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Adv Biomed Res 2023,  12:148

Biotinidase deficiency in the second decade with atypical neuroimaging findings

1 Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
2 Department of Pediatric Radiology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India

Date of Submission20-Mar-2022
Date of Acceptance14-Nov-2022
Date of Web Publication28-Jun-2023

Correspondence Address:
Dr. Vykuntaraju K Gowda
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Near NIMHANS, Bengaluru - 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/abr.abr_98_22

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Biotinidase deficiency is a rare autosomal recessive neurometabolic disorder resulting in biotin deficiency. Our patient presented with seizures and developmental delay since infancy and was started on megavitamin supplements. At 14 years, she presented with motor regression with encephalopathy after discontinuation of vitamins. There were no skin and hair changes. Magnetic resonance imaging (MRI) of the brain showed bilateral symmetrical posterior putamen signal changes. Tandem mass spectroscopy showed increased methyl malonyl carnitine and 3-OH isovaleryl carnitine. There was a low biotinidase level, and a pathogenic variant in the BTD gene in the next-generation sequencing was identified. Special importance is placed on the unusual symmetric posterior putamen involvement seen in MRI of the brain.

Keywords: Biotin, biotinidase deficiency, BTD gene variants, enzyme activity, neonatal screening

How to cite this article:
Gowda VK, Avaragollapuravarga Mathada A, Srinivasan VM, Vamyanmane DK. Biotinidase deficiency in the second decade with atypical neuroimaging findings. Adv Biomed Res 2023;12:148

How to cite this URL:
Gowda VK, Avaragollapuravarga Mathada A, Srinivasan VM, Vamyanmane DK. Biotinidase deficiency in the second decade with atypical neuroimaging findings. Adv Biomed Res [serial online] 2023 [cited 2023 Sep 28];12:148. Available from:

  Introduction Top

Biotinidase deficiency is a rare genetic disorder inherited in an autosomal recessive fashion. It is caused due to the deficiency of the enzyme biotinidase. The resulting biotin deficiency leads to reduced activity of multiple carboxylase enzymes. The incidence is estimated to be about 1 in 60,000.[1] It presents with developmental delay, ataxia, and seizures. Hair and skin changes like alopecia, atopic dermatitis, and eczema are commonly seen. Some patients develop long-term complications such as hearing loss and optic atrophy. Neuroimaging usually shows cerebral atrophy and patchy signal in cerebral white matter. The symmetric involvement of posterior putamen as seen in this case is unusual, hence, we are reporting this atypical case.

  Case Report Top

A 14-year-old girl born to third-degree consanguineous marriage with a normal birth history presented with global developmental delay and seizures. The child had the first episode of seizure at two months of age. At nine months of age, she was admitted with an episode of metabolic acidosis. Tandem mass spectrometry had shown elevated methyl malonyl carnitine and 3-OH isovaleryl carnitine. She was on carnitine, vitamin-B12, and biotin on and off. She has poor cognition, difficulty in daily activities, poor school performance, and visual difficulty. She developed motor regression with unable to walk, lethargy, and drowsiness for the past six months after discontinuation of megavitamins.

On examination, the weight of 43 kg, and head circumference of 49 cm. Neurological examination showed a Glasgow coma scale of 12/15, dystonia [Figure 1]a, depressed deep tendon reflexes in bilateral lower limbs, strabismus [Figure 1]b, and optic atrophy. Arterial blood gas analysis showed pH of 7.34, serum bicarbonate of 11.5 mEq/L, pCO2 of 15.8 mmHg, and base excess of −9.1 mmol/L indicative of compensated metabolic acidosis. The serum lactate of 41.98 mg/dL (normal: 4.5–19.8 mg/dL) and Vitamin B12 of more than 2,000 pg/mL (normal: 160–950 pg/mL) levels were increased. Magnetic resonance imaging (MRI) of the brain revealed symmetric posterior putamen changes [Figure 1]c on FLAIR, T2-weighted sequences [Figure 1]d, hyperintense areas in the upper cervical spinal cord suggestive of myelomalacia [Figure 1]e in axial T2 W images, thinning of optic chiasma with hyperintensity suggesting atrophy [Figure 1]f. The biotinidase enzyme levels were low at −5.03 units (normal ≥40 units). Whole-exome sequencing detected a pathogenic variant of the BTD gene (ENST00000643237.3): c.1553G>A(p. Arg518His) in exon 4 in the homozygous state. The child was started on biotin tablets of 20 mg per day and is improving on follow-up after three months.
Figure 1: Clinical picture showing dystonia in the bilateral upper limbs (a), and strabismus (b). MRI of the brain showing, symmetrical hyperintense areas in bilateral posterior putamen (arrows-c) on FLAIR, T2 Weighted sequences (arrows -d), hyperintense areas in the upper cervical spinal cord suggestive of myelomalacia (arrowheads-e) in axial T2 W images, thinning of optic chiasma with hyperintensity suggesting atrophy (arrow- f)

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  Discussion Top

We describe an adolescent girl with infantile-onset global developmental delay with adolescent-onset motor regression and encephalopathy without unique involvement of posterior putamen in neuroimaging.

Karimzadeh et al.,[2] studied 16 patients with 10 showing cutaneous manifestations, 8 having alopecia, and 12 patients having abnormal neuroimaging with one patient having abnormal signal changes in basal ganglia. Desai et al.,[3] studied 4 patients, all of whom had hypopigmentation, sparse hair, and abnormal brain MRI with one showing focal hyperintense lesion in bilateral caudate nuclei, and the caudothalamic groove involvement. Fallah et al.,[4] reported severe degeneration of the putamen and caudate nucleus in a 10-year-old girl. Sweeney et al.,[5] studied two cases, one showed sparse hair and the other had no skin or hair changes. MRI showed symmetrical involvement of the medial thalamus and extending caudally into the tectum and periaqueductal grey in one and medial thalamic nuclei in the second patient. Schulz et al.,[6] reported a case of basal ganglia calcification in biotinidase deficiency. Bousounis et al.,[7] reported gradual hair loss in one patient and extensive eczema in the other with both showing diffuse brain atrophy. Viyannan et al.,[8] reported skin peeling, alopecia, and loss of brain volume with symmetric involvement of frontoparietal regions, cerebellar white matter, and vermis. Gowda et al.,[9] found a 6-year-old with skin changes and alopecia with MRI brain showing changes in periaqueductal Gray, dorsal midbrain, pons and medulla, and cervical spinal cord. Gowda et al.,[10] in a retrospective review of diagnosed cases of BD showed partial alopecia, subtle dermatitis with demyelinating leukoencephalopathy, and subcortical cysts on MRI in three infants. Our case has no skin and hair changes probably due to the child being on biotin treatment earlier. MRI changes of posterior putamen involvement alone have not been described in the literature.

The variant is a nonsynonymous variant c.1553G>A which causes a change in amino acid from arginine to histidine at position 518 in the BTD protein sequence. According to ACMG criteria[11] for variant classification, the variant fulfills the following criteria, PS1 – same amino acid change reported as pathogenic, PM1 – mutation in a hot spot region of a gene, PM2 – absent in population database (gnomAD) in the homozygous state, PP3 – multiple computational tools like MutationTaster, SIFT, and PolyPhen-2 predict the variant to be damaging, PP5 – The variant is reported as Pathogenic in ClinVar ID VCV000025099.6.[12] Hence, the variant in the current case can be classified as likely pathogenic. MutationTaster predicts the variant to be disease causing.[13]

  Conclusion Top

Biotinidase deficiency should be considered even in the second decade of life with unusual bilateral putamen signal changes in the MRI of the brain.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. J Inherit Metab Dis 1991;14:923-7.  Back to cited text no. 1
Karimzadeh P, Ahmadabadi F, Jafari N, Jabbehdari S, Alaee MR, Ghofrani M, et al. Biotinidase deficiency: A reversible neurometabolic disorder (an Iranian pediatric case series). Iran J Child Neurol 2013;7:47-52.  Back to cited text no. 2
Desai S, Ganesan K, Hegde A. Biotinidase deficiency: A reversible metabolic encephalopathy. Neuroimaging and MR spectroscopic findings in a series of four patients. Pediatr Radiol 2008;38:848-56.  Back to cited text no. 3
Fallah R, Akhavan Karabasi S, Shafii A. A case of biotinidase deficiency with unchanged basal ganglia lesions in MRI during an eight-year follow-up. J Case Rep Pract 2013;3:82-4.  Back to cited text no. 4
Mc Sweeney, Grunewald S, Bhate S, Ganesan V, Chong WK, Hemingway C. Two unusual clinical and radiological presentations of biotinidase deficiency. Eur J Paediatr Neurol 2010;14:535-8.  Back to cited text no. 5
Schulz PE, Weiner SP, Belmont JW, Fishman MA. Basal ganglia calcifications in a case of biotinidase deficiency. Neurology 1988;38:1326-8.  Back to cited text no. 6
Bousounis DP, Camfield PR, Wolf B. Reversal of brain atrophy with biotin treatment in biotinidase deficiency. Neuropediatrics 1993;24:214-7.  Back to cited text no. 7
Viyannan M, Palanisamy S, Balalakshmoji D. Congenital biotinidase deficiency-clinching the diagnosis with classic imaging features. J Dental Med Sci 2019;18:17-20.  Back to cited text no. 8
Gowda VK, Kerur C, Vamyanmane DK, Kumar P, Nagarajappa VH, Shivappa SK. A treatable cause of myelopathy: Biotinidase deficiency presenting as acute flaccid paralysis. J Pediatr Genet 2020;11:257-60.  Back to cited text no. 9
Gowda VK, Vignesh S, Nagarajan B, Srinivasan VM, Battina M, Bhat M, et al. Rare treatable cause of demyelinating leukoencephalopathy that one cannot afford to miss. J Pediatr Genet 2020;11:87-90.  Back to cited text no. 10
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 2015;17:405-24.  Back to cited text no. 11
National Center for Biotechnology Information. ClinVar [VCV000025099.6]. Available from: [Last accessed on 2022 Aug 31].  Back to cited text no. 12
Schwarz J, Cooper D, Schuelke M, Seelow D. MutationTaster2: Mutation prediction for the deep-sequencing age. Nat Methods 2014;11:361-2.  Back to cited text no. 13


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