Biotin-thiamine responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder characterized by diverse and variable phenotypic features, which can make diagnosis challenging. However, prompt treatment with thiamine and biotin can effectively manage the condition. Diagnosis relies on the identification of biallelic pathogenic variants in the SLC19A3 gene. This case report describes two novel variants of uncertain significance in the SLC19A3 gene, which may be correlated with the phenotypic manifestations of BTBGD. Our case is a 7-month-old female infant who presented with a 3-week history of irritability, altered behavior, and refusal of newly introduced solid foods. Symptoms started with an upper respiratory tract infection, followed by lethargy, floppiness, and abnormal movements. The patient was admitted to the pediatric ward with a broad differential diagnosis. Extensive laboratory evaluations revealed lactic acidosis. MRI brain showed symmetric restricted diffusion affecting the bilateral basal ganglia, thalami, and cortical regions. Whole genome sequencing identified biallelic variants of the SLC19A3: a c.1364T>G p.Met455Arg missense variant in the maternal allele and a 2.3 kb deletion of intron 3 of the paternal allele. Both variants were identified as variants of uncertain significance. However, given the clinical picture, MRI brain findings, resolution of symptoms with empiric biotin and thiamine supplementation, and biallelic SLC19A3 variants of unknown significance, the patient most likely suffers from BTBGD. Patient continues to show sustained developmental progress on biotin and thiamine supplementation. This case highlights the fact that genetic testing remains a vital but improvable tool for the diagnosis of BTBGD. As of yet, genetic testing and diagnosis of BTBGD continues to be limited by the knowledge of which SLC19A3 variants are established to be pathogenic variants. Thus, further research is required to study other SCL19A3 variants of unknown significance to further improve genetic testing and diagnosis of BTBGD in the future. Biotin-thiamine-responsive basal ganglia disease (BTBGD) may present in early infancy, childhood, or adulthood. Early-infantile BTBGD presents before age three months with vomiting, feeding difficulties, encephalopathy, hypotonia, seizures, and respiratory failure. Classic BTBGD presents between ages three and ten years with recurrent subacute encephalopathy manifesting as confusion, seizures, ataxia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia that, if left untreated, can eventually lead to coma and even death. Dystonia and cogwheel rigidity are nearly always present; hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness or mild trauma or stress. Simple partial or generalized seizures are easily controlled with anti-seizure medication. Adult Wernicke-like encephalopathy BTBGD, described in three individuals to date, presents after age ten years with acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in classic and adult BTBGD; however, most infants with early-infantile BTBGD have a poor outcome. The diagnosis of BTBGD is established in a proband with biallelic pathogenic variants in SLC19A3 identified by molecular genetic testing. Targeted therapies: Biotin (5-10 mg/kg/day) and thiamine (up to 40 mg/kg/day with a maximum of 1,500 mg daily) are given orally as early in the disease course as possible and are continued lifelong. During acute decompensations thiamine may be increased to double the regular dose and given intravenously. Disease manifestations typically resolve within days in classic and adult BTBGD. Supportive care: Acute encephalopathic episodes may require care in an ICU to manage seizures and increased intracranial pressure; thiamine may be increased to double the regular dose and given intravenously. Anti-seizure medication is used to control seizures. Treatment of dystonia is symptomatic and includes administration of trihexyphenidyl or levodopa. Rehabilitation, physical therapy, occupational therapy, and speech therapy as needed and adaptation of educational programs to meet individual needs. Education of the family regarding the importance of lifelong adherence to medical therapy. Surveillance: At each visit, review neurologic status and assess developmental progress, educational needs, social support, and need for care coordination. Agents/circumstances to avoid: Avoid use of sodium valproate to treat epilepsy. Use of ACTH to treat epileptic spasms can induce status dystonicus. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual to identify as early as possible those who would benefit from prompt initiation of treatment with biotin and thiamine and information about agents/circumstances to avoid. Pregnancy management: Affected women should continue thiamine and biotin during pregnancy. BTBGD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC19A3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC19A3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing for BTBGD are possible.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, autosomal recessive neurometabolic disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy. Patients with BTBGD have classical neuroimaging findings and a dramatic response to high doses of thiamine. To highlight the advantages of administering a higher dose of thiamine for patients with BTBGD who have not shown improvement with the standard recommended dosage. Herein, we report on two Saudi girls with classical clinical and radiological findings of BTBGD. Hallmark symptoms in these patients included an acute onset of ataxia, tremor, slurred speech, dystonia, and dysphagia. The initial routine laboratory workups were unremarkable. Brain magnetic resonance imaging revealed extensive hyperintense signals in the bilateral basal ganglia, which suggested the diagnosis of a BTBGD. Hence started empirically on biotin 10 mg/kg/day and thiamine 40 mg/kg/day, but there was no noticeable improvement. After increasing the thiamine to 75 mg/kg/day the patients started to improve significantly. Genetic testing was requested and came positive for the mutation of the SLC19A3 gene. After two months of initiating the management, thiamine was reduced to 30 mg/kg/day. Subsequent follow-ups showed complete improvement in their condition with no apparent long-term sequel or relapse. we conclude that administration of thiamine at a dosage of up to 40 mg/kg/day may not be sufficient in treating certain patients with BTBGD. Thus, considering a significantly higher dosage could potentially contribute to achieving remission.

Inborn errors of metabolism are a prevalent cause of pediatric neurological abnormalities, often resulting from enzyme deficiencies that disrupt metabolic pathways. Understanding the radiological manifestations of these disorders is critical for timely diagnosis and therapy. This study aimed to elucidate the magnetic resonance imaging (MRI) brain characteristics and magnetic resonance spectroscopy (MRS) findings of specific treatable pediatric neurometabolic disorders through clinical vignettes, thereby enhancing diagnostic accuracy and informing therapeutic approaches. The study includes four cases with varying presentations, all confirmed by genetic testing, and utilized magnetic resonance imaging and spectroscopy to identify characteristic features. The first case, diagnosed as thiamine metabolism dysfunction syndrome type 4, exhibits bilateral corpus striatum T2 hyperintensities with diffusion restriction on MRI brain, increased lactate peak, and reduced N-acetylaspartate (NAA) on magnetic resonance spectroscopy (MRS), and SLC25A19 gene mutation on genetic analysis - features consistent with biotin-thiamine-responsive basal ganglia disease. The second case, identified as thiamine metabolism dysfunction syndrome type 2, reveals T2 hyperintensities in the bilateral corpus striatum, medial thalami, and cerebellar white matter, along with restricted diffusion, reduced NAA, and an inverted lactate doublet on MRS, with genetic analysis confirming an SLC19A3 mutation, also falling under the spectrum of biotin-thiamine-responsive basal ganglia disease. The third case, representing cerebral creatine deficiency syndrome type 2, demonstrates bilateral symmetric T2 hyperintensities in the globus pallidus and central tegmental tracts, a characteristic absence of a creatine peak on MRS, and a confirmed guanidomethyl transferase (GAMT) deficiency gene mutation. The fourth case, diagnosed as hypermanganesemia with dystonia type 2, is characterized by T1 hyperintensity and T2 hypointensity involving the bilateral globus pallidi, substantia nigra, and dentate nuclei, with genetic testing revealing an SLC39A14 mutation. The study emphasizes the importance of MR imaging and spectroscopy in identifying pediatric neurometabolic diseases that can be treated.

This report details the case of an infant with confirmed propionic acidemia who presented with progressive neurological deterioration and recurrent episodes of metabolic decompensation with elevated lactate levels, but without hyperammonemia. The child's clinical course and neuroradiological findings increasingly deviated from the known clinical and neuroradiological spectrum of propionic acidemia. A rapid trio exome sequencing identified SLC19A3-related thiamine metabolism dysfunction syndrome 2 as a second genetic disease. The pathomechanisms of both diseases synergize in the impairment of brain energy metabolism, and the associated clinical phenotypes partially overlap, which explains the severe and atypical course of propionic acidemia in the reported case.