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Table of Contents    
Year : 2022  |  Volume : 70  |  Issue : 2  |  Page : 733-736

Biotin-Responsive Basal Ganglia Disease: Treatable Metabolic Disorder with SLC19A3 Mutation Presenting as Rapidly Progressive Dementia

Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

Date of Submission09-May-2020
Date of Decision27-Sep-2021
Date of Acceptance30-Sep-2021
Date of Web Publication3-May-2022

Correspondence Address:
Dr. M Netravathi
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore - 560 029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.344659

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 » Abstract 

Background and Aims: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive disorder due to mutations in the SLC19A3-gene, typically seen in early childhood.
Materials and Methods: We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration. The magnetic resonance imaging (MRI) of the brain revealed T2-hyperintensities in the basal ganglia, thalamus, cortical, subcortical regions with striatal necrosis suggestive of BTBGD that was confirmed by genetic analysis. She was treated with thiamine and biotin following which there was significant clinical and MRI improvement.
Conclusions: BTBGD requires a high index of suspicion in any patient presenting with unexplained rapidly progressive dementia. High doses of biotin and thiamine are the mainstay of the treatment to achieve a favorable outcome.

Keywords: BBGD, biotin-responsive basal ganglia disease, biotin-thiamine-responsive basal ganglia disease, BTBGD, SLC19A3 mutation
Key Message: BTBGD is usually noticed in infants and children. We report the first case of adult-onset BTBGD in the literature confirmed by MRI and genetic analysis. It is a treatable metabolic disorder with almost complete improvement with high doses of biotin and thiamine.

How to cite this article:
Oommen AT, Polavarapu K, Christopher R, Netravathi M. Biotin-Responsive Basal Ganglia Disease: Treatable Metabolic Disorder with SLC19A3 Mutation Presenting as Rapidly Progressive Dementia. Neurol India 2022;70:733-6

How to cite this URL:
Oommen AT, Polavarapu K, Christopher R, Netravathi M. Biotin-Responsive Basal Ganglia Disease: Treatable Metabolic Disorder with SLC19A3 Mutation Presenting as Rapidly Progressive Dementia. Neurol India [serial online] 2022 [cited 2022 Jul 3];70:733-6. Available from: https://www.neurologyindia.com/text.asp?2022/70/2/733/344659

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutation in the SLC19A3 gene (606152) that encodes the human thiamine transporter 2 (hTHTR2) on chromosome 2q36. It is known by other terminologies such as biotin-responsive basal ganglia disease (BBGD), thiamine metabolism dysfunction syndrome-2 (THMD2), thiamine-responsive encephalopathy, SCL19A3 (solute carrier family 19-thiamine transporter-member 3) gene defect. The name BBGD was coined by Ozand et al. in 1998, when they observed a dramatic response of their cohort to biotin.[1],[2] The SLC19A3 gene identified in BBGD encodes the second thiamine transporter, but the initial literature did not highlight the importance of thiamine in the treatment of these patients. Alfadhel et al. in 2013[1] reported the importance of both thiamine and biotin for the treatment regimen and recommended the name of BTBGD. It is typically seen in children between 0.5 and 15 years of age; with a median of 3–7 years in various studies.[2] Here, we describe this disorder in an adult in the fifth decade of illness which is a late-onset phenotype of this rare disorder.

 » Methods Top

A 49-year-old lady of Indian origin (South Asian ethnicity) presented with a 3-week complaint of occasional intermittent paresthesias of the left hand. The paresthesias would occur in multiple episodes in a day lasting for a few seconds, not associated with weakness. One week later, she developed transient episodes of diplopia which was present at all gaze. These were followed by multiple episodes of right focal seizures with and without generalization, hypersomnolence, cognitive impairment, gait disturbances, and abnormal posturing of the head and body. She had gradually become bed-bound and was not indicating her needs for 1 week before her presentation in our hospital. There was no history of preceding fever, vomiting, headache, or any other infection prior to onset. She had a significant history of hypothyroidism and hypertension on regular treatment. At admission, her vitals and systemic examination were within normal limits. Neurological examination revealed a drowsy person, easily responding to verbal commands. Cognitive examination showed reduced attention, fluency, memory, and visuospatial function with MMSE (Mini-Mental State Examination) of 14/30. The cranial nerve examination revealed bilateral ptosis, mild gaze restriction in all fields, normal pupil size and reaction, decreased palatal and tongue movements, and cerebellar type of dysarthria. The motor system examination revealed forward head drop, cervical and truncal dystonia, mild rigidity in both the upper limbs and the ability to move all the limbs in the bed against gravity. She was not amenable to a formal power examination. Her deep tendon reflexes were brisk with extensor plantar response. She had bilateral finger-nose incoordination, ataxic gait requiring two-person support to walk. Clinically, she had a rapidly progressive neurological impairment affecting cognition, seizures, hypersomnolence with generalized dystonia, ataxia, and pyramidal signs. In view of the rapidity and multi-axial involvement, she was suspected to have autoimmune encephalitis/Hashimoto's encephalopathy or mitochondrial encephalopathy, and was investigated.

Her hematological and biochemical parameters were within normal limits. The serum autoimmune (anti-TPO, NMDA, AMPA1, AMPA2, VGKC, LGI-1, GABA-B1, GABA-B2) and paraneoplastic profile (Anti-Hu, Ri, Yo, CV2, PNMA2, PNMA1, amphiphysin, PCA-2, SOX-1, AGNA, Tr, MAG, GAD-65, Zic4, titin, recoverin, myelin) were negative. The thyroid function tests and Vitamin B12 levels were within the normal range. The Cerebrospinal fluid (CSF) was acellular with elevated protein (55 mg/dL), with elevated sugar (149 mg/dL), lactate 28.9 mg/dL, oligoclonal bands not done, and no growth. Her MRI of the brain [Figure 1] revealed diffuse symmetrical non-enhancing hypo to isointense on T1, hyperintense on T2, and Fluid-attenuated inversion recovery (FLAIR) with subtle areas of DWI restriction in bilateral cerebral hemispheres in cortical-subcortical distribution, bilateral medial thalami, and areas of necrosis in bilateral basal ganglia. Following the MRI of the brain, the possibilities considered were: (i) BTBGD and (ii) mitochondrial disorders. The patient was born of a non-consanguineous parentage with no significant family history. The age of onset being 49 years with no preceding history of fever nor any other intercurrent illness was considered as odd-point for BTBGD and was investigated with a biceps muscle biopsy and genetic testing. The muscle biopsy showed mild Cyclooxygenase (COX)-deficient fibers (<2%) not fulfilling modified Walker's criteria in muscle histochemistry for mitochondrial disorders. Clinical exome sequencing (CES) using a custom-designed gene panel was performed on genomic Deoxyribonucleic acid (DNA) extracted from the patient's blood. Sequence alignment was done to the human reference genome (GRCh37/hg19) and variant annotation was performed using the Visual evoked potential (VEP) program against the Ensemble release 91 human gene model.[3],[4] A homozygous missense variation c.68G>T (p.Gly23Val) in exon 2 of the SLC19A3 gene in chromosome 2 was identified, thus, confirming the diagnosis of BTBGD. She was started on thiamine (125 mg/day) and biotin (40 mg/day) supplements and made significant improvement. A follow-up after 1 year of illness revealed a significantly improved lady independently doing all activities and household chores. Neurologically, she had significant improvement in cognition (with an improvement of MMSE to 30/30), dystonia. She had a mild tandem gait ataxia with brisk reflexes. The follow-up imaging after 1 year showed significant improvement in the MRI lesions; the cortical, subcortical lesions had disappeared with persistent striatal necrosis of the caudate and putamen.
Figure 1: (a and b) T2-flair hyperintensities of the basal ganglia and the cortical, subcortical region. Similar changes of T2-hyperintensities in T2-weighted images (c and d). (e-h) MRI brain images after 1 year of illness showing improvement of the lesions with persistent striatal necrosis

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 » Discussion Top

BTBGD is an inherited metabolic disorder found more commonly in children of Saudi Arabian descent.[1],[5] The causative mutation for BTBGD has been mapped to the SLC19A3 gene in 2005.[6] SLC19A3 belongs to a family of solute carrier genes family 19: (i) member-1: SLC19A1 -encodes reduced folate transporter (RFC-1), (ii) member-2: SLC19A2 -encodes thiamine transporter 1 (hTHTR1). (iii) member-3: SLC19A3 –encodes human thiamine transporter 2 (hTHTR2).[7] Both SLC19A2 and SLC19A3 together are responsible for the transportation and homeostasis of thiamine (Vitamin B1/Aneurine). In BTBGD, there is defective or non-functional SLC19A3. It does not result in global thiamine deficiency as evidenced by normal thiamine levels in the blood; however, the CSF levels of free thiamine are significantly reduced.[8]

Ozand et al. reported remarkable improvement in the clinical symptoms to high doses of biotin.[1],[5] Biotin is not a substrate for the thiamine transporter,[7] hence, the reasons for the response to biotin supplementation are unclear. There have been conflicting reports of the effectiveness of the supplements: whether biotin or thiamine act alone or synergistically.[2] The current treatment protocols recommend the combined use of both biotin and thiamine. Biotin is required for the transcription of the SLC19A3 gene and probable synergistic effects of both thiamine and biotin help in the treatment of BTBGD.[9]

A homozygous missense variation c.68G>T (p.Gly23Val) in exon 2 of the SLC19A3 gene in chromosome 2 was identified in our patient. This variant has been reported previously in multiple patients with BTBGD both in homozygous and compound heterozygous forms.[5],[6] This substitution lies in the highly conserved region of transmembrane domain 1 (TM1) of SLC19A3.[7] Subramanian et al.,[3] showed that p.Gly23Val transfected the canine kidney and the human duodenal cell lines showed reduced the expression of SLC19A3 (Thiamine transporter 2) protein with inhibition of thiamine transport, while no correlation was observed with respect to biotin transport.[7] The novelty in our patient that has not been reported previously is the late-onset phenotype of BTBGD with a well-known mutation. The phenotypic variability may raise the possibility that other regulating factors like? variable expression of transporters or other epigenetic factors may play a role in the pathogenesis of the disease.

SCL19A3 gene defect is classified into three categories based on the age of onset: early infantile Leigh-like syndrome, classical childhood BTBGD, and adult Wernicke's-like encephalopathy.[2] All three subtypes have heterogenous clinical presentation and imaging changes. The MRI changes in the three subtypes are (i) early infantile Leigh-like syndrome: T2 hyperintensities involving the perirolandic area, bilateral putamen, and medial thalamic nuclei with lactate peak on spectroscopy, (ii) classical childhood BTBGD: In acute crisis states, there are T2-hyperintensities of the basal ganglia (caudate and putamen), and diffuse swelling in the cortical, subcortical white matter, and infratentorial brain. In the chronic stage, there is atrophy and necrosis of caudate and putamen, (iii) adult Wernicke's-like encephalopathy: T2 hyperintensities of the bilateral medial thalamus and periaqueductal gray. Though our patient was adult-onset, she had MRI and genetic changes of BTBGD.

The awareness of these MRI changes are important for diagnostic purpose as the striatal necrosis can be observed in other neurological disorders including mitochondrial encephalopathies, Wilson disease, glutaric acidemia type-I, 3-methylglutaconic academia, Huntington disease, and Central nervous system (CNS) infection.[10] The clinical picture can be mistaken for other causes of rapidly progressive cognitive and basal ganglion involvement in the form of autoimmune encephalitis, mitochondrial disease, or acute demyelinating encephalomyelitis. Hence, recognition of the clinical features and the pathognomonic MRI changes helps in the diagnosis that can be confirmed genetically.

 » Conclusions Top

BTBGD requires a high index of suspicion based on history, neurologic signs, and consistent magnetic resonance imaging findings in any patient presenting with unexplained rapidly progressive dementia. High doses of biotin and thiamine are the mainstay of the treatment. Early diagnosis and treatment are pivotal to achieve a favorable outcome. The disease is reversible if the treatment is started promptly.


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 » References Top

Alfadhel M, Tabarki B. SLC19A3 gene defects sorting the phenotypes and acronyms: Review. Neuropediatrics 2018;49:83-92.  Back to cited text no. 1
McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 2010;26:2069-70.  Back to cited text no. 2
Subramanian VS, Marchant JS, Said HM. Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: Biotin is not a substrate for hTHTR2. Am J Physiol Cell Physiol 2006;291:C851-9.  Back to cited text no. 3
Ortigoza-Escobar JD, Molero-Luis M, Arias A, Oyarzabal A, Darín N, Serrano M, Pérez-Dueñas B, et al. Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: A treatable cause of Leigh syndrome. Brain 2016;139:31-8.  Back to cited text no. 4
Ozand PT, Gascon GG, Al-Essa M, Joshi S, Al-Jishi E, Bakheet S, et al. Biotin-responsive basal ganglia disease: A novel entity. Brain 1998;121:1267-79.  Back to cited text no. 5
Tabarki B, Al-Shafi S, Al-Shahwan S, Azmat Z, Al-Hashem A, Al-Adwani N, et al. Biotin-responsive basal ganglia disease revisited: Clinical, radiologic, and genetic findings. Neurology 2013;80:261-7.  Back to cited text no. 6
Whitford W, Hawkins I, Glamuzina E, Wilson F, Marshall A, Ashton F, et al. Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease. Cold Spring Harb Mol Case Stud 2017;3:a001909.  Back to cited text no. 7
Ygberg S, Naess K, Eriksson M, Stranneheim H, Lesko N, Barbaro M, et al. Biotin and Thiamine Responsive Basal Ganglia Disease –A vital differential diagnosis in infants with severe encephalopathy. Eur J Paediatr Neurol 2016;20:457-61.  Back to cited text no. 8
Zeng WQ, Al-Yamani E, Acierno Jr JS, Slaugenhaupt S, Gillis T, MacDonald ME, et al. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 2005;77:16-26.  Back to cited text no. 9
Zerbino DR, Achuthan P, Akanni W, Ridwane Amode M, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res 2018;46:D754-61.  Back to cited text no. 10


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