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.