Biotin-Thiamine-Responsive Basal Ganglia Disease

Excerpt

Clinical characteristics: 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.

Diagnosis/testing: The diagnosis of BTBGD is established in a proband with biallelic pathogenic variants in SLC19A3 identified by molecular genetic testing.

Management: 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.

Genetic counseling: 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.