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MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency

Synonym: Allan-Herndon-Dudley Syndrome

, MD, PhD, , MD, , MS, and , MD.

Author Information
, MD, PhD
Assistant Professor, University of Chicago Medical Center
Chicago, Illinois
, MD
Visiting Graduate Student, University of Chicago Medical Center
Chicago, Illinois
, MS
Certified Genetic Counselor, Parkview Health
Fort Wayne, Indiana
, MD
Professor of Medicine, Pediatrics & Genetics
University of Chicago Medical Center
Chicago, Illinois

Initial Posting: ; Last Update: April 11, 2013.

Summary

Disease characteristics. MCT8-specific thyroid hormone cell-membrane transporter deficiency is characterized by severe cognitive deficiency, infantile hypotonia, diminished muscle mass and generalized muscle weakness, progressive spastic quadriplegia, joint contractures, and dystonic and/or athetoid movement with characteristic paroxysms or kinesigenic dyskinesias. Seizures occur in about 25% of cases. Most affected males never sit or walk independently or lose these abilities over time; most never speak or have severely dysarthric speech. Brain MRI obtained in the first few years of life shows transient delayed myelination, which improves by age four years. Although psychomotor findings observed in affected males do not occur in heterozygous females, the latter often have thyroid test abnormalities intermediate between affected and normal individuals.

Diagnosis/testing. All affected males tested to date have had pathognomonic thyroid test results including high serum 3,3’,5-triiodothyronine (T3 ) concentration and low serum 3,3’,5’-triiodothyronine (reverse T3 or rT3) concentration. Serum tetraiodothyronine (thyroxine or T4) concentration is often reduced, but may be within the low normal range; serum TSH concentrations are normal or slightly elevated. SLC16A2 (also known as MCT8) is the only gene in which mutations are known to cause this disorder.

Management. Treatment of manifestations: Physical, occupational, and speech therapies, if necessary. Anticholinergics, L-DOPA, carbamazepine, or lioresol for the treatment of dystonia. Glycopyrolate or scopolamine to reduce drooling. Standard antiepileptic drugs to control seizures, if present. Placement of permanent feeding tube to maintain caloric intake.

Prevention of secondary complications: Braces to prevent joint contractures and orthopedic surgery, if necessary. Dietary restrictions to prevent aspiration.

Surveillance: Regular orthopedic evaluations to monitor scoliosis or joint problems; ongoing developmental assessments.

Agents/circumstances to avoid: Administration of L-T4 or L-T3 alone can exacerbate the high serum T3 levels and the resulting hypermetabolism.

Other: Thyroid hormone treatment, in replacement doses, during childhood has no beneficial effect. Combined treatment with high doses of levothyroxine (L-T4) and propylthiouracil (PTU), which inhibits deiodinase 1, has been shown to ameliorate the hypermetabolic state, with beneficial effects on body weight and heart rate. Similarly a thyromimetic compound diiodothyropropionic acid (DITPA) given to four affected children improved the hypermetabolic state. However, both therapies resulted in no significant neurologic improvement.

Genetic counseling. MCT8-specific thyroid hormone cell-membrane transporter deficiency is inherited in an X-linked manner. Women who are carriers have a 50% chance of transmitting the SLC16A2 mutation in each pregnancy. Male offspring who inherit the mutation will be affected; female offspring who inherit the mutation will be carriers and will usually not be affected although they may have minor thyroid test abnormalities. No affected male has reproduced. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

The features described in 100% of individuals with MCT8-specific thyroid hormone cell-membrane transporter deficiency are hypotonia and severe intellectual disability. Thus, the diagnosis should be suspected in males with at least two of the following:

  • Hypotonia/dystonia and feeding difficulties in the first months of life
  • Truncal hypotonia
  • Muscle hypoplasia/asthenic build
  • Poor head control
  • Spastic paraparesis with dystonic/athetoic movements (with extensor posturing mainly affecting the distal upper limbs)
  • Paroxysmal dyskinesia
  • Dysarthric or no speech
  • Severe psychomotor retardation and cognitive impairment

Other findings include poor weight gain, limb rigidity with contractures, brisk deep tendon reflexes, clonus, and seizures.

Brain MRI shows absent or markedly delayed myelination that may not be appreciated after age four years [Holden et al 2005, Kakinuma et al 2005, Sijens et al 2008, Gika et al 2010, Tonduti et al 2012, Tsurusaki et al 2011]. Note: Early reports of normal MRI in this disorder were from older individuals.

Testing

Affected males. See Figure 1. Males with MCT8-specific thyroid hormone cell-membrane transporter deficiency have pathognomonic thyroid test results including the following:

Figure 1

Figure

Figure 1. Thyroid function tests from six families with MCT8-specific thyroid hormone cell-membrane transporter deficiency studied at the University of Chicago

• 7 affected males (M, in red squares)
• 11 carrier (more...)

  • High serum 3,3’,5-triiodothyronine (T3 ) concentration and low serum 3,3’,5’-triiodothyronine (reverse T3 or rT3) concentration

    Note: All individuals with SLC16A2 mutations had high serum T3 concentration and, when obtained, low serum rT3 concentration. This holds true for both total and free hormone concentrations in serum.
  • Serum tetraiodothyronine (thyroxine or T4) concentration that is often reduced, but may be within the low normal range
  • Serum TSH concentrations that are normal or slightly elevated (Figure 1) [Refetoff & Dumitrescu 2007, Dumitrescu & Refetoff 2009]

Carrier females. Thyroid hormone concentrations in female carriers are intermediate between affected males and unaffected family members (Figure 1) [Refetoff & Dumitrescu 2007, Dumitrescu & Refetoff 2009]. However, results of thyroid tests in females cannot be reliably used to identify carrier females; carrier status determination requires molecular genetic testing.

Molecular Genetic Testing

Gene. SLC16A2 is the only gene in which mutations are known to cause MCT8-specific thyroid hormone cell-membrane transporter deficiency.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Affected MalesCarrier Females 2
SLC16A2 Sequence analysisSequence variants 3Unknown 4Unknown 5
Deletion / duplication analysis 6Exonic, multiexonic, or whole-gene deletionUnknown 7Unknown

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. When no affected males in the family are available for testing

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Sequence analysis of SLC16A2 is expected to identify a mutation in most affected individuals with the typical thyroid test results; however, the exact mutation detection rate is unknown.

5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Exonic and multiexonic deletions have been reported but the frequency is unknown [Vaurs-Barrière et al 2009, Visser et al 2009].

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • See Table 1 footnotes 4 and 5 for additional issues related to interpretation of test results for an X-linked disorder.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of MCT8-specific thyroid hormone cell-membrane transporter deficiency can be established in a male with psychomotor delays and the characteristic thyroid test results.

  • To date, no persons with SLC16A2 mutations have been reported with normal or non-characteristic thyroid test results; thus, it is recommended that thyroid testing (including T3 and rT3 concentrations) be performed first.
  • The diagnosis is confirmed when a mutation or deletion is identified in SLC16A2 through sequence analysis or deletion/duplication analysis, respectively.

Carrier testing for at-risk female relatives can be done either (a) after prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for thyroid hormone testing, by sequence analysis. If no mutation is identified, other methods to detect deletion/duplication abnormalities can be used.

Note: Carrier females are heterozygous for this X-linked disorder and usually do not develop clinical findings related to the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Neonatal period. Infants with MCT8-specific thyroid hormone cell-membrane transporter deficiency have normal length, weight, and head circumference measurements at birth. Hypotonia and feeding difficulties can appear in the first weeks or months of life.

Growth. Linear growth is typically normal, but approximately 20% of males have short stature [Schwartz & Stevenson 2007]. Weight gain lags behind linear growth; microcephaly becomes apparent with advancing age.

Craniofacial. Common facial findings that may be attributed to prenatal and infantile hypotonia include ptosis, open mouth, and a tented upper lip. Ear length is above the 97th centile in about half of adults. Cup-shaped ears, thickening of the nose and ears, upturned earlobes, and a decrease in facial creases are also reported.

Neuromuscular. Truncal hypotonia persists into adulthood. Progressive hypertonicity of the limbs leads to spastic quadriplegia and joint contractures. Overall, muscle mass is diminished and associated with generalized muscle weakness. Affected males are described with “limber neck” or poor head control even as adults.

It is common for affected males to experience purposeless movements described as dystonic and/or athetoid and characteristic paroxysms or kinesigenic dyskinesias [Brockmann et al 2005, Fuchs et al 2009]. These can be triggered by somatosensory stimuli, including changing clothes or lifting the affected child. During attacks, the body extends and the mouth opens; stretching or flexing of the limbs lasts as long as one to two minutes.

Seizures occur in approximately 25% of individuals with onset during infancy or early childhood [Schwartz & Stevenson 2007].

Brisk reflexes, ankle clonus, and extensor plantar responses (Babinski sign) are common. Rotary nystagmus and disconjugate eye movements have been reported but are not common [Dumitrescu et al 2004].

Skeletal. Pectus excavatum and scoliosis are common, most likely the result of hypotonia and reduced muscle mass.

Behavior. Generally, affected individuals are attentive, friendly, and docile. They are not aggressive or destructive.

Development. Psychomotor retardation is observed in 100% of affected males. Most affected males either never sit or walk independently or lose these abilities over time. In addition, most affected males never speak or may develop only garbled sounds secondary to severely dysarthric speech.

Other. Findings typical of hypothyroidism in infancy (i.e., prolonged neonatal jaundice, myxedematous skin changes, macroglossia, hoarseness, umbilical hernias, and short stature) are absent [Schwartz et al 2005].

Life span. Early death has occurred in some individuals, usually caused by recurrent infections and/or aspiration pneumonia. In a few instances survival beyond age 70 years has been reported.

Affected heterozygous females. A female with typical features of MCT8-specific thyroid hormone cell-membrane transporter deficiency with a de novo translocation disrupting SLC16A2 and unfavorable nonrandom X-inactivation was reported [Frints et al 2008].

Although most of the psychomotor findings described above do not occur in heterozygous females, intellectual delay and intellectual disability have in rare instances been reported [Dumitrescu et al 2004, Schwartz et al 2005, Herzovich et al 2007]. However, whether a causative relationship exists between SLC16A2 mutations and cognitive impairments in heterozygous females has yet to be proven [Schwartz et al 2005].

Genotype-Phenotype Correlations

A few missense mutations (p.Ser194Phe, p.Leu434Trp, p.Leu492Pro, p.Leu568Pro) and the deletion of a single amino acid (p.Phe501del) have been associated with milder psychomotor delays, including some speech development, some reading/writing, and/or the ability to walk without support despite ataxia [Schwartz et al 2005, Jansen et al 2008, Visser et al 2009, Visser et al 2013]. Independent walking and speech development are unusual in affected males with other mutations.

Penetrance

No unaffected males with SLC16A2 mutations have been reported; thus, penetrance appears to be 100%.

Heterozygous females are typically clinically normal.

Anticipation

Anticipation has not been observed.

Nomenclature

MCT8-specific thyroid hormone cell-membrane transporter deficiency was given as a name of this condition, following the identification of the gene and the defect in thyroid hormone metabolism.

Because of the overlap between the clinical phenotype in individuals with SLC16A2 abnormalities and in those with a previously described syndrome, Allan-Herndon-Dudley syndrome (AHDS), Schwartz et al [2005] analyzed SLC16A2 in six families with AHDS. SLC16A2 mutations were identified in all six; therefore, AHDS is now synonymous with MCT8-specific thyroid hormone cell-membrane transporter deficiency due to mutations in SLC16A2.

Prevalence

Prevalence of MCT8-specific thyroid hormone cell-membrane transporter deficiency remains unknown. However, the identification of more than 100 families in approximately ten years suggests that the syndrome is more common than previously expected.

Differential Diagnosis

Many disorders demonstrate hypotonia and severe intellectual disability in an X-linked inheritance pattern. Several disorders, described below, also demonstrate spasticity, seizures, or other features that overlap with the neurologic phenotype of the MCT8-specific thyroid hormone cell-membrane transporter deficiency and should be considered.

  • Pelizaeus-Merzbacher disease (PMD) and other PLP1-related disorders display a wide spectrum of phenotypes but can manifest in infancy or early childhood with nystagmus, hypotonia, and severe cognitive impairment and eventually progress to severe spasticity and ataxia. As with males with SLC16A2 mutations, males with PMD present with delayed myelination during early childhood; however, they do not have the thyroid test abnormalities characteristic of MCT8-specific thyroid hormone cell-membrane transporter deficiency. PLP1-related disorders are inherited in an X-linked pattern, and 80%-95% of males with a PLP1-related disorder have a mutation in PLP1.

    Of note, in one study SLC16A2 mutations were reported in 11% of 53 families with a severe form of Pelizaeus-Merzbacher-like disease with an unusual improvement in myelination with age [Vaurs-Barrière et al 2009].
  • Individuals with leukodystrophies, including metachromatic leukodystrophy (arylsulfatase A deficiency), X-linked adrenoleukodystrophy, Krabbe disease, and Canavan disease have hypotonia, muscle wasting, and spasticity with no speech or ambulation. However, MRI, nerve conduction velocity (NCV) and evoked potentials are usually abnormal in these disorders.
  • Males with MECP2 duplication syndrome have infantile hypotonia, severe intellectual disability, absent speech, progressive spasticity, and seizures. Approximately 75% also have recurrent respiratory infections.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

No current published guidelines exist to establish the extent of disease or proper management in an individual diagnosed with MCT8-specific thyroid hormone cell-membrane transporter deficiency. The following recommendations are based on current literature and the authors’ experience.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an affected individual, the following are recommended:

  • Growth parameters
  • Developmental assessment
  • Neurologic evaluation and EEG to assess possible seizures
  • Orthopedic evaluation to assess for possible developing scoliosis or pectus deformities
  • Medical genetics consultation

Treatment of Manifestations

The following treatment is appropriate:

  • Physical, occupational, and speech therapies, if necessary
  • Medications, such as anticholinergics, L-DOPA, carbamazepine, or lioresol, for the treatment of dystonia
  • Glycopyrolate or scopolamine to improve drooling
  • Standard anticonvulsant medication to control seizures, if present
  • Placement of permanent feeding tube to avert malnutrition

Note: Thyroid hormone treatment with replacement doses during childhood has no beneficial effect. However, combined treatment with high doses of levothyroxine (L-T4) and propylthiouracil (PTU), which inhibits deiodinase 1, has been shown to ameliorate the hypermetabolic state, with beneficial effects on body weight and heart rate, as seen in several affected individuals [Wemeau et al 2008, Visser et al 2013]. See also Therapies Under Investigation.

Prevention of Secondary Complications

Appropriate measures include the following:

  • Braces to prevent joint contractures and orthopedic surgery, if necessary
  • Diet restrictions to prevent aspiration

Surveillance

Appropriate surveillance includes the following:

  • Regular orthopedic evaluations to monitor scoliosis or joint problems
  • Ongoing developmental assessments

Agents/Circumstances to Avoid

Aspiration of food should be avoided to prevent pneumonia.

Administration of L-T4 or L-T3 alone can exacerbate the high serum T3 levels and the resulting hypermetabolism.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In a recent report, two unaffected heterozygous pregnant women with unaffected fetuses were treated with L-T4 in the second half of pregnancy [Ramos et al 2011]. It is unclear if this had any effect, either beneficial or detrimental, on the fetus. Of note, many unaffected heterozygous mothers have given birth to normal unaffected children without any prenatal treatment.

Therapies Under Investigation

Diiodothyropropionic acid (DITPA), a thyroid hormone analog that does not require MCT8 for transfer into cells, has been evaluated as a treatment in both a mouse model of Mct8 deficiency and in humans with MCT8-specific thyroid hormone cell-membrane transporter deficiency [Di Cosmo et al 2009, Verge et al 2012]. DITPA therapy was given to four affected children with subsequent improvement in the hypermetabolic state; however, no significant neurologic improvement was obtained with this therapy. Consideration is being given to DITPA treatment during pregnancy, however such treatment has not been used to date, and there is no information on whether it will be effective.

Recently another analog TETRAC (3, 3’, 5, 5’-tetraiodothyroacetic acid) has been tested in mice with Mct8 deficiency [Horn et al 2013]. TETRAC treatment was able to promote TH-dependent neuronal differentiation in some brain areas but was ineffective in suppressing TRH (thyrotropin releasing hormone) in the hypothalamus. The efficacy of TETRAC therapy may vary among distinct neuronal populations or among different genes that are controlled by TH in a positive or negative manner. However, peripheral tissue thyrotoxicity in Mct8-deficient mice was not significantly ameliorated by TETRAC therapy.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MCT8-specific thyroid hormone cell-membrane transporter deficiency is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

  • The father of an affected male will not have the disease nor will he be a carrier of the mutation.
  • In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • If pedigree analysis reveals that the proband is the only affected family member, the possible genetic explanations are:
    • The proband has a de novo mutation. In this instance, the proband’s mother does not have a gene mutation. De novo mutations have been reported in MCT8-specific thyroid hormone cell-membrane transporter deficiency [Author, personal communication; Dumitrescu et al 2004].
    • The proband’s mother has a de novo mutation. Two types of de novo mutations may be present in the mother:
      • A germline mutation that was present at the time of her conception, is present in every cell of her body, and is detectable in her leukocytes; or
      • A mutation that is present only in her ovaries (termed "germline mosaicism") in which some germ cells have the mutation and some do not, and in which the mutation is not detectable in leukocyte DNA. Germline mosaicism has not been reported in MCT8-specific thyroid hormone cell-membrane transporter deficiency but has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members.
      • In either of the preceding scenarios: all offspring of the proband’s mother are at risk of inheriting the mutation; sibs of the proband’s mother are not at risk of inheriting the mutation.
    • The mother is a carrier and has inherited the disease-causing mutation either from her mother, who has a de novo disease-causing mutation, or from her asymptomatic father, who has germline mosaicism for the mutation.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the parents:

  • If the mother of the proband has a disease-causing mutation, the chance of transmitting the SLC16A2 mutation in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected but may have minor thyroid test abnormalities.
  • If the family-specific SLC16A2 sequence abnormality is not detected in the mother, the risk to the sibs of a proband is much reduced, but greater than that of the general population. The risk depends on the probability of germline mosaicism in a parent of the proband and the spontaneous mutation rate of SLC16A2. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a male proband. Affected males do not reproduce.

Offspring of a female proband. Affected females may not reproduce; the only affected female reported had hypogonadotropic hypogonadism [Frints et al 2008]. Women carrying an SLC16A2 mutation have a 50% chance of transmitting the disease-causing mutation to each child: sons who inherit the mutation will be affected; daughters who inherit the mutations will be carrier and may have minor thyroid test abnormalities.

Other family members of a proband. If the mother of the proband has a disease-causing mutation, her female relatives may be at risk of being carriers (typically asymptomatic, although they may have minor thyroid test abnormalities) and her male relatives may be at risk of being affected depending on their genetic relationship to the proband. Phenotypically normal males are unlikely to carry the mutation.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • MCT8 Organization
    c/o Susan D. Fidek
    1023 Kingsmere Blvd
    Saskatoon Saskatchewan S7J 5A7
    Canada
    Phone: 306-668-6149
    Email: susan@mct8organization.org
  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 800-424-3688 (toll-free); 202-387-1968
    Fax: 202-387-2193
    Email: anam@aaidd.org
  • Medline Plus
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SLC16A2Xq13​.2Monocarboxylate transporter 8SLC16A2 @ LOVDSLC16A2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency (View All in OMIM)

300095SOLUTE CARRIER FAMILY 16 (MONOCARBOXYLIC ACID TRANSPORTER), MEMBER 2; SLC16A2
300523ALLAN-HERNDON-DUDLEY SYNDROME; AHDS

Molecular Genetic Pathogenesis

Monocarboxylate transporter 8 (MCT8) the protein product of SLC16A2, is thought to play a role in neuronal T3 uptake and in endothelial cells allowing partial entry of thyroid hormone through the blood-brain barrier. MCT8 deficiency results in an insufficient supply of T3 to nuclear T3 receptors. Thyroid hormone plays a crucial role in brain development. Thus, it is presumed that the decreased access of T3 to brain cells can lead to the severe defects in neurologic development seen in males with MCT8-specific thyroid hormone cell-membrane transporter deficiency [Friesema et al 2006, Roberts et al 2008, Ceballos et al 2009].

Normal allelic variants. SLC16A2 consists of six coding exons. It has two translation start sites (see Normal gene product). The only reported nonsynonymous allelic variant is c.319T>C (p.Ser107Pro) in exon 1; two independent studies have confirmed a lack of association between this variant and either serum thyroid hormone levels or SLC16A2 mRNA levels [Lago-Leston et al 2009, van der Deure et al 2009]. The synonymous normal allelic variant c.1095A>T in exon 3 has a frequency of 3.3% in the African American population. Several synonymous variants have been recently reported but their frequencies is not known [Frints et al 2008, Visser et al 2013].

Pathologic allelic variants. More than 70 mutations have been identified in SLC16A2. Reported mutations are distributed throughout the coding region of the gene. They include full-gene and intragenic deletions, frameshift, nonsense, splice site, and missense mutations. Functional studies have confirmed the pathogenesis of many of the missense mutations. A particularly interesting mutation, c.1834delC, results in bypassing the natural stop codon, extending the MCT8 protein by 65 amino acids and probably adding a thirteenth transmembrane domain [Maranduba et al 2006].

Table 2. SLC16A2 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
Normalc.319T>C
rs6647476 2
p.Ser107ProNM_006517​.3
NP_006508​.1
c.1095A>T
rs12849161 2
p.(=) 3
(p.Pro365Pro)
Pathologicc.581C>Tp.Ser194Phe
c.1301T>Gp.Leu434Trp
c.1475T>Cp.Leu492Pro
c.1501_1503del
(1497_1499delCTT)
p.Phe501del
c.1703T>Cp.Leu568Pro
c.1835delC
(1834delC)
p.Pro612Glnfs*68
(Pro612fsX679)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Reference SNP

3. p.(=) designates that protein has not been analyzed, but no change is expected

Normal gene product. SLC16A2 has two translation start sites, which generate proteins of either 613 amino acids or 539 (NP_006508.2) amino acids. Both of these MCT8 proteins contain 12 putative transmembrane domains.

Abnormal gene product. MCT8-specific thyroid hormone cell-membrane transporter deficiency results from a loss of function of the MCT8 protein. Most mutations cause decreased activity or complete inactivation of the MCT8 transporter [Friesema et al 2006]. This leads to a decrease in thyroid hormone uptake into neurons, which is presumably the cause of the neurologic phenotype. Other as-yet unknown mechanisms cannot be excluded.

References

Literature Cited

  1. Brockmann K, Dumitrescu AM, Best TT, Hanefeld F, Refetoff S. X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene. J Neurol. 2005;252:663–6. [PubMed: 15834651]
  2. Ceballos A, Belinchon MM, Sanchez-Mendoza E, Grijota-Martinez C, Dumitrescu AM, Refetoff S, Morte B, Bernal J. Importance of Monocarboxylate transporter 8 (Mct8) for the Blood-Brain Barrier Dependent Availability of 3,5,3'-Triiodo-L-Thyronine (T3). Endocrinology. 2009;150:2491–6. [PMC free article: PMC2671898] [PubMed: 19147674]
  3. Di Cosmo C, Liao XH, Dumitrescu AM, Weiss RE, Refetoff S. A thyroid hormone analogue with reduced dependence on the monocarboxylate transporter 8 (MCT8) for tissue transport. Endocrinology. 2009;150:4450–8. [PMC free article: PMC2736078] [PubMed: 19497976]
  4. Dumitrescu AM, Liao X-H, Best TD, 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;74:168–76. [PMC free article: PMC1181904] [PubMed: 14661163]
  5. Dumitrescu AM, Refetoff S. Cell transport defects. In: Wondisford FE, Radovick S, eds. Clinical Management of Thyroid Disease. Chap 22. Philadelphia, PA: Elsevier Saunders; 2009:317-23.
  6. Visser WE, Vrijmoeth P, Visser FE, Arts WF, van Toor H, Visser TJ. Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation. Clin Endocrinol (Oxf) 2013;78:310–5. [PubMed: 22924588]
  7. Friesema ECH, Jansen J, Heuer H, Trajkovic M, Bauer K, Visser TJ. Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8. Nat Clin Pract Endocrinol Metab. 2006;2:512–23. [PubMed: 16957765]
  8. Frints SGM, Lenzner S, Bauters M, Jensen LR, Esch HV, des Portes V, Moog U, Macville MVE, van Roozendaal K, Schrander-Stumpel CTRM, Tzschach A, Marynen P, Fryns J, Hamel B, van Bokhoven H, Chelly J, Beldjord C, Turner G, Gecz J, Moraine C, Raynaud M, Ropers HH, Froyen G, Kuss AW. MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression. Eur J Hum Genet. 2008;16:1029–37. [PubMed: 18398436]
  9. Fuchs O, Pfarr N, Pohlenz J, Schmidt H. Elevated serum triiodothyronine and intellectual and motor disability with paroxysmal dyskinesia caused by a monocarboxylate transporter 8 gene mutation. Dev Med Child Neurol. 2009;51:240–4. [PubMed: 19018842]
  10. Gika AD, Siddiqui A, Hulse AJ, Edward S, Fallon P, McEntagart ME, Jan W, Josifova D, Lerman-Sagie T, Drummond J, Thompson E, Refetoff S, Bönnemann CG, Jungbluth H. White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene. Dev Med Child Neurol. 2010;52:475–82. [PubMed: 19811520]
  11. Herzovich V, Vaiani E, Marino R, Dratler G, Lazzati JM, Tilitzky S, Ramirez P, Iorcansky S, Rivarola MA, Belgorosky A. Unexpected peripheral markers of thyroid function in a patient with a novel mutation of the MCT8 thyroid hormone transporter gene. Horm Res. 2007;67:1–6. [PubMed: 16974106]
  12. Holden KR, Zuñiga OF, May MM, Su H, Molinero MR, Rogers RC, Schwartz CE. X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype. J Child Neurol. 2005;20:852–7. [PubMed: 16417886]
  13. Horn S, Kersseboom S, Mayerl S, Müller J, Groba C, Trajkovic-Arsic M. et al. Tetrac Can Replace Thyroid Hormone During Brain Development in Mouse Mutants Deficient in the Thyroid Hormone Transporter Mct8. Endocrinology. 2013;154:968–79. [PubMed: 23307789]
  14. Jansen J, Friesema EC, Kester MH, Schwartz CE, Visser TJ. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8. Endocrinology. 2008;149:2184–90. [PMC free article: PMC2734492] [PubMed: 18187543]
  15. Kakinuma H, Itoh M, Takahashi H. A novel mutation in the monocarboxylate transporter 8 gene in a boy with putamen lesions and low free T4 levels in cerebrospinal fluid. J Pediatr. 2005;147:552–4. [PubMed: 16227048]
  16. Lago-Lestón R, Iglesias MJ, San-José E, Areal C, Eiras A, Araújo-Vilar D, Lado-Abeal J, Domínguez-Gerpe L. Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of north-west Spain (Galicia). Clin Endocrinol (Oxf) 2009;70:636–43. [PubMed: 18710470]
  17. Maranduba CM, Friesema EC, Kok F, Kester MH, Jansen J, Sertié AL, Passos-Bueno MR, Visser TJ. 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;43:457–60. [PMC free article: PMC2649011] [PubMed: 15980113]
  18. Ramos HE, Morandini M, Carre A, Tron E, Floch C, Mandelbrot L. et al. Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care. Eur J Endocrinol. 2011;164:309–14. [PubMed: 21098685]
  19. Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007;21:277–305. [PubMed: 17574009]
  20. Roberts LM, Woodford K, Zhou M, Black DS, Haggerty JE, Tate EH, Grindstaff KK, Mengesha W, Raman C, Zerangue N. Expression of the thyroid hormone transporters MCT8 (SLC16A2) and OATP14 (SLCO1C1) at the blood-brain barrier. Endocrinology. 2008;149:6251–61. [PubMed: 18687783]
  21. Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, Ward J, Sanabria J, Marsa S, Lewis JA, Echeverri R, Lubs HA, Voeller K, Simensen RJ, Stevenson RE. Allan-Herndon-Dudley syndrome and the MCT8 thyroid hormone transporter. Am J Hum Genet. 2005;77:41–53. [PMC free article: PMC1226193] [PubMed: 15889350]
  22. Schwartz CE, Stevenson RE. The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. Best Pract Res Clin Endocrinol Metab. 2007;21:307–21. [PMC free article: PMC2094733] [PubMed: 17574010]
  23. Sijens PE, Rödiger LA, Meiners LC, Lunsing RJ. 1H magnetic resonance spectroscopy in monocarboxylate transporter 8 gene deficiency. J Clin Endocrinol Metab. 2008;93:1854–9. [PubMed: 18319316]
  24. Tonduti D, Vanderver A, Berardinelli A, Schmidt JL, Collins CD, Novara F, Di Genni A, Mita A, Triulzi F, Brunstrom-Hernandez JE, Zuffardi O, Balottin U, Orcesi S. MCT8 Deficiency: Extrapyramidal Symptoms and Delayed Myelination as Prominent Features. J Child Neurol. 2012 [PMC free article: PMC4155008] [PubMed: 22805248]
  25. Tsurusaki Y, Osaka H, Hamanoue H, Shimbo H, Tsuji M, Doi H, Saitsu H, Matsumoto N, Miyake N. Rapid detection of a mutation causing X-linked leucoencephalopathy by exome sequencing. J Med Genet. 2011;48:606–9. [PubMed: 21415082]
  26. van der Deure WM, Peeters RP, Visser TJ. Molecular aspects of thyroid hormone transporters, including MCT8, MCT10 and OATPs, and the effects of genetic variation in these transporters. J Mol Endocrinol. 2009;44:1–11. [PubMed: 19541799]
  27. Vaurs-Barrière C, Deville M, Sarret C, Giraud G, Des Portes V, Prats-Vinas JM, De Michele G, Dan B, Brady AF, Boespflug-Tanguy O, Touraine R. Pelizaeus-Merzbacher-like disease presentation of MCT8 mutated male subjects. Ann Neurol. 2009;65:114–18. [PubMed: 19194886]
  28. Verge CF, Konrad D, Cohen M, Di Cosmo C, Dumitrescu AM, Marcinkowski T. et al. Diiodothyropropionic Acid (DITPA) in the Treatment of MCT8 Deficiency. J Clin Endocrinol Metab. 2012;97:4515–23. [PMC free article: PMC3513545] [PubMed: 22993035]
  29. Visser WE, Jansen J, Friesema EC, Kester MH, Mancilla E, Lundgren J, van der Knaap MS, Lunsing RJ, Brouwer OF, Visser TJ. Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations. Hum Mutat. 2009;30:29–38. [PubMed: 18636565]
  30. Wémeau JL, Pigeyre M, Proust-Lemoine E, d'Herbomez M, Gottrand F, Jansen J, Visser TJ, Ladsous M. Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8. J Clin Endocrinol Metab. 2008;93:2084–8. [PubMed: 18334584]

Chapter Notes

Acknowledgments

Drs. Dumitrescu and Refetoff are supported in part by grants DR15070, DK07011, RR04999 and DK091016 from the National Institutes of Health. Dr. Fu is funded by an award from China Scholarship Council.

Revision History

  • 11 April 2013 (me) Comprehensive update posted live
  • 9 March 2010 (me) Review posted live
  • 6 July 2009 (mad) Original submission
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