Also known as: Thiamine metabolism dysfunction syndrome 2; Basal ganglia disease, biotin-responsive; Thiamine-responsive encephalopathy
1. The Disease:
BTRE is an autosomal recessive metabolic disorder characterized by episodic encephalopathy, often triggered by febrile illness, presenting as confusion, seizures, external ophthalmoplegia, dysphagia, and sometimes coma and death. Administration of high doses of biotin, and sometimes thiamine, during these crises results in partial or complete improvement within days. If untreated, encephalopathies can result in permanent dystonia. Brain imaging may show characteristic bilateral lesions of the basal ganglia. It is not known why biotin administration results in clinical improvement, as the molecular basis of the disorder is mutation in a gene encoding a thiamine transporter.
2. The symptoms:
The classic presentation occurs in childhood (age 3-10 years) and is characterized by recurrent subacute encephalopathy manifests as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia which, 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 antiepileptic drugs. Lack of early signs or symptoms does not exclude the diagnosis.
An early-infantile Leigh-like syndrome / atypical infantile spasms presentation occurs in the first three months of life with poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis.
An adult-onset Wernicke-like encephalopathy presentation is characterized by acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia in the second decade of life.
3. Actions to take in case of early diagnosis:
Babies with a positive genetic test (having biallelic pathogenic variants in the SLC19A3 gene) should be referred immediately to a paediatric neurologist for clinical evaluation.
Brain imaging shows cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, and white matter abnormalities. Laboratory studies show low plasma serine, increased serum citrulline, lactate and ammonia.
BTRE is a lifelong disease requiring lifetime management and regular follow-up with a Paediatric Neurology Center Management is provided by multidisciplinary team.
Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in the childhood and adult presentations, but most with the infantile presentation have had poor outcome even after supplementation with biotin and thiamine.
Biotin (5-10 mg/kg/day) and thiamine (up to 40 mg/kg/day with a maximum of 1500 mg daily) are given orally as early as possible and are continued lifelong. Symptoms typically resolve within days.
Acute encephalopathic episodes may require care in an ICU to manage seizures and increased intracranial pressure; during acute decompensations thiamine may be increased to double the regular dose and be given intravenously. Antiepileptic drugs are used to control seizures. Treatment of dystonia is symptomatic and includes administration of trihexyphenidyl or L-dopa.
Rehabilitation, physiotherapy, 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 compliance with medical therapy.
Genetic counselling is highly recommended for family planning and evaluation of at-risk family members such as siblings.