Guidelines on Hereditary Leukodystrophies
MCT8 deficiency (Allan-Herndon-Dudley syndrome)
Disease description: MCT8-specific thyroid hormone cell-membrane transporter deficiency is a genetic disease characterized by severe intellectual disability, language disorder, hypotonia, and abnormal movements. MCT8 transports T3 in particular, and its dysfunction means that T3 is not taken up by cells, which increases its blood concentration. Because myelin formation in the cerebral white matter of affected patients is delayed, in most cases it is distinguished by signs indicative of dysmyelination on cranial magnetic resonance imaging. The SLC16A2 gene that encodes MCT8 is located on Xq13.2, and the disease exhibits X-linked recessive inheritance. All patients are thus in principle male, and in most cases the mother is an asymptomatic carrier.
1. Overview
Definition
In 1944, Allan, Herndon, and Dudley reported a family including a total of 24 men with severe intellectual disability over six generations. Other similar reports followed, and the disease concept of Allan-Herndon-Dudley syndrome was established. In 2004, Dumitrescu et al. identified SLC16A2 mutations in two unrelated boys with severe intellectual disability and elevated thyroid T3 levels [1]. Nearly 100 genetic mutations have subsequently been reported.
Epidemiology
Allan-Herndon-Dudley syndrome is extremely rare, with only about 10 cases having been reported to date in Japan [2, 3] .
Etiology and pathophysiology
Thyroid hormone is essential for neuron activity. Neurological symptoms appear when T3 transporter function is lost, meaning that T3 in the blood is not taken up by the neurons. It is believed that if T3 is not taken into cells and its blood concentration remains high, other organs will be affected.
Clinical symptoms
Hypotonia and developmental delay are apparent from infancy, while growth is severely impaired. Epileptic seizures may also occur. Developmental delay is severe, and affected patients are often completely bedridden. Dysphagia, scoliosis, and other problems gradually lead to progressive respiratory failure, which affects the prognosis.
Imaging and other investigations
High blood T3 in the absence of other forms of thyroid dysfunction is characteristic. Cranial magnetic resonance imaging (MRI) between 1 and 3 years of age, when the myelination of cerebral white matter occurs, usually reveals signs of hypomyelination (hyperintense on T2-weighted imaging), which is useful for the diagnosis. However, since myelination subsequently improves, this should be described as delayed myelination rather than hypomyelination.
Genetic diagnosis
As Allan-Herndon-Dudley syndrome is caused by a missense mutation, deletion, or other aberration of the SLC16A2 gene located on Xq13.2, all-exon Sanger sequencing is used. A deletion can be diagnosed by the fact that it is not amplified on polymerase chain reaction.
2. Treatment and care
Thyroid hormone supplementation is ineffective. Although research to develop new therapeutic drugs is underway in other countries, there is currently no curative treatment [4]. Symptomatic therapies are therefore provided, such as antiepileptic drugs for epilepsy, enteral nutrition or gastrostomy for difficulty in oral ingestion, and tracheotomy for respiratory failure.
3. Diet and nutrition
No particular diet or type of nutrition is recommended.
4. Prognosis
Respiratory failure affects survival prognosis.
5. Differential diagnosis
If cranial MRI reveals delayed myelination, Pelizaeus-Merzbacher disease is the form of cerebral leukodystrophy most commonly considered in the differential diagnosis. However, if a high blood T3 is present, the diagnosis is comparatively easy to make.
6. Recent topics
Although there has been news of attempted clinical trials overseas, no specific assessments are available.
References
(Unless otherwise noted at the end, all are evidence level 6.)
- Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004; 74: 168-175.
- Yamamoto T, Shimojima K, Umemura A, Uematsu M, Nakayama T, Inoue K. SLC16A2 mutations in two Japanese patients with Allan-Herndon-Dudley syndrome. Hum Genome Var 2014; 1: 14010.
- Shimojima K, Maruyama K, Kikuchi M, Imai A, Inoue K, Yamamoto T. Novel SLC16A2 mutations in patients with Allan-Herndon-Dudley syndrome. Intractable Rare Dis Res 2016; 5: 214-7.
- Braun D, Schweizer U. The chemical chaperone phenylbutyrate rescues MCT8 mutations associated with milder phenotypes in patients with Allan-Herndon-Dudley syndrome. Endocrinology 2017; 158: 678-691.
Literature search
PubMed
- slc16a2[All Fields] OR mct8[All Fields] 334 results
