Recommended panel testing at Breda Genetics for this condition:
Affecting thyroid hormone levels
Allan-Herndon-Dudley syndrome (AHDS), also known as MCT8-specific thyroid hormone cell-membrane transporter deficiency, is a rare disorder of brain development with neuromuscular involvement accompanied by specific changes in circulating thyroid hormone levels (high T3, low to normal T4).
The disorder causes severe cognitive deficiency, infantile hypotonia that progresses to spastic quadriplegia with hyperreflexia, contractures, Babinski sign, and clonus, diminished muscle mass (muscle hypoplasia) associated to generalized muscle weakness typically manifesting as difficulty in supporting the head and delayed motor milestones. Involuntary movements of the arms and legs (dystonic and/or athetoid movements) with characteristic paroxysms or kinesigenic dyskinesias are also seen and limit mobility. As a result, many people with Allan-Herndon-Dudley syndrome are unable to walk independently and become wheelchair-bound by adulthood. Some patients may develop seizures. Typical facial features include: open mouth, tented upper lip, ptosis, abnormal folding of the ears, thickening of the soft tissue of the nose and ears, and upturned earlobes. Long and thin everted feet are also typical. Pectus excavatum and scoliosis are sometimes present, perhaps as a result of the hypotonia and muscle hypoplasia. A patient with profound sensorineural hearing loss ha also been described (probably as a consequence of a coexisting nonsense mutation in the MITF gene. Although affected males have impaired speech and a limited ability to communicate, they seem to enjoy interaction with other people.
The syndrome is caused by mutations in the SLC16A2 gene and show X-linked recessive inheritance pattern. The syndrome is mostly seen in males, however, a female with typical features of Allan-Herndon-Dudley syndrome with a de novo translocation disrupting SLC16A2 and unfavourable non-random X-inactivation was reported.
Allan-Herndon-Dudley syndrome is a rare disorder. About 25 families with individuals affected by this condition have been reported worldwide. Although the prevalence is unknown, one study identified AHDS in 1.4% males with mental retardation of unknown etiology.
Diagnosis is based on clinical findings and on the presence of disturbances in serum levels of the thyroid hormones: abnormally high free T3, but low to normal free T4 levels and TSH levels. In general, full thyroid studies on individuals with the non-specific findings of severe hypotonia, failure to thrive, and gross motor delay may be recommended. The diagnosis must be confirmed by genetic testing (SLC16A2 gene analysis, see below).
Mutations in the SLC16A2 gene cause Allan-Herndon-Dudley syndrome. The SLC16A2 gene, also known as MCT8, provides instructions for making a protein that plays a critical role in the development of the nervous system. This protein transports the thyroid hormone T3 into nerve cells in the developing brain. Identified SLC16A2 mutations include truncations, in-frame deletions, nonsense and missense mutations and large exonic and multi-exonic deletion (exon 1 deletions are common). A interesting variant, c.1834delC, results in bypassing the natural stop codon, extending the MCT8 protein by 65 amino acids. This condition is inherited in an X-linked recessive pattern. De novo SLC16A2 mutations have been reported.
Advancement in treatment research
Treatment options currently explored the focus on finding thyroid hormone-like compounds that bypass MCT8 and enter cells through different transporters. A recent study revealed that certain pathogenic SLC16A2 mutants may be responsive to (co-)treatment with readily available compounds which increase endogenous protein function.
As experimental studies demonstrated that high serum T3 causes increased energy expenditure, a TH analog, diiodothyropropionic acid (DITPA), has ben administered in Mct8 knock-out mice showing to ameliorate the hypermetabolism. DITPA is therefore thought to be suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.
The differential diagnosis of Allan-Herndon-Dudley syndrome includes the following:
- Pelizaeus-Merzbacher disease (PLP1 gene mutations)
- Snyder-Robinson syndrome (SMS gene mutations)
- Metachromatic leukodystrophy (ARSA gene mtuations)
- X-linked adrenoleukodystrophy (ABCD1 gene mutations)
- Krabbe disease (GALC gene mutations)
- Canavan disease (ASPA gene mutations)
- MECP2 duplication syndrome (MECP2 gene duplication)
Recommended testing workflow
For the diagnosis of Allan-Herndon-Dudley syndrome Breda Genetics recommends the following panel:
Efficient Activation of Pathogenic ΔPhe501 Mutation in Monocarboxylate Transporter 8 by Chemical and Pharmacological Chaperones. Braun D, Schweizer U. Endocrinology. 2015 Dec;156(12):4720-30 PMID 26368820
The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency. Ferrara AM, Liao XH, Ye H, Weiss RE, Dumitrescu AM, Refetoff S. Endocrinology. 2015 Nov;156(11):3889-94. PMID: 26322373