MCT8-Specific Thyroid Hormone Cell Transporter Deficiency

Disease Overview

MCT8-specific thyroid hormone cell transporter deficiency (MCT8 deficiency) is a genetic disorder characterized by severe intellectual disability, an impaired ability to speak, low muscle tone (hypotonia), disorganized movements and specific thyroid test abnormalities.

Except for poor muscle tone, most affected infants appear to develop normally during the first months of life. However, by about two months of age, an affected infant may seem weak and be unable to hold up their head. Due to hypotonia, severely reduced motor development and other abnormalities, affected children very rarely develop the ability to walk and when they do, it is with a shuffling gait. Associated features often include underdevelopment (hypoplasia) and decreasing (atrophy) of muscle tissue; weakness and stiffness of the legs (spastic paraplegia) with exaggerated reflexes (hyperreflexia) and relatively slow, involuntary, purposeless (dyskinetic) movements. Writhing movements (athetoid movements) and/or other movement abnormalities are less common. Affected individuals may also have characteristic features of the skull and face. MCT8 deficiency is an X-linked genetic disorder.

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Synonyms

• AHDS
• Allan-Herndon-Dudley syndrome
• MCT8 deficiency
• THCT deficiency

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Signs & Symptoms

MCT8 deficiency is primarily characterized by severe intellectual disability, hypotonia and movement abnormalities. As mentioned above, an affected infant typically appears to develop normally (except for hypotonia) until about 2 months of age, when they may seem to have generalized weakness and be unable to hold up their head. Family members have described this feature as “limber neck.” Due to low muscle tone, weakness, severely reduced motor development and/or other factors, affected children are unable to walk or walk with great difficulty.

Associated findings may include underdevelopment (hypoplasia) and decreasing (atrophy) of various skeletal (voluntary) muscles; an impaired ability to coordinate certain voluntary movements (ataxia); weakness and stiffness of the legs (spastic paraplegia) with associated hyperreflexia and involuntary, rapid, repeated involuntary contractions and relaxations of the legs (clonus). Movement abnormalities are common and include dyskinetic attacks or relatively slow, writhing movements (athetoid movements) and/or other movement abnormalities. Typical dyskinetic attacks last a few minutes or less and consist of body extension, opening of the mouth and stretching or flexing of the limbs. They are usually triggered by physical and emotional stimuli such as changing diapers or clothes. While these episodes are commonly interpreted as being seizures, true epilepsy is uncommon.

As noted earlier, infants and children with the disorder are also affected by severe intellectual disability and delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor delay). In addition, affected children are unable to speak, or rarely, acquire garbled speech. Children with MCT8 deficiency are generally good natured and have agreeable behavior.

As adults, affected individuals may have a generalized decrease of muscle (atrophy), permanent fixation of multiple small and large joints in various fixed postures (joint contractures) and/or decreased reflex reactions (hyporeflexia).

Individuals with MCT8 deficiency may also have characteristic craniofacial features and/or additional skeletal abnormalities. The head is usually of normal size but may be narrow at the temples (bitemporal narrowing). The face may appear long and thin with large, poorly developed ears. Some people with MCT8 deficiency have side-to-side curvature of the spine (scoliosis); depression of the breastbone (“funnel chest” or pectus excavatum) and/or foot abnormalities.

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Causes

MCT8 deficiency is caused by a change (pathogenic variant or mutation) in the MCT8 (SLC16A2) gene leading to an altered structure and function of the MCT8 protein. So far, 210 distinct MCT8 gene variants have been identified in patients with MCT8 deficiency. The severity of clinical symptoms can vary depending on the type of gene variant.

The abnormal MCT8 protein is unable to transport thyroid hormones produced by the thyroid gland into the brain. The lack of thyroid hormones in the brain before birth and in early childhood affects brain development. The excess T3 thyroid hormone in the blood can increase metabolism (hypermetabolism), so more calories are needed for an affected child to gain weight.

MCT8 deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene but affected females have been reported.

Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.

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Affected populations

MCT8 deficiency is a rare inherited disorder that affects mostly males. More than 300 families have been identified with 210 different MCT8 gene variants. The frequency of MCT8 deficiency among people with intellectual disability is not known, though estimated to occur in 1 in 70,000 newborns.

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Disorders with Similar Symptoms

Symptoms of the following disorders may be similar to those of MCT8 deficiency. Comparisons may be useful for a differential diagnosis:

Angelman syndrome (AS) is a rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Additional symptoms may occur in some patients including seizures, sleep disorders and feeding difficulties. Some affected children may have distinctive facial features. AS is caused by deletion of or abnormal expression of the UBE3A gene. Most cases of AS appear to occur spontaneously. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)

Juberg-Marsidi syndrome is an extremely rare X-linked genetic disorder that is fully expressed in males only and is apparent at birth or during the first few weeks of life. Affected children have severe intellectual disability; delays in reaching developmental milestones (e.g., crawling, walking, etc.); muscle weakness; low muscle tone (hypotonia) and/or delayed bone growth as well as growth delay, resulting in short stature. Affected infants also have hearing loss; underdevelopment of the genitals and/or characteristic head and facial features such as a small head (microcephaly), a flat (depressed) nasal bridge and eye (ocular) abnormalities. The range and severity of symptoms varies from person to person. (For more information on this disorder, choose “Juberg Marsidi” as your search term in the Rare Disease Database.)

Renpenning syndrome is one of the X-linked intellectual disability disorders that mostly affects males. It is characterized by intellectual disability that can be severe, short stature, a small head circumference (microcephaly) and small testes. Renpenning syndrome is caused by variants in the PQBP1 gene and is inherited in an X-linked pattern.

L1 syndrome is a genetic condition occurring in males that usually includes hydrocephalus, intellectual disability, spasticity of legs and clasped (adducted) thumbs. L1 syndrome is caused by variants in the L1CAM gene. The variable types of L1 syndrome were once thought to be different diseases, but all the following conditions are now known to be caused by variants in the L1CAM gene:

X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS) is characterized by severe hydrocephalus that often begins prenatally, adducted (clasped) thumbs, spasticity and severe intellectual disability. HASA syndrome is characterized by mild to moderate intellectual disability, aphasia (delayed speech), hypotonia that progresses to spasticity, adducted thumbs and variable widening of the third ventricle in the brain. X-linked complicated hereditary spastic paraplegia type 1 is characterized by spastic paraplegia (shuffling gait), mild to moderate intellectual disability and normal findings on MRI of the brain. X-linked complicated corpus callosum agenesis is characterized by variable spastic paraplegia, mild to moderate intellectual disability and abnormalities in the corpus callosum of the brain. (For more information on this disorder, choose “L1 syndrome” as your search term in the Rare Disease Database.)

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain. Symptoms develop due to lack of fatty covering of nerve cells (myelin sheath). Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities and the slow progressive deterioration of intellectual function. PMD disease is associated with variants in the PLP1 gene. Some individuals with MCT8 deficiency have been incorrectly diagnosed as having PMD. (For more information on this disorder, choose “Pelizeaus-Merzbacher” as your search term in the Rare Disease Database.)

There are additional congenital disorders that may be characterized by X-linked intellectual disability and occur in association with movement abnormalities, psychomotor delay and/or other features similar to those associated with MCT8 deficiency. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database).

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Diagnosis

The diagnosis of MCT8 deficiency may be suspected in infants with low muscle tone (hypotonia) and poor head control that causes the head to droop (limber neck). Although hypotonia and muscle weakness may be obvious during early infancy, other symptoms (e.g., dyskinetic attacks, spastic paraplegia, etc.) may not become apparent until late infancy. Therefore, the disorder may not be diagnosed until childhood, based upon a thorough clinical evaluation, detailed patient history and specialized tests.

Thyroid hormone testing is necessary to determine if MCT8 deficiency is a possible diagnosis. If results show elevated serum triiodothyronines (T3) and reduced reverse T3 concentrations, molecular genetic testing is indicated to determine if a MCT8 gene variant is present. In addition, serum thyroxine (T4) level tends to be low, and thyrotropin (TSH) may be slightly elevated.

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Standard Therapies

Treatment
The treatment of MCT8 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, neurologists, specialists who assess and treat skeletal abnormalities (orthopedists), speech-language pathologists, physical therapists and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.

Specific therapies for the treatment of MCT8 deficiency are symptomatic and supportive. Affected individuals who have scoliosis may be treated with orthopedic braces, physical therapy and/or other orthopedic measures. When abnormal depression of the breastbone (pectus excavatum) is present, corrective surgery may be recommended in some patients.

Early intervention is important to ensure that children with MCT8 deficiency reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy and/or other medical, social and/or vocational services.
Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

The combined use of propylthiouracil (PTU) and L-thyroxine (L-T4) has been proposed as a possible treatment to improve the nutritional status of affected patients. Both are approved drugs used to treat thyroid diseases. For patients with MCT8 deficiency, L-T4 provides a thyroid hormone more readily available to the brain. PTU reduces T3 in peripheral tissue, thus decreasing hypermetabolism.

Several treatments are actively being tested or are undergoing trials. These are: (1) thyroid hormone analogues (TRIAC and DITPA) that reduce the hypermetabolism caused by the high T3 in blood but have no documented effect on neurodevelopment; (2) phenylbutyrate that moves MCT8 molecules to the cell membrane and might be effective in patients with gene variants that produce functional MCT8 protein but don’t reach the brain. (3) gene therapy that targets the brain to correct the neurodevelopmental abnormality but not the hypermetabolism. It is undergoing active development but is several years away from trials in humans.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Bialer MG. Allan-Herndon-Dudley Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:149.

JOURNAL ARTICLES
Groeneweg S, van Geest FS, Abaci A, Alcantud A, Ambegaonkar GP, Armour CM, et al. Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study. Lancet Diabetes Endocrinol. 2020;8(7):594-605.

Vatine GD, Al-Ahmad A, Barriga BK, Svendsen S, Salim A, Garcia L, et al. Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood-brain barrier. Cell Stem Cell. 2017;20(6):831-43 e5.

Capri Y, Friesema EC, Kersseboom S, Touraine R, Monnier A, Eymard-Pierre E, et al. Relevance of different cellular models in determining the effects of mutations on SLC16A2/MCT8 thyroid hormone transporter function and genotype-phenotype correlation. Hum Mutat. 2013;34(7):1018-25.

Ceballos A, Belinchon MM, Sanchez-Mendoza E, et al. Importance of monocarboxylate transporter 8 (Mct8) for the blood-brain barrier dependent availability of 3,5,3′-triiodo-L-thyronine (T3). Endocrinology. 2009;150:2491-2496.

Wemeau JL. Pigeyre E, Proust-Lemoine, et al. Beneficial effects of Propylthioruracil plus L-thyroxine treatment in a patient with a mutation in MCT8. J Clin Endocrinol Metab. 2008;93(6):2084-2088.

Jansen J, Friesema EC, Kester MH, et al. Functional analysis of MCT8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine. J Clin Endocrinol Metab. 2007;92(6):2378-81.

Friesema EC, Jansen J, Heuer H, et al. Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8. Nat Clin Pract Endocrinol Metab. 2006;2(9):512-23.

Maranduba CM, Friesema EC, Kok F, et al. Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter. J Med Genet. 2006;43(5):457-60.

Schwartz CE, May MM, Carpenter NJ, et al. Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am J Hum Genet. 2005 ;77(1):41-53.

Holden KR, Zuniga OF, May MM, et al. X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype. J Child Neurol. 2005 Oct;20(10):852-7.

Dumitrescu AM, Liao X-H, Best TB, et al. 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.

INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:300523 Last Update: 02/27/2020. Available at: https://www.omim.org/entry/300523 Accessed July 24, 2023.

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