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Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

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TPK1-Related Thiamine Metabolism Dysfunction Syndrome

Synonyms: Thiamine Metabolism Dysfunction Syndrome 5 (TMDS5), Thiamine Pyrophosphokinase Deficiency, TPK1 Deficiency

, MSc, , PhD, , DNB, DM, and , MD, DM.

Author Information and Affiliations

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Estimated reading time: 23 minutes

Summary

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.

Diagnosis

No consensus clinical diagnostic criteria for TPK1-related thiamine metabolism dysfunction syndrome (TPK1 deficiency) have been published.

Suggestive Findings

TPK1 deficiency should be suspected in probands with the following clinical, laboratory, and imaging findings and family history.

Clinical findings

  • Episodic encephalopathy with or without regression
  • Mild-to-profound developmental delay
  • Mild-to-profound intellectual disability
  • Dystonia (generalized or focal)
  • Ataxia
  • Abnormal muscle tone
  • Seizures

Laboratory findings

  • Elevated lactate in blood and cerebrospinal fluid
  • 2-ketoglutaric aciduria
  • Low biotin concentration in plasma
  • Elevated urinary biotin
  • Normal thiamine levels in plasma
  • Significantly reduced blood thiamine pyrophosphate concentration

Imaging findings on brain MRI

  • Symmetric T2 hyperintensities involving the basal ganglia, thalami, and cerebellar dentate nuclei (most affected individuals)
  • Hyperintensities of cerebellar dentate nuclei and periventricular white matter (common)
  • Cerebral and cerebellar atrophy and MRI findings resembling a Leigh-like pattern (few individuals)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). The absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of TPK1 deficiency is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in TPK1 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic TPK1 variants of uncertain significance (or of one known TPK1 pathogenic variant and one TPK1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic, laboratory, and brain imaging findings suggest the diagnosis of TPK1 deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of TPK1 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes TPK1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other neurodevelopmental disorders, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. ACMG and the American Academy of Pediatrics recommend exome/genome sequencing as first- or second-tier diagnostic testing for children with developmental delay, intellectual disability, and/or multiple congenital anomalies [Manickam et al 2021, Rodan et al 2025].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
TPK1 Sequence analysis 394% 4
Gene-targeted deletion/duplication analysis 56% 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

To date, two individuals with a copy number variant (CNV) involving TPK1 have been reported. One individual had a deletion encompassing TPK1 exons 3 and 4 [Invernizzi et al 2017]. The second individual had an approximately 8-kb deletion on chromosome 7 that affected only TPK1 [Cilli et al 2024].

Clinical Characteristics

Clinical Description

TPK1-related thiamine metabolism dysfunction syndrome (TPK1 deficiency) is characterized by episodic encephalopathy-induced regression with or without developmental delay, dystonia, spasticity, ataxia, abnormal muscle tone, and seizures. To date, 41 individuals including three fetuses have been identified with biallelic pathogenic variants in TPK1 [Li et al 2021, Wang et al 2021, Thompson et al 2023, Zhao et al 2023, Cilli et al 2024, Fortin et al 2024, Mascarenhas et al 2024, Norouzi Rostami et al 2024, Dallan et al 2025]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Frequency of Select Features

Feature% of Persons w/Feature
Neuroregression (developmental regression)28/32 (88%)
Dystonia18/25 (72%)
Encephalopathy24/34 (71%)
Spasticity14/22 (64%)
Ataxia17/27 (63%)
Hypotonia20/34 (59%)
Seizures12/24 (50%)
Feeding difficulty7/21 (33%)
Developmental delay prior to onset of encephalopathy episodes9/30 (30%)

Developmental delay. Most affected individuals have normal initial achievement of developmental milestones followed by a febrile illness precipitating neuroregression. Less commonly, developmental delay is observed with or without neuroregression. One individual was reported with normal development followed by acute encephalopathy and regression but regained age-appropriate milestones without any residual neurologic deficits at follow-up evaluation more than two years later [Zhu et al 2020]. Another adult had normal development and an episode of encephalopathy followed by residual dystonia; however, no other regression in neurologic features was identified [Au et al 2020]. Prompt treatment with thiamine results in moderate to near-complete improvement in developmental outcomes [Banka et al 2014, Fraser et al 2014, Huang et al 2018, Eckenweiler et al 2021, Thompson et al 2023].

Encephalopathy episodes with or without neuroregression. Approximately half of the individuals developed acute or episodic encephalopathy, often triggered by a febrile illness. The onset of encephalopathic episodes is in infancy or early childhood (range: age 2 days to 7 years). The episodes are usually followed by neuroregression and precipitation of neurologic abnormalities (e.g., ataxia, dystonia, dyskinesias, spasticity, and dysphagia). Notably, recovery following encephalopathic episodes is variable, and most individuals have shown only partial recovery with residual neurologic deficits. Almost complete recovery was noted after encephalopathic episodes in only four individuals [Huang et al 2018, Zhu et al 2020, Eckenweiler et al 2021]. Thiamine supplementation has been reported to reduce the frequency and severity of encephalopathic episodes [Zhu et al 2020, Eckenweiler et al 2021, Thompson et al 2023].

Movement disorder. Dystonia is frequently observed in individuals with TPK1 deficiency. Other abnormal movements include ataxia and tremors. These motor abnormalities might lead to significant gait disturbances and progress to loss of ambulation, with improvement noted following thiamine treatment [Huang et al 2019, Eckenweiler et al 2021, Rüsch et al 2021].

Abnormal muscle tone. Tone abnormalities in affected individuals include generalized hypotonia or spasticity, with some individuals manifesting truncal hypotonia and peripheral spasticity. Thiamine treatment has been associated with improvement in muscle tone [Fraser et al 2014, Eckenweiler et al 2021, Rüsch et al 2021, Li et al 2022].

Seizures. Less than half of affected individuals have seizures. Seizures are usually observed during encephalopathic episodes. The most common type of seizure observed is tonic-clonic. The age of onset usually ranges from infancy to early childhood. The seizures are known to respond well to thiamine supplementation and anti-seizure medication (ASM); thiamine reduces the need for ASMs [Zhao et al 2023].

Brain imaging. Characteristic brain MRI findings include symmetric T2 hyperintensities involving the basal ganglia and thalami in almost all affected individuals. Other frequently observed findings include hyperintensities of cerebellar dentate nuclei and periventricular white matter. Few individuals also manifested cerebral and cerebellar atrophy and MRI findings resembling a Leigh-like pattern. These findings may resolve with timely treatment with thiamine [Huang et al 2018]. In some individuals, the initial brain MRI may be normal. Characteristic abnormalities may become apparent only on follow-up imaging. Interval MRI scans are likely to be helpful for monitoring the disease course and therapeutic response [Mayr et al 2011, Dallan et al 2025].

Three fetuses with TPK1 deficiency had brain MRI findings of ventriculomegaly, agenesis of the corpus callosum, cerebellar hypoplasia, microcephaly, and enlargement of the ganglionic eminences with cystic cavitations [Cilli et al 2024, Fortin et al 2024].

Other

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Prevalence

To date, 41 individuals have been identified with biallelic pathogenic variants in TPK1.

Differential Diagnosis

Genetic disorders of interest in the differential diagnosis of TPK1-related thiamine metabolism dysfunction syndrome (TPK1 deficiency) are listed in Table 3.

Table 3.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Genetic Differential Diagnosis

Gene(s)DisorderMOIFeatures Similar to TPK1 DeficiencyFeatures Distinct from TPK1 Deficiency
SLC19A3 Biotin-thiamine-responsive basal ganglia disease AR
  • Encephalopathy
  • Seizures
  • Dystonia
  • 2-ketoglutaric aciduria in urinary organic acid analysis; lactic acidosis; elevated lactate concentration in CSF
Normal blood TPP concentration
SLC25A19 SLC25A19-related thiamine metabolism dysfunction AR
  • Febrile illness-assoc episodic encephalopathy, seizures, dystonia, & lactic acidosis
  • Brain MRI findings of basal ganglia & thalamic T2 hyperintensities
  • Drastic depletion in mitochondrial TPP levels & 2-ketoglutaric aciduria in urine
Peripheral neuropathy
>135 genesNuclear gene-encoded Leigh syndrome spectrum & mitochondrial DNA-associated Leigh syndrome spectrumAD
AR
MT
XL
  • Episodic encephalopathy
  • Seizures
  • Developmental delay
  • Brain MRI findings of basal ganglia & thalamic T2 hyperintensities
  • Lactic acidosis
Progressive w/no response to thiamine

AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; MOI = mode of inheritance; MT = mitochondrial; TPP = thiamine pyrophosphate; XL = X-linked

Management

No clinical practice guidelines for TPK1-related thiamine metabolism dysfunction syndrome (TPK1 deficiency) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder along with literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TPK1 deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Neurologic Neurologic eval
  • To incl brain MRI
  • Consider EEG if seizures are a concern.
Movement disorder Physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Musculoskeletal Assess for contractures.
Dysphagia Gastroenterology / nutrition / feeding team eval
  • To incl eval of aspiration risk & nutritional status
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Eyes Ophthalmology exam incl fundus for optic atrophy
Hearing Audiology evalTo assess for hearing loss
Cardiac EchocardiogramTo assess for left ventricular hypertrophy & ventricular function
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of TPK1 deficiency to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Targeted Therapy

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Table 5.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Targeted Therapy

TreatmentDosageConsideration
Thiamine
(vitamin B1)		30 mg/kg/day 1 in 2-3 divided dosesThiamine should be administered immediately upon diagnosis.

To date, 26 individuals have been treated with thiamine supplementation. In the majority of these individuals, treatment was initiated after a genetic diagnosis was established. The response to thiamine supplementation is available for 22 individuals, who showed either a significant improvement (7 individuals) [Huang et al 2019, Eckenweiler et al 2021], partial improvement (6 individuals) [Banka et al 2014, Fraser et al 2014, Invernizzi et al 2017, Zhu et al 2020, Thompson et al 2023, Zhao et al 2023], or no improvement following treatment (9 individuals) [Mayr et al 2011, Banka et al 2014, Mahajan & Sidiropoulos 2017, Bugiardini et al 2019, Zhu et al 2019, Au et al 2020, Dallan et al 2025]. Of the treated individuals with no improvement, one individual succumbed due to encephalopathy and respiratory failure [Zhao et al 2023].

Untreated individuals have been reported to experience significant morbidity and mortality [Mayr et al 2011, Fraser et al 2014, Mascarenahas et al 2024]. Discontinuation of treatment generally leads to recurrence of clinical manifestations [Li et al 2022, Zhao et al 2023]. Early treatment is generally recommended and is likely to result in better treatment outcomes.

There are reports of individuals treated with biotin in combination with thiamine; the specific contribution of biotin to clinical outcomes remains unclear [Fraser et al 2014, Eckenweiler et al 2021, Rüsch et al 2021, Thompson et al 2023].

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Acute encephalopathy ICU mgmt per intensivist incl treatment of seizures & increased intracranial pressure
  • Thiamine can be given intravenously.
  • Empiric treatment w/antimicrobial/antiviral agents is recommended until infectious causes of acute/subacute encephalopathy are ruled out.
Developmental delay / Intellectual disability See Developmental Delay / Intellectual Disability Management Issues.
Dystonia Symptomatic treatment per neurologist
Spasticity Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices & disability parking placard.
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Poor weight gain / Growth deficiency
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Vision issues Mgmt per ophthalmologist
Hearing impairment Mgmt per audiologist
Cardiac manifestations Treatment per cardiologist
Transition to adult care Develop realistic plans for adult life.Starting by age ~10 yrs
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ASM = anti-seizure medication; ICU = intensive care unit; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Speech, language, and communication issues. Speech-language evaluation should be considered early in development for children who have delayed communication milestones or who are not yet talking. Evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) is appropriate for individuals who have speech or receptive and expressive language difficulties. An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically takes into account cognitive abilities, sensory impairments, and motor skills to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development. Many children will continue to require AAC into later childhood and adulthood, while some may use their AAC for a shorter time to help aid speech and language development.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Recommended Surveillance

System/ConcernEvaluationFrequency
Development Monitor developmental progress & educational needs.Every 6-12 mos or as clinically indicated
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Feeding
  • Measure growth parameters.
  • Evaluate nutritional status & safety of oral intake.
Musculoskeletal Physical medicine & OT/PT assessment of mobility & self-help skills
Eye Eval of optic atrophy
Hearing Audiology eval
Cardiac
  • Eval by cardiologist
  • Echocardiogram
Family/Community
  • Assess & emphasize importance of adherence to thiamine supplementation.
  • Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

OT = occupational therapy; PT = physical therapy

Evaluation of Relatives at Risk

It is appropriate to 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 in order to identify as early as possible those who would benefit from prompt initiation of thiamine treatment.

  • For at-risk newborn sibs when prenatal testing was not performed, prior to genetic testing or while it is under way, metabolic testing (urine organic acids, pyruvate, and lactate) should be considered.
  • Supplementation with pharmacologic doses of thiamine (vitamin B1) (30 mg/kg/day) is recommended as early as possible for at-risk sibs until their genetic status can be determined.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

TPK1-related thiamine metabolism dysfunction syndrome (TPK1 deficiency) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a TPK1 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a TPK1 pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with TPK1 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in TPK1. (Note: To date, individuals with TPK1 deficiency are not known to reproduce.)

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TPK1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TPK1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the TPK1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

TPK1-Related Thiamine Metabolism Dysfunction Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
TPK17q35Thiamine pyrophosphokinase 1TPK1TPK1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for TPK1-Related Thiamine Metabolism Dysfunction Syndrome (View All in OMIM)

606370THIAMINE PYROPHOSPHOKINASE; TPK1
614458THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE); THMD5

Molecular Pathogenesis

TPK1 encodes thiamine pyrophosphokinase 1 (TPK1), a cytosolic enzyme that catalyzes the ATP-dependent phosphorylation of thiamine (vitamin B1) into thiamine pyrophosphate (TPP). TPP is the biologically active form of thiamine, required for multiple mitochondrial and cytosolic enzymes that mediate oxidative energy metabolism. Disease-causing variants in TPK1 reduce or abolish thiamine phosphorylation, leading to TPP deficiency.

Mechanism of disease causation. Loss of function, which can occur through decreased stability/levels of TPK1 and/or dimerization of the protein, thereby resulting in impaired enzyme activity [Banka et al 2014, Huang et al 2019, Eckenweiler et al 2021].

Chapter Notes

Author Notes

Dr Anju Shukla is interested in hearing from clinicians treating families affected by mitochondrial disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Acknowledgments

National Institutes of Health, United States, for funding the study "Genetic Diagnosis of Neurodevelopmental Disorders in India" (1R01HD093570-01A1)

DBT/Wellcome Trust India Alliance for funding the study "Centre for Rare Disease Diagnosis, Research and Training" (IA/CRC/20/1/600002)

Revision History

  • 23 June 2026 (sw) Review posted live
  • 1 December 2025 (as) Original submission

References

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