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Molecular Genetics and Metabolism... Dec 2020The biotinidase (BTD) enzyme is essential for recycling biotin, a water-soluble B-complex vitamin that is the coenzyme of four carboxylases involved in fatty acid...
The biotinidase (BTD) enzyme is essential for recycling biotin, a water-soluble B-complex vitamin that is the coenzyme of four carboxylases involved in fatty acid synthesis, amino acid catabolism and gluconeogenesis. If untreated, total or partial BTD deficiencies lead to an autosomal recessive inherited organic aciduria whose clinical features, mainly presenting in the first years of life, include, seizures, skin rash, and alopecia. Based on residual BTD enzyme activity it is possible to identify partial or total biotinidase deficiency. The incidence of profound and partial biotinidase deficiency worldwide is estimated to be about 1 in 60.000. We report twelve years of experience in the newborn screening of biotinidase deficiency on 466.182 neonates. When a positive screening result occurred, a clinical evaluation was made of the patient and genetic counselling was offered to the family. Molecular analysis the BTD gene was carried out in all recalled neonates. Newborn screening lead to the identification of 75 BTD deficiencies with an incidence of about 1:6.300 births, ten times higher than the reported worldwide incidence. BTD deficiency was confirmed at a genomic level in all patients, demonstrating a high frequency of the p.(Asp444His) amino acid substitution and the complex allele p.(Ala171Thr)/p.(Asp444His) in the analyzed Italian newborns. Four new mutations (two small deletions, one stop mutation and one missense mutation) and a new combined allelic alteration were identified. Our data suggests that there is a high incidence of the biotinidase defect in the Italian population, most likely due to the high frequency of certain mutations.
PubMed: 33312878
DOI: 10.1016/j.ymgmr.2020.100689 -
Clinical Biochemistry May 2023This study set out to examine pre-analytical factors affecting the frequency of positive results in newborn screening for biotinidase deficiency. This investigation was...
This study set out to examine pre-analytical factors affecting the frequency of positive results in newborn screening for biotinidase deficiency. This investigation was prompted by an increase in the annual screen positive rate for biotinidase deficiency in Ontario from 2.65x10 in 2016 to 6.57x10 in 2017. Season and trend decomposition was used to separate seasonality from an underlying trend in the time series of biotindase activity measurements for the period 2014-01-12 to 2019-07-27 (n = 798,770). This analysis revealed a marked seasonal effect (winter = median + ⩽ 17 MRU, summer = mean - ⩽20 MRU) and a non-linear negative trend. Seasonal temperature was correlated with biotinidase results (Pearson's r = 0.79) but not with the observed negative trend (Pearson's r = 0.0025). Time series analysis of biotinidase results grouped by print lot of filter paper revealed that recently printed filter paper cards inhibit biotinidase and that this inhibition resolved over time. This study demonstrates that biotindase activity is inhibited by both increased seasonal temperature and collection on newly printed filter cards.
Topics: Humans; Infant, Newborn; Biotinidase; Biotinidase Deficiency; Seasons; Temperature; Neonatal Screening
PubMed: 35398329
DOI: 10.1016/j.clinbiochem.2022.03.010 -
International Journal of Environmental... Jul 2022Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not...
Biotinidase deficiency (BD) is an autosomal recessive inherited disorder in which the enzyme biotinidase is totally or partially defective and the vitamin biotin is not recycled. BD meets the major criteria for a population screening program. Newborn bloodspot screening (NBS) allows early diagnosis of BD, thus preventing the high morbidity and mortality associated with untreated disease. Both profound and partial BD variant can be detected by NBS test, and serum enzyme activity and/or mutational analysis are required for definitive diagnosis. In Italy, BD is included in the screening panel for inborn errors of metabolism (IEMs) that has been declared mandatory in 2016. We analyzed the data of the first 3 years of the NBS for BD in our region (Abruzzo, Italy), with the aim to describe the outcomes of this recently introduced screening program. In over 26,393 newborns screened, we found 2 carriers and 16 cases with genotype associated with partial BD. Since the serum biotinidase assay has been recently introduced in our algorithm, only three of our newborns met the criteria of genetic and biochemical confirmation, with an incidence of 1:8797, which is in the high range of what has been reported in the literature. All affected infants carried the 1330G>C (D444H) variant in compound heterozygosis, with variants known to be associated with profound BD. A variant previously not described and likely pathogenic was found in one newborn. None of the infants had signs or symptoms. The study of the distribution of the enzyme activity in our population allowed us to validate the adopted cutoff with which the program has a positive predictive value of 18% and to analyze some preanalytical factors influencing biotinidase activity: A correlation of the enzyme activity with gestational age and time at specimen collection was found. Lower mean values of enzyme activity were found in infants born in the summer.
Topics: Biotinidase; Biotinidase Deficiency; Humans; Incidence; Infant; Infant, Newborn; Mutation; Neonatal Screening
PubMed: 35805799
DOI: 10.3390/ijerph19138141 -
Molecular Genetics & Genomic Medicine Feb 2021Biotinidase deficiency (OMIM 253260) is an autosomal recessively inherited disorder affecting about 1/60,000 people worldwide. The absence or deficiency of biotinidase...
BACKGROUND
Biotinidase deficiency (OMIM 253260) is an autosomal recessively inherited disorder affecting about 1/60,000 people worldwide. The absence or deficiency of biotinidase impairs free biotin recycling and affects biotin-dependent carboxylase functions.
METHODS
A Chinese patient with spontaneous recurrent epilepsy, an eczema-like rash, hair loss, hypotonia, and hearing loss began at three months of age. Her biotinidase activity was 1.0 nmol/ml/min, 9.5% of the mean control activity, which confirmed profound biotinidase deficiency.
RESULTS
Compound heterozygous for c.250-1G > C and c.878dupT variants in the BTD gene were identified in this patient. These two variants were novel and absent in the population matched controls and any databases.
CONCLUSIONS
This study expanded the mutation spectrum of alterations of the BTD gene. Our patient also emphasized the critical role of biotinidase activity measurement combined with mutation analysis in early diagnosis of biotinidase deficiency.
Topics: Adolescent; Biotinidase; Biotinidase Deficiency; Female; Humans; Mutation; Phenotype
PubMed: 33452876
DOI: 10.1002/mgg3.1591 -
International Journal of Environmental... Feb 2021Biotinidase (BTD) deficiency is an autosomal recessive inherited neurocutaneous disorder. BTD recycles the vitamin biotin, a coenzyme essential for the function of four...
Biotinidase (BTD) deficiency is an autosomal recessive inherited neurocutaneous disorder. BTD recycles the vitamin biotin, a coenzyme essential for the function of four biotin-dependent carboxylases, including propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase. Due to deficient activities of the carboxylases, BTD deficiency is also recognized as late-onset multiple carboxylase deficiency and is associated with secondary alterations in the metabolism of amino acids, carbohydrates, and fatty acids. BTD deficiency can be classified as "profound", with less than 10% of mean normal activity, and as "partial" with 10-30% of mean normal activity. Newborn screening (NBS) of BTD deficiency is performed in most countries and is able to detect both variants. Moreover, mild metabolic alterations related to carboxylase deficiency in profound BTD deficiency could result and possibly be revealed in the metabolic profile by tandem mass spectrometry (MS/MS) NBS. Here, we report the case of a newborn female infant with an initial suspected BTD deficiency at the NBS test, finally confirmed as a partial variant by molecular testing. Although BTD deficiency was partial, interestingly her metabolic profile at birth and during the follow-up tests revealed, for the first time, alterations in specific acylcarnitines as a possible result of the deficient activity of biotin-dependent carboxylases.
Topics: Biotinidase; Biotinidase Deficiency; Carnitine; Female; Humans; Infant; Infant, Newborn; Neonatal Screening; Tandem Mass Spectrometry
PubMed: 33572391
DOI: 10.3390/ijerph18041659 -
Annals of Medicine and Surgery (2012) May 2023Biotinidase deficiency (BTD) is an autosomal recessive disorder and causes the deficiency of four biotin-containing carboxylases. The prevalence is estimated at 1 in...
UNLABELLED
Biotinidase deficiency (BTD) is an autosomal recessive disorder and causes the deficiency of four biotin-containing carboxylases. The prevalence is estimated at 1 in 60 000 births. BTD is associated with a wide spectrum of clinical manifestations, including abnormalities of the neurological, dermatological, immunological, and ophthalmological systems. Spinal cord demyelination as a manifestation of BTD has been infrequently described.
CASE PRESENTATION
The authors present a case of 2.5-year-old boy complained of progressive weakness in all four limbs, with difficulties in breathing.
CLINICAL DISCUSSION
Abdominal examination revealed hepatomegaly and splenomegaly. Also, her parents were first-degree cousins. Therefore, tandem mass spectroscopy and urine organic acid analysis were planned to exclude metabolic disorders. Urinary organic acid analysis revealed elevated levels of methylmalonic acid and 3-hydroxyisovaleric acid. Serum biotinidase activity was found to be 3.9 nmol/min/ml. Oral biotin at a dose of 1 mg/kg daily was initiated. A marked improvement of his neurological deficit was noted over a period of 15 days after treatment and cutaneous manifestations resolved within 3 weeks.
CONCLUSION
Myelopathy due to BTD is a challenging diagnosis. Spinal cord impairment is a rare complication of this disease and is frequently unrecognized. BTD should be included in the differential diagnosis of children presenting with demyelinating spinal cord disease.
PubMed: 37229044
DOI: 10.1097/MS9.0000000000000099 -
Journal of Pediatric Genetics Jun 2022Biotinidase deficiency is a treatable neurometabolic disorder. It usually presents during the first year of life with seizures, ataxia, hypotonia, vision and hearing...
Biotinidase deficiency is a treatable neurometabolic disorder. It usually presents during the first year of life with seizures, ataxia, hypotonia, vision and hearing disturbance, alopecia, and skin rashes. It can have various neuroimaging findings but demyelinating leukoencephalopathy is an unusual finding in children with biotinidase deficiency that can cause diagnostic challenge as it can radiologically mimic perinatal hypoxic-ischemic encephalopathy or other leukodystrophies. It reverses with early diagnosis and treatment with biotin supplementation and the outcome is rewarding.
PubMed: 35769961
DOI: 10.1055/s-0040-1721678 -
Journal of Pediatric Genetics Sep 2022Biotinidase deficiency (BD) is a rare treatable cause of neurometabolic disorders. It is an autosomal recessive disorder that manifests with cutaneous and neurological...
Biotinidase deficiency (BD) is a rare treatable cause of neurometabolic disorders. It is an autosomal recessive disorder that manifests with cutaneous and neurological manifestations. Spinal cord involvement is uncommon with only a few cases reported in the literature. A 6-year-old female child presented with progressive difficulty in walking since 2 months. At 6 months of age, the child was elsewhere evaluated for global developmental delay and suspected as metabolic disorders and started on megavitamins, following which the child was improved. For the past 2 years, she has stopped medicines. On examination, irritable, alopecia, eczema, hypotonia, and power of two-fifths in all four limbs, and exaggerated deep tendon reflexes. The magnetic resonance imaging (MRI) brain and spine showed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities in periaqueductal gray matter, dorsal midbrain, pons, medulla, and cervical cord. She was suspected to have BD and confirmed by low enzyme levels and pathogenic variant in . She was started on biotin supplements that resulted clinically dramatic improvement and MRI became normal within 4 weeks. Any child presenting with acute flaccid paralysis with brainstem and spinal cord noncompressive lesions on MRI, rare treatable conditions like BD should be considered in developing countries, like India, where still no universal newborn screening facilities are available.
PubMed: 35990026
DOI: 10.1055/s-0040-1718537 -
Cureus May 2020Biotinidase deficiency (BTD) is a rare yet treatable metabolic autosomal recessive (AR) disorder in which the body is unable to recycle the vitamin biotin. Early...
Biotinidase deficiency (BTD) is a rare yet treatable metabolic autosomal recessive (AR) disorder in which the body is unable to recycle the vitamin biotin. Early diagnosis and treatment can be life-saving, but some symptoms of the disease are irreversible, and the condition can even prove to be fatal if not correctly diagnosed and managed. Here we present a case of a six-month-old child who presented with cough, fever, and difficulty in breathing. Respiratory examination revealed deep subcostal and intercostal recessions, bilateral crepitations, and wheezes. On central nervous system (CNS) examination, the baby had a low Glasgow Coma Scale (GCS) score of 10 while the tone was decreased, and bulk was increased in all four limbs. Chest X-ray revealed haziness at the right middle and lower lobes. Antibiotics were started keeping pneumonia, bronchiolitis, and sepsis in mind along with an initial diagnosis of inborn error of metabolism (IEM). As the patient's condition deteriorated, nasal bubble continuous positive airway pressure (CPAP) and nebulization were provided and later put on a ventilator. Arterial blood gases (ABGs) showed severe metabolic acidosis and compensatory respiratory alkalosis with an anion gap of 15. Urine profile for organic acid was performed, and the diagnosis of sepsis with BTD was made. Unfortunately, our patient expired on the fourth day of admission before a biotin injection could be searched and administered. Moreover, our patient was also suspected of a possible Sotos syndrome, which is a rare genetic disorder characterized by excessive growth in the initial years of life. The case highlights the significance of the diagnosis of such metabolic disorders in the natal period of life and their immediate management.
PubMed: 32523854
DOI: 10.7759/cureus.8000 -
Indian Journal of Pediatrics Jun 2022Biotinidase deficiency (BD) is an autosomal recessive disorder caused by bi-allelic mutation in the BTD gene. Clinical manifestations in BD mainly depends on residual...
Biotinidase deficiency (BD) is an autosomal recessive disorder caused by bi-allelic mutation in the BTD gene. Clinical manifestations in BD mainly depends on residual biotinidase enzyme activity, although there are some exceptions. Broadly BD disorders are classified as profound BD and partial BD. Further profound BD can be early onset, late onset, and sometimes may be asymptomatic. Clinically late-onset profound BD can present with spectrum of manifestations ranging from single organ to multiple organ involvement, typically affecting function of brain, eye, ear, and skin. Here, a first-born child to consanguineous parents with late-onset profound BD presenting with hyperventilation secondary to lactic acidosis, hypotonia, evolving spasticity, and abnormal neuroimaging findings caused by novel homozygous variant, c.466-3T>G in the BTD gene is reported.
Topics: Alleles; Biotinidase; Biotinidase Deficiency; Child; Homozygote; Humans; Mutation
PubMed: 35032020
DOI: 10.1007/s12098-021-04000-3