Biotin thiamine responsive basal ganglia disease–A potentially treatable inborn error of metabolism
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.193797
Source of Support: None, Conflict of Interest: None
Biotin thiamine responsive basal ganglia disease (BTRBGD) is a rare genetic disorderwhich may be misdiagnosed due to lack of awareness regarding its existence. The disorder presents with varied neurological manifestations, early identification and treatment of which prevents the associated mortality and morbidity. We present a genetically confirmed case with typical clinical and radiological findings and an excellent response to treatment.
A 12-year-old girl presented with generalized dystonia and recurrent seizures. She was born of third-degree consanguinity with an uneventful perinatal period and normal development. She had recurrent seizures since 5 years of age. From 11 years of age, she developed progressive imbalance while walking, associated with dystonic posturing of both hands. The current presentation was with status epilepticus precipitated by a febrile illness. There was no history of cognitive decline or myoclonic jerks. She did not have visual or hearing impairment. Her elder sister was affected with a similar illness and succumbed to the illness during status epilepticus provoked by an intercurrent illness.
On examination, she was in altered sensorium with intermittent brief multifocal clonic seizures and dystonic posturing of all four extremities. Ophthalmological examination was normal. There was no Kayser–Fleischer ring or organomegaly. Blood count, electrolytes, renal and liver functions, ammonia, aminoacidogram, acyl carnitine profile, and creatinine phosphokinase, copper, and ceruloplasmin levels were normal. Blood lactate was 2.1 mmol/L (0.3–1.3 mmol/L). Urine organic acids were not detectable. Magnetic resonance imaging (MRI) of the brain [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d revealed T2 hyperintensities symmetrically involving the caudate nuclei, putamen, and posteromedial thalami along with cystic changes. There were patchy hyperintensities in the cerebral and cerebellar cortices with minimal restricted diffusion in the medial thalamus. MR spectroscopy was noncontributory.
The possibility of BTRBGD or Leigh's disease were considered. She was initiated on biotin (100 mg/kg/day), thiamine, 100 mg thrice daily, the mitochondrial cocktail, and anticonvulsants. She improved significantly over the next 3 days and started verbalizing. She was noticed to have generalized dystonia involving all four limbs, trunk, and orofacial muscles while she was improving from encephalopathy. She improved gradually and was able to walk with minimal support and there were no further seizures. She was discharged on biotin, thiamine, the mitochondrial cocktail, levetiracetam, symptomatic medications, and physiotherapy.
Over a period of regular 3-year follow-up, she has shown a steady improvement and restarted schooling. She walks unassisted, and is able to write, although with difficulty, due to residual dystonia of her hands. She did not have further seizures or encephalopathy. A repeat imaging [Figure 1]e,[Figure 1]f,[Figure 1]g,[Figure 1]h done 3 years after the acute crisis revealed significant resolution of the hyperintensities and swelling in the cerebral and cerebellar cortices. The long TR hyperintensity in the basal ganglia and thalamus also had shown reduction with persistent cystic changes in the basal ganglia.
Sanger sequencing of the SCL19A3 coding exons, untranslated regions, and exon–intron boundaries was done in the Genetics laboratory (CMC, Vellore). Three variants were identified [c. 368A > G (p.Y123C), IVS 4-4del T, c. 1288 G > A (p.G430R)] in heterozygous state in the proband with possible pathogenic potential. The unaffected sister was heterozygous for variant 2 and 3. The father was heterozygous for variant 1 and 2. The mother's DNA was not available for testing. The intronic variant (variant number 2) was present in the heterozygous state in the unaffected father, unaffected sister, as well as the proband. This variant rs11334205 has a high global as well as regional frequency as per 100 genome data (0.98 and 1.0, respectively) and is less likely to be pathogenic. The other two variants are previously unreported. Both variants (1, 3) lie in the area of the gene that encodes domains of thiamine transporter. These sites are evolutionarily conserved across species. The mutations, thus, can alter the function significant enough to cause the disease.
After the genetic confirmation, the mitochondrial cocktail was stopped; antiepileptics were gradually tapered and stopped. She is currently under follow-up with supplementation of both biotin and thiamine and is doing well without any further neurological deterioration or new events.
Biotin thiamine responsive basal ganglia disease is a rare metabolic disorder with autosomal recessive inheritance because of defective thiamine transporter across the blood–brain barrier. The disorder was described as a novel entity in 1998 by Ozand et al., who described a unique group of clinico-radiological evidence of basal ganglia involvement with biotin responsiveness. In 2005, the responsible gene SLC19A3 was discovered and mapped to chromosome 2q36.3. Initially described patients were of Saudi, Syrian, and Yemeni ancestry; later reports from Europe in 2010, made it a pan ethnic condition.
Symptoms usually begin in the toddler age, even though they reported as early as 1 month of life and as late as 20 years of age., The characteristic presentation include recurrent subacute encephalopathy precipitated by intercurrent illness, seizures, dysarthria, external ophthalmoplegia, dystonia, and quadriparesis progressing to coma and death, if left untreated. Less frequently, chronic and slowly progressive forms, as seen in our case, are reported. The original radiological abnormality reported was central necrosis of the head of caudate and complete or partial involvement of putamen. The radiological spectrum has widened with subsequent description of the associated cerebral and cerebellar atrophy by Yamada et al. The cortical and deep gray hyperintensities show restricted diffusion during the acute presentation. There is a single report of spinal cord hyperintensities with long segment involvement. The signal abnormality of the cortex disappears after treatment whereas the caudate and putamen necrosis usually persists. MR spectroscopy reveals lactate peak in the involved areas which resolves with treatment.
Initially postulated to be a defective biotin transport across the blood–brain barrier, only later the responsible mutation of SLC19A3 gene in chromosome 2 with resultant loss or dysfunctional thiamine transporter hTHTR2 was identified. Subramaniam et al., confirmed that biotin is not a substrate for hTHTR2. The initial response to biotin in this disorder remained unexplained; however, the cases who relapsed on biotin responded to thiamine, resulting in long term remission. The initial biotin responsiveness is possibly due to an increase in the SLC19A3 expression through biotinylation of histones or an alternative pathway leading to efficient energy utilization. As most of the reported patients attain long-term remission only after adding thiamine, it is prudent to administer both biotin and thiamine and continue them lifelong. The initial name of biotin responsive basal ganglia disease was suggested to be “Biotin thiamine responsive basal ganglia disease.”
Thiamine, as a thiamine pyrophosphate, is a cofactor for a number of enzymes in the pathway of energy development. The transport of this inside the cell is carried out by thiamine transporter 1 and 2 (THTR1 and THTR2). SLC19A3 encodes the second transporter. Defective uptake via this is responsible for the phenotype of BTRBGD. The defective binding of the enzyme cofactor complex can usually be reversed by increasing the concentration of the cofactor. Kono et al., (2009) found a high SLC19A3 expression in human thalamus compared to other brain regions, the defect in which causes Wernicke-like encephalopathy.
This is the first genetic proven case from India (suggesting its panethnic prevalence) although there was a single previous case reported with a documented clinical response to biotin. Biotin thiamine responsive basal ganglia disease, even though rare, is a potentially treatable metabolic disorder. A high index of suspicion and an empiric trail of biotin and thiamine is warranted in cases where clinicoradiological involvement of the basal ganglia with recurrent encephalopathy may occur. The importance of genetic counseling and prenatal diagnosis also needs to be emphasized.
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