1.Expert consensus on screening, diagnosis and treatment of multiple carboxylase deficiency.
Journal of Zhejiang University. Medical sciences 2022;51(1):129-135
Multiple carboxylase deficiency (MCD) includes autosomal recessive holocarboxylase synthetase (HLCS) deficiency and biotinidase (BTD) deficiency, which are caused by and gene mutations respectively. Neonatal screening for HLCS deficiency is based on 3-hydroxyisovaleryl carnitine in dry blood filter paper, and BTD deficiency is based on BTD activity determination. HLCS deficiency and BTD deficiency are characterized by neurocutaneous syndrome and organic aciduria, however, they are different in onset age, neurological symptoms and metabolic decompensation, which needed to be differentiated from acquired biotin deficiency or other genetic metabolic diseases. The diagnosis of the disease requires a combination of biochemical characteristics of hematuria, enzyme activity determination and genetic test. Routine biotin doses are effective for most MCD patients. This consensus is intended to benefit early screening and diagnosis of MCD.
Biotin/therapeutic use*
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Biotinidase Deficiency/therapy*
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Carbon-Nitrogen Ligases/metabolism*
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Consensus
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Holocarboxylase Synthetase Deficiency/genetics*
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Humans
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Infant, Newborn
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Multiple Carboxylase Deficiency/drug therapy*
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Neonatal Screening
2.Diagnosis and treatment of biotinidase deficiency-clinical study of six patients.
Yan-ling YANG ; Seiji YAMAGUCHI ; Yasuko TAGAMI ; Yue-hua ZHANG ; Hui XIONG ; Yuki HASEGAWA ; Masahiko KIMURA ; Junji HANAI ; Kozo FUJITA ; Ning QIAN ; Xiao-ju HE ; Ye WU ; Xin-hua BAO ; Jiong QIN ; Xiru WU
Chinese Journal of Pediatrics 2003;41(4):249-251
OBJECTIVETo investigate the clinical and neurodevelopmental profiles of patients with biotinidase deficiency and to determine the efficacy of current therapy with respect to outcome.
METHODSSix patients aged from 3 months to 14 years with biotinidase deficiency were confirmed by urinary organic acid analysis with gas chromatography/mass spectrometry (GC/MS) and biotinidase assay on dried blood spots. Biotin was supplemented individually (10-40 mg/d). Their clinical features, laboratory findings, and treatment regimen were reviewed.
RESULTSAll the 6 patients presented with some extent of neurological abnormalities and dermatological lesions. Cases 1 - 3 had poor feeding, vomiting, seizures, mental retardation, and lethargy onset from their early infancy, with varied degree of anemia, ketosis, acidosis, and hypoglycemia. Case 2 exhibited eczema and dermatitis from his age of 7 months. Case 4 displayed motor deficit and ataxia after 6 months of age, and generalized pustular psoriasis when he was 8 months old. Cases 5 and 6 gradually showed muscle weakness and paraplegia at the age of 7 years and 5 years, respectively. Inflammatory demyelination changes of cervical cord were evident on magnetic resonance imaging in these two patients. Case 6 had progressive optic atrophy, eczema and alopecia. Remarkable elevations of urinary lactate, pyruvate, 3-OH-propionate, methylcitrate, propionylglycine, 3-OH-isovalerate, 3-methylcrontonylglycine were confirmed in cases 1, 2, 3 and 5. Slight increase of urinary lactate, pyruvate, and 3-methylcrontonylglycine was observed in cases 4 and 6. Biotinidase activities assayed on dried blood spots from all the patients were below 0.1 pmol/(min.3 mm) Biotin supplementation for all the patients, except for case 3 who was not treated, resulted in pronounced and rapid clinical and biochemical improvement. Cases 4 and 6 had residual neurological damage comprising ataxia and motor handicap of legs, due to prolonged disease course.
CONCLUSIONSBiotinidase deficiency intensively impairs nervous system and skin in the affected patients. Urinary organic acid analysis and blood biotinidase assay are crucial to the diagnosis. Early diagnosis and biotin supplementation can contribute significantly to the improvement of prognosis.
Adolescent ; Biotin ; administration & dosage ; therapeutic use ; Biotinidase Deficiency ; diagnosis ; drug therapy ; urine ; Child ; Child, Preschool ; Gas Chromatography-Mass Spectrometry ; Humans ; Infant ; Male ; Treatment Outcome
3.Diagnosis, treatment and gene mutation analysis in children with holocarboxylase synthetas deficiency.
Tong WANG ; Jun YE ; Lian-Shu HAN ; Wen-Juan QIU ; Hui-Wen ZHANG ; Ya-Fen ZHANG ; Xiao-Lan GAO ; Yu WANG ; Xue-Fan GU
Chinese Journal of Contemporary Pediatrics 2009;11(8):609-612
OBJECTIVETo report the clinical diagnosis, treatment and follow-up of children with holocarboxylase synthetas(HCS) deficiency and explore the gene mutation spectrum of the disease.
METHODSEleven children with HCS deficiency were enrolled. Mass spectrometry analysis and biotinidase activity determination were used for diagnosis of HCS deficiency. HCS gene mutations were analyzed by PCR directed sequencing methods. Ten patients received oral biotin treatment (10-40 mg/d). Clinical effects of biotin treatment were observed.
RESULTSAll 11 cases developed apathetic, lethargy and metabolic acidosis at different degrees, and 10 cases presented with skin lesions. The average blood 3-hydroxyisovaleryl-carnitine concentrations and urinary 3-methylcrontonylglycine and methylcitrate concentrations increased significantly. The biotinidase activity increased, being higher over 30% of the normal reference value. Four mutations in HCS gene were identified, and they were c.1522C>T (R508W), c.1088T>A (V363D), c.126G>T (E42D) and c.1994G>C (R665P) (a new variant) and the frequency was 50%, 29%, 7% and 14% respectively. The symptoms disappeared in 10 cases 1-2 weeks after biotin treatment, and blood and urinary abnormal metabolites were gradually reduced to normal 2-6 months after treatment.
CONCLUSIONSHCS deficiency is characterized by nervous system damage, skin lesions and metabolic acidosis. Mass spectrometry analysis, biotinidase activity determination and gene mutation analysis may be helpful in the definite diagnosis of this disorder. The effect of early biotin treatment is satisfactory. The mutations R508W and V363D might be hot-spots in Chinese children with HCS deficiency.
Biotin ; therapeutic use ; Biotinidase ; metabolism ; Carbon-Nitrogen Ligases ; genetics ; Child, Preschool ; Female ; Holocarboxylase Synthetase Deficiency ; diagnosis ; therapy ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation