Allan–Herndon–Dudley syndrome is a rare X-linked inherited disorder of
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
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,Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
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 (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 a potential manifestation of many different diseases a ...
) 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 permanent shortening of a muscle or joint. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spasti ...
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 chair with wheels, used when walking is difficult or impossible due to illness, injury, problems related to old age, or disability. These can include spinal cord injuries ( paraplegia, hemiplegia, and quadriplegia), cerebr ...
-reliant by adulthood.
Genetics
This condition is inherited in an
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
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 sig ...
''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
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 highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes 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 thyroxine ( ...
or T3, is produced by the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
. T3 appears to be critical for the normal formation and growth of
nerve cell
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
s, as well as the development of junctions between nerve cells (
synapses
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
) 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.
Several studies have documented the potentially dangerous effects of the
silymarin
Silibinin (International Nonproprietary Name, INN), also known as silybin (both from ''Silybum'', the Genus–differentia definition, generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standard ...
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 sig ...
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, d ...
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 25 ...
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 sig ...
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 sig ...
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 sig ...
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 genericised tradem ...
(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 DeficiencyAllan–Herndon–Dudley syndromeat National Library of Medicine
{{DEFAULTSORT:Allan-Herndon-Dudley Syndrome
Membrane transport protein disorders
Neurogenetic disorders
Syndromes