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

Abstract

Background: Biotin-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.

Methods: A retrospective review of the data registry in Kuwait Medical Genetics Center for all cases diagnosed clinically and radiographically and confirmed genetically with BTBGD.

Results: Twenty 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.

Conclusion: This 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.

Keywords: Basal ganglia; Biotin-thiamine-responsive; Encephalopathy; Genetic; Neurometabolic; SLC19A3.

Fig. 1

a Schematic showing the location of all the SLC19A3 variants identified in this study and in the literature on the six-exon SLC19A3 structure (transcript NM 025243.4). The novel variants identified in this study are highlighted in red. The previously reported Saudi founder reported in this study in green. The lower part of the figure represents all the SLC19A3 variants reported in the literature. b Pedigree of Case 9 with segregation of the novel variant c.952G > A;p.(Ala318Thr). c Pedigree of Case 15 with segregation of the novel variant c.175T > C;p.(Trp59Arg). d Multiple sequence alignment of the two novel variants reported in this study

Fig. 2

a–o Radiological Findings of six individuals diagnosed with Biotin Thiamine Responsive Basal Ganglia Disease in Kuwait (Cases 4, 7, 9, 15, 19, 20): a Case 4. Plain brain computed tomography (CT) showing bilateral swelling and diffuse hypodensity of putamen. b Case 4. Follow up T2-weighted brain magnetic resonance imaging (MRI) revealing bilateral caudate, putamen and external capsule atrophy sparing globus pallidus and sub-insular regions, with multiple T2 hyperintense cystic foci of necrosis/injury. c Case 7. T1 post contrast brain MRI showing bilateral T1 faint enhancement in the caudates, peripheral putamen, thalami, and some occipital leptomeningeal regions. d Case 7. T2-FLAIR image revealing bright hyperintense lesions again in the basal ganglia and thalami with diffuse bilateral subcortical involvement. e Case 7. T1-weighted post contrast image showing faint subtle enhancement of the T2-FLAIR hyperintense lesion in the vermis; (f). g, h Case 9. T2-FLAIR brain MRI showing cortical and subcortical hyperintensities at both cerebral hemispheres and subtle cerebellar changes, as well as caudate and putamen bilaterally. i Case 9. T1-weighted brain MRI image correlated with T2-weighted image j showing the basal ganglia lesions as T1 hypointense and T2 hyperintense, k Case 15. Axial and l coronal T2 weighted MR images of the brain showing bilateral symmetric hyperintense signals in the midbrain/cerebral peduncles, as well as the basal ganglia and medial thalami There are multiple cortical/subcortical and bilateral sub-insular T2 hyperintensities. m Case 19. T2-FLAIR brain MRI showing multiple scattered hyperintense lesions at the cortical and subcortical cerebral parenchyma, as well as bilateral caudate, putamen and medial thalamic nuclei. n Some of these areas showed partial diffusion restriction on DWI. o Case 20. T2-weighted brain MRI showing hyperintensity of both putamina, representing atrophy with central necrosis/injury

Fig. 2

a–o Radiological Findings of six individuals diagnosed with Biotin Thiamine Responsive Basal Ganglia Disease in Kuwait (Cases 4, 7, 9, 15, 19, 20): a Case 4. Plain brain computed tomography (CT) showing bilateral swelling and diffuse hypodensity of putamen. b Case 4. Follow up T2-weighted brain magnetic resonance imaging (MRI) revealing bilateral caudate, putamen and external capsule atrophy sparing globus pallidus and sub-insular regions, with multiple T2 hyperintense cystic foci of necrosis/injury. c Case 7. T1 post contrast brain MRI showing bilateral T1 faint enhancement in the caudates, peripheral putamen, thalami, and some occipital leptomeningeal regions. d Case 7. T2-FLAIR image revealing bright hyperintense lesions again in the basal ganglia and thalami with diffuse bilateral subcortical involvement. e Case 7. T1-weighted post contrast image showing faint subtle enhancement of the T2-FLAIR hyperintense lesion in the vermis; (f). g, h Case 9. T2-FLAIR brain MRI showing cortical and subcortical hyperintensities at both cerebral hemispheres and subtle cerebellar changes, as well as caudate and putamen bilaterally. i Case 9. T1-weighted brain MRI image correlated with T2-weighted image j showing the basal ganglia lesions as T1 hypointense and T2 hyperintense, k Case 15. Axial and l coronal T2 weighted MR images of the brain showing bilateral symmetric hyperintense signals in the midbrain/cerebral peduncles, as well as the basal ganglia and medial thalami There are multiple cortical/subcortical and bilateral sub-insular T2 hyperintensities. m Case 19. T2-FLAIR brain MRI showing multiple scattered hyperintense lesions at the cortical and subcortical cerebral parenchyma, as well as bilateral caudate, putamen and medial thalamic nuclei. n Some of these areas showed partial diffusion restriction on DWI. o Case 20. T2-weighted brain MRI showing hyperintensity of both putamina, representing atrophy with central necrosis/injury

Fig. 2

a–o Radiological Findings of six individuals diagnosed with Biotin Thiamine Responsive Basal Ganglia Disease in Kuwait (Cases 4, 7, 9, 15, 19, 20): a Case 4. Plain brain computed tomography (CT) showing bilateral swelling and diffuse hypodensity of putamen. b Case 4. Follow up T2-weighted brain magnetic resonance imaging (MRI) revealing bilateral caudate, putamen and external capsule atrophy sparing globus pallidus and sub-insular regions, with multiple T2 hyperintense cystic foci of necrosis/injury. c Case 7. T1 post contrast brain MRI showing bilateral T1 faint enhancement in the caudates, peripheral putamen, thalami, and some occipital leptomeningeal regions. d Case 7. T2-FLAIR image revealing bright hyperintense lesions again in the basal ganglia and thalami with diffuse bilateral subcortical involvement. e Case 7. T1-weighted post contrast image showing faint subtle enhancement of the T2-FLAIR hyperintense lesion in the vermis; (f). g, h Case 9. T2-FLAIR brain MRI showing cortical and subcortical hyperintensities at both cerebral hemispheres and subtle cerebellar changes, as well as caudate and putamen bilaterally. i Case 9. T1-weighted brain MRI image correlated with T2-weighted image j showing the basal ganglia lesions as T1 hypointense and T2 hyperintense, k Case 15. Axial and l coronal T2 weighted MR images of the brain showing bilateral symmetric hyperintense signals in the midbrain/cerebral peduncles, as well as the basal ganglia and medial thalami There are multiple cortical/subcortical and bilateral sub-insular T2 hyperintensities. m Case 19. T2-FLAIR brain MRI showing multiple scattered hyperintense lesions at the cortical and subcortical cerebral parenchyma, as well as bilateral caudate, putamen and medial thalamic nuclei. n Some of these areas showed partial diffusion restriction on DWI. o Case 20. T2-weighted brain MRI showing hyperintensity of both putamina, representing atrophy with central necrosis/injury