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Background: Biotinidase deficiency (BTD) is a rare autosomal recessive metabolic disease, which develops neurological symptoms because of the impaired biotin recycling. Pathogenic mutations on BTD gene cause BTD deficiency. The clinical features and mutation analysis of Pakistani children with BTD deficiency have rarely been described. Herein, for the first time, we report the clinical features, BTD gene mutations and biochemical analysis of seven symptomatic children with BTD deficiency from Pakistan.

Methods: Seven suspected BTD-deficient patients who presented abnormal organic acid profiles and clinical features were subjected to Sanger sequencing to identify pathogenic mutations in the BTD gene. The results were analyzed by Mutation Surveyor Software.

Results: All seven patients exhibited common biotinidase deficiency symptoms including hypotonia, developmental delay and seizures. Biochemical analysis shows marked excretion of 3-hydroxy isovalerate in all cases, followed by 3-hydroxy propionate and methyl citrate. Sanger sequencing revealed one frame-shift mutation, c.98_104delinsTCC (p.Cys33Phefs), and two missense mutations, c.1612C>A (p.Arg538Ser) and c.1330G>C (p.Asp444His). All mutations were in the homozygous state and classified as pathogenic in published studies and mutation databases.

Conclusions: This study has validated the BTD variants as the underlying cause of biotinidase deficiency in which molecular testing of BTD is supported by urinary organic acid analysis and clinical diagnosis. Secondly, the strength of the local availability of this test in Pakistan will paved the way for the neonatal screening of biotinidase deficiency.

Titel:	Sequence variants in the BTD underlying biotinidase deficiency in families of Pakistani origin.
Autor/in / Beteiligte Person:	Moatter, T ; Ahmed, S ; Majid, H ; Jafri, L ; Bilal, M ; Najumuddin ; Faisal ; Khan, AH
Link:	Zum Volltext
Zeitschrift:	The journal of gene medicine, Jg. 26 (2024), Heft 1, S. e3597
Veröffentlichung:	Chichester, UK : John Wiley & Sons,, 2024
Medientyp:	academicJournal
ISSN:	1521-2254 (electronic)
DOI:	10.1002/jgm.3597
Schlagwort:	Infant, Newborn Child Humans Biotinidase genetics Biotinidase metabolism Pakistan Mutation Neonatal Screening Biotinidase Deficiency diagnosis Biotinidase Deficiency genetics Biotinidase Deficiency pathology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [J Gene Med] 2024 Jan; Vol. 26 (1), pp. e3597. <i>Date of Electronic Publication: </i>2023 Sep 26. MeSH Terms: Biotinidase Deficiency* / diagnosis ; Biotinidase Deficiency* / genetics ; Biotinidase Deficiency* / pathology ; Infant, Newborn ; Child ; Humans ; Biotinidase / genetics ; Biotinidase / metabolism ; Pakistan ; Mutation ; Neonatal Screening References: Wolf B, Grier RE, Secor McVoy JR, Heard GS. Biotinidase deficiency: a novel vitamin recycling defect. J Inherit Metab Dis. 1985;8(1):53-58. doi:10.1007/BF01800660. ; Hymes J, Stanley CM, Wolf B. Mutations in BTD causing biotinidase deficiency. Hum Mutat. 2001;18(5):375-381. doi:10.1002/humu.1208. ; Wolf B, Jensen KP, Barshop B, et al. Biotinidase deficiency: novel mutations and their biochemical and clinical correlates. Hum Mutat. 2005;25(4):413. doi:10.1002/humu.9329. ; Wolf B. 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Sequence variants in the BTD underlying biotinidase deficiency in families of Pakistani origin.