SLC16A1 – ketoacidosis due to monocarboxylate transporter-1 deficiency

Monocarboxylate transporter 1 (MCT1) deficiency is an autosomal recessive disorder characterized by recurrent ketoacidosis in infancy, often triggered by fasting or infection. Patients with homozygous loss-of-function (LoF) variants exhibit severe ketoacidosis, persistent lactic acidosis, global developmental delay, and epilepsy. Brain MRI frequently reveals distinctive gray–white matter junction abnormalities and corpus callosum agenesis, supporting early neuroimaging as a diagnostic clue.

Initial exome sequencing in a cohort of 96 patients with suspected ketolytic defects identified eight probands harboring homozygous or heterozygous inactivating SLC16A1 variants (e.g., c.427C>T (p.Arg143Ter)) correlating with decreased MCT1 protein levels and transport capacity (PMID:25390740). This study established an autosomal recessive inheritance pattern and variant spectrum including frameshift and nonsense mutations.

Subsequent multicenter reporting described an additional 13 patients, expanding the phenotypic range to include individuals with heterozygous missense variants. One developmentally normal male with cyclic vomiting and ketoacidosis carried c.303T>G (p.Ile101Met) in heterozygosity, underscoring variable expressivity (PMID:36082648).

Neuroimaging in two affected siblings with homozygous SLC16A1 mutations revealed a conserved pattern of signal abnormalities in the cortical gray–white junction, basal ganglia, and thalami, accompanied by seizures and moderate developmental delay, further delineating the CNS involvement (PMID:32318771).

A recent case with homozygous c.747_750del (p.Asn250SerfsTer5) demonstrated not only ketoacidosis but also lactic acidosis and mitochondrial bioenergetic impairment in patient fibroblasts, highlighting pleiotropic metabolic consequences (PMID:35729663).

Functional assays in cellular models and mouse knockouts confirm that LoF in MCT1 disrupts ketone and lactate transport, leading to neuronal energy deficits concordant with the human phenotype.

References

• The New England journal of medicine • 2014 • Monocarboxylate transporter 1 deficiency and ketone utilization. PMID:25390740
• The Turkish journal of pediatrics • 2022 • Rare cause of ketolysis: Monocarboxylate transporter 1 deficiency. PMID:36082648
• Neuroradiology • 2020 • The neuroimaging findings of monocarboxylate transporter 1 deficiency. PMID:32318771
• Orphanet journal of rare diseases • 2022 • Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature. PMID:35729663

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