Allan-Herndon-Dudley Syndrome or Monocarboxylate Transporter 8 Deficiency via the SLC16A2 Gene

Monocarboxylate transporter 8 deficiency results in Allan-Herndon-Dudley syndrome (Schwartz et al. 2005). Allan-Herndon-Dudley syndrome is characterized by infancy and childhood severe intellectual disability, hypotonia, dysarthria or absence of speech, involuntary movements, muscle hypoplasia, delay of developmental milestone, and spastic paraplegia with hyperreflexia, clonus, and Babinski reflexes. Of note, the affected males usually present disturbances in blood levels of thyroid hormones such as high free triiodothyronine T3 and low free T4 levels in serum. However, their serum TSH levels and thyroid functions are normal. The alterations in free T3 and free T4 levels provide a convenient biomarker of selecting males with intellectual disability for molecular testing in monocarboxylate transporter 8 deficiency (Müller and Heuer 2012).

Allan-Herndon-Dudley syndrome is inherited in an X-linked recessive manner and is caused by pathogenic variants in the SLC16A2 gene encoding monocarboxylate transporter 8. Penetrance is complete, however, the severity is variable (Armour et al. 2015). Pathogenic variants in SLC16A2 include missense, nonsense, small deletion/insertion, splice site variants, and large deletions/duplications (Schwartz et al. 2005; Zung et al. 2011; Kersseboom et al. 2013; Yamamoto et al. 2013; Fischer et al. 2015).

Overall, monocarboxylate transporter 8 deficiency results in tissue-specific alterations in transportation, metabolism and targeted action of thyroid hormone. Monocarboxylate transporter 8 is highly expressed in different tissues such as liver, kidney, thyroid, pituitary and brain (Müller and Heuer 2012). The function of this transporter is to transport triiodothyronine into neurons. Thyroid hormone is essential during different stages in brain development. Loss of transporter function causes intellectual disability and leads to elevated T3 and lowered T4 levels in the blood.

Neurological involvement of Allan-Herndon-Dudley syndrome occurs predominantly in males. Manifestation in females is doubtful, but has not been studied systematically or longitudinally. Female carriers have abnormal thyroid hormone tests with no neurologic deficits (Schwartz et al 2005). The first female case with full-blown Allan-Herndon-Dudley syndrome was reported due to a de novo translocation t(X;9)(q13.2;p24) that interrupted the SLC16A2 gene. In addition, this patient's fibroblasts showed complete loss of protein expression attributed to skewed X inactivation (Frints et al. 2008).

To date, SLC16A2 is the only gene reported to be responsible for Allan-Herndon-Dudley syndrome. Clinical sensitivity of SLC16A2 in a large cohort of patients with Allan-Herndon-Dudley syndrome relevant phenotypes is unavailable in the literature, because most of studies are case reports. Clinical sensitivity should be high in patients who meet clinical and diagnostic criteria for this disorder.

This test provides full coverage of all coding exons of the SLC16A2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).