1.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*
2.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
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Female
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Heterozygote
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Humans
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Isovaleryl-CoA Dehydrogenase/genetics*
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Male
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Mutation
3.Pancytopenia and metabolic decompensation in a neonate.
Jian-Qiang TAN ; Da-Yu CHEN ; Zhen-Qin MO ; Zhe-Tao LI ; Ji-Wei HUANG ; Ren CAI ; Ti-Zhen YAN
Chinese Journal of Contemporary Pediatrics 2016;18(11):1150-1153
A 9-day-old male patient was admitted to the hospital because of cough, anhelation, feeding difficulty and lethargy. The diagnostic examinations indicated pulmonary infection, severe metabolic acidosis, hyperglycemia, hyperammonemia and pancytopenia in the patient. Blood and urine screening and isovaleryl-CoA dehydrogenase (IVD) gene detection for inherited metabolic diseases were performed to clarify the etiology. Tandem mass spectrometric screening for blood showed an elevated isovalerylcarnitine (C5) level. The organic acid analysis of urine by gas chromatography-mass spectrometry showed significantly increased levels in isovaleryl glycine and 3-hydroxyisovaleric acid. Homozygous mutations (c.1208A>G, p.Tyr403Cys) in the IVD gene were identified in the patient. His parents were heterozygous carriers. After the treatment with low-leucine diets and L-carnitine for 3 days, the patient showed a significant improvement in symptoms, but he died one week later. It is concluded that the neonates with pneumonia and metabolic decompensation of unknown etiology should be screened for genetic metabolic disease.
Amino Acid Metabolism, Inborn Errors
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diagnosis
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genetics
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Humans
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Infant, Newborn
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Isovaleryl-CoA Dehydrogenase
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deficiency
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genetics
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Male
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Mutation
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Pancytopenia
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etiology
4.Clinical and mutational study of a Chinese infant with isovaleric acidemia.
Wen-juan QIU ; Xue-fan GU ; Jun YE ; Lian-shu HAN ; Hai-tao BAI ; Xia WANG ; Xiao-lan GAO ; Yu WANG ; Jing JIN ; Hui-wen ZHANG
Chinese Journal of Pediatrics 2008;46(7):526-530
OBJECTIVESIsovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. IVA is considered to be a severe, potentially life-threatening disorder that manifests with acute neonatal encephalopathy in approximately half of affected individuals, and recurrent episodes of vomiting, lethargy, coma and varying degrees of developmental delay in the other half of patients. This study was conducted to investigate the clinical features and IVD gene mutations of a Chinese patient with IVA.
METHODSThe clinical features, routine laboratory data, blood amino acid and acylcarnitine profiles and urinary organic acid profiles of a patient with IVA were reviewed. Whole coding exons of IVD gene were PCR-amplified for DNA sequencing. The novel mutation c.466G > C (G127A) was confirmed by RFLP with restriction endonuclease Hph I.
RESULTSThe patient was a 2 year and 7 month-old boy. At 3 days of age, he began to show severe vomiting and acidosis. He was treated with pyloromyotomy at 10 days of age. His recurrent vomiting was not ameliorated until beginning transition to a diet that included more carbohydrate from 4 months. He had 3 recurrent severe vomiting and acidosis later and showed obvious psychomotor retardation. Blood spot acylcarnitine profiles by MS-MS demonstrated an elevation of C5-carnitine with a peak concentration of 12.89 micromol/L (< 0.5 micromol/L). Organic acid analysis of urine by GC-MS revealed a relatively high level of isovaleric glycine. Mutational analysis of the patient's IVD gene revealed heteroallelic mutations of c.149G > A (R21H) and c.466G > C (G127A) which is a novel missense mutation. G127A mutation was not detected in any of 50 normal controls.
CONCLUSIONSFrom the clinical course, obvious elevation of blood C5-carnitine and urine isovaleric glycine, this patient's disorder should be classified as "metabolically severe" type of IVA which suggest that c.466G > C (G127A) mutation could severely damage the function of the IVD protein. To our knowledge, this is the first characterization of IVD gene mutations in the mainland of China.
Amino Acid Metabolism, Inborn Errors ; enzymology ; genetics ; Child, Preschool ; DNA Mutational Analysis ; Exons ; Gas Chromatography-Mass Spectrometry ; Humans ; Isovaleryl-CoA Dehydrogenase ; genetics ; Male ; Mutation ; Tandem Mass Spectrometry
5.Screening and clinical analysis of isovaleric acidemia newborn in Zhejiang province.
Zhenzhen HU ; Jianbin YANG ; Lingwei HU ; Yunfei ZHAO ; Chao ZHANG ; Rulai YANG ; Xinwen HUANG
Journal of Zhejiang University. Medical sciences 2020;49(5):556-564
OBJECTIVE:
To investigate the incidence,clinical,biochemical and genetic characteristics of isovaleric acidemia (IVA) in Zhejiang province.
METHODS:
Between January 2009 and December 2019, a total of 3 510 004 newborns were screened for IVA using tandem mass spectrometry. Patients of IVA were confirmed by urine organic acid and
RESULTS:
A total of 15 patients with IVA were diagnosed, with an incidence of 1/234 000. Three patients had acute neonatal IVA, and the rest were asymptomatic. The isovalerylcarnitine (C5) levels were increased in all patients. Twelve children underwent urinary organic acid analysis, of which 11 cases had elevated isovalerylglycine levels, 4 cases with 3-hydroxyisovalerate increased simultaneously. Eleven IVA patients underwent genetic testing, 9 patients were compound heterozygous variants in
CONCLUSIONS
The clinical manifestations of IVA are non-specific, and the gene spectrum is scattered. Newborn patients screened by tandem mass spectrometry can receive early diagnosis and treatment, so as to correct metabolic defects and pathophysiological changes.
Amino Acid Metabolism, Inborn Errors/epidemiology*
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Child
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China/epidemiology*
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Humans
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Infant, Newborn
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Isovaleryl-CoA Dehydrogenase/genetics*
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Mutation
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Neonatal Screening
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Tandem Mass Spectrometry