Allan-Herndon-Dudley Syndrome and the Monocarboxylate Transporter 8 (MCT8) Gene

Abstract

Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome 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.

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

“…About 25% (4 of the 16 tested females) of the MCT8 mutation female carriers show thyroid functional problems with elevated serum T3 levels. 7 Six affected MCT8 mutation female carriers have been reported: one female carrier described in this study (P030, Figure 1b; II.2) with mild to severe MR, family Fi with mild MR in maternal grandmother and severe MR in maternal aunt, 2,21 one affected female carrier in family K9248 with unexplained prenatal injury 4 and two carrier females; a mother with mild developmental delay and her daughter with severe MR, hydrocephalus and myelomeningocele. 6 We believe that unfavorable nonrandom X-inactivation can occur in MCT8 mutation female carriers leading to AHDS clinical features and that MR can be part of the phenotype in MCT8 mutation carriers.…”

“…However, based on the available literature, individual clinical features do not seem to correlate with specific MCT8 mutations except for elevated levels of serum T3, which are the most consistent feature in AHDS male patients and it has previously been put forward to use the assessment of T3 as a method for screening a high-risk MR population. 4 We therefore determined serum T3 in the two patients with missense changes in MCT8 but only found an increased concentration in the patient carrying the c.1673G4A change, which segregated with MR in the family. An in silico estimation of its impact on the three-dimensional protein structure and function using the Polyphen tool (http://genetics.bwh.harvard.edu/pph/; Sunyaev et al 18 ) predicts this change to be possibly damaging.…”

“…2,3 This clinical entity was earlier reported as the Allan -Herndon -Dudley syndrome (AHDS; OMIM 300523) and Schwartz et al, 4 Maranduba et al 5 as well as Herzovich 6 described additional patients with MCT8 mutations.…”

“…Serum (free) T3 levels are not routinely measured in diagnostic laboratories and it is thus not known to which extent loss of function or hypomorphic MCT8 proteins play a role in cognitive disabilities. Schwartz et al 4 have speculated that MCT8 mutations may rank among the more prevalent X-chromosomal causes of MR. In order to determine whether MCT8 mutations also occur in non-AHDS MR patients we performed MCT8 sequence analysis in a cohort of XLMR families and male MR sibships 9 in comparison with sporadic MR patients presenting AHDS(-like) clinical features.…”

Thyroid hormone action during brain development: More questions than answers

“…The physiological significance of thyroid hormone transport for proper brain development and function was highlighted by the identification of patients exhibiting inactivating mutations in the X-linked MCT8 gene (Dumitrescu et al, 2004;Friesema et al, 2004;Schwartz et al, 2005). All patients suffered from a unique syndrome consisting of a severe form of psychomotor retardation in combination with abnormal serum thyroid hormone levels (Friesema et al, 2006).…”