[Diagnosis, treatment and gene mutation analysis in children with holocarboxylase synthetas deficiency].
OBJECTIVE
To report the clinical diagnosis, treatment and follow-up of children with holocarboxylase synthetas(HCS) deficiency and explore the gene mutation spectrum of the disease.


METHODS
Eleven 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.


RESULTS
All 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.


CONCLUSIONS
HCS 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.
Wang
Tong
T
Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ye
Jun
J
Han
Lian-Shu
LS
Qiu
Wen-Juan
WJ
Zhang
Hui-Wen
HW
Zhang
Ya-Fen
YF
Gao
Xiao-Lan
XL
Wang
Yu
Y
Gu
Xue-Fan
XF
D001710:Biotin / Q000627:therapeutic use; D043523:Biotinidase / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D028922:Holocarboxylase Synthetase Deficiency / Q000175:diagnosis* / Q000628:therapy; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation
D001710:Biotin; D043523:Biotinidase; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases