SLC16A2 – Allan-Herndon-Dudley Syndrome

Monocarboxylate transporter 8 (MCT8), encoded by SLC16A2 (HGNC:10923), is a highly specific thyroid hormone (T3) importer essential for neuronal uptake of T3 and normal brain development. Pathogenic SLC16A2 variants disrupt cellular T3 transport, leading to central hypothyroidism and peripheral thyrotoxicosis that define Allan-Herndon-Dudley syndrome (AHDS) (PMID:19018842).

AHDS is inherited in an X-linked recessive pattern, affecting predominantly hemizygous males. Clinically, affected males present in infancy with congenital hypotonia, progressive spastic paraplegia, severe intellectual disability, dysarthria, and movement disorders (athetoid/dystonic features). A characteristic endocrine profile of elevated serum T3, low-normal T4, and normal TSH supports the diagnosis (PMID:19811520).

Genetic evidence includes over 60 distinct SLC16A2 variants reported in more than 45 unrelated families worldwide, spanning missense, nonsense, frameshift, splice-site, and intronic deletion alleles. One recurrent example is the hemizygous nonsense variant c.46C>T (p.Gln16Ter) identified de novo in a male proband with classic AHDS features (PMID:19018842). Segregation of pathogenic alleles across up to four generations has been documented (PMID:23419639). These variants are absent or extremely rare in population databases, consistent with X-linked recessive inheritance.

Functional assessment in cell models and patient fibroblasts demonstrates that most pathogenic mutations abolish T3 uptake and metabolism, confirming loss-of-function as the mechanism of disease. Some missense variants (e.g., p.Ser290Phe) retain residual transport activity correlating with milder phenotypes (PMID:26426690). In vivo, Mct8/Dio2 double-knockout mice recapitulate brain hypothyroidism and myelination defects, while triiodothyroacetic acid (Triac) and AAV9-mediated SLC16A2 gene delivery restore neural T3 action in murine models, providing proof-of-concept for therapeutic strategies.

While most AHDS patients show delayed myelination on MRI, some exhibit normal imaging despite classical neurological and endocrine findings. Variable thyroid function tests have been reported in a minority of patients, underscoring the need for comprehensive genetic testing in unexplained X-linked developmental delay with movement disorder features.

In summary, the association between SLC16A2 and AHDS is definitive: robust genetic and functional data confirm that SLC16A2 loss-of-function causes AHDS. Early recognition via serum T3/T4 profiling and targeted sequencing permits timely genetic counseling. Emerging therapies, including thyroid hormone analogs and gene therapy, offer hope for modifying peripheral thyrotoxicosis and ameliorating central deficits.

References

• Developmental Medicine and Child Neurology • 2009 • Elevated serum triiodothyronine and intellectual and motor disability with paroxysmal dyskinesia caused by a monocarboxylate transporter 8 gene mutation. PMID:19018842
• Developmental Medicine and Child Neurology • 2010 • White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene. PMID:19811520
• Molecular and Cellular Endocrinology • 2010 • Genetics and phenomics of thyroid hormone transport by MCT8. PMID:20083155
• PLoS ONE • 2015 • Further insights into the Allan-Herndon-Dudley syndrome: clinical and functional characterization of a novel MCT8 mutation. PMID:26426690

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