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.
"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    . Due to the similarity of clinical, biochemical, and MRI findings, BTBGD can be misdiagnosed as a mitochondrial disease  "
[Show abstract][Hide abstract] 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.
Molecular Genetics and Metabolism Reports 12/2014; 1:368–372. DOI:10.1016/j.ymgmr.2014.07.008
"Initial reports described a good response to biotin as a monotherapy . 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 . "
[Show abstract][Hide abstract] 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. However, also late-onset cases have been reported. Since its first description by Denis Archibald Leigh in 1951, it has evolved from a postmortem diagnosis, strictly defined by histopathological observations, to a clinical entity with indicative laboratory and radiological findings. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. Examinations of fresh muscle tissue or cultured fibroblasts are important tools to establish a biochemical and genetic diagnosis. Numerous causative mutations in mitochondrial and nuclear genes, encoding components of the oxidative phosphorylation system have been described in the past years. Moreover, dysfunctions in pyruvate dehydrogenase complex or coenzyme Q10 metabolism may be associated with Leigh syndrome. To date, there is no cure for affected patients, and treatment options are mostly unsatisfactory. Here, we review the most important clinical aspects of Leigh syndrome, and discuss diagnostic steps as well as treatment options.
Journal of neurology, neurosurgery, and psychiatry 06/2013; 85(3). DOI:10.1136/jnnp-2012-304426 · 6.81 Impact Factor
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