NORD gratefully acknowledges Samuel Refetoff, MD, Frederick H. Rawson Professor in Medicine, Professor of Pediatrics the Committees on Genetics and Molecular Medicine, Director of the Endocrinology Laboratory, University of Chicago, for assistance in the preparation of this report.
MCT8-specific thyroid hormone cell transporter deficiency (THCT deficiency) is an inherited disorder that is characterized by severe mental retardation, an impaired ability to speak, diminished muscle tone (hypotonia), and/or movement abnormalities.
With the exception of poor muscle tone, most affected infants appear to develop normally during the first months of life. However, by about two months of age, affected infants may seem weak and have an inability to hold up the head. Due to hypotonia, severely reduced motor development, and other abnormalities, affected children very rarely develop any ability to walk and when they do, it is with shuffling gait. Associated features often include underdevelopment (hypoplasia) and wasting (atrophy) of muscle tissue; weakness and stiffness of the legs (spastic paraplegia) with exaggerated reflexes (hyperreflexia); relatively slow, involuntary, purposeless, commonly dyskinetic (abnormal movement) attacks. Writhing movements (athetoid movements); and/or other movement abnormalities are less common. Affected individuals may also have abnormalities of the skull and facial (craniofacial) region. THCT deficiency is inherited as an X-linked genetic disorder.
THCT deficiency is primarily characterized by severe mental retardation, poor muscle tone (hypotonia), and movement abnormalities. As mentioned above, affected infants typically appear to develop normally (with the exception of hypotonia) until about 2 months of age, when they may seem to have generalized weakness and be unable to hold up their heads. Family members have described the latter feature as “limber neck.” Due to low muscle tone, weakness, severely reduced motor development, and/or other factors, affected children are unable to or may walk with great difficulty. Associated findings may include underdevelopment (hypoplasia) and wasting (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 contractions and relaxations of the legs (clonus); involuntary. Movement abnormalities are common and include, most commonly, dyskinetic attacksor 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 (changing diapers or clothes) and emotional stimuli
As noted earlier, infants and children with the disorder are also affected by severe mental retardation and delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation). In addition, affected children are unable to speak or rarely acquire garbled speech.
As adults, affected individuals may have generalized muscular wasting (atrophy), permanent fixation of multiple small and large joints in various fixed postures (joint contractures) and/or decreased reflex reactions (hyporeflexia).
Individuals with THCT deficiency may also have unusual craniofacial features and/or additional skeletal abnormalities. The head is usually of normal size but may be abnormally narrow at the temples (bitemporal narrowing). In addition, the face may appear abnormally long (elongated) and thin with large, poorly developed ears. In some cases, THCT deficiency may also be associated with abnormal side-to-side curvature of the spine (scoliosis); depression of the breastbone (“funnel chest” or pectus excavatum); and/or foot defects.
THCT deficiency is caused by an abnormality (mutation) in the MCT8 (SLC16A2) gene leading to alteration in the structure and function of the MCT8 protein. The abnormal protein is unable to transport thyroid hormone produced by the thyroid gland into the brain, thus affecting its development.
THCT deficiency is inherited as an X-linked genetic condition. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifests mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective 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 X-linked disorders is able to reproduce, he will pass the defective gene to all of 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 offspring.
THCT deficiency is a rare inherited disorder that manifests in males only. One hundred and forty four cases involving males from 56 separate families (kindreds) have been identified two thirds of whom have reported in the medical literature. They involves 49 distinct MCT8 gene mutations. The frequency of THCT deficiency in the general population with mental retardation is not known.
The diagnosis of THCT deficiency may be suspected in infants with diminished muscle tone (hypotonia) with 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, a detailed patient history, and specialized tests.
Thyroid hormone testing is necessary to determine if THCT deficiency is a possible diagnosis. If results elevated serum T3 and reduced reverse T3 concentrations, molecular genetic testing is indicated to determine if an abnormal MCT8 gene is present. In addition, serum T4 level has the tendency to be low and TSH may be slightly elevated.
The treatment of THCT 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 systematically and comprehensively plan an affected child's treatment.
Specific therapies for the treatment of THCT 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 cases.
Early intervention is important to ensure that children with THCT 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. Other treatment for this disorder is symptomatic and supportive.
Propylthiouracil plus L-Thyroxine has been proposed as a possible treatment to improve the nutritional status of affected patients.
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
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., mental retardation, impaired speech, movement abnormalities, etc.)
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FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:300523 Last Update:11/18/09. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300523.
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