Evaluation of the efficiency of serum biotinidase activity as a newborn screening test in Turkey

BackgroundBiotinidase Deficiency (BD) is an autosomal recessive metabolic disorder. However, the relationship between genotype and biochemical phenotype has not been completely elucidated yet. But still, some mutations are accepted to be associated with profound or partial deficiency. We aimed to evaluate the results of biochemical enzyme activity in accordance with the presence of genetic mutations and investigate the correlation between genotype and biochemical phenotype together in the study.MethodsThis retrospective study was carried out using data from medical records of 133 infants detected by the newborn screening followed by serum biotinidase activity (BA) detection with semi-quantitative colorimetric method. Mutation analysis was performed to confirm the diagnosis. In addition, the expected biochemical phenotype based on the known mutant alleles were compared with the observed biochemical phenotype.ResultsWhen confirmed with mutation analysis results, the diagnostic sensitivity and specificity of serum BA with spectrophotometric method was 93.1% and 95.1%, respectively. In 93.98% of the cases conformity was observed between the biochemical phenotype and the genotype. The c.1330 G>C(p.D444H) and c.470 G>A (p.Arg157His) were the most common allelic variants with frequencies of 63.69% and 33.75%, respectively.ConclusionsThe diagnostic test is supposed to have a high sensitivity to identify asymptomatic BD patients. Apparently healthy cases with almost normal enzyme activity and a variant allele in the genetic analysis were reported to present symptoms under stress conditions, which should be kept in mind. This study can be accepted as an informative report as it may contribute to the literature in terms of the allelic frequency and determination of the relation between genotype and biochemical phenotype. Also, method verification including the assessment of possible effects of non-genetic factors on BA according to the certain mutation types is warranted.

Frequency of biotinidase gene variants and incidence of biotinidase deficiency in the Newborn Screening Program in Minas Gerais, Brazil

Objective The prevalence of biotinidase deficiency and the frequency of biotinidase gene variants in Brazil are not documented. We aimed to determine the incidence of partial and profound biotinidase deficiency in the state of Minas Gerais, Brazil, and to calculate the frequency of biotinidase gene variants in the newborn screening program of Minas Gerais. Methods Neonates (1,168,385) were screened from May 2013 to June 2018. Those detected with abnormal biotinidase activity based on semi-quantitative assays underwent confirmatory serum tests. The biotinidase gene was sequenced in all confirmed cases. Results The combined incidence of partial and profound biotinidase deficiency was estimated at 1:13,909 live births (95% confidence limit 1:11,235–1:17,217), much higher than the incidence rates reported in other populations worldwide. The most frequent biotinidase gene variants were p.D444H (allele frequency, 0.016), haplotype c.1330G>C;c.511G>A (p.D444H;A171T), p.D543E, c.310-15delT (intronic), p.V199M, and p.H485Q. Together these accounted for 74.6% of the alleles analysed. Conclusion Newborn screening for biotinidase deficiency, which revealed a higher incidence in Minas Gerais, is feasible and plays a critical role in the early identification of affected neonates and prevention of symptoms and irreversible sequelae. Biotinidase gene sequencing is a useful tool to confirm the diagnosis, and also provides valuable information about genetic variability among different populations.

Investigation of alanine, propionylcarnitine (C3) and 3-hydroxyisovalerylcarnitine (C5-OH) levels in patients with partial biotinidase deficiency

Background Biotinidase deficiency is a treatable metabolic disease that can be seen with various neurological and dermatological complications. Biomarkers such as alanine, propionylcarnitine (C3) and 3-hydroxyisovalerylcarnitine (C5-OH), which are used to diagnose biotinidase deficiency, are also present. Materials and methods In cases with partial biotinidase deficiency and normal biotinidase activity, alanine, C3 and C5-OH levels were compared in the field by liquid chromatography-tandem mass spectrometry. Results There was no significant difference between subjects with partial biotinidase deficiency and those with normal biotinidase activity between C3 and C5-OH levels. The mean alanine levels in heel blood and plasma were significantly higher than those with normal biotinidase activity in patients with partial biotinidase deficiency. Conclusion In cases with partial biotinidase deficiency, the heel blood alanine level that can be detected in the neonatal screening program may be a leading marker in diagnosis.

Wrodzony niedobór biotynidazy o późnym początku – opis przypadku

Biotinidase deficiency is a genetically conditioned congenital disorder of biotin metabolism. The disease is caused by mutations in the BTD-3p25 gene, located on the short strand of chromosome 3. The BTD gene conditions proper biotinidase synthesis. So far, approximately 150 mutations of this gene have been identified. The incidence proportion is one case per 61 000 births, and the carrier state – one case per 120 births. Biotin (vit. H, B7) is essential in numerous metabolic processes. The initial phase of the disease can be acute, chronic including exacerbations/remissions, progressive, and the symptoms can appear at any age. The diagnosis of patients with late-onset disease is particularly difficult, since the symptoms suggest disorders of different nature, especially neurologic. The diagnosis is based on the analysis of clinical symptoms and laboratory tests, including biotinidase activity. The supplementation of biotin is the treatment of choice. It leads to rapid resolution of symptoms and can protect against permanent consequences of the disease such as optic atrophy, hearing loss or retarded psychomotor development.

Twenty-seven mutations with three novel pathologenic variants causing biotinidase deficiency: a report of 203 patients from the southeastern part of Turkey

Background: Biotinidase deficiency (BD) is an autosomal recessive inborn error of metabolism characterized by neurologic and cutaneous symptoms and can be detected by newborn screening. Newborn screening for BD was implemented in Turkey at the end of 2008. Methods: In total, 203 patients who were identified among the infants detected by the newborn screening were later confirmed to have BD through measurement of serum biotinidase activity. We also performed BTD mutation analysis to characterize the genetic profile. Results: Twenty-seven mutations were identified. The most commonly found variants were c.1330G>C (p.D444H), c.1595C>T (p.T532M), c.470G>A (p.R157H), and c.198_104delGCGGCTGinsTCC (p.C33Ffs ) with allele frequencies of 0.387, 0.175, 0.165 and 0.049, respectively. Three novel pathogenic and likely pathogenic variants were identified: p.W140* (c.419G>A), p.S319F (c.956C>T) and p.L69Hfs*24 (c.192_193insCATC). We also identified three mutations reported in just one patient in the past (p.V442Sfs*59 [c.1324delG], p.H447R [c.1340A>G] and p.198delV [c.592_594delGTC]). Although all of the patients were asymptomatic under the treatment of biotin, only one patient, who had the novel c.419G>A homozygous mutation became symptomatic during an episode of acute gastroenteritis with a presentation of ketosis and metabolic acidosis. Among the screened patients, 156 had partial and 47 had profound BD. Conclusions: We determined the mutation spectra of BD from the southeastern part of Turkey. The results of this study add three more mutations to the total number of mutations described as causing BD.

Background History, Clinical Presentation and Laboratory Profile in Cases of Suspected Neurometabolic Disorders

Background : Neurometabolic disorders (NMD) in children may present at any age with a wide range of clinical manifestations. Unexplained or intractable seizure is one of the important associations. Consanguinity, regression of development and sibling death are the clues to suspect neurometabolic disorders when laboratory support is limited. Laboratory findings however, provide the confirmatory diagnosis which is unavailable in Bangladesh.Objectives : To determine the association of consanguinity, regression of development, seizures, EEG findings and other laboratory investigations in children suspected to have neurometabolic disorders and to aid clinicians working in resourcepoor countries.Methodology : A retrospective analysis was done from the records of the patients suspected to have neurometabolic disorders admitted in the department of Neurosciences, Dhaka Shishu Hospital, Dhaka during the period of July 2007 to February 2011. Tandem Mass Spectrometry (TMS), biotinidase activity and other enzyme assay were done through a private laboratory in New Delhi, India.Results : Total 128 children were studied and the parents of 39 (31%) had history of consanguineous marriage. Seizure was associated with 96 (75%) children and abnormal EEG findings were recorded in 83 (65%). Plasma ammonia was done in 98 cases and found to be increased in 53 (54%) cases. Plasma lactate was done in 94 cases and found high in 40 (43%). TMS were done in 111 (85%) children and abnormality were found in 70 (63%) cases. Serum biotinidase activity was advised for 41 children as per TMS result and measured in 25 children of which deficient activity was found in 17(68%); borderline in 4 (16%) and normal activity in 4 (16%) cases.Conclusion: Background history and clinical presentation followed by stepwise laboratory investigation is necessary to identify neurometabolic disorders. Early and appropriate intervention can reduce neurodisability in many situations.Bangladesh J Child Health 2015; VOL 39 (1) :24-29