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Clinical, biochemical and mutational findings in biotinidase deficiency among Malaysian population.

ABSTRACT: Introduction:Biotinidase deficiency (BD) is an autosomal recessively inherited disorder characterized by developmental delay, seizures, hypotonia, ataxia, skin rash/eczema, alopecia, conjunctivitis/visual problem/optic atrophy and metabolic acidosis. Delayed diagnosis may lead to irreversible neurological damage. Methodology:Clinically suspected patients were screened for biotinidase level by a fluorometry method. Profound BD patients were confirmed by mutation analysis of BTD gene. Results:9 patients had biotinidase activity of less than 77 U. 3 patients (33%) had profound BD while 6 patients (67%) had partial BD. Compound heterozygous mutations were detected at c.98_104delinsTCC p.(Cys33Phefs*36) in Exon 2 and c.833T>C p.(Leu278Pro) in Exon 4 in two patients and a homozygous mutation at c.98_104delinsTCC p.(Cys33Phefs*36) in Exon 2 in another patient. Conclusion:Correct diagnosis lead to early treatment and accurate management of patient. Biochemical screening of BD in symptomatic child is prerequisite to determine enzyme status however molecular confirmation is vital in differentiating individuals with profound biotinidase deficiency from partial biotinidase deficiency and also individuals' carriers.

SUBMITTER: Mardhiah M

PROVIDER: S-EPMC7144277 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Clinical, biochemical and mutational findings in biotinidase deficiency among Malaysian population.

Mardhiah M M Azize Nor Azimah Abdul NAA Yakob Yusnita Y Affandi O O Hock Ngu Lock NL Rowani M R MR Habib Anasufiza A

Molecular genetics and metabolism reports 20191219

<h4>Introduction</h4>Biotinidase deficiency (BD) is an autosomal recessively inherited disorder characterized by developmental delay, seizures, hypotonia, ataxia, skin rash/eczema, alopecia, conjunctivitis/visual problem/optic atrophy and metabolic acidosis. Delayed diagnosis may lead to irreversible neurological damage.<h4>Methodology</h4>Clinically suspected patients were screened for biotinidase level by a fluorometry method. Profound BD patients were confirmed by mutation analysis of <i>BTD< ...[more]

PMID: 32300527

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Project description:IntroductionThe association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity.MethodsAll exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed.ResultsMost individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients.ConclusionsThe variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.

Project description:BACKGROUND: Biotinidase deficiency (BD) is an inborn error of metabolism in which some genetic variants correlate with the level of enzyme activity. Biotinidase activity, however, may be artifactually low due to enzyme lability, premature birth, and jaundice; this hinders both phenotypic classification and the decision to implement therapy. This study sought to characterize the clinical and genetic profile of a sample of Brazilian patients exhibiting reduced biotinidase activity. METHODS: This observational, multicenter study used a convenience sampling strategy, with sequencing of exons 2, 3, and 4 of the BTD gene. RESULTS: The sample comprised 38 individuals with biochemical phenotypes defined a priori on the basis of biotinidase activity in serum/plasma (2 with profound deficiency, 9 with partial deficiency, 15 heterozygous, 1 borderline between partial deficiency and heterozygosity, 2 borderline between heterozygous and normal) or dried blood spot sample (n?=?9, all with unspecified deficiency). Most patients were from Southern Brazil (n?=?29/38) and were identified by neonatal screening (n?=?33/38). Parental consanguinity was reported in two cases. The most commonly found genetic variants were c.1330G?>?C (p.D444H), c.755A?>?G (p.D252G), and c.[511G?>?A;1330G?>?C] (p.[A171T;D444H]), with allele frequencies of 50%, 9.4%, and 5.4% respectively. Three novel pathogenic variants were identified (c.119 T?>?C or p.L40P, c.479G?>?A or p.C160Y, and c.664G?>?A or p.D222N). Twenty-nine patients had two pathogenic variants detected (with cis/trans status ascertained in 26/29), six had only one variant, and three had no pathogenic variants detected. Genotyping confirmed the original phenotypic classification based on enzyme activity in 16/26 cases. Three polymorphic variants were identified in control individuals, of which two were nonpathogenic (c.1171C?>?T or p.P391S and c.1413 T?>?C or p.C471C, with a frequency of 1.5% and 5.5% respectively) and one pathogenic (c.1330G?>?C, frequency 4%). CONCLUSIONS: Our findings suggest that partial BD is the most common form of BD in Brazil, and expand current knowledge on the allelic heterogeneity of this condition.

Project description:Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.

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Clinical, biochemical and mutational findings in biotinidase deficiency among Malaysian population.

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Clinical, biochemical and mutational findings in biotinidase deficiency among Malaysian population.

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