GeneReviews®: TPK1-Related Thiamine Metabolism Dysfunction SyndromeGeneReviews®. University of Washington, Seattle: Seattle (WA).BOOK
CLINICAL CHARACTERISTICS
TPK1-related thiamine metabolism dysfunction syndrome (TPK1 deficiency) is characterized by mild-to-profound developmental delay and intellectual disability with or without regression, dystonia, episodes of encephalopathy, spasticity, ataxia, seizures, and abnormal muscle tone. Most individuals have normal initial achievement of developmental milestones followed by a febrile illness precipitating episodic encephalopathy and neuroregression. Less commonly, developmental delay is observed prior to the onset of encephalopathy episodes. Early treatment with thiamine supplementation can lead to partial or near-complete alleviation of neurologic manifestations. Untreated individuals often experience significant neurologic morbidity.
DIAGNOSIS/TESTING
The diagnosis of TPK1 deficiency is established in a proband with biallelic pathogenic variants in TPK1 identified by molecular genetic testing.
MANAGEMENT
Targeted therapy: Thiamine supplementation. Treatment of manifestations: Management of acute encephalopathy per intensivist; developmental and educational support; symptomatic treatment for dystonia per neurologist; standard treatment for spasticity, seizures, and feeding issues; management of vision and hearing impairment per ophthalmologist and audiologist; management of cardiac manifestations per cardiologist; transitional care plan; social work and family support. Surveillance: Assess developmental progress, educational needs, seizures, changes in tone and movement disorders, growth, nutritional status, feeding, mobility, self-help skills, vision, hearing, cardiac function, adherence to thiamine treatment, and family needs every six to 12 months or as clinically indicated. Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual by molecular genetic testing for the TPK1 pathogenic variants in the family to identify as early as possible those who would benefit from prompt initiation of thiamine treatment.
GENETIC COUNSELING
TPK1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TPK1 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 TPK1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
