SLC25A19-Related Thiamine Metabolism Dysfunction

Clinical characteristics.

SLC25A19-related thiamine metabolism dysfunction (SLC25A19 deficiency) is characterized by two phenotypes: Amish lethal microcephaly and thiamine metabolism dysfunction syndrome 4 (THMD-4).

Amish lethal microcephaly is characterized by severe congenital microcephaly, developmental delay, seizures, 2-oxoglutaric aciduria, and often premature death.

THMD-4 is characterized by febrile illness-associated episodic encephalopathy, progressive polyneuropathy, and bilateral striatal necrosis.

Diagnosis/testing.

The diagnosis of SLC25A19 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in SLC25A19 identified by molecular genetic testing.

Management.

Targeted therapy: Oral thiamine treatment (400-600 mg daily) starting at diagnosis. Thiamine dose must be increased (by 25%) during febrile illness, surgery, or acute decompensation.

Supportive care: Acute encephalopathic episodes may require admission to an ICU to manage seizures and increased intracranial pressure; during acute decompensations thiamine may be increased to double the regular dose (up to 1,500 mg daily) and given intravenously. Anti-seizure medication is 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. Management of routine childhood illnesses to avoid acidosis and/or fever. Education of the family regarding the importance of lifelong compliance with medical therapy.

Surveillance: Clinical review of neurologic status every six months; annual assessment of developmental progress and educational needs; assessment of growth and nutritional needs, mobility and therapy needs, and social support and care coordination needs at each visit.

Agents/circumstances to avoid: Contact with individuals with communicable respiratory diseases; the anti-seizure medication sodium valproate.

Evaluation of relatives at risk: It is appropriate to clarify the status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of thiamine treatment.

Genetic counseling.

SLC25A19 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC25A19 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 SLC25A19 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for SLC25A19 deficiency are possible.

Suggestive Findings

Amish lethal microcephaly should be suspected in probands with the following findings:

• Severe congenital microcephaly
• Developmental delay
• Seizures
• Lactic acidosis
• Highly elevated (≥10-fold increase) levels of acid 2-ketoglutarate on urine organic acids

THMD-4 should be suspected in probands with the following findings:

• Acute episodic encephalopathy and weakness triggered by fever
• Hypotonia with developmental delay
• Seizures
• Progressive peripheral neuropathy
• Lactic acidosis
• Brain MRI shows T₂ hyperintensity and necrosis in the caudate and putamen in all individuals. The thalamus, brain stem, and cortex may also demonstrate T₂ hyperintensities and necrosis.

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

Establishing the Diagnosis

The diagnosis of SLC25A19 deficiency is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SLC25A19 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP 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 any likely pathogenic variants. (2) Identification of biallelic SLC25A19 variants of uncertain significance (or of one known SLC25A19 pathogenic variant and one SLC25A19 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) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SLC25A19 deficiency has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 2

When the diagnosis of SLC25A19 deficiency has not been considered because an individual has atypical phenotypic features, 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.

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

Table 1.

Molecular Genetic Testing Used in SLC25A19-Related Thiamine Metabolism Dysfunction

Clinical Description

The two phenotypes observed in SLC25A19-related thiamine metabolism dysfunction (SLC25A19 deficiency) are Amish lethal microcephaly and thiamine metabolism dysfunction syndrome 4 (THMD-4).

Genotype-Phenotype Correlations

c.530G>C (p.Gly177Ala) is the only SLC25A19 variant reported in individuals with Amish lethal microcephaly to date. This variant is associated with a severe phenotype.

In those with other SLC25A19 variants and THMD-4, no genotype-phenotype correlations have been identified.

Nomenclature

Thiamine metabolism dysfunction syndrome 4 may also be referred to as SLC25A19-related bilateral striatal degeneration and progressive polyneuropathy based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors from Lancaster County, Pennsylvania. At least 61 affected infants have been born to 33 nuclear families in the past 40 years. In this population, incidence is approximately one in 500 births.

THMD-4 is a rare disorder, with only 16 individuals reported to date.

Amish Lethal Microcephaly

Microcephaly has a wide variety of causative factors. It can be syndromic or isolated, environmental or genetic, congenital or acquired [Battaglia & Carey 2003]. Metabolic testing (including urine organic acids, plasma amino acids, lactate, pyruvate, and electrolytes) is indicated for all children with congenital microcephaly. Further specific evaluations are performed as indicated based on the results of this testing.

The primary microcephalies are a group of rare, phenotypically and etiologically heterogeneous disorders of brain growth characterized by (1) a head circumference two or more standard deviations (SD) below the mean at birth and three or more SD below the mean by age one year, and (2) mild-to-severe intellectual disability. Additional clinical or neuroimaging features can be associated. Most primary microcephalies are inherited in an autosomal recessive manner. To date, pathogenic variants in more than 100 genes are known to cause primary microcephaly (for review, see Jayaraman et al [2018]). (See also WDR62 Primary Microcephaly and ASPM Primary Microcephaly.)

The degree of microcephaly is much greater in Amish lethal microcephaly than in any of these other genetically defined microcephaly syndromes. Additionally, 2-ketoglutaric aciduria is a good clue for the diagnosis of Amish lethal microcephaly, as 2-ketoglutaric aciduria has not been reported as a finding in other genetically defined microcephaly syndromes.

Alpha-ketoglutarate. Among other genetic malformation syndromes, a similar level of urinary 2-ketoglutarate is also characteristic of DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [formerly known as mental retardation], seizures) syndrome, caused by biallelic pathogenic variants in TBC1D24. Microcephaly is noted in one third of individuals with DOORS syndrome. (See TBC1D24-Related Disorders.)

Thiamine Metabolism Dysfunction Syndrome 4

Table 2.

Genes of Interest in the Differential Diagnosis of Thiamine Metabolism Dysfunction Syndrome 4

Evaluation Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with SLC25A19 deficiency, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with SLC25A19-Related Thiamine Metabolism Dysfunction

Treatment of Manifestations

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 4).

Table 4.

Treatment of Manifestations in Individuals with SLC25A19-Related Thiamine Metabolism Dysfunction

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.
  • 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, Botox^®, 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.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments 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.

Surveillance

To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Table 5.

Recommended Surveillance for Individuals with SLC25A19-Related Thiamine Metabolism Dysfunction

Agents/Circumstances to Avoid

Avoidance of contact with individuals with communicable respiratory diseases is appropriate.

Avoid sodium valproate as an anti-seizure medication.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the SLC25A19 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, urine organic acids and pyruvate and lactate levels should be considered.

Supplementation with pharmacologic doses of thiamine (vitamin B₁) (400-600 mg/day compared to US recommended dietary allowance of 1.5 mg/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.

Mode of Inheritance

SLC25A19-related thiamine metabolism dysfunction (SLC25A19 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 an SLC25A19 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC25A19 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:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC25A19 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.
• Intrafamilial clinical variability has not been reported to date.
• Heterozygotes (carriers) are asymptomatic, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder.

Offspring of a proband

• Amish lethal microcephaly is lethal before reproductive age.
• To date, individuals with thiamine metabolism dysfunction syndrome 4 are not known to reproduce.

Other family member. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC25A19 pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members requires prior identification of the SLC25A19 pathogenic variants in the family.

Related Genetic Counseling Issues

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.
• Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors in Lancaster County, Pennsylvania. In this population, incidence is approximately one in 500 births (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the SLC25A19 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for SLC25A19 deficiency are possible.

Fetal ultrasound examination. Three fetal ultrasound examinations performed after 20 weeks' gestation in two pregnancies of babies ultimately found to have Amish lethal microcephaly revealed marked deceleration of head growth [Kelley et al 2002]. The sensitivity and specificity of fetal ultrasound for the prenatal diagnosis of Amish lethal microcephaly has not been evaluated.

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

Molecular Pathogenesis

SLC25A19 encodes the mitochondrial thiamine pyrophosphate (TPP) carrier. TPP, the active form of thiamine, is an essential cofactor for transketolase in the cytoplasm. It is attached to 2-hydroxyacyl-CoA lyase (HACL1) in the cytoplasm before this enzyme is transported into the peroxisomes. Also, TPP is transported by the mitochondrial TPP carrier into mitochondria, where it binds to pyruvate dehydrogenase and stimulates conversion of pyruvate to acetyl-CoA and binds to alpha-ketoglutarate and branched-chain alpha-keto acid dehydrogenase, entering the tricarboxylic acid cycle for energy production and biosynthesis.

SLC25A19 pathogenic variants lead to a drastic depletion in mitochondrial TPP levels, which is causative for two different clinical diseases: Amish lethal microcephaly and thiamine metabolism dysfunction syndrome 4.

A bacterially expressed human SLC25A19 protein containing the p.Gly177Ala substitution reconstituted in proteoliposomes was unable to catalyze the exchange of alpha-S³⁵-dATP (deoxyadenosine triphosphate) for ADP (adenosine diphosphate), TPP, or TMP (thiamine monophosphate) at 37 °C and had reduced activity at 25 °C [Rosenberg et al 2002].

Knockout mouse embryos homozygous for a null allele of Slc25a19 have a neural tube closure defect, yolk sac erythropoietic failure, and elevated alpha-ketoglutarate in the amniotic fluid, and are lethal by embryonic day 12 [Lindhurst et al 2006]. Fibroblasts generated from E10.5 mouse embryos had normal levels of mitochondrial ribo- and deoxyribonucleoside triphosphates, but TPP and TMP were not detectable in their mitochondria. Ribo- and deoxyribonucleoside triphosphate levels were also normal in mitochondria of lymphoblasts from individuals with Amish lethal microcephaly; TPP and TMP levels were markedly reduced, indicating that the p.Gly177Ala substitution is a hypomorphic allele. Activity of the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes was greatly reduced in both the mouse and human cells, which explains the alpha-ketoglutaric aciduria in individuals with Amish lethal microcephaly and emphasizes the importance of oxidative metabolism in early embryogenesis.

Mechanism of disease causation. Loss of function

Table 6.

Notable SLC25A19 Pathogenic Variants

Author History

Majid Alfadhel, MD, FCCMG (2023-present)
Leslie G Biesecker, MD; National Human Genome Research Institute (2003-2023)
Marjorie J Lindhurst, PhD; National Human Genome Research Institute (2003-2017)
Brahim Tabarki, MD (2023-present)
Farah Thabet, MD (2023-present)

Revision History

• 30 March 2023 (sw) Comprehensive update posted live
• 7 December 2017 (ha) Comprehensive update posted live
• 16 June 2011 (me) Comprehensive update posted live
• 5 May 2009 (me) Comprehensive update posted
• 20 December 2005 (me) Comprehensive update posted live
• 4 September 2003 (me) Review posted live
• 24 June 2003 (mjl) Original submission

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