Article

Biotinidase deficiency: The importance of adequate follow-up for an inconclusive newborn screening result

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Unlabelled: Biotinidase deficiency is an inherited metabolic disorder characterized by inability to recycle protein-bound biotin. It usually presents with ataxia and seizures, though atypical presentations have also been described. We report a 15-month-old boy with profound biotinidase deficiency who presented with laryngeal stridor and subsequently developed severe ataxia and lactic acidosis. Subsequently, it was discovered that the patient's newborn screening test for biotinidase activity had been inconclusive, but confirmatory testing had not been done. Brain magnetic resonance imaging showed multiple white matter non-enhancing T2 hyperintensities, which largely resolved following 6 months of biotin therapy; however, there was residual deafness and mental retardation. Conclusion: An argument is made for universal newborn screening in biotinidase deficiency and improved mechanisms for follow-up of positive screens, because delay in diagnosis results in irreversible morbidity, newborn screening is cost effective, and early therapy prevents the neurologic sequelae.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... iotinidase deficiency is an autosomal recessive metabolic disease causing the deficiency of biotin which acts as a cofactor for carboxylases including propionyl-CoA carboxylase, methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and acetyl-CoA carboxylase (1)(2)(3)(4) . The exact diagnosis of the lack of biotinidase is made by demonstrating the absence of enzyme activity in the serum. ...
... The lack of biotin causes multiple carboxylase deficiency resulting in lactic acidosis and organic aciduria (2) . If untreated, individuals with biotinidase deficiency usually develop skin rash, alopecia, ataxia, seizures, respiratory problems, fungal infections, developmental delay, hypotonia and also hearing loss and visual problems such as optic atrophy (3)(4)(5) . The disease may also lead to death from lactic acidosis (2) . ...
... The disease may also lead to death from lactic acidosis (2) . The reported age at presentation is from the second week of life in neonates (2) , but the typical age of presentation ranges from 3 to 12 months (4) . Fortunately, early diagnosis and treatment with pharmacological doses of oral biotin can prevent all symptoms if treatment is initiated at birth or before the symptoms develop; but the hearing loss, visual abnormalities and neurological sequelae do not appear to be reversible once they occur -even with biotin therapy (3)(4)(5) . ...
Article
Full-text available
Biotinidase deficiency is an autosomal recessive metabolic disease that causes biotin deficiency. The exact diagnosis of the lack of biotinidase is made by demonstrating the absence of enzyme activity in the serum. Biotinidase deficiency is treated with oral biotin taken for lifetime. Early diagnosis and treatment are very important and prevent a number of complications. In this case report, a newborn baby was referred for periodic healthcare assessments to a family medicine centre, where biotinidase deficiency was diagnosed. Screening performed as part of periodic health assessment in the primary care setting is important for the detection of certain diseases, as many disease-related disabilities can be prevented with early diagnosis. In family practice, “shared decision-making,” which represents one of the elements of the patient-centred clinical method, is very effective, provided that patients and their relatives adapt to preventive healthcare.
... p.Cys33PhefsTer36 is a variant resulting from a reading frame change and premature termination of protein synthesis in exon 2 due to the deletion of the coding sequence from G at position 98 to G at position 104 and insertion of the TCC sequence [39]. This change results in a profound biotinidase deficiency [23,31,38], the enzymatic activity of patients who are homozygotes of the p.Cys33PhefsTer36 variant is close to 0% [28,[40][41][42]. Eight Hungarian patients with the p.Cys33PhefsTer36/p.Asp444His genotype have been shown with enzyme activity between 10% and 17% [33]. ...
... A case of a symptomatic patient diagnosed with profound biotinidase deficiency who was a p.Cys33PhefsTer36/Cys33PhefsTer36 homozygote has been described [41]. Neurological abnormalities-including hearing loss and central nervous system lesions-predominated among the symptoms that appeared at 15 months of age. ...
Article
Full-text available
Biotinidase deficiency (BD) is a rare autosomal recessive metabolic disease. Previously the disease was identified only by clinical signs and symptoms, and since recently, it has been included in newborn screening programs (NBS) worldwide, though not commonly. In Europe, BD prevalence varies highly among different countries, e.g., from 1:7 116 in Turkey to 1:75 842 in Switzerland. This paper aimed to present the molecular spectrum of BD (profound and partial forms) in Polish patients diagnosed within the national NBS of 1,071,463 newborns. The initial suspicion of BD was based on an abnormal biotinidase activity result determined in a dry blood spot (DBS) by colorimetric and by fluorimetric methods while biochemical verification was determined by serum biotinidase activity (as quantitative analysis). The final diagnosis of BD was established by serum enzyme activity and the BTD gene direct sequencing. The obtained results allowed for the estimation of disease prevalence (1:66,966 births, while 1:178,577 for profound and 1:107,146 for partial forms), and gave novel data on the molecular etiology of BD.
... Enzyme activity o10% of normal is consistent with profound deficiency, providing that the proper controls were in place to exclude sample mishandling as the source of decreased activity. 84,91 Confirmation by molecular testing is often useful, but may not be necessary in all cases. ...
Article
Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these Standards and Guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory scientists and geneticists are encouraged to document in the patient’s record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
... Enzyme activity Ͻ10% of normal is consistent with profound deficiency, providing that the proper controls were in place to exclude sample mishandling as the source of decreased activity. 57,64 Confirmation by molecular testing is often useful but may not be necessary in all cases. ...
Article
Biotinidase deficiency is an autosomal recessively inherited disorder of biotin recycling that is associated with neurologic and cutaneous consequences if untreated. Fortunately, the clinical features of the disorder can be ameliorated or prevented by administering pharmacological doses of the vitamin biotin. Newborn screening and confirmatory diagnosis of biotinidase deficiency encompasses both enzymatic and molecular testing approaches. These guidelines were developed to define and standardize laboratory procedures for enzymatic biotinidase testing, to delineate situations for which follow-up molecular testing is warranted, and to characterize variables that can influence test performance and interpretation of results.
... Clinicians should actively work to eliminate incorrect and inaccurate NBS program nicknames. Likewise, failure to timely and adequately follow-up NDBS results has been reported to result in adverse consequences, including unnecessary surgery, dehydration, pneumonia and at least one death [84,85]. The lack of a NDBS result should never be interpreted as a sign that increased risk for screened conditions is absent. ...
Article
Full-text available
Newborn screening (NBS) serves as an important preventive public health program to assist families in obtaining early diagnoses, medical interventions and services for newborns affected with rare congenital conditions. Recent advances in screening techniques using tandem mass spectrometry have vastly increased the number of metabolic conditions that can be detected at birth and many NBS programs have expanded their screening panels accordingly, some now screening for more than 50 conditions. Ongoing program expansions and continuing advances in screening technology and medical care means that today, more than ever, clinicians must be fully informed about NBS. We review some of the issues impacting NBS in the USA as food for thought for clinicians faced with fulfilling their expanded role in NBS systems support. This article reviews the current status of NBS using experiences in the USA as an example of how current NBS systems are changing throughout the world. We provide information on recent publications of interest, significant policy and program issues and resources available to assist in coping with NBS advances. For clarification, we will refer to the classical form of NBS (i.e., laboratory analyses from dried blood spots) as newborn dried blood-spot screening (NDBS) and screening for congenital hearing deficiencies in newborns as newborn hearing screening (NHS). The abbreviation 'NBS' Will be used to denote the more comprehensive integrated system that can include both NDBS and NHS. Use of the term 'state programs' refers to programs in the 50 US states and the District of Columbia (i.e., a total of 51 state programs nationally).
... Furthermore, screening and treatment are both inexpensive and effective, and the incidence of the disease is well within the range of other similar metabolic diseases for which screening is performed in the neonatal period [21]. Even when the test result is inconclusive, the treatment with biotin, which is extremely cheap, can result in unpredictable significant clinical improvement [33,41]. Counterarguments on the other hand insist that the current test is not cost-effective enough, that the true prevalence of BTD is unclear and that further clinical research is required [25]. ...
Article
Full-text available
Biotinidase deficiency (BTD) is an autosomal recessive metabolic disorder characterized by neurodevelopmental and cutaneous disorders. Individuals with a biotinidase deficiency have either homozygous or compound heterozygous variants of biotinidase (BT) enzyme. We aimed to analyze the pattern and outcome of investigations for BTD among for children and young people in a Scottish NHS Board. We retrospectively analysed the clinical and laboratory data of all children within the Fife area who were screened for BTD between July 2014 and July 2016. BTA levels ranged between 2.7 and 14.1 nmol/min/mL from a total of 191 patients. 262 tests were requested for 243 children aged between 1 month and 17 years-6 months (Mean 70 months). 75 of the samples (29%) were ordered to be repeated. 59 samples from 53 patients (22%) could not be analysed for reasons including “insufficient sample” (34), “unsuitable bottle” (10), “missed in error” (7), and “samples leaked in transit” (3). The commonest indications for the BTD screening were developmental delay (63%) and social communication concerns (49%). The commonest professionals requesting the tests were the either the consultant or specialist Community Paediatricians (93%). None of the 191 patients analysed had BTD. However a substantial proportion of the patients (22%) could not be analysed due to various problems with their blood samples. It is therefore difficult to determine precisely the prevalence of BT deficiency in this small cohort of children and adolescents. A larger prospective study is required to verify the true prevalence of BTD in the population. Biotinidase deficiency (BTD) is an autosomal recessive metabolic disorder characterized by neurodevelopmental and cutaneous disorders. Individuals with a biotinidase deficiency have either homozygous or compound heterozygous variants of biotinidase (BT) enzyme. We aimed to analyze the pattern and outcome of investigations for BTD among for children and young people in a Scottish NHS Board. We retrospectively analysed the clinical and laboratory data of all children within the Fife area who were screened for BTD between July 2014 and July 2016. BTA levels ranged between 2.7 and 14.1 nmol/min/mL from a total of 191 patients. 262 tests were requested for 243 children aged between 1 month and 17 years-6 months (Mean 70 months). 75 of the samples (29%) were ordered to be repeated. 59 samples from 53 patients (22%) could not be analysed for reasons including “insufficient sample” (34), “unsuitable bottle” (10), “missed in error” (7), and “samples leaked in transit” (3). The commonest indications for the BTD screening were developmental delay (63%) and social communication concerns (49%). The commonest professionals requesting the tests were the either the consultant or specialist Community Paediatricians (93%). None of the 191 patients analysed had BTD. However a substantial proportion of the patients (22%) could not be analysed due to various problems with their blood samples. It is therefore difficult to determine precisely the prevalence of BT deficiency in this small cohort of children and adolescents. A larger prospective study is required to verify the true prevalence of BTD in the population. Full text: http://www.itspoa.com//UploadFiles/2018-01/369/2018012314520551985.pdf
Chapter
Most inborn errors of metabolism (IEMs) have neurological symptoms, and many cause injury to the developing central nervous system (CNS). Diagnosis can be challenging, as a number of these neurometabolic disease processes manifest similar signs and symptoms. Disorders may present with acute encephalopathy and metabolic crisis; these are the most critical to recognize and prevent as the risk for repeated, intermittent, or ongoing injury is significant. On the other hand, some IEMS can cause progressive injury resulting in chronic encephalopathy and may be amenable to lifelong therapies. MRI can be used to identify patterns of injury to help classify the nature of the neural injury, and in many cases, MRI provides key clues or biomarkers to identify the underlying disease. Herein, we review some of the most common disorders classified as acute or chronic encephalopathy-associated IEMs. Disease-specific MRI and MR spectroscopy patterns are showcased.
Article
Full-text available
La espectrometría de masas en tándem permite procesar muchas muestras de sangre seca, enviadas por correo ordinario, para detectar anomalías congénitas. En varios países, estas pruebas se hacen de manera rutinaria. En este trabajo se estudia la posibilidad de instaurar un programa nacional de tamización neonatal de cobertura universal.
Article
Biotinidase deficiency is an inherited disorder which has autosomal recessive pattern; it occurs in approximately 1 in 60,000 live births. Usually it manifests seborrheic dermatitis, alopecia, ataxia, convulsions, hypotonia, developmental delay, hearing loss, chronic lactic acidosis and immune deficiency. Its diagnosis is made by the measurement of serum biotinidase enzyme activity and determination of the enzyme. Herein presented that a two and half-month-old boy with biotinidase enzyme deficiency which had cerebral atrophy without any skin signs. In the patients presented with refractory convulsions with unexplainable etiology without any skin lesions, as in our patient, biotinidase enzyme deficiency should be considered and the treatment should be established in early period to prevent many complications that may develop.
Article
Full-text available
With the rapid expansion of newborn screening to include more newborns and more pathologic conditions comes an additional pool of individuals presenting to primary care providers, community hospitals, or tertiary care genetic centers for follow-up evaluation. With the exception of conditions that have historically been included in screening programs, this population presents with potential disorders that have not previously been encountered with great frequency in asympto- matic patients. For example, in the symptomatic phase, urea cycle disorders would present in the context of severe hyper- ammonemic encephalopathy, methylmalonic aciduria with acute acidosis and encephalopathy, and medium-chain acyl CoA dehydrogenase (MCAD) deficiency with hypoketotic hypoglycemia and liver failure. Metabolic findings in acute circumstances are usually pronounced and enable unequivocal diagnosis. In today's newborn screening environment, there is a high likelihood that neonates will present in an asymptomatic clinical phase of the illness requiring that laboratory tests and those that interpret them detect ever more subtle metabolic abnormalities. In this context, the biochemical genetics laboratory plays a pivotal role in recommending and interpreting initial studies as well as dictating the necessity and type of further testing. The focus of this Chapter, therefore, is not on the diagnostic accuracy of newborn screening per se, but on the sensitivity and specificity of the sophisticated testing applied to infants referred for follow-up of a positive newborn screening result. Primary literature and expert opinion has guided the testing recommendations to follow. The rarity of these disorders gen- erally precludes large, randomized studies of diagnostic accu- racy. An exhaustive review of the literature, primarily case reports and series, were reviewed for evidence of biochemical abnormalities in affected, generally asymptomatic children.
Article
We report a patient with biotinidase deficiency with peculiar findings on her MRI brain. Subcortical cysts combined with Dandy Walker cyst on the brain MRI have never been reported. There are many documented case reports of biotinidase deficiency and several of them have included findings on neuroimaging. Subcortical cysts have been documented in one patient with biotinidase deficiency previously and on autopsy in one other patient. Video EEG on the same patient showed evidence of symptomatic generalized epilepsy.
Article
Biotinidase deficiency is due to a defect in recycling of biotin and is a treatable autosomal recessive inherited disorder. We describe two cases with unusual presenting symptoms and rarely described MRI findings. We propose that the diagnosis of biotinidase deficiency should be considered when there are symmetrical MRI changes in the medial thalamus, dorsal brainstem, medulla and spinal cord as in our two cases. As long as there isn't newborn screening for biotinidase deficiency in the UK; increased awareness of this disorder and recognition of biotinidase deficiency as a cause of bilateral symmetrical MRI patterns similar to our patients, would facilitate early diagnosis and prevent many of the devastating neurological sequelae associated with missing the condition.
Article
Full-text available
Almost all newborns in the US are screened at birth for multiple inborn errors of metabolism using tandem mass spectrometry. Screening tests are designed to be sufficiently sensitive so that cases are not missed. The NACB recognized a need for standard guidelines for laboratory confirmation of a positive newborn screen such that all babies would benefit from equal and optimal follow-up by confirmatory testing. A committee was formed to review available data pertaining to confirmatory testing. The committee evaluated previously published guidelines, published methodological and clinical studies, clinical case reports, and expert opinion to support optimal confirmatory testing. Grading was based on guidelines adopted from criteria derived from the US Preventive Services Task Force and on the strength of recommendations and the quality of the evidence. Three primary methods of analyte measurement were evaluated for confirmatory testing including measurement of amino acids, organic acids, and carnitine esters. The committee graded the evidence for diagnostic utility of each test for the screened conditions. Ample data and experience were available to make strong recommendations for the practice of analyzing amino acids, organic acids, and acylcarnitines. Likewise, strong recommendations were made for the follow-up test menu for many disorders, particularly those with highest prevalence. Fewer data exist to determine the impact of newborn screening on patient outcomes in all but a few disorders. The guidelines also provide an assessment of developing technology that will fuel a refinement of current practice and ultimate expansion of the diseases detectable by tandem mass spectrometry. Guidelines are provided for optimal follow-up testing for positive newborn screens using tandem mass spectrometry. The committee regards these tests as reliable and currently optimal for follow-up testing. .
Article
Nutritional deficiency, a global problem, remains uncommon in developed nations. Associated morbidity and mortality make it imperative that clinicians remain familiar with the clinical signs and symptoms of nutritional deficiencies to facilitate diagnosis. This article will review the cutaneous findings and recent literature regarding B12, niacin, zinc, vitamin A, kwashiorkor, biotin and selenium deficiencies, along with the clinical entities of noma and phrynoderma. Much of our understanding of the clinical manifestations of nutritional deficiencies comes from old literature; however, recent case reports and series have highlighted several patient populations that may be at risk from acquired deficiencies, including patients with anorexia nervosa, cystic fibrosis, patients receiving long-term tube-feeding and those with perceived or real food allergy. There can be significant clinical overlap between various micronutrient, protein and vitamin deficiencies. Additionally, providers should consider the possibility of multiple deficiencies coexisting in individual patients. Reports of nutritional deficiency continue to surface in developed nations and pediatricians need to have a basic understanding of their clinical manifestations. The skin is commonly affected and can be the presenting sign of illness. A higher clinical suspicion needs to be maintained in certain populations.
Article
Biotinidase deficiency is a metabolic disorder characterized by inability to recycle biotin with resultant delayed myelination. Clinical findings include seizures, ataxia, alopecia and dermatitis with atypical findings of myoclonic jerks, neuropathy and spastic paraparesis. Neuroradiological findings include cerebral atrophy, encephalopathy and widened extracerebral CSF spaces. Many of the clinical and neuroradiological features are reversible except sensorineural hearing loss and optic atrophy. To understand and describe the neuroimaging and spectroscopic findings of biotinidase deficiency. We evaluated the spectrum of neuroimaging and spectroscopic findings in four patients with biotinidase deficiency with follow-up studies in three patients. The imaging findings were encephalopathy, low cerebral volume, ventriculomegaly and widened extracerebral CSF spaces. Uncommon findings were caudate involvement, parieto-occipital cortical abnormalities and one patient with restricted diffusion. Two patients had subdural effusions, which is uncommon in biotinidase deficiency. 1H-MR spectroscopy revealed elevated lactate, reversal of the choline/creatine ratio and decreased NAA peaks. Follow-up studies revealed complete reversal of imaging findings in two patients. Biotinidase deficiency is a reversible metabolic encephalopathy. This study highlights the importance of early and prompt cliniconeuroradiological diagnosis of biotinidase deficiency as it has an extremely good clinical outcome if treatment is initiated from early infancy.
Article
Full-text available
Biotinidase deficiency is an autosomal recessive inherited disorder that is characterized by neurological and cutaneous symptoms. Biotinidase-deficient children cannot recycle endogenous biotin, an essential water-soluble B vitamin. Biotin is covalently attached to epsilon-amino groups of lysyl residues of four carboxylases. These carboxylases are subsequently degraded to biocytin (biotin-epsilon-lysine). Biotinidase cleaves biocytin to biotin and lysine, thereby completing the biotin cycle. The symptoms of biotinidase deficiency can be resolved or prevented by treatment with biotin. Therefore, it is important that biotinidase deficiency is diagnosed early so that permanent neurological damage can be prevented. Many states and countries currently perform newborn screening for biotinidase deficiency. We have recently isolated and characterized the cDNA for normal human biotinidase and localized the gene to chromosome 3p25 (ref. 9). We have now identified the first mutation that causes profound biotinidase deficiency. It occurs in a distinct region of the gene that encodes the putative signal peptide. Fifty percent of symptomatic children studied have a 7-bp deletion coupled with a 3-bp insertion in at least one of their alleles of the biotinidase gene. This mutation appears to be a common cause of biotinidase deficiency in symptomatic children.
A case of a child with a biotinidase deficiency who had a laryngeal stridor as a leading symptom is presented. This rare disease is distressing for diagnosis but easily treatable, if recognized. This condition, unless suspect clinically, could easily be overlooked and unnecessary tracheotomy could be done.
Article
Neonatal screening for biotinidase deficiency has been conducted in 14 countries since 1984. To 31 December 1990, 8,532,617 newborns were screened. One hundred and forty-two infants with biotinidase deficiency were identified; 76 infants with profound deficiency (less than 10% of mean normal serum activity) and 66 infants with partial deficiency (10-30% of mean normal activity). The estimated incidence of profound biotinidase deficiency is 1:112,271 (1:85,000 to 1:145,000; 95% confidence limits) and the incidence of partial deficiency is 1:129,282 (1:112,700 to 1:177,000). The incidence of combined profound and partial deficiency is 1:60,089 newborns (1:49,500 to 1:73,100). The estimated frequency of the allele for biotinidase deficiency is 0.004 and an estimated 1 in 123 individuals is heterozygous for the disorder.
Article
We screened 163,000 newborn filter-paper blood samples for serum biotinidase deficiency (McKusick 25326) and found 15 probands: three had complete deficiency (incidence 18.4 cases per million live births, 95% confidence interval 4-54 cases per million); the others had partial deficiency. The positive predictive value of the test for either form of biotinidase deficiency was 9.86%. We found seasonal variation in biotinidase activity in filter-paper blood samples. The cost per test was Can.$0.27 (1987 dollar value) and per case of complete deficiency ascertained, $15,500. Family studies indicated that complete serum biotinidase deficiency is a homozygous phenotype and partial deficiency is the heterozygous form. Homozygous cases were treated with biotin and have shown no clinical manifestations (55 patient-months of observation). None of the heterozygotes (n = 42, age 3 months - 62 years) has clinical manifestations. The number of heterozygotes found by screening was much less than predicted probably because the screening test detects mainly the samples with very low (outlier) biotinidase activity. The variant allele(s) for biotinidase deficiency was more common in French Canadians than in other ethnic groups in Quebec; there was no evidence of regional clustering or founder effect.
Article
An unusual clinical course of a patient with biotinidase deficiency, causing Leigh syndrome, is reported. Laryngeal stridor was the major presenting symptom followed by progressive neurologic deterioration and death at the age of 21.5 mo. Absence of skin and hair abnormalities as well as of organic aciduria delayed the correct diagnosis. Necropsy revealed subacute necrotizing encephalopathy (Leigh syndrome). Carboxylase activities (propionyl CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase) measured in lymphocytes 1 day before death were decreased to 10% of normal values. Propionyl-CoA carboxylase was shown to be the only stable carboxylase in human postmortem tissue; in our patient it was moderately decreased in postmortem liver (29% of control) and kidney (42%), but severely decreased in brain (3%). These findings might explain the severity of neurological symptoms in the absence of marked organic aciduria. They indicate that in biotinidase deficiency the CNS may become biotin depleted earlier and more severely than other organs. Biotinidase deficiency should be included in the differential diagnosis of Leigh syndrome and of unexplained respiratory problems.
Article
The main symptoms of late-onset multiple carboxylase deficiency (biotinidase deficiency, McKusick 25326) include ataxia, seizures, hypotonia, psychomotor retardation, alopecia, skin rash, progressive deafness, optic atrophy and life-threatening episodes of metabolic acidosis. Biochemically, increased lactate and propionate are found in plasma, and, in urine, augmented excretion of lactate, 3-methylcrotonylglycine and 3-hydroxyisovaleric and methylcitric acids. Biotin administration allows the complete remission of clinical and biochemical abnormalities, except for hearing loss and optic atrophy (Sweetman and Nyhan, 1986). EN, a female child, was admitted to the hospital because of acute spastic laryngitis at the age of 32 months. Repeated miscarriages were reported in the maternal family. Before the hospitalization, the patient experienced frequent and prolonged episodes of dyspnoea associated with laryngeal stridor. At the age of one and two years, seborrhoeic dermatitis of the scalp had been followed by sudden alopecia.
Article
The previously reported method for the estimation of biotinidase (EC 3.5.1.12) is an endpoint colorimetric assay based on the hydrolysis of biotinyl-4-aminobenzoate, followed by diazotization, and is not suitable for our studies of biotinidase. A fluorimetric rate assay of biotinidase which uses a newly synthesized derivative biotinyl-6-aminoquinoline is described here.
Article
Two children with biotinidase deficiency presented with seizures at 2 months of age. The first child had a fluctuating course with continual developmental progress and cessation of seizures despite symptoms of chronic neurologic dysfunction until he was diagnosed at 17 months. The second child had a progressive course with uncontrolled seizures leading to an unresponsive state until she was diagnosed at 6 1/2 months. Neither child had dermatologic symptoms until shortly before the time of diagnosis. Both children improved markedly with biotin treatment. Serial CT-scan and MRI studies of the brain showed a distinct pattern of changes. Shortly after initial presentation, diffuse low attenuation of the white matter was seen followed by progressive marked cerebral atrophy, which was reversed following biotin treatment. Because this is a reversible condition, clinicians should screen for biotinidase deficiency in all children with symptoms of chronic neurologic dysfunction, especially when radiologic findings of low attenuation of the white matter are followed by cerebral atrophy.
Article
Two infants with early presentation of biotinidase deficiency (age 3 weeks and 2 weeks) are described. On admission, both children had severe neurological symptoms. In the first patient, magnetic resonance imaging (MRI) of the brain showed frontal and temporal atrophy, and in the second patient, CT of the brain showed diffuse periventricular hypodensities, particularly in the frontal region. Oral treatment with biotin (15mg and 10mg per day respectively) made all symptoms disappear within a few weeks. On follow-up 13 and 16 months later, both children were still asymptomatic on this treatment. Their psychomotor development was normal. MRI and CT of the brain had normalized. Later, a moderate hearing loss was detected in the first patient. In biotinidase deficiency, early diagnosis and treatment with oral biotin are essential in order to prevent irreversible damage to the central nervous system and early death from metabolic acidosis. Neonatal screening for biotinidase deficiency would fulfil this goal.
Biotinidase deficiency: two cases of very early presentation
  • A Haagerup
  • J Anderson
  • S Blichfeldt
  • M Christensen
  • Haagerup
The metabolic and molecular Basies of inherited disease
  • B Wolf