Alternative titles; symbols
SNOMEDCT: 702327009; ORPHA: 280270, 59; DO: 0050631;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq13.2 | Allan-Herndon-Dudley syndrome | 300523 | X-linked | 3 | SLC16A2 | 300095 |
A number sign (#) is used with this entry because Allan-Herndon-Dudley syndrome (AHDS) is caused by mutation in the MCT8 gene (SLC16A2; 300095) on chromosome Xq13.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked condition characterized by severely impaired intellectual development, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia. There is large phenotypic interfamilial and intrafamilial variability. In severe cases, patients never gain the ability to walk or talk (summary by Maranduba et al., 2006).
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 had 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.
Schwartz et al. (1990) presented linkage data on the original family reported by Allan et al. (1944). A putative AHDS disease locus was identified on chromosome Xq21 near marker DYX1 (maximum multipoint lod score of 3.58).
Bialer et al. (1992) linked the family reported by Davis et al. (1981) to Xq21 with a maximum lod score of 2.88 at marker DXS72. A maximum multipoint lod score of 4.14 was obtained showing close linkage to DXS72, a position slightly more proximal in Xq21 than was suggested by the data from the original AHDS family.
Schwartz (1993) noted that 35% (10 of 43) of mapped mental retardation loci on the X chromosome show linkage to markers in the region Xq12-q21. The observation of males with cytogenetically visible deletions in Xq21 and mental retardation is consistent with the clustering of X-linked mental retardation entities to Xq12-q21. The mental retardation is invariably associated with some other entity, usually choroideremia (CHM; 303100), but sometimes both choroideremia and X-linked deafness (DFN3; 304400). Molecular analysis of 4 males with mental retardation and deletions of Xq21 led May et al. (1995) to place the putative MR region in Xq21.1 between DXS233 and the CHM locus.
Zorick et al. (2004) reported fine mapping of a large Brazilian family originally reported by Passos-Bueno et al. (1993). A critical region was identified between markers at Xp11.2 and Xq13, thus showing overlap with the candidate AHDS region identified by Schwartz et al. (1990) and Bialer et al. (1992).
Bohan and Azizi (2004) suggested that AHDS is a fourth locus for X-linked spastic paraplegia, distinct from SPG1 (303350) on Xq28, SPG2 (312920), on Xq22, and SPG16 (300266) on Xq11. The authors noted that the X-linked SPG families reported by Claes et al. (2000) (see 300534) and Starling et al. (2002) suggested linkage to the AHDS region on Xq21. Bohan and Azizi (2004) proposed the term 'SPG22' for the locus at Xq21 that encompasses the AHDS region. In a reply, Fink (2004) stated that AHDS could be considered a form of complicated SPG, but noted that the family reported by Starling et al. (2002) had a pure form of the disorder (SPG34; 300750).
Frints et al. (2008) reported a woman with full-blown AHDS associated with a de novo translocation t(X;9)(q13.2;p24) that interrupted the SLC16A2 gene. Patient fibroblasts showed complete loss of protein expression due to nonrandom X inactivation. The patient was severely developmentally retarded. She had axial hypotonia, spastic paraplegia, and athetoid movements of the upper limbs. Dysmorphic facial features included hypotonia, long palpebral fissures, midface hypoplasia, anteverted nares with bulbous nasal tip, and elongated open mouth with prominent teeth. Other features included scoliosis, contractures of the knees and ankles, and increased serum T3.
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.
Capri et al. (2013) found that the pathogenicity of SLC16A2 mutations could be evaluated in both patient fibroblasts and JEG3 human placental choriocarcinoma cells by measuring T3 uptake activity. Fibroblasts from 6 unrelated patients with SLC16A2 mutations showed significantly decreased T3 uptake (about 50%) compared to controls, but the amount of uptake did not accurately reflect phenotype severity. In contrast, the decrease in T3 uptake in JEG3 cells transfected with the mutations did correlate with phenotypic severity: those with a severe phenotype showed a greater than 80% decrease in T3 uptake, whereas an intermediate decrease (mean -66.11%) was associated with a milder phenotype. Capri et al. (2013) noted that transfected JEG3 cells represent a good alternative cell model from patient cells because T3 transport relies mainly on expression of the SLC16A2 transporter after transfection, whereas patient fibroblasts may also express other transporters.
Allan, W., Herndon, C. N., Dudley, F. C. Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am. J. Ment. Defic. 48: 325-334, 1944.
Bialer, M. G., Lawrence, L., Stevenson, R. E., Silverberg, G., Williams, M. K., Arena, J. F., Lubs, H. A., Schwartz, C. E. Allan-Herndon-Dudley syndrome: clinical and linkage studies on a second family. Am. J. Med. Genet. 43: 491-497, 1992. [PubMed: 1605231] [Full Text: https://doi.org/10.1002/ajmg.1320430173]
Bohan, T. P., Azizi, P. Allan-Herndon-Dudley syndrome: should the locus for this hereditary spastic paraplegia be designated SPG 22? (Letter) Arch. Neurol. 61: 1470-1471, 2004. [PubMed: 15364700] [Full Text: https://doi.org/10.1001/archneur.61.9.1470-c]
Bundey, S., Comley, L. A., Blair, A. Allan-Herndon syndrome--or X-linked cerebral palsy? (Letter) Am. J. Hum. Genet. 48: 1214 only, 1991. [PubMed: 2035542]
Bundey, S. E., Hill, E. E. Recessive microcephaly with spastic quadriplegia. : Unpublished 1975.
Bundey, S., Griffiths, M. I. Recurrence risks in families of children with symmetrical spasticity. Dev. Med. Child Neurol. 19: 179-191, 1977. [PubMed: 870357] [Full Text: https://doi.org/10.1111/j.1469-8749.1977.tb07968.x]
Capri, Y., Friesema, E. C. H., Kersseboom, S., Touraine, R., Monnier, A., Eymard-Pierre, E., Des Portes, V., De Michele, G., Brady, A. F., Boespflug-Tanguy, O., Visser, T. J., Vaurs-Barriere, C. Relevance of different cellular models in determining the effects of mutations on SLC16A2/MCT8 thyroid hormone transporter function and genotype-phenotype correlation. Hum. Mutat. 34: 1018-1025, 2013. [PubMed: 23568789] [Full Text: https://doi.org/10.1002/humu.22331]
Claes, S., Devriendt, K., Van Goethem, G., Roelen, L., Meireleire, J., Raeymaekers, P., Cassiman, J. J., Fryns, J. P. Novel syndromic form of X-linked complicated spastic paraplegia. Am. J. Med. Genet. 94: 1-4, 2000. [PubMed: 10982473] [Full Text: https://doi.org/10.1002/1096-8628(20000904)94:1<1::aid-ajmg1>3.0.co;2-v]
Davis, J. G., Silverber, G., Williams, M. K., Spiro, A., Shapiro, L. R. A new X-linked recessive mental retardation syndrome with progressive spastic quadriparesis. (Abstract) Am. J. Hum. Genet. Suppl. 33: 75A only, 1981.
Dumitrescu, A. M., Liao, X.-H., Best, T. B., 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. 74: 168-175, 2004. Note: Erratum: Am. J. Hum. Genet. 74: 598 only, 2004. [PubMed: 14661163] [Full Text: https://doi.org/10.1086/380999]
Fink, J. K. Reply to Bohan and Azizi. (Letter) Arch. Neurol. 61: 1471 only, 2004.
Friesema, E. C. H., Grueters, A., Biebermann, H., Krude, H., von Moers, A., Reeser, M., Barrett, T. G., Mancilla, E. E., Svensson, J., Kester, M. H. A., Kuiper, G. G. J. M., Balkassmi, S., Uitterlinden, A. G., Koehrle, J., Rodien, P., Halestrap, A. P., Visser, T. J. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 364: 1435-1437, 2004. [PubMed: 15488219] [Full Text: https://doi.org/10.1016/S0140-6736(04)17226-7]
Friesema, E., Grueters, A., Halestrap, A., Reeser, M., Visser, T. Mutations in a thyroid hormone transporter in patients with severe psychomotor retardation and high serum T3 levels. (Abstract) Thyroid 13: 672 only, 2003.
Frints, S. G. M., Lenzner, S., Bauters, M., Jensen, L. R., Van Esch, H., des Portes, V., Moog, U., Macville, M. V. E., van Roozendaal, K., Schrander-Stumpel, C. T. R. M., Tzschach, A., Marynen, P., and 12 others. MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression. Europ. J. Hum. Genet. 16: 1029-1037, 2008. [PubMed: 18398436] [Full Text: https://doi.org/10.1038/ejhg.2008.66]
Maranduba, C. M. C., Friesema, E. C. H., Kok, F., Kester, M. H. A., Jansen, J., Sertie, A. L., Passos-Bueno, M. R., Visser, T. J. Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter. (Letter) J. Med. Genet. 43: 457-460, 2006. [PubMed: 15980113] [Full Text: https://doi.org/10.1136/jmg.2005.035840]
May, M., Colleaux, L., Murgia, A., Aylsworth, A., Nussbaum, R., Fontes, M., Schwartz, C. Molecular analysis of four males with mental retardation and deletions of Xq21 places the putative MR region in Xq21.1 between DXS233 and CHM. Hum. Molec. Genet. 4: 1465-1466, 1995. [PubMed: 7581391] [Full Text: https://doi.org/10.1093/hmg/4.8.1465]
Morales Diaz, J., Ortiz de Zarate, J. Ataxia cerebelosa congenita hereditaria. Neuropsiquiatria 3: 51-60, 1952.
Opitz, J. M., Sutherland, G. R. International workshop on the fragile X and X-linked mental retardation. Am. J. Med. Genet. 17: 5-94, 1984. [PubMed: 6369987] [Full Text: https://doi.org/10.1002/ajmg.1320170103]
Papadimitriou, A., Dumitrescu, A. M., Papavasiliou, A., Fretzayas, A., Nicolaidou, P., Refetoff, S. A novel monocarboxylate transporter 8 gene mutation as a cause of severe neonatal hypotonia and developmental delay. Pediatrics 121: e199-e292, 2008. Note: Electronic Article. [PubMed: 18166539] [Full Text: https://doi.org/10.1542/peds.2007-1247]
Passos-Bueno, M. R., Byth, B. C., Rosenberg, S., Takata, R. I., Bakker, E., Beggs, A. H., Pavanello, R. C., Vainzof, M., Davies, K. E., Zatz, M. Severe nonspecific X-linked mental retardation caused by a proximally Xp located gene: intragenic heterogeneity or a new form of X-linked mental retardation? Am. J. Med. Genet. 46: 172-175, 1993. [PubMed: 8484404] [Full Text: https://doi.org/10.1002/ajmg.1320460214]
Roboz, P., Pitt, D. Studies on 782 cases of mental deficiency. Part IV. Aust. Paediat. J. 5: 137-148, 1969.
Schwartz, C. E., May, M. M., Carpenter, N. J., Rogers, R. C., Martin, J., Bialer, M. G., Ward, J., Sanabria, J., Marsa, S., Lewis, J. A., Echeverri, R., Lubs, H. A., Voeller, K., Simensen, R. J., Stevenson, R. E. Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am. J. Hum. Genet. 77: 41-53, 2005. [PubMed: 15889350] [Full Text: https://doi.org/10.1086/431313]
Schwartz, C. E., Ulmer, J., Brown, A., Pancoast, I., Goodman, H. O., Stevenson, R. E. Allan-Herndon syndrome. II. Linkage to DNA markers in Xq21. Am. J. Hum. Genet. 47: 454-458, 1990. [PubMed: 2393020]
Schwartz, C. E. X-linked mental retardation: in pursuit of a gene map. (Editorial) Am. J. Hum. Genet. 52: 1025-1031, 1993. [PubMed: 8503437]
Sijens, P. E., Rodiger, L. A., Meiners, L. C., Lunsing, R. J. 1H magnetic resonance spectroscopy in monocarboxylate transporter 8 gene deficiency. J. Clin. Endocr. Metab. 93: 1854-1859, 2008. [PubMed: 18319316] [Full Text: https://doi.org/10.1210/jc.2007-2441]
Starling, A., Rocco, P., Cambi, F., Hobson, G. M., Passos Bueno, M. R., Zatz, M. Further evidence for a fourth gene causing X-linked pure spastic paraplegia. Am. J. Med. Genet. 111: 152-156, 2002. [PubMed: 12210342] [Full Text: https://doi.org/10.1002/ajmg.10551]
Stevenson, R. E., Goodman, H. O., Schwartz, C. E., Simensen, R. J., McLean, W. T., Jr., Herndon, C. N. Allan-Herndon syndrome. I. Clinical studies. Am. J. Hum. Genet. 47: 446-453, 1990. [PubMed: 2393019]
Vaurs-Barriere, C., Deville, M., Sarret, C., Giraud, G., Des Portes, V., Prats-Vinas, J.-M., De Michele, G., Dan, B., Brady, A. F., Boespflug-Tanguy, O., Touraine, R. Pelizaeus-Merzbacher-like disease presentation of MCT8 mutated male subjects. Ann. Neurol. 65: 114-118, 2009. [PubMed: 19194886] [Full Text: https://doi.org/10.1002/ana.21579]
Zorick, T. S., Sertie, A., Zatz, M., Passos-Bueno, M. R., Kleimann, S., Rosenberg, S. Fine mapping and clinical reevaluation of a Brazilian pedigree with a severe form of X-linked mental retardation associated with other neurological dysfunction. (Letter) Am. J. Med. Genet. 127A: 321-323, 2004. [PubMed: 15150789] [Full Text: https://doi.org/10.1002/ajmg.a.30009]