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Last updated: 7/25/2023
Years published: 1996, 2001, 2003, 2007, 2009, 2010, 2023
NORD gratefully acknowledges Samuel Refetoff, MD, Frederick H. Rawson Professor Emeritus of Medicine, Director, Endocrinology Laboratory, The University of Chicago Medicine, for assistance in the preparation of this report.
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.
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 โlimber neck.โ 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 (โfunnel chestโ or pectus excavatum) and/or foot abnormalities.
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.
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.
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.
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 childโs 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.
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 donโt 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: [email protected]
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/
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 3,5,3โฒ-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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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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