Biotin-responsive basal ganglia disease revisited: Clinical, radiologic, and genetic findings

From the Divisions of Pediatric Neurology (B.T., S. Al-Shafi, S. Al-Shahwan) and Genetics (A.A.-H.), Department of Pediatrics
Neurology (Impact Factor: 8.29). 12/2012; 80(3). DOI: 10.1212/WNL.0b013e31827deb4c
Source: PubMed


To investigate the clinical, genetic, and neuroradiologic data of biotin-responsive basal ganglia disease (BBGD) and clarify the disease spectrum.

We first investigated all patients attending our Division of Pediatric Neurology with a genetically proven diagnosis of BBGD between 2009 and 2011. All patients underwent a detailed medical history and clinical examination, extensive laboratory investigations including genetic tests, and brain MRI. Finally, we conducted a systematic review of the literature.

We enrolled 10 patients meeting the diagnostic criteria for BBGD, and analyzed the data on 14 patients from 4 previous reports. The BBGD occurred predominantly in preschool/school-aged patients in the Saudi population, but it was also observed in other ethnic groups. The typical clinical picture consisted of recurrent subacute encephalopathy leading to coma, seizures, and extrapyramidal manifestations. The brain MRI typically showed symmetric and bilateral lesions in the caudate nucleus and putamen, infra- and supratentorial brain cortex, and in the brainstem. Vasogenic edema characterized the acute crises as demonstrated by diffusion-weighted imaging/apparent diffusion coefficient MRI. Atrophy and gliosis in the affected regions were observed in patients with chronic disease. Early treatment with a combination of biotin and thiamine resulted in clinical and neuroradiologic improvement. Death and neurologic sequelae including dystonia, mental retardation, and epilepsy were observed in those who were not treated or were treated late.

BBGD is an underdiagnosed pan-ethnic treatable condition. Clinicians caring for patients with unexplained encephalopathy and neuroimaging showing vasogenic edema in the bilateral putamen and caudate nuclei, infra- and supratentorial cortex, and brainstem should consider this disorder early in the hospital course because a therapeutic trial with biotin and thiamine can be lifesaving.

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Available from: Amal Alhashem, Jan 08, 2016
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    • "It presents in normally developing children as episodes of acute and recurrent encephalopathy , dystonia, seizures and brain lesions in the cerebral cortex, basal ganglia, thalami, brainstem and cerebellum (Ozand et al., 1998; Gerards et al., 2013; Kevelam et al., 2013). Early administration of biotin and thiamine in patients with hTHTR2 deficiency can potentially reverse the clinical and radiological abnormalities and improve neurological outcome (Kono et al., 2009; Debs et al., 2010; Serrano et al., 2012; Alfadhel et al., 2013; Pérez-Dueñ as et al., 2013; Tabarki et al., 2013; Distelmaier et al. 2014; Haack et al., 2014). "
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    ABSTRACT: Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.
    Full-text · Article · Jan 2016 · Brain
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    • "Typical MRI findings include cortical, subcortical white matter lesions, and bilateral abnormal signal intensity in the basal ganglia with less frequent involvement of thalami, brain stem, cerebellum and cervical spine [1] [3] [5] [11]. Due to the similarity of clinical, biochemical, and MRI findings, BTBGD can be misdiagnosed as a mitochondrial disease [4] "
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    ABSTRACT: Biotin-thiamine responsive basal ganglia disease (BTBGD) is a rare metabolic condition caused by mutations in the SLC19A3 gene. BTBGD presents with encephalopathy and significant disease progression when not treated with biotin and/or thiamine. We present a patient of Mexican and European ancestry diagnosed with BTBGD found to have compound heterozygous frameshift mutations, one novel. Our report adds to the genotype-phenotype correlation, highlighting the clinical importance of considering SLC19A3 gene defects as part of the differential diagnosis for Leigh syndrome.
    Full-text · Article · Dec 2014 · Molecular Genetics and Metabolism Reports
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    • "Initial reports described a good response to biotin as a monotherapy [8]. However, a recent description by Tabarki et al. reported that a high proportion of patients treated with biotin only showed recurrences of encephalopathy compared with those who received biotin and thiamine simultaneously [14]. "
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    ABSTRACT: Background The clinical characteristics distinguishing treatable thiamine transporter-2 deficiency (ThTR2) due to SLC19A3 genetic defects from the other devastating causes of Leigh syndrome are sparse. Methods We report the clinical follow-up after thiamine and biotin supplementation in four children with ThTR2 deficiency presenting with Leigh and biotin-thiamine-responsive basal ganglia disease phenotypes. We established whole-blood thiamine reference values in 106 non-neurological affected children and monitored thiamine levels in SLC19A3 patients after the initiation of treatment. We compared our results with those of 69 patients with ThTR2 deficiency after a review of the literature. Results At diagnosis, the patients were aged 1 month to 17 years, and all of them showed signs of acute encephalopathy, generalized dystonia, and brain lesions affecting the dorsal striatum and medial thalami. One patient died of septicemia, while the remaining patients evidenced clinical and radiological improvements shortly after the initiation of thiamine. Upon follow-up, the patients received a combination of thiamine (10–40 mg/kg/day) and biotin (1–2 mg/kg/day) and remained stable with residual dystonia and speech difficulties. After establishing reference values for the different age groups, whole-blood thiamine quantification was a useful method for treatment monitoring. Conclusions ThTR2 deficiency is a reversible cause of acute dystonia and Leigh encephalopathy in the pediatric years. Brain lesions affecting the dorsal striatum and medial thalami may be useful in the differential diagnosis of other causes of Leigh syndrome. Further studies are needed to validate the therapeutic doses of thiamine and how to monitor them in these patients.
    Full-text · Article · Jun 2014 · Orphanet Journal of Rare Diseases
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