Allan–Herndon–Dudley syndrome
Allan–Herndon–Dudley syndrome | |
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This condition is inherited in an X-linked recessive manner | |
Specialty | Medical genetics, neurology, pediatrics |
Named after |
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Allan–Herndon–Dudley syndrome is a rare X-linked inherited disorder of brain development that causes both moderate to severe intellectual disability and problems with speech and movement.[1]
Allan–Herndon–Dudley syndrome, which is named eponymously for William Allan, Florence C. Dudley, and C. Nash Herndon,[2][3] results from a mutation of the thyroid hormone transporter MCT8 (also referred to as SLC16A2). Consequently, thyroid hormones are unable to enter the nervous system, which depends on thyroid signaling for proper function and development.[citation needed]
Signs and symptoms
It is estimated that 80–99% of people with Allan–Herndon–Dudley syndrome will have biparietal narrowing (narrowing of skull), ataxia, abnormalities of the neck, and both absent speech development and aphasia. Weak muscle tone (hypotonia) and underdevelopment of many muscles (muscle hypoplasia) are common in children with Allan–Herndon–Dudley syndrome. Development of joint deformities called contractures, which restrict the movement of certain joints, are common as people age. Mobility is further limited by abnormal muscle stiffness (spasticity), muscle weakness, and involuntary movements of the arms and legs. Many people with Allan–Herndon–Dudley syndrome are unable to walk independently and become wheelchair-reliant by adulthood.[4]
Endocrine phenotype
The typical hormonal signature of AHDS is marked by low free
Genetics
This condition is inherited in an
In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the mutated gene, but usually does not experience signs and symptoms of the disorder. Carriers of SLC16A2 mutations have normal intelligence and do not experience problems with movement. Some carriers have been diagnosed with thyroid disease, a condition which is relatively common in the general population. It is unclear whether thyroid disease is related to SLC16A2 mutations in these cases.[citation needed]
Pathogenesis
Mutations in the
Gene mutations alter the structure and function of the SLC16A2 protein. As a result, this protein is unable to transport T3 into nerve cells effectively. A lack of this critical hormone in certain parts of the brain disrupts normal brain development, resulting in intellectual disability and problems with movement. Excess amounts of T3 circulate in the bloodstream. It is unclear if this is a consequence of compensatory hyperdeiodination or if it results from impaired uptake by certain cell types. Increased T3 levels in the blood may be toxic to some organs and contribute to the signs and symptoms of Allan–Herndon–Dudley syndrome.[citation needed]
The signature of low T4 and high T3 was for a long time assumed to be caused by either compensatory hyperdeiodination or impaired uptake of T3 in target tissues. A third hypotheses suggested it to ensue from impaired outward transport of thyroxine from thyroid cells and subsequently substrate-mediated overactivity of intrathyroidal deiodinases.[8] This latter hypothesis is supported by results of in silico experiments with computer simulations.[9]
Several studies have documented the potentially dangerous effects of the
Treatment
In May 2013, the US FDA granted Orphan drug status to Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. This was following the use of DITPA towards a child in Australia, under compassionate grounds.[11]
Theoretical considerations suggested TRIAC (triiodothyroacetate or tiratricol, a natural non-classical thyroid hormone) to be beneficial. In 2014, a case was demonstrated in which therapy with TRIAC in early childhood led to significant improvement of cognition and mobility.[12] A first clinical trial[13] demonstrated TRIAC to be safe and effective.[14]
References
- ^ "Allan-Herndon-Dudley syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17.
- Who Named It?
- ^ Allan, William; Herndon, C. N.; Dudley, Florence C. (1944). "Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly". American Journal of Mental Deficiency. 48: 325–34.
- ^ "Allan-Herndon-Dudley syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17.
- PMID 17574010.
- PMID 33650046.
- PMID 37245112.
- PMID 24783000.
- PMID 36568087.
- PMID 26910310.
- PMID 22993035.
- hdl:10261/125597.
- ^ Clinical trial number NCT02060474 for "Triac Trial in MCT8 Patients" at ClinicalTrials.gov
- PMID 31377265.
External links
- GeneReviews/NCBI/NIH/UW entry on MCT8 (SLC16A2)-Specific Thyroid Hormone Cell Transporter Deficiency
- Allan–Herndon–Dudley syndrome at National Library of Medicine