Biotin-thiamine Responsive Basal Ganglia Research Articles

Oculogyric Crisis as the First Presentation of Biotin-Thiamine-Responsive Basal Ganglia Disease: A Case Report.

Oculogyric Crisis as the First Presentation of Biotin-Thiamine-Responsive Basal Ganglia Disease: A Case Report.

Biotin-thiamine responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of cases in Kuwait with novel variants

BackgroundBiotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder that is caused by biallelic pathogenic SLC19A3 variants and is characterized by subacute encephalopathy associated with confusion, convulsions, dysphagia, dysarthria, or other neurological manifestations.MethodsA retrospective review of the data registry in Kuwait Medical Genetics Center for all cases diagnosed clinically and radiographically and confirmed genetically with BTBGD.ResultsTwenty one cases from 13 different families were diagnosed with BTBGD in Kuwait. Most cases (86%) presented with confusion, dystonia, convulsions, or dysarthria, while three individuals were diagnosed pre-symptomatically during familial targeted genetic screening. Symptoms resolved completely within 2-week of treatment in two-thirds of the symptomatic cases but progressed in six of them to a variety of severe symptoms including severe cogwheel rigidity, dystonia and quadriparesis due to delayed presentation and management. Neuroradiological findings of the symptomatic cases revealed bilateral central changes in the basal ganglia. Two novel homozygous missense SLC19A3 variants were detected in a Kuwaiti and a Jordanian individuals, in addition to the previously reported Saudi founder homozygous variant, c.1264A > G; p.(Thr422Ala) in the remaining cases. Age of diagnosis ranged from newborn to 32 years, with a median age of 2–3 years. All cases are still alive receiving high doses of biotin and thiamine.ConclusionThis is the first study reporting the phenotypic and genotypic spectrum of 21 individuals with BTBGD in Kuwait and describing two novel SLC19A3 variants. BTBGD is a treatable neurometabolic disease that requires early recognition and treatment initiation. This study highlights the importance of performing targeted molecular testing of the founder variant in patients presenting with acute encephalopathy in the region.

45-Year-Old Woman With Fever and Malaise

45-Year-Old Woman With Fever and Malaise

Biotin–Thiamine Responsive Basal Ganglia Disease Presented as Intractable Seizure in a 1-Month-Old Infant

AbstractBiotin–thiamine responsive basal ganglia disease is a neurometabolic disorder, seen in children presenting with encephalopathy, seizures, and positive family history. The disease is diagnosed based on typical magnetic resonance imaging (MRI) findings and whole exome sequencing but may be initially misdiagnosed as a mitochondrial encephalopathy or an inborn error of metabolism (IEM). We describe the case of an infant who presented with uncontrolled seizures and encephalopathy, responding to high doses of thiamine and biotin. Life-long supplementation of biotin (2–10 mg/kg/day) and thiamine (200–300 mg/day) improves the symptomatology and prevents relapse. Outcomes of the disease are heterogeneous, ranging in scope from complete remission to severe neurological sequelae.

Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes.

Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole-exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin-thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

Biotin–Thiamine Responsive Basal Ganglia Disease: A Treatable Metabolic Encephalopathy—Not to Be Missed!

AbstractBiotin–thiamine responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder, characterized by encephalopathy, extrapyramidal signs following mild infection, trauma or surgery and is potentially reversible with treatment. We describe a 15-month-old female child of Indian-Muslim origin with characteristic clinical and radiological features of BTBGD that showed complete resolution with treatment. A comparison with previously reported cases reveals a different mutation (exon 2 vs. exon 5 in middle east cases) in the SLC19A3 gene that could be specific for the Indian subcontinent. We also emphasize the importance of a trial of vitamins in patients with acute metabolic encephalopathy.

Are diagnostic magnetic resonance patterns life-saving in children with biotin-thiamine-responsive basal ganglia disease?

Biotin-thiamine responsive basal ganglia disease (BTBGD) is an autosomal recessive disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy that typically starts in early childhood. This study describes characteristic clinical and magnetic resonance imaging (MRI) findings of six cases of BTBGD diagnosed with newly identified mutations and genetically confirmed, with very early and different presentations compared to cases in the previous literature. Six patients referred from different centers with similar clinical findings were diagnosed with BTBGD with newly identified mutations in the SLC19A3 gene. Two novel mutations in the SLC19A3 gene were identified in two patients at whole exome sequencing analysis. The clinical characteristics, responses to treatment, and electroencephalography (EEG) and MRI findings of these patients were examined. The other four patients presented with similar clinical and cranial MRI findings. These patients were therefore started on high-dose biotin and thiamine therapy, and mutation analysis concerning the SLC19A3 gene was performed. Responses to treatment, clinical courses, EEG findings and follow-up MRI were recorded for all these patients. Age at onset of symptoms ranged from 1 to 3 months. The first symptoms were generally persistent crying and restlessness. Seizures occurred in five of the six patients. Cranial magnetic resonance imaging revealed involvement in the basal ganglia, brain stem, and the parietal and frontal regions in general. The first two patients were siblings, and both exhibited a novel mutation of the SLC19A3 gene. The third and fourth patients were also siblings and also exhibited a similar novel mutation of the SLC19A3 gene. The fifth and sixth patients were not related, and a newly identified mutation was detected in both these subjects. Three novel mutations were thus detected in six patients. BTBGD is a progressive disease that can lead to severe disability and death. Early diagnosis of treatable diseases such as BTBGD is important in order to prevent long-term complications and disability.

Biotin Thiamine Responsive Basal Ganglia Disease: Clinical Improvement after Initiation of Biotin and Thiamine Therapy

Biotin Thiamine Responsive Basal Ganglia Disease: Clinical Improvement after Initiation of Biotin and Thiamine Therapy

Biotin–thiamine–responsive basal ganglia disease: catastrophic consequences of delay in diagnosis and treatment

Background: Biotin–thiamine–responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder caused by mutations in the SLC19A3 gene. The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures.Methods: We diagnosed a family affected by BTBGD and studied them including prognosis of cases when diagnosed and treated early in the disease process. We also review the literature comprehensively and summarize all published data about this disorder.Results: Since its first description, a total of 89 cases (46 females and 43 males) have been published in the literature. We studied six patients in this article in which three died before a diagnosis was established, one was diagnosed lately and is currently severely affected, and two were diagnosed early and are currently stable on treatment. The clinical phenotype of each family member was studied in details. In addition, a genetic testing was performed using whole exome sequencing and Sanger sequencing which demonstrated a previously reported homozygous mutation in exon 5 of the SLC19A3 gene c.1264A>G (p.Thr422Ala).Conclusion: BTBGD is a treatable condition if recognized early and managed appropriately. The recognition of this disorder is important to avoid incorrect diagnosis and mismanagement. Children presenting with unexplained encephalopathy and MRI abnormalities including bilateral signal alteration of caudate nucleus and putamen should raise the suspicion for BTBGD and be started immediately on biotin and thiamine regimen since the prognosis of the disease is affected by the timing of treatment initiation. We present a large family affected with this disorder with severe interfamilial variability and different prognosis despite having the same mutation and same environment. A clear genotype–phenotype correlation and the clinical heterogeneity remain to be elucidated. Bad prognostic factors observed in our review include early onset of the disease, missed or delayed diagnosis, systemic involvements including respiratory failure and rhabdomyolysis, and severe neurological deficit or radiological changes at the time of diagnosis and treatment initiation. We observed during our literature review that all patients who presented since birth died despite aggressive treatment. This observation may illustrate that early presentation and disease process leads to a more catastrophic outcome.

Whole exome sequencing reveals compound heterozygous mutations in SLC19A3 causing biotin-thiamine responsive basal ganglia disease

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.