View source for Medicine:Allan–Herndon–Dudley syndrome

{{Infobox medical condition (new)
| name            = Allan–Herndon–Dudley syndrome
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| caption         = This condition is inherited in an X-linked recessive manner
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| named after     = {{ubl|William Allan|Florence C. Dudley|C. Nash Herndon}}
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'''Allan–Herndon–Dudley syndrome''' is a rare X-linked inherited disorder of [[Biology:Brain|brain]] development that causes both moderate to severe [[Medicine:Intellectual disability|intellectual disability]] and problems with speech and movement.<ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/5617/allan-herndon-dudley-syndrome|title=Allan-Herndon-Dudley syndrome {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|language=en|access-date=2018-04-17}}</ref>

Allan–Herndon–Dudley syndrome, which is named eponymously for William Allan, Florence C. Dudley, and C. Nash Herndon,<ref>{{WhoNamedIt|synd|1438}}</ref><ref>{{cite journal |last1=Allan |first1=William |last2=Herndon |first2=C. N. |last3=Dudley |first3=Florence C. |title=Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly |journal=American Journal of Mental Deficiency |volume=48 |pages=325–34 |year=1944 }}</ref> 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|date=November 2016}}

==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 ([[Medicine:Hypotonia|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 [[Engineering:Wheelchair|wheelchair]]-reliant by adulthood.<ref>{{Cite web|url=https://rarediseases.info.nih.gov/diseases/5617/allan-herndon-dudley-syndrome|title=Allan-Herndon-Dudley syndrome {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|website=rarediseases.info.nih.gov|language=en|access-date=2018-04-17}}</ref>

==Endocrine phenotype==

The typical hormonal signature of AHDS is marked by low free T4 and normal or elevated free [[Chemistry:Triiodothyronine|T3]] concentration, which translates to increased calculated [[Biology:Deiodinase|deiodinase]] activity (SPINA-GD).<ref>{{cite journal |last1=Schwartz |first1=CE |last2=Stevenson |first2=RE |title=The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. |journal=Best Practice & Research. Clinical Endocrinology & Metabolism |date=June 2007 |volume=21 |issue=2 |pages=307–21 |doi=10.1016/j.beem.2007.03.009 |pmid=17574010|pmc=2094733 }}</ref><ref>{{cite journal |last1=van Geest |first1=FS |last2=Groeneweg |first2=S |last3=Visser |first3=WE |title=Monocarboxylate transporter 8 deficiency: update on clinical characteristics and treatment. |journal=Endocrine |date=March 2021 |volume=71 |issue=3 |pages=689–695 |doi=10.1007/s12020-020-02603-y |pmid=33650046|pmc=8016746 }}</ref><ref>{{cite journal |last1=Schupper |first1=A |last2=Barash |first2=G |last3=Benyamini |first3=L |last4=Ben-Haim |first4=R |last5=Heyman |first5=E |last6=Lahat |first6=E |last7=Bassan |first7=H |title=Simple Evaluation of Thyroid Function Leading to the Diagnosis of Allan-Herndon-Dudley Syndrome, a Rare Neurodevelopmental Disorder. |journal=The Israel Medical Association Journal |date=May 2023 |volume=25 |issue=5 |pages=374–376 |pmid=37245112}}</ref>

==Genetics==

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.{{citation needed|date=November 2016}}

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|date=November 2016}}

==Pathogenesis==

Mutations in the ''SLC16A2'' [[Biology:Gene|gene]] cause Allan–Herndon–Dudley syndrome. The ''SLC16A2'' gene, also known as ''MCT8'', provides instructions for making a protein that plays a critical role in the development of the [[Biology:Nervous system|nervous system]]. This protein transports a particular hormone into nerve cells in the developing brain. This hormone, called [[Chemistry:Triiodothyronine|triiodothyronine]] or T3, is produced by the [[Biology:Thyroid|thyroid]]. T3 appears to be critical for the normal formation and growth of nerve cells, as well as the development of junctions between nerve cells (synapses) where cell-to-cell communication occurs. T3 and other forms of thyroid hormone also help regulate the development of other organs and control the rate of chemical reactions in the body.{{citation needed|date=November 2016}}

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|date=November 2016}}

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.<ref>{{cite journal |last1=Müller |first1=J |last2=Heuer |first2=H |title=Understanding the hypothalamus-pituitary-thyroid axis in mct8 deficiency. |journal=European Thyroid Journal |date=July 2012 |volume=1 |issue=2 |pages=72–9 |doi=10.1159/000339474 |pmid=24783000|pmc=3821472 }}</ref> This latter hypothesis is supported by results of [[Biology:In silico|in silico]] experiments with [[Computer simulation|computer simulation]]s.<ref>{{cite journal |last1=Wolff |first1=TM |last2=Veil |first2=C |last3=Dietrich |first3=JW |last4=Müller |first4=MA |title=Mathematical modeling and simulation of thyroid homeostasis: Implications for the Allan-Herndon-Dudley syndrome. |journal=Frontiers in Endocrinology |date=2022 |volume=13 |pages=882788 |doi=10.3389/fendo.2022.882788 |pmid=36568087 |pmc=9772020 |doi-access=free }}</ref>

Several studies have documented the potentially dangerous effects of the silymarin mixture on the [[Biology:Monocarboxylate transporter 8|MCT8]] transporter. All of the [[Chemistry:Flavonolignan|flavonolignan]] compounds found in the silymarin mixture seem to block the uptake of [[Biology:Thyroid hormones|thyroid hormones]] into the cells by selectively blocking the [[Biology:Monocarboxylate transporter 8|MCT8]] transmembrane transporter.<ref name="Johannes Jayarama-Naidu Meyer Wirth pp. 1694–1701">{{cite journal | last1=Johannes | first1=Jörg | last2=Jayarama-Naidu | first2=Roopa | last3=Meyer | first3=Franziska | last4=Wirth | first4=Eva Katrin | last5=Schweizer | first5=Ulrich | last6=Schomburg | first6=Lutz | last7=Köhrle | first7=Josef | last8=Renko | first8=Kostja | title=Silychristin, a Flavonolignan Derived From the Milk Thistle, Is a Potent Inhibitor of the Thyroid Hormone Transporter MCT8 | journal=Endocrinology | publisher=The Endocrine Society | volume=157 | issue=4 | date=24 February 2016 | issn=0013-7227 | doi=10.1210/en.2015-1933 | pages=1694–1701| pmid=26910310 | doi-access=free }}</ref> The authors of several studies noted that especially [[Chemistry:Silychristin|silychristin]], one of the compounds of the silymarin mixture seems to be perhaps the most powerful and selective inhibitor for the [[Biology:Monocarboxylate transporter 8|MCT8]] transporter. Due to the essential role played by the thyroid hormone in human metabolism in general it is believed that the intake of silymarin can lead to disruptions of the thyroid system. Because the thyroid hormones and the [[Biology:Monocarboxylate transporter 8|MCT8]] as well are known to play a critical role during early and fetal development, the administration of silymarin during pregnancy is especially thought to be dangerous, potentially leading to the Allan–Herndon–Dudley syndrome.{{citation needed|date=September 2021}}

== 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.<ref>{{cite journal |last1=Verge |first1=Charles F. |last2=Konrad |first2=Daniel |last3=Cohen |first3=Michal |last4=Di Cosmo |first4=Caterina |last5=Dumitrescu |first5=Alexandra M. |last6=Marcinkowski |first6=Teresa |last7=Hameed |first7=Shihab |last8=Hamilton |first8=Jill |last9=Weiss |first9=Roy E. |last10=Refetoff |first10=Samuel |title=Diiodothyropropionic Acid (DITPA) in the Treatment of MCT8 Deficiency |journal=The Journal of Clinical Endocrinology & Metabolism |volume=97 |issue=12 |pages=4515–23 |year=2012 |pmid=22993035 |pmc=3513545 |doi=10.1210/jc.2012-2556 }}</ref>

Theoretical considerations suggested [[Chemistry:Tiratricol|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.<ref>{{cite conference |last1=Iglesias |first1=Ainhoa |last2=Palomares |first2=María |last3=Morte |first3=Beatriz |last4=Obregón |first4=María Jesús |last5=Bernal |first5=Juan |date=September 10, 2014 |title=TRIAC treatment of an infant with Allan-Herndon-Dudley Syndrome (AHDS): Effects on iodothyronines in serum and cerebrospinal fluid |conference=38th Annual Meeting of the European Thyroid Association |location=Santiago de Compostela |hdl=10261/125597 }}</ref> A first clinical trial<ref>{{ClinicalTrialsGov|NCT02060474|Triac Trial in MCT8 Patients}}</ref> demonstrated TRIAC to be safe and effective.<ref>{{cite journal |last1=Groeneweg |first1=S |last2=Peeters |first2=RP |last3=Moran |first3=C |last4=Stoupa |first4=A |last5=Auriol |first5=F |last6=Tonduti |first6=D |last7=Dica |first7=A |last8=Paone |first8=L |last9=Rozenkova |first9=K |last10=Malikova |first10=J |last11=van der Walt |first11=A |last12=de Coo |first12=IFM |last13=McGowan |first13=A |last14=Lyons |first14=G |last15=Aarsen |first15=FK |last16=Barca |first16=D |last17=van Beynum |first17=IM |last18=van der Knoop |first18=MM |last19=Jansen |first19=J |last20=Manshande |first20=M |last21=Lunsing |first21=RJ |last22=Nowak |first22=S |last23=den Uil |first23=CA |last24=Zillikens |first24=MC |last25=Visser |first25=FE |last26=Vrijmoeth |first26=P |last27=de Wit |first27=MCY |last28=Wolf |first28=NI |last29=Zandstra |first29=A |last30=Ambegaonkar |first30=G |last31=Singh |first31=Y |last32=de Rijke |first32=YB |last33=Medici |first33=M |last34=Bertini |first34=ES |last35=Depoorter |first35=S |last36=Lebl |first36=J |last37=Cappa |first37=M |last38=De Meirleir |first38=L |last39=Krude |first39=H |last40=Craiu |first40=D |last41=Zibordi |first41=F |last42=Oliver Petit |first42=I |last43=Polak |first43=M |last44=Chatterjee |first44=K |last45=Visser |first45=TJ |last46=Visser |first46=WE |title=Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. |journal=The Lancet. Diabetes & Endocrinology |date=September 2019 |volume=7 |issue=9 |pages=695–706 |doi=10.1016/S2213-8587(19)30155-X |pmid=31377265|pmc=7611958 }}</ref>

==References==
{{reflist}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=thctd  GeneReviews/NCBI/NIH/UW entry on MCT8 (SLC16A2)-Specific Thyroid Hormone Cell Transporter Deficiency]
* [http://ghr.nlm.nih.gov/condition=allanherndondudleysyndrome?wf=1 Allan–Herndon–Dudley syndrome] at National Library of Medicine

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{{Solute carrier disorders}}

{{DEFAULTSORT:Allan-Herndon-Dudley Syndrome}}
[[Category:Neurogenetic disorders]]
[[Category:Syndromes]]

{{Sourceattribution|Allan–Herndon–Dudley syndrome}}