Expert consensus on screening, diagnosis and treatment of multiple carboxylase deficiency / 浙江大学学报·医学版

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.

Gene variant analysis of a patient with multiple carboxylase deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a patient featuring multiple carboxylase deficiency (MCD).@*METHODS@#PCR and Sanger sequencing were used to detect variant in the coding region of BT and HLCS genes in the patient. Suspected variants were verified in her parents and 80 unrelated healthy controls by a PCR-restriction fragment length polymorphism (PCR-RFLP) method.@*RESULTS@#The patient was found to carry compound heterozygous variants of the HLCS gene, namely c.286delG (p.Val96Leufs*162) and c.1648G>A (p.Val550Met). The c.286delG (p.Val96Leufs*162) was verified to be novel variant based on the result of PCR-RFLP analysis. No variant was found in the coding regions of BT gene in the patient.@*CONCLUSION@#The compound c.286delG (p.Val96Leufs*162) and c.1648G>A (p.Val550Met) variants probably underlie the MCD disorder in this patient. Above results have enriched the variant spectrum of MCA.

Gene mutation analyses in Chinese children with multiple carboxylase deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To confirm the diagnosis of multiple carboxylase deficiency (MCD) on the gene level and explore the mutations in Chinese children with MCD.</p><p><b>METHODS</b>Biotinidase (BT) and holocarboxylase synthetase (HLCS) genes were analyzed by PCR and direct sequencing for the 4 BT deficiency patients and 8 HLCS deficiency patients, respectively. The identified mutations in the parents of the patients and 50 normal controls were screened by PCR-restriction fragment length polymorphism and direct DNA sequencing.</p><p><b>RESULTS</b>Total detection rate of gene mutation is 100% in the 12 children with MCD. Six mutations were detected in the 4 children with BT deficiency, they were c. 98-104del7ins3, c. 1369G>A (V457M), c. 1157G>A(W386X), c. 1284C>A(Y428X), c. 1384delA and c. 1493_1494insT. The last four were novel mutations. Four mutations were found in the 8 children with HLCS deficiency. They were c. 126G>T (E42D), c. 1994G>C (R665P), c. 1088T>A (V363D) and c. 1522C>T (R508W). The last two were hot-spot mutations [75%(12/16)], and c. 1994G>C (R665P) was a novel mutation.</p><p><b>CONCLUSION</b>This study confirmed the diagnosis of 12 patients with MCD on the gene level. Six mutations were found in the BT gene and 4 in the HLCS gene, including 5 novel mutations. Two mutations of the HLCS gene are probably hot-spot mutations in Chinese children with HLCS deficiency.</p>