Allan et al. (1944) described a kindred of 24 males affected by severe mental retardation spanning 6 generations. The patients had hypotonia at birth, but otherwise appeared normal. By 6 months, they developed an inability to hold up ... Allan et al. (1944) described a kindred of 24 males affected by severe mental retardation spanning 6 generations. The patients had hypotonia at birth, but otherwise appeared normal. By 6 months, they developed an inability to hold up the head, leading to the family's description of the patients as having a 'limber-neck.' Motor development was markedly reduced, few ever walked, and most had generalized muscular atrophy, joint contractures, and hyporeflexia as adults. At least 15 women of reproductive age or younger were potential heterozygotes. Stevenson et al. (1990) restudied this family, extending the typical X-linked recessive pedigree pattern with 5 additional affected males in 2 generations. In all, 29 males were affected in 7 generations. Clinical features included severe mental retardation, dysarthria, ataxia, athetoid movements, muscle hypoplasia, and spastic paraplegia with hyperreflexia, clonus, and Babinski reflexes. The facies appeared elongated with normal head circumference, bitemporal narrowing, and large, simple ears. Contractures developed at both small and large joints. Statural growth was normal and there was no macroorchidism. Longevity was not impaired. High-resolution chromosome analysis, serum creatine kinase, and amino acids were normal. In 2 ostensibly unrelated Jamaican black families living in Birmingham, England, Bundey and Hill (1975) found 3 cases of severe microcephaly with spastic quadriplegia beginning between 4 and 16 months of age. The authors concluded that Roboz and Pitt (1969) and perhaps others have reported the same condition. The paper by Bundey and Hill (1975) was not published, but the patients were referred to by Bundey and Griffiths (1977). The microcephaly was 'postnatal;' head circumference was normal at birth and at 7 months. There were no neonatal problems. The first abnormalities noted by the parents were unresponsiveness and delayed milestones. On reevaluation of the family, Bundey et al. (1991) concluded that the disorder may represent the Allan-Herndon syndrome. Bialer et al. (1992) restudied a family reported in abstract by Davis et al. (1981). Clinical characteristics of 8 living affected males included severe mental retardation, spastic paraplegia, dysarthria, muscle wasting, scoliosis, broad shallow pectus excavatum, long face, large ears with minor modeling anomalies, foot deformities, joint contractures, and neck drop, which was illustrated by photographs with the head hanging forward when the patients were in the sitting position. Bialer et al. (1992) suggested that the unusual appearance of the ears was due to abnormalities of ear muscle development in utero. Similarly, the long thin face, which from some of the photographs might be called myopathic, and asthenic body habitus were possibly due to muscle hypoplasia. Bialer et al. (1992) suggested that this was the second reported family with AHDS. Passos-Bueno et al. (1993) reported a large Brazilian family in which 7 males had a severe form of X-linked mental retardation with severe generalized muscle atrophy. Affected individuals were never able to hold their head against gravity, to sit unsupported, or to walk or speak. All had urinary and fecal incontinence. The disorder was not progressive, and the oldest patient was 47 years old. Passos-Bueno et al. (1993) noted the phenotypic similarity to the family reported by Allan et al. (1944). Zorick et al. (2004) reported additional clinical findings identified in 2 of the patients from the family reported by Passos-Bueno et al. (1993). Features included spastic paraplegia, joint contractures, chest malformation, scoliosis, and facial dysmorphism, all of which were consistent with AHDS. Dumitrescu et al. (2004) reported 2 unrelated families in which males showed neurologic abnormalities from infancy, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Serum thyroxine (T4) was decreased, TSH was normal to mildly increased, and serum T3 was increased. Some female family members had mild serum thyroid hormone abnormalities but no neurologic manifestations. Friesema et al. (2004) reported 5 unrelated boys, aged 18 months to 6 years, who had a disorder characterized by severe proximal hypotonia with poor head control and inability to stand, involuntary writhing movements, and severe mental retardation with lack of speech and basic communication skills. Serum T4 and free T4 were at the lower limits of normal, and serum TSH ranged from normal to high. Serum T3 concentrations were greatly increased. Schwartz et al. (2005) summarized clinical features of AHDS. Infancy and childhood are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations. Schwartz et al. (2005) stated that the pattern of findings in their patients with AHDS was the same as that in other individuals reported by Dumitrescu et al. (2004) and Friesema et al. (2004). Dumitrescu et al. (2004) had reported rotary nystagmus, disconjugate eye movements, and feeding difficulties in 2 affected boys from different kindreds, findings that were not noted in other reports. Using magnetic resonance imaging (MRI) and MR spectroscopy, Sijens et al. (2008) found that compared with controls, 2 children with MCT8 mutations had increased choline and myoinositol and decreased N-acetyl aspartate in supraventricular gray and white matter, phenomena associated with the degree of dysmyelinization. The authors concluded that different mutations in the MCT8 gene lead to differences in the severity of the clinical spectrum, dysmyelinization, and MR spectroscopy-detectable changes in brain metabolism. Vaurs-Barriere et al. (2009) identified mutations in the MCT8 gene in 6 (11%) of 53 families in which a male was affected with a hypomyelinating leukodystrophy of unknown etiology. The 12 patients initially presented a Pelizaeus-Merzbacher (312080)-like phenotype with a later unusual improvement of MRI white matter changes, but absence of clinical improvement. All patients presented before age 6 months with delayed motor development associated with nystagmus and/or choreoathetosis and ataxia progressing to para- or quadriplegia and dystonia. There was poor head control and lack of language acquisition. MRI showed myelin defects affecting the first myelinated areas before age 2 years, which appeared to improve with age, but was not associated with neurologic improvement. These findings were consistent with an overall delay in myelination rather than persistent hypomyelination, as seen in classic PMD. Thyroid parameters in the 3 patients available for serum dosages showed increased T3, decreased T4, and normal TSH. Vaurs-Barriere et al. (2009) concluded that males with a PMD-like phenotype should be screened for MCT mutations. Papadimitriou et al. (2008) reported an 11-month-old boy referred for severe hypotonia and global developmental delay. He had decreased muscle strength, hyperactive deep tendon reflexes, severe head lag, was unable to sit independently. Although he showed no signs of thyroid dysfunction, and thyrotropin was within the reference range, laboratory studies showed high serum triiodothyronine (T3), low thyroxine (T4), and mildly increased serum lactate. The increased serum lactate was considered to be consistent with peripheral thyrotoxicosis. Brain MRI showed decreased myelination of the subcortical tissue and thalamus. Family history was significant for a maternal uncle with an unidentified neurologic disorder leading to death at age of 8 years, and a brother with muscular hypotonia since birth and death at age 9 months. Treatment with T4 did not improve the patient's neurologic condition. Genetic analysis confirmed a defect in the MCT8 gene.
In affected members of 2 unrelated families in which males had mental retardation associated with increased serum T3, Dumitrescu et al. (2004) identified 2 different mutations in the SLC16A2 gene (300095.0001; 300095.0002). Heterozygous females had a milder thyroid ... In affected members of 2 unrelated families in which males had mental retardation associated with increased serum T3, Dumitrescu et al. (2004) identified 2 different mutations in the SLC16A2 gene (300095.0001; 300095.0002). Heterozygous females had a milder thyroid phenotype with no neurologic deficits. In 2 young boys with highly elevated serum T3 and severe mental retardation, Friesema et al. (2003) identified 2 different mutations in the MCT8 gene (300095.0003; 300095.0004). Friesema et al. (2004) identified mutations in the MCT8 gene in 5 unrelated boys with severe neurologic abnormalities and increased serum T3 (see, e.g., 300095.0005-300095.0006). The identification by Dumitrescu et al. (2004) and Friesema et al. (2004) of mutations in the SLC16A2 gene, encoding monocarboxylate transporter-8 (MCT8), in males with hypotonia, involuntary movements, and mental retardation made that gene an attractive candidate for the site of the mutation in Allan-Herndon-Dudley syndrome. Schwartz et al. (2005) found that each of 6 large families with Allan-Herndon-Dudley had mutations in MCT8. One essential function of the protein encoded by this gene appeared to be the transport of triiodothyronine into neurons. Abnormal transporter function was reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. In affected members of a large Brazilian family with AHDS originally reported by Passos-Bueno et al. (1993), Maranduba et al. (2006) identified a mutation in the SLC16A2 gene (300095.0011). Serum T3 and free T3 levels were elevated in all affected males, whereas normal levels were found among obligate female carriers. Among 13 families with X-linked mental retardation, 401 male sibships with mental retardation, and 47 male patients with sporadic AHDS-like clinical features, Frints et al. (2008) identified 2 patients with pathogenic SLC16A2 mutations. The authors concluded that SLC16A2 mutations are not a common cause of X-linked mental retardation.
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:...
DiagnosisClinical 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 lifeTruncal hypotoniaMuscle hypoplasia/asthenic buildPoor head controlSpastic paraparesis with dystonic/athetoic movements (with extensor posturing mainly affecting the distal upper limbs)Paroxysmal dyskinesiaDysarthric or no speechSevere psychomotor retardation and cognitive impairmentOther 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.TestingAffected males. See Figure 1. Males with MCT8-specific thyroid hormone cell-membrane transporter deficiency have pathognomonic thyroid test results including the following:FigureFigure 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 rangeSerum 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 testingTable 1. Summary of Molecular Genetic Testing Used in MCT8-Specific Thyroid Hormone Cell-Membrane Transporter DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected MalesCarrier Females 2SLC16A2 Sequence analysisSequence variants 3Unknown 4Unknown 5Clinical Deletion / duplication analysis 6Exonic, multiexonic, or whole-gene deletionUnknown 7Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. When no affected males in the family are available for testing3. 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. Genetically Related (Allelic) DisordersSLC16A2 mutations have been suspected as a cause of nonsyndromic X-linked intellectual disability (i.e., without thyroid hormone abnormalities); however, one study that examined 401 male sibships with intellectual disability who had had no preliminary thyroid testing found an SLC16A2 mutation in only one family. Subsequent thyroid testing revealed that the affected individuals did have the typical thyroid test results [Frints et al 2008].
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. ...
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].
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....
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.
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....
Differential DiagnosisMany 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
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....
ManagementNo 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 parametersDevelopmental assessmentNeurologic evaluation and EEG to assess possible seizuresOrthopedic evaluation to assess for possible developing scoliosis or pectus deformitiesMedical genetics consultationTreatment of ManifestationsThe following treatment is appropriate:Physical, occupational, and speech therapies, if necessaryMedications, such as anticholinergics, L-DOPA, carbamazepine, or lioresol, for the treatment of dystoniaGlycopyrolate or scopolamine to improve droolingStandard anticonvulsant medication to control seizures, if presentPlacement of permanent feeding tube to avert malnutritionNote: 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 ComplicationsAppropriate measures include the following:Braces to prevent joint contractures and orthopedic surgery, if necessaryDiet restrictions to prevent aspirationSurveillanceAppropriate surveillance includes the following:Regular orthopedic evaluations to monitor scoliosis or joint problemsOngoing developmental assessmentsAgents/Circumstances to AvoidAspiration 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 RiskSee 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 InvestigationDiiodothyropropionic 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC16A2Xq13.2Monocarboxylate transporter 8SLC16A2 @ LOVDSLC16A2Data 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) View in own window 300095SOLUTE CARRIER FAMILY 16 (MONOCARBOXYLIC ACID TRANSPORTER), MEMBER 2; SLC16A2 300523ALLAN-HERNDON-DUDLEY SYNDROME; AHDSMolecular 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 GeneReviewView in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1) Reference SequencesNormalc.319T>C rs6647476 2p.Ser107ProNM_006517.3 NP_006508.1c.1095A>T rs12849161 2p.(=) 3(p.Pro365Pro)Pathologicc.581C>Tp.Ser194Phec.1301T>Gp.Leu434Trpc.1475T>Cp.Leu492Proc.1501_1503del (1497_1499delCTT)p.Phe501delc.1703T>Cp.Leu568Proc.1835delC (1834delC)p.Pro612Glnfs*68 (Pro612fsX679)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Reference SNP 3. p.(=) designates that protein has not been analyzed, but no change is expectedNormal 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.