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Table of Contents    
Year : 2013  |  Volume : 61  |  Issue : 4  |  Page : 411-413

Biotinidase deficiency in childhood

Department of Pediatric Neurology, Kanchi Kamakoti Childs Trust Hospital, Nungambakkam, Chennai, Tamil Nadu, India

Date of Submission22-Mar-2013
Date of Decision12-Jun-2013
Date of Acceptance23-Jul-2013
Date of Web Publication4-Sep-2013

Correspondence Address:
Viswanathan Venkataraman
Department of Pediatric Neurology, Kanchi Kamakoti Childs Trust Hospital, 12-A-Nageswara Road, Nungambakkam, Chennai - 600 034, Tamil Nadu
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Source of Support: Childs Trust Medical Research Foundation, Conflict of Interest: None

DOI: 10.4103/0028-3886.117614

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 » Abstract 

This study reports the clinical, laboratory profile and outcome in seven patients with biotinidase deficiency. The serum biotinidase activity was assayed using spectrophotometric analysis. The age at presentation varied from day 1 of life to the 5 th month. Seizures were the presenting complaint in six patients and clonic seizures were the predominant seizure type. Sparse hair was seen in four patients, while three did not have any cutaneous manifestation. None of the patients had acidosis or hyperammonemia. The clinical response to biotin was dramatic with seizure control in all patients. One patient had neurological deficit at follow-up, while none had optic atrophy or sensorineural hearing loss. Biotinidase deficiency, a potentially treatable condition, should be thought of in any child presenting with neurological symptoms, especially seizures, even in the absence of cutaneous or laboratory manifestations.

Keywords: Biotinidase deficiency, seizures, sparse hair

How to cite this article:
Venkataraman V, Balaji P, Panigrahi D, Jamal R. Biotinidase deficiency in childhood. Neurol India 2013;61:411-3

How to cite this URL:
Venkataraman V, Balaji P, Panigrahi D, Jamal R. Biotinidase deficiency in childhood. Neurol India [serial online] 2013 [cited 2023 Jun 8];61:411-3. Available from:

 » Introduction Top

Biotinidase deficiency (BD) is an autosomal recessive disorder caused due to deficiency of the enzyme biotinidase. The reported incidence of combined (partial and profound) BD is 1 per 60,089 and that of profound BD is 1 per 112,271. [1] Biotinidase cleaves biotin from biocyclin and, thus, provides the cofactor for the biotin-dependent carboxylases which are involved in fatty acid synthesis, amino acid catabolism, and gluconeogenesis. Hence, its deficiency results in multiple carboxylase deficiency and secondary ketoacidosis, hyperammonemia, and organic aciduria. Classically described to have a neurocutaneous manifestation, its presentation can be varied. The neurological manifestations include seizures, developmental delay, hypotonia, spastic paraparesis, ataxia, sensorineural hearing loss, and optic atrophy with seizures (40-55%), with hypotonia being the most common. The cutaneous abnormalities include alopecia and eczematous dermatitis. [2],[3] BD is known as late-onset multiple carboxylase deficiency due to its later presentation. The reported age at presentation varies from 2 weeks to 12 years. [4],[5]

The diagnosis of BD is based on demonstration of deficient enzyme activity in serum or plasma. Patients with profound BD have less than 10% mean normal serum activity, whereas patients with the partial deficiency variant have 10-30% of mean normal serum activity and are largely asymptomatic. Confirmation can be done by DNA analysis, by either allele-targeted methods or full gene sequencing, and may be useful in some cases. [6] Biotin therapy results in excellent improvement with resolution of symptoms and signs, laboratory parameters, and resolution of changes on neuroimaging. In symptomatic children, developmental delay, seizures, optic atrophy, and sensorineural hearing loss have been described even after treatment with biotin. However, presymptomatic children detected by newborn screening remain asymptomatic. [7],[8] Being a treatable disorder in the absence of routine newborn screening, a trial of biotin or investigations for BD must be considered in all children presenting with neurological symptoms, even in the absence of cutaneous or laboratory findings. [8],[9] This study reports the clinical, laboratory profile, and outcome in patients with BD.

 » Case Report Top

This was a prospective study of all patients diagnosed with BD between January 2006 and January 2013 carried out at the Department of Pediatric Neurology of Kanchi Kamakoti Childs Trust Hospital, a tertiary child care hospital in Chennai, India. During the study period, seven patients were diagnosed to have BD. Patients with confounding factors were excluded from the study. The serum biotinidase activity was assayed using spectrophotometric analysis. The relevant clinical characteristics including age, sex, history of consanguinity, clinical presentations, drugs used, response to biotin, laboratory findings, imaging, and neurological and development status at follow-up were analyzed. Serum electrolytes, serum ammonia, blood gas analysis, urine organic acid, serum amino acid and acylcarnitine profile were measured in all our patients.

The clinical characteristics and outcome of the patients are given in [Table 1]. Age at presentation varied from as early as day 1 of life to the 5 th month of life. One of the patients diagnosed by newborn screening elsewhere and on biotin supplementation since birth had presented to us at 2½ years after stopping biotin for a month. There was a female predominance. Parental consanguinity was noted in two patients. Sibling history of developmental delay, myoclonic jerks, hyperammonemia, acidosis, and death was seen in one patient. Seizures were the presenting complaint in six of the patients, and the seizure frequency varied from single episode to 20 episodes per day. The predominant seizure semiology was clonic jerking of upper limbs with behavioral arrest seen in three out of six patients. Developmental delay at presentation was seen in three of our patients. Total alopecia was seen in one of the patients and sparse hair was seen in three of our patients. Seborrheic dermatitis was seen in one patient who had sparse hair as well. Three did not have any cutaneous manifestation. None of our patients had acidosis or hyperammonemia. The clinical response to biotin was dramatic with seizure control in all the patients. One of the patients had residual gait ataxia at follow-up and none had optic atrophy or sensorineural hearing loss.
Table 1: Demographic profile, symptoms, type and frequency of seizures and Anti epileptic drugs of the patients

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 » Discussion Top

BD has been reported to have a varied neurologic presentation. The cutaneous abnormalities include alopecia and eczematous dermatitis. [2],[3] Seizures were the presenting complaint in six of our patients. Myoclonic seizures were the predominant seizure pattern reported in the study by Salbert et al. [10] However, the predominant seizure semiology in our study was in the form of clonic jerking of both upper limbs with behavioral arrest. Cases of BD without cutaneous changes have been reported. [2] Sparse hair without dermatitis was seen in three of our patients, while three did not have any cutaneous manifestations.

The earliest age at presentation reported was 2 weeks. [5] Till date, presentation of BD on day 1 of life has not been reported and diagnostic confusion with the probability of holocarboxylase deficiency does exist. The response to low-dose biotin, especially considering the sibling history, does warrant the consideration of BD. Subtle neurologic abnormalities may appear as early as 2 months of age and the developmental abnormalities may occur even in the absence of episodes of overt metabolic decompensation. [11] Earlier reports have suggested that organic aciduria and multiple carboxylase deficiency are delayed, secondary manifestations of the disease and that biotin deficiency should be considered in any infant or child with any of these neurologic or cutaneous findings, with or without ketoacidosis or organic aciduria. [9] None of our patients had acidosis or hyperammonemia, except for the sibling of one of our patients. The time from the onset of symptoms to diagnosis of the first three patients was 1-2 months. However, with high index of suspicion, the time lag decreased to 1 week in the later cases. Earlier reports have suggested a 5.5-month time lag from presentation to diagnosis. [12] Some symptomatic children have shown developmental delay and residual impairments in hearing and optic atrophy. However, none of our patients had optic atrophy or sensorineural hearing loss. One patient had residual gait ataxia at 3½ years follow-up. Pre-symptomatic children diagnosed by newborn screening remain asymptomatic on biotin therapy. [7] However, continued biotin therapy needs to be emphasized.

 » References Top

1.Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis 1991;14:923-7.  Back to cited text no. 1
2.Wastell HJ, Bartlet K, Dale G, Shein A. Biotinidase deficiency: A survey of 10 cases. Arch Dis Child 1988;63:1244-9.  Back to cited text no. 2
3.Wolf B. Biotinidase deficiency: "if you have to have an inherited metabolic disease, this is the one to have". Genet Med 2012;14:565-75.  Back to cited text no. 3
4.Casado de Frías E, Campos-Castelló J, Careaga Maldonado J, Pérez Cerdá C. Biotinidase deficiency: Result of treatment with biotin from age 12 years. Eur J Paediatr Neurol 1997;1:173-6.  Back to cited text no. 4
5.Haagerup A, Andersen JB, Blichfeldt S, Christensen MF. Biotinidase deficiency: Two cases of very early presentation. Dev Med Child Neurol 1997;39:832-5.  Back to cited text no. 5
6.Cowan TM, Blitzer MG, Wolf B. Working Group of the American College of Medical Genetics (ACMG) Laboratory Quality Assurance Committee. Technical standards and guidelines for the diagnosis of biotinidase deficiency. Genet Med 2010;12:464-70.  Back to cited text no. 6
7.Weber P, Scholl S, Baumgartner ER. Outcome in patients with profound biotinidase deficiency: Relevance of newborn screening. Dev Med Child Neurol 2004;46:481-4.  Back to cited text no. 7
8.Micó SI, Jiménez RD, Salcedo EM, Martínez HA, Mira AP, Fernández CC. Epilepsy in Biotinidase deficiency after biotin treatment. JIMD Rep 2012;4:75-8.  Back to cited text no. 8
9.Wolf B, Grier RE, Allen RJ, Goodman SI, Kien CL, Parker WD, et al. Phenotypic variation in biotinidase deficiency. J Pediatr 1983;103:233-7.  Back to cited text no. 9
10.Salbert BA, Pellock JM, Wolf B. Characterization of seizures associated with biotinidase deficiency. Neurology 1993;43:1351-5.  Back to cited text no. 10
11.Wolf B, Heard GS, Jefferson LG, Proud VK, Nance WE, Weissbecker KA. Clinical findings in four children with biotinidase deficiency detected through a statewide neonatal screening program. N Engl J Med 1985;313:16-9.  Back to cited text no. 11
12.Grünewald S, Champion MP, Leonard JV, Schaper J, Morris AA. Biotinidase deficiency: A treatable leukoencephalopathy. Neuropediatrics 2004;35:211-6.  Back to cited text no. 12


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