies</subject><subject>Critical Care Medicine</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Homocystinuria</subject><subject>Humans</subject><subject>Imaging</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Intensive</subject><subject>Male</subject><subject>Maternal and Child Health</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mutation</subject><subject>Neonatal Screening</subject><subject>Original</subject><subject>Original Article</subject><subject>Oxidoreductases - genetics</subject><subject>Pediatric Surgery</subject><subject>Pediatrics</subject><subject>Phenotype</subject><subject>Radiology</subject><subject>Retrospective Studies</subject><subject>Surgery</subject><subject>Vitamin B 12 Deficiency - congenital</subject><issn>1708-8569</issn><issn>1867-0687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9Uctu1TAQtRCIlsIPsED-AZex87DDAnQVlRapVTeFreVM7BtXuXFkO1RdIHXLb_Il5HKhgg2L0czRmXNGmkPIaw6nHEC-TVxUvGEgCrZCCUw8Icdc1ZJBreTTdZagmKrq5oi8SOkWoBa8hufkqFAgAZr6mHz7YqI33WjpPNgp5PvZJmqmnoYlY9jtQUoBvcm2p3c-DzQPll5dbdqLluJpqcT5j4fv79fa0N2STfZhekddGMdwx5aZ-okaOpq4tbTtxpb2PlmTLMUwhJhfkmfOjMm--t1PyOePZzftBbu8Pv_Ubi4ZFo3KTHWuAMObSvLSWaxQOS6wMKUxPSK6urK8kgJKrMBylA0vuq6q0WGHjqu-OCEfDr7z0u1sj3bK0Yx6jn5n4r0Oxut_mckPehu-as5LEKoUq4M4OGAMKUXrHsUc9D4NfUhDr2noX2novejN32cfJX_evy4Uh4W0UtPWRn0bljitr_if7U-TxJl3</recordid><startdate>20240801</startdate><enddate>20240801</enddate><creator>Wu, Sheng-Nan</creator><creator>E, Hui-Shu</creator><creator>Yu, Yue</creator><creator>Ling, Shi-Ying</creator><creator>Liang, Li-Li</creator><creator>Qiu, Wen-Juan</creator><creator>Zhang, Hui-Wen</creator><creator>Shuai, Rui-Xue</creator><creator>Wei, Hai-Yan</creator><creator>Yang, Chi-Ju</creator><creator>Xu, Peng</creator><creator>Chen, Xi-Gui</creator><creator>Zou, Hui</creator><creator>Feng, Ji-Zhen</creator><creator>Niu, Ting-Ting</creator><creator>Hu, Hai-Li</creator><creator>Zhang, Kai-Chuang</creator><creator>Lu, De-Yun</creator><creator>Gong, Zhu-Wen</creator><creator>Zhan, Xia</creator><creator>Ji, Wen-Jun</creator><creator>Gu, Xue-Fan</creator><creator>Chen, Yong-Xing</creator><creator>Han, Lian-Shu</creator><general>Springer Nature Singapore</general><scope>C6C</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>5PM</scope><orcidid>https://orcid.org/0000-0003-4209-5119</orcidid></search><sort><creationdate>20240801</creationdate><title>Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort</title><author>Wu, Sheng-Nan ; E, Hui-Shu ; Yu, Yue ; Ling, Shi-Ying ; Liang, Li-Li ; Qiu, Wen-Juan ; Zhang, Hui-Wen ; Shuai, Rui-Xue ; Wei, Hai-Yan ; Yang, Chi-Ju ; Xu, Peng ; Chen, Xi-Gui ; Zou, Hui ; Feng, Ji-Zhen ; Niu, Ting-Ting ; Hu, Hai-Li ; Zhang, Kai-Chuang ; Lu, De-Yun ; Gong, Zhu-Wen ; Zhan, Xia ; Ji, Wen-Jun ; Gu, Xue-Fan ; Chen, Yong-Xing ; Han, Lian-Shu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-8bf30a195714fec5c8f12c3a4aadcccf65e157204c50e1c7913bb56cfcbcf18d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adolescent</topic><topic>Amino Acid Metabolism, Inborn Errors - genetics</topic><topic>Carrier Proteins - genetics</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>China - epidemiology</topic><topic>Cohort Studies</topic><topic>Critical Care Medicine</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Homocystinuria</topic><topic>Humans</topic><topic>Imaging</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Intensive</topic><topic>Male</topic><topic>Maternal and Child Health</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mutation</topic><topic>Neonatal Screening</topic><topic>Original</topic><topic>Original Article</topic><topic>Oxidoreductases - genetics</topic><topic>Pediatric Surgery</topic><topic>Pediatrics</topic><topic>Phenotype</topic><topic>Radiology</topic><topic>Retrospective Studies</topic><topic>Surgery</topic><topic>Vitamin B 12 Deficiency - congenital</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wu, Sheng-Nan</creatorcontrib><creatorcontrib>E, Hui-Shu</creatorcontrib><creatorcontrib>Yu, Yue</creatorcontrib><creatorcontrib>Ling, Shi-Ying</creatorcontrib><creatorcontrib>Liang, Li-Li</creatorcontrib><creatorcontrib>Qiu, Wen-Juan</creatorcontrib><creatorcontrib>Zhang, Hui-Wen</creatorcontrib><creatorcontrib>Shuai, Rui-Xue</creatorcontrib><creatorcontrib>Wei, Hai-Yan</creatorcontrib><creatorcontrib>Yang, Chi-Ju</creatorcontrib><creatorcontrib>Xu, Peng</creatorcontrib><creatorcontrib>Chen, Xi-Gui</creatorcontrib><creatorcontrib>Zou, Hui</creatorcontrib><creatorcontrib>Feng, Ji-Zhen</creatorcontrib><creatorcontrib>Niu, Ting-Ting</creatorcontrib><creatorcontrib>Hu, Hai-Li</creatorcontrib><creatorcontrib>Zhang, Kai-Chuang</creatorcontrib><creatorcontrib>Lu, De-Yun</creatorcontrib><creatorcontrib>Gong, Zhu-Wen</creatorcontrib><creatorcontrib>Zhan, Xia</creatorcontrib><creatorcontrib>Ji, Wen-Jun</creatorcontrib><creatorcontrib>Gu, Xue-Fan</creatorcontrib><creatorcontrib>Chen, Yong-Xing</creatorcontrib><creatorcontrib>Han, Lian-Shu</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>World journal of pediatrics : WJP</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Sheng-Nan</au><au>E, Hui-Shu</au><au>Yu, Yue</au><au>Ling, Shi-Ying</au><au>Liang, Li-Li</au><au>Qiu, Wen-Juan</au><au>Zhang, Hui-Wen</au><au>Shuai, Rui-Xue</au><au>Wei, Hai-Yan</au><au>Yang, Chi-Ju</au><au>Xu, Peng</au><au>Chen, Xi-Gui</au><au>Zou, Hui</au><au>Feng, Ji-Zhen</au><au>Niu, Ting-Ting</au><au>Hu, Hai-Li</au><au>Zhang, Kai-Chuang</au><au>Lu, De-Yun</au><au>Gong, Zhu-Wen</au><au>Zhan, Xia</au><au>Ji, Wen-Jun</au><au>Gu, Xue-Fan</au><au>Chen, Yong-Xing</au><au>Han, Lian-Shu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort</atitle><jtitle>World journal of pediatrics : WJP</jtitle><stitle>World J Pediatr</stitle><addtitle>World J Pediatr</addtitle><date>2024-08-01</date><risdate>2024</risdate><volume>20</volume><issue>8</issue><spage>848</spage><epage>858</epage><pages>848-858</pages><issn>1708-8569</issn><eissn>1867-0687</eissn><abstract>Background
The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (
MMACHC
) c.482G > A mutation in 195 Chinese cases with CblC disease.
Methods
We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the
MMACHC
c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months.
Results
Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (
P
< 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (
P
> 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (
P
< 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group).
Conclusions
The c.482G > A variant in
MMACHC
is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes.
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Video Abstract (MP4 136794 kb)</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>38070096</pmid><doi>10.1007/s12519-023-00770-2</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-4209-5119</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1708-8569 |
| ispartof | World journal of pediatrics : WJP, 2024-08, Vol.20 (8), p.848-858 |
| issn | 1708-8569 1867-0687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11402842 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adolescent Amino Acid Metabolism, Inborn Errors - genetics Carrier Proteins - genetics Child Child, Preschool China - epidemiology Cohort Studies Critical Care Medicine Female Follow-Up Studies Homocystinuria Humans Imaging Infant Infant, Newborn Intensive Male Maternal and Child Health Medicine Medicine & Public Health Mutation Neonatal Screening Original Original Article Oxidoreductases - genetics Pediatric Surgery Pediatrics Phenotype Radiology Retrospective Studies Surgery Vitamin B 12 Deficiency - congenital |
| title | Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort |
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