2.Analysis of clinical phenotypes and MMACHC gene variants in 65 children with Methylmalonic acidemia and homocysteinemia.
Chongfen CHEN ; Yaodong ZHANG ; Lili GE ; Lei LIU ; Xiaoman ZHANG ; Shiyue MEI ; Shuying LUO
Chinese Journal of Medical Genetics 2023;40(9):1086-1092
OBJECTIVE:
To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis.
METHODS:
Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products.
RESULTS:
The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection.
CONCLUSION
Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.
Humans
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Amino Acid Metabolism, Inborn Errors/genetics*
;
Hydrocephalus
;
Oxidoreductases
3.A preliminary study of plasma microRNA levels in children with methylmalonic acidemia.
Yan-Fei LI ; Tao PENG ; Ran-Ran DUAN ; Xiao-Han WANG ; Hui-Li GAO ; Jing-Tao WANG ; Jun-Fang TENG ; Yan-Jie JIA
Chinese Journal of Contemporary Pediatrics 2014;16(6):629-633
OBJECTIVETo screen out differentially expressed microRNAs (miRNAs) in the plasma of children with methylmalonic acidemia (MMA), to determine the expression of miR-9-1 in plasma and to preliminarily evaluate the significance of miR-9-1 as a biomarker in MMA.
METHODSPlasma was obtained from 17 MMA children, 10 hyperhomocysteinemia (HHcy) children without MMA (HHcy group), and 10 normal controls. Of 17 MMA children, 12 had HHcy (MMA+HHcy group), and 5 had no HHcy (MMA group). The differentially expressed miRNAs were screened out by miRNA microarray. Differentially expressed miR-9-1 was selected, and plasma miR-9-1 levels were determined by RT-PCR. Urine was collected from MMA patients who received vitamin B12 treatment, and plasma miR-9-1 levels were determined by RT-PCR after treatment.
RESULTSThe miRNA microarray analysis showed that 26 miRNAs were differentially expressed, among which 16 miRNAs (including miR-9-1) were down-regulated over 2 times, while 10 miRNAs were up-regulated over 2 times. The MMA+HHcy , MMA and HHcy groups had significantly down-regulated miR-9-1 compared with the normal control group (P<0.01). The patients who showed a good response to vitamin B12 treatment had significantly increased plasma miR-9-1 levels, without significant difference compared with the normal control group.
CONCLUSIONSPlasma miR-9-1 is significantly down-regulated in MMA patients, but it is significantly up-regulated after vitamin B12 treatment, suggesting that miR-9-1 may act as a biomarker in monitoring the progression of MMA.
Adolescent ; Amino Acid Metabolism, Inborn Errors ; genetics ; Child ; Female ; Humans ; Hyperhomocysteinemia ; genetics ; Male ; MicroRNAs ; blood
5.A Chinese boy with methylmalonic aciduria cblB type and a novel mutation in the MMAB gene.
Yu-Peng LIU ; Hai-Jun WANG ; Tong-Fei WU ; Xi-Yuan LI ; Jin-Qing SONG ; Yuan DING ; Yao ZHANG ; Qiao WANG ; Yan-Ling YANG
Chinese Journal of Contemporary Pediatrics 2015;17(2):172-175
cblB defect is a rare type of methylmalonic aciduria. In this study, a Chinese boy was diagnosed with methylmalonic aciduria cblB type and a novel mutation in the MMAB gene. The clinical presentations, blood acylcarnitines profiles, urine organic acids and genetic features of the patient were reported. The boy presented with fever, feeding difficulty and lethargy at the age of 2 months. Seven days later, he had coma, cold limb, thrombocytopenia, metabolic acidosis and liver damage. His blood propionylcarnitine and urinary methylmalonic acid levels increased significantly, but the plasma total homocysteine level was in the normal range, which supported the diagnosis of isolated methylmalonic aciduria. Gene analysis was performed by direct sequencing. No mutation in the MUT gene was found. However, a reported mutation c.577G>A (p.E193K) and a novel mutation c.562G>A (p.V188M) in the MMAB gene were identified, which confirmed the diagnosis of methylmalonic aciduria cblB type. Progressive clinical and biochemical improvement has been observed after hydroxylcobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine. He is currently 3 years and 11 months old and has a normal development condition. The phenotypes of the patients with cblB defect are nonspecific. Metabolic analysis and MMAB gene analysis are keys for the diagnosis of the disorder.
Alkyl and Aryl Transferases
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genetics
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Amino Acid Metabolism, Inborn Errors
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genetics
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Humans
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Infant
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Male
;
Mutation
6.Isovaleric acidemia due to compound heterozygous variants of IVD gene in a case.
Fengyu CHE ; Ying YANG ; Zhi WANG ; Guoxia WANG ; Haibin WU ; Liyu ZHANG ; Jiakai WEI ; Yujuan ZHAO ; Jiangang ZHAO
Chinese Journal of Medical Genetics 2021;38(2):150-153
OBJECTIVE:
To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia.
METHODS:
Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene.
RESULTS:
The patient presented with poor weight gain, poor feeding, lethargy, and a "sweaty feet" odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5: 3. 044, reference range 0.04 - 0.4 μmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 - 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported.
CONCLUSION
The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.
Amino Acid Metabolism, Inborn Errors/genetics*
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Child
;
Female
;
Heterozygote
;
Humans
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Isovaleryl-CoA Dehydrogenase/genetics*
;
Male
;
Mutation
7.Current understanding and progress of research on isovaleric acidemia.
Yunfei ZHAO ; Shasha ZHU ; Xinwen HUANG
Chinese Journal of Medical Genetics 2022;39(1):99-102
Isovaleric acidemia is a type of organic acidemia for which the earliest definite diagnosis was attained. It features an autosomal recessive inheritance, with the onset of age varying from newborn to adulthood. The clinical manifestations are complex and variable, which include feeding difficulty, vomiting, lethargy, coma, metabolic acidosis, sweaty feet odor and mental retardation. The mortality and mobility rates of isovaleric acidemia are quite high, and early diagnosis and rational treatment can significantly improve the prognosis. This article has provided a summary for the current understanding and research progress on isovaleric acidemia.
Adult
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Amino Acid Metabolism, Inborn Errors/genetics*
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Humans
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Infant, Newborn
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Isovaleryl-CoA Dehydrogenase/genetics*
8.Analysis of gene variant in an infant with succinic semialdehyde dehydrogenase deficiency.
Dandan YAN ; Xiaowei XU ; Xuetao WANG ; Xinjie ZHANG ; Xiufang ZHI ; Hong WANG ; Yuqing ZHANG ; Jianbo SHU
Chinese Journal of Medical Genetics 2022;39(2):216-221
OBJECTIVE:
To explore the genetic basis for a child with succinate semialdehyde dehydrogenase deficiency.
METHODS:
Peripheral blood samples of the proband and his parents were collected and subjected to Sanger sequencing. High-throughput sequencing was used to verify the gene variants. Bioinformatic software was used to analyze the pathogenicity of the variant sites.
RESULTS:
Sanger sequencing showed that the proband carried a homozygous c.1529C>T (p.S510F) variant of the ALDH5A1 gene, for which his mother was a carrier. The same variant was not detected in his father. However, high-throughput sequencing revealed that the child and his father both had a deletion of ALDH5A1 gene fragment (chr6: 24 403 265-24 566 986).
CONCLUSION
The c.1529C>T variant of the ALDH5A1 gene and deletion of ALDH5A1 gene fragment probably underlay the disease in the child. High-throughput sequencing can detect site variation as well as deletion of gene fragment, which has enabled genetic diagnosis and counseling for the family.
Amino Acid Metabolism, Inborn Errors/genetics*
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Child
;
Developmental Disabilities
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Humans
;
Infant
;
Mutation
;
Succinate-Semialdehyde Dehydrogenase/genetics*
9.Genetic analysis of 21 cases of methylmalonic acidemia.
Xing WANG ; Xiaohong SUN ; Shengju HAO ; Furong LIU ; Qinghua ZHANG ; Lei ZHENG ; Chuan ZHANG
Chinese Journal of Medical Genetics 2022;39(4):362-365
OBJECTIVE:
To carry out genetic analysis for 21 patients with methylmalonic acidemia (MMA) and provide genetic counseling for their families.
METHODS:
Next generation sequencing (panel) was used to detect the pathogenic variants underlying the disease.
RESULTS:
In total 29 variant sites of MMUT, MMAA, MMUT were identified in the 21 patients, with common variants including c.323G>A (10%), c.917C>T (10%), c.984delC (10%) of MMUT gene, and c.609G>A (45%), c.80A>G (10%) , c.567dupT (10%) of MMACHC gene. Among these, c.2000A>G of MMUT, c.298G>T of MMACHC and c.734-7A>G of MMAA gene were unreported previously.
CONCLUSION
Genetic testing for MMA patients can clarify the cause of the disease and provide a basis for the clinical diagnosis. Discovery of novel variants has enriched the mutational spectrum of MMA.
Amino Acid Metabolism, Inborn Errors/genetics*
;
Genetic Testing
;
High-Throughput Nucleotide Sequencing
;
Humans
;
Mutation
;
Oxidoreductases/genetics*
10.Hyperprolinemia type Ⅰ caused by PRODH gene variation: 2 cases report and literature review.
Zhen Hua XIE ; Xian LI ; Meng Jun XIAO ; Jing LIU ; Qiang ZHANG ; Zhen Kun ZHANG ; Yan Ling YANG ; Hai Jun WANG ; Yong Xing CHEN ; Yao Dong ZHANG ; Dong Xiao LI
Chinese Journal of Pediatrics 2023;61(10):935-937