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Allan–Herndon–Dudley syndrome (AHDS) is a rare X-linked inherited disorder of
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
development that causes both moderate to severe
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
and problems with speech and movement. Allan–Herndon–Dudley syndrome, which is named eponymously for William Allan, Florence C. Dudley, and C. Nash Herndon, results from a mutation of the thyroid hormone transporter
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical ...
(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.


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 Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...
) and underdevelopment of many muscles ( muscle hypoplasia) are common in children with Allan–Herndon–Dudley syndrome. Development of joint deformities called
contracture In pathology, a contracture is a shortening of muscles, tendons, skin, and nearby soft tissues that causes the joints to shorten and become very stiff, preventing normal movement. A contracture is usually permanent, but less commonly can be temp ...
s, which restrict the movement of certain joints, are common as people age. Mobility is further limited by abnormal muscle stiffness (
spasticity Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles. ...
), 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 A wheelchair is a mobilized form of chair using two or more wheels, a footrest, and an armrest usually cushioned. It is used when walking is difficult or impossible to do due to illnesses, injury, disabilities, or age-related health conditio ...
-reliant by adulthood.


Endocrine phenotype

The typical hormonal signature of AHDS is marked by low free T4 and normal or elevated free T3 concentration, which translates to increased calculated
deiodinase Deiodinase (monodeiodinase) is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones. Types Types of deiodinases include: Iodothyronine deiodinases catalyze release of iodine directly from the thyronine ...
activity (
SPINA-GD The sum activity of peripheral deiodinases (''GD'', also referred to as deiodination capacity, total deiodinase activity or, if calculated from levels of thyroid hormones, as SPINA-GD) is the maximum amount of triiodothyronine produced per time-un ...
).


Genetics

This condition is inherited in an
X-linked recessive ''Main Article'': Sex linkage X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...
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. 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.


Pathogenesis

Mutations in the ''
SLC16A2 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical ...
''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
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
nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...
. This protein transports a particular hormone into nerve cells in the developing brain. This hormone, called
triiodothyronine Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate. Production of T3 and its prohormone thyroxi ...
or T3, is produced by the
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
. T3 appears to be critical for the normal formation and growth of
nerve cell A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...
s, as well as the development of junctions between nerve cells (
synapses In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...
) 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. 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. 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. This latter hypothesis is supported by results of
in silico In biology and other experimental sciences, an ''in silico'' experiment is one performed on a computer or via computer simulation software. The phrase is pseudo-Latin for 'in silicon' (correct ), referring to silicon in computer chips. It was c ...
experiments with
computer simulation Computer simulation is the running of a mathematical model on a computer, the model being designed to represent the behaviour of, or the outcome of, a real-world or physical system. The reliability of some mathematical models can be determin ...
s. Several studies have documented the potentially dangerous effects of the
silymarin Silibinin (INN), also known as silybin (both from ''Silybum'', the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the milk thistle, containing a mixture of flavon ...
mixture on the
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical ...
transporter. All of the
flavonolignan Flavonolignans are natural phenols composed of a part flavonoid and a part phenylpropane. Examples Flavonolignans identified in ''Silybum marianum'' (milk thistle) silymarin complex include silibinin, silychristin, silydianin, dehydrosilybin, ...
compounds found in the silymarin mixture seem to block the uptake of
thyroid hormones File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 386 ...
into the cells by selectively blocking the
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical ...
transmembrane transporter. The authors of several studies noted that especially
silychristin Silychristin (also known as silichristin) is a natural product and one of the constituents of silymarin, the standardized, active extract of the fruit of milk thistle, ''Silybum marianum''. It is the second most abundant constituent in silymarin ...
, one of the compounds of the silymarin mixture seems to be perhaps the most powerful and selective inhibitor for the
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical ...
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
MCT8 Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the ''SLC16A2'' gene. Function MCT8 actively transports a variety of iodo- thyronines including the thyroid hormones T3 and T4. Clinical ...
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.


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. Theoretical considerations suggested
TRIAC A TRIAC (triode for alternating current; also bidirectional triode thyristor or bilateral triode thyristor) is a three-terminal electronic component that conducts current in either direction when triggered. The term TRIAC is a genericized trad ...
(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. A first clinical trial demonstrated TRIAC to be safe and effective.


References


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 {{DEFAULTSORT:Allan-Herndon-Dudley Syndrome Membrane transport protein disorders Neurogenetic disorders Syndromes Diseases named after discoverers