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Deficiency of the biotinidase (BTD) enzyme is an inborn error of biotin metabolism caused by biallelic pathogenic variants in the BTD gene. There are two forms, partial and profound BTD deficiency, which both can be successfully treated with pharmacological doses of biotin, justifying the inclusion of this disorder in the newborn screening in numerous countries. We investigated the BTD deficiency cohort (N = 87) in our metabolic center, as it was detected upon newborn screening since 2005, and aimed to better understand the long-term course of BTD enzyme activity and how it may relate to the patients' genetic background. We observed that individuals with partial BTD deficiency display an elevation of BTD enzyme activity with increasing age in 48% of cases-a recovery which allowed adjustment or stop of biotin supplementation in 20% of all individuals. In addition, we were able to recruit 56 patients (64%) for genetic testing, revealing 19 different variants (2 novel), and constituting 22 different genotypes. Genotype-phenotype correlations revealed that the most abundant allele in our cohort p.(Asp444His) was also the most common variant in patients displaying recovery of BTD enzyme activity. Based on our results, we recommend to retest all patients with partial BTD deficiency at the age of 5 years, as this may result in an impact on therapy. Moreover, genetic testing of BTD deficient individuals can allow prediction of the severity of BTD deficiency and of the likelihood of BTD enzyme activity recovery with age., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Biotinidase deficiency is an autosomal recessive metabolic disorder included in many newborn screening programmes. Prior to the introduction of screening for biotinidase deficiency in Sweden in 2002, the disorder was almost unknown, with only one case diagnosed clinically. Biotinidase activity was measured in dried blood spots with a semiquantitative method using biotin-6-amidoquinoline as substrate. The cutoff value was set at 25% (later lowered to 20%) of the mean activity of all samples measured on that day. The disorder was confirmed by quantitative determination of biotinidase activity in plasma and DNA analyses. Over a period of 6 years, 13 patients were identified among 637,452 screened newborns and 5,068 adoptive/immigrant children. None of the patients had clinical symptoms at the time of diagnosis. Six patients had profound biotinidase deficiency, with an activity of 0-5% of normal in plasma. Four of these patients were born to parents who were first cousins of Middle Eastern or African origin. Eighteen gene alterations were identified, nine of which have not previously been described: seven mutations p.L83S (c.248T > C), p.R148H (c.443G > A), p.N202I (c.605A > T), p.I255T (c.764T > C), p.N402S (c.1205A > G), p.L405P (c.1214T > C), p.G445R (c.1333G > A) and two silent mutations p.L71L (c.211C > T) and p.L215L (c.645C > T). The predicted severity of the novel mutations was analyzed by sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), predicting p.L83S, p.L405P and p.G445R as severe mutations. Due to the high rate of immigrants since 1990 from non-Nordic countries, the incidence of biotinidase deficiency is similar to that found in many other Western countries.

Biotinidase deficiency, an autosomal recessively inherited disorder, is characterized by neurologic and cutaneous symptoms and can be detected by newborn screening. In Hungary the national screening programme was launched in 1989 with two screening centres. Over 1,070,000 neonates from western Hungary were screened for biotinidase deficiency in the Budapest Screening Centre between 1989 and December 2008. In this period, 57 patients with profound or partial biotinidase deficiency from 50 families were identified through routine newborn screening. The incidence of the disorder in western Hungary is 1 in 18,700, which is about three times the worldwide incidence. Twenty-four different mutations were identified in patients including the c.406delC novel mutation in exon 3, which is a frameshift mutation. To better understand the background of the unusually high disease incidence, 100 healthy subjects from the Hungarian population were screened by PCR and RFLP for the frequencies of p.D444H, p.Q456H and p.A171T;p.D444H, the three most common BTD mutations. The frequencies were found to be 5.5, 0.5 and 0%, respectively. The results demonstrate that the frequencies of two of the most common biotinidase variant alleles are higher in the Hungarian population than in other Caucasian populations. This and the presence of a unique Hungarian mutation may explain the high incidence of biotinidase deficiency in Hungary.

Objective: To report the clinical course and explore the gene mutation spectrum of four Chinese children with biotinidase deficiency., Methods: Four Chinese patients aged 4 months to 8 years were referred to this study. Tandem mass spectrometry, gas chromatography-mass spectrometry and the determination of biotinidase activities were performed for selective screening of biotinidase deficiency. Four patients with biotinidase deficiency were diagnosed, treated with biotin and followed., Results: (1) Four patients with biotinidase deficiency were diagnosed by characteristic metabolites, such as elevated blood levels of 3-hydroxyisovalerylcarnitine (6.22 +/- 3.1 mumol/L), elevated 3-methylcrontonylglycine, methylcitrate and 3-hydroxypropionate in urine and very low biotinidase activities. (2) These patients have been treated with biotin for 1-8 years; two of them still have mental retardation, and two have irreversible hearing or vision disability. (3) In the four patients, six different mutations in the biotinidase gene were identified: c.98G:del7ins3, c.1369G>A (p. V457M), c.1384delA, c.1493_1494insT, c.1284C>A (p.Y428X) and c.1157G>A (p.W386X). The latter four mutations are novel variations. Seven out of eight mutations are located on exon 4 of the biotinidase gene., Conclusions: Early recognition of biotinidase deficiency is crucial to avoid permanent damage. Determination of biotinidase activity should be included in neonatal screening in China. Exon 4 may be a hot-spot for biotinidase gene mutations in Chinese patients. Four novel gene variations may be disease-causing mutations and should be confirmed by expression studies.

This report outlines the status of neonatal screening in Europe in 2004. Out of the 45 member states of the Council of Europe plus the regions Scotland and Wales (in total 47 'countries'), no data at all were available from 3 (Albania, Azerbaijan and Georgia). From the other 44, varying amounts of data were received. Apart from Armenia, Finland and Malta, all countries have a national programme for phenylketonuria (PKU), although in some countries those programmes do not yet have 100% coverage. Moldova and Ukraine have no national programme for congenital hypothyroidism (CH), the other countries do. Twelve countries screen for congenital adrenal hyperplasia (CAH), 6 for cystic fibrosis (CF) and 7 for galactosaemia (GAL), 6 for biotinidase deficiency (BD) and 4 for medium-chain acyl-CoA dehydrogenase deficiency (MCAD). Some countries have pilot programmes for certain conditions or different programmes per screening laboratory. The prevalences for PKU vary from 1:3000 to 1:30,000, and for CH from 1:1300 to 1:13,000. Methodologies vary within and between countries. There appears to be no relationship between the cut-off limits and the recall rate. A first priority is to help those countries where the basic screening programmes have less than 100% coverage. In addition, continuous monitoring of the European programmes will help to decrease the variation in design and methodology by making use of the knowledge and expertise available from the global membership of the International Society for Neonatal Screening (ISNS). The huge difference of recall rates illustrate one obvious and important area for improvement of programme performances that could be aided by strengthened European cooperation.

Two cases of molecular genetically proven lipoprotein lipase deficiency are reported. Both patients were detected owing to a false-positive neonatal screening test for biotinidase deficiency. We conclude that both the fluorimetric and the colorimetric screening tests for biotinidase deficiency used with dried blood samples are affected by severe hyperchylomicronaemia and that, most probably, severe plasma turbidity interferes with the assay.

A group of 28 patients with inherited metabolic disease (homocystinuria galactosaemia, maple syrup urine disease and biotinidase deficiency) diagnosed by screening were compared with a group of 17 similar patients identified clinically. The rate of hospitalization was similar for the two groups. The patients diagnosed clinically showed a higher incidence of mental retardation and their parents experienced greater stress and found greater difficulty in meeting their child's needs.