Allan-Herndon-Dudley Syndrome - Clinical Features, Cause, Diagnosis, and Treatment

Introduction:

Allan-Herndon-Dudley syndrome is a type of genetic disorder that affects the development of the brain and causes intellectual disability that can range from mild to severe, along with movement disorder. This syndrome mainly affects males, and the symptoms occur before birth. Individuals affected by this syndrome enjoy communicating with people even though their ability to talk is limited. Individuals with this syndrome cannot walk and are bound to a wheelchair. Affected individuals have short life expectancies due to severe infections, malnutrition, and aspiration pneumonia. But there are few reports where the individuals have lived up to 70 years.

What Is Allan-Herndon-Dudley Syndrome?

Allan-Herndon-Dudley syndrome is a rare inherited genetic disorder caused by a mutation in the SLC16A2 (solute carrier family 16 member 2) gene which encodes a protein called MCT8 which helps in transferring T3 (triiodothyronine). Therefore, mutated genes fail to intake T3 by the nerve cells and increase the levels of T3 in the body.

What Are the Other Names for Allan-Herndon-Dudley Syndrome?

The other names for Allan-Herndon-Dudley syndrome are:

• AHDS.

• Monocarboxylate transporter-8 deficiency.

• Triiodothyronine (T3) resistance.

• X-linked intellectual disability with hypotonia.

• Intellectual disability and muscular atrophy.

What Is the Cause of Allan-Herndon-Dudley Syndrome?

The Allan-Herndon-Dudley syndrome occurs due to a mutation in the SLC16A2 gene, inherited in an X-linked recessive pattern in which the mutated gene is present on X-chromosome. One mutated gene is enough for males with one X and one Y chromosome to cause this condition. In contrast, females with two X-chromosomes require two mutated genes to cause this condition, and the presence of one mutated gene makes them a carrier and unaffected by this condition. X-linked traits cannot be passed down from father to son, but a carrier female who carries one mutated gene can pass down the disease. The features of the SLC16A2 gene include:

• The SLC16A2 gene is located on the X-chromosome.

• The SLC16A2 gene provides information for producing a protein called MCT8 (monocarboxylate transporter 8) which is essential for brain development.

• The protein produced by this gene helps transport a hormone called triiodothyronine or T3, which is formed by the thyroid gland in front of the neck. The kidney, liver, heart, and other tissue also form T3.

• This T3 hormone in a nerve cell interacts with the nucleus receptors that can activate the inactive specific genes.

• The T3 hormone plays an essential role in nerve cell development (maturation), formation of dendrites (projections at the ends of the neuron), development of synapses (ends of neurons that connect with other neurons), and cell migration.

• T3 also plays a vital role during brain development in the embryo and early childhood.

A mutation in the SLC16A2 gene can alter the function of the MCT8 protein and cause problems in the transportation of T3. Therefore the absence of T3 can result in abnormal brain development, causing problems in movement and intellectual disability. This also results in increased levels of T3 in the blood, causing hyperthyroidism.

What Are the Clinical Features of Allan-Herndon-Dudley Syndrome?

Clinical features in individuals affected by this syndrome may vary. Males are severely affected, and carrier females are not affected severely but have increased levels of T3 and rarely intellectual disability and delay in development due to X-chromosome inactivation can occur.

The neurological features of Allan-Herndon-Dudley syndrome include:

• Intellectual disability.

• Dystonia (involuntary muscle movements).

• Choreoathetosis (uncontrolled movements throughout the body).

• Inability to walk.

• Late-onset seizures are resistant to drugs.

Skeletomuscular features include:

• Hypotonia (low muscle tone).

• Contractures (stiffness of joints due to tightened parts around them such as tendons, muscles, and tissues) causing restriction in movements.

• Muscle hypoplasia (underdeveloped muscles).

• Hypokinesia (inability to move).

• Spasticity (muscle stiffness).

• Weak muscles.

• Pectus excavatum (sunken chest).

• Kyphoscoliosis (curved spine).

• Short stature.

• Low weight.

Facial features include:

• Ptosis (stooping eyelids).

• Tented upper lip (triangular appearance of the opening of the mouth).

• Thickened nose and ears.

• Cup-shaped ears.

• Long face.

• Upturned earlobes.

• Hypomimia (expressionless face).

Neonatal findings include:

• Fetal arrhythmia (irregular heartbeat of the fetus).

• Premature birth.

• Weak fetal movements.

• Congenital microcephaly or macrocephaly (decreased or increased head size).

• Hydramnios (increased amniotic fluid).

• Neonatal hypotonia.

• Neonatal jaundice (increased levels of total serum bilirubin in the blood, which results in yellowish skin, eyes, and nails).

Due to reduced uptake of T3 by nerve cells, there is increased accumulation of T3 in the body resulting in hyperthyroidism which causes:

• Intellectual disability.

• Restless sleep.

• Arrhythmia (irregular heartbeat).

• Tachycardia (increased heart rate, which is more than 100 beats per minute).

• Failure to gain weight.

• Decreased muscle mass.

• Cold intolerance.

• Sweating.

• Life-threatening infections.

• Cardio-respiratory failure.

How Is the Diagnosis of Allan-Herndon-Dudley Syndrome Done?

The diagnosis of Allan-Herndon-Dudley syndrome includes:

• A blood test to detect the levels of thyroid hormone. The blood test reveals increased levels of T3 with normal or elevated TSH (thyroid stimulating hormone) and T4 levels.

• Magnetic resonance imaging (MRI) of the brain shows delayed myelination (formation of the myelin sheath around the nerves) and brain atrophy.

• Molecular genetic testing shows a mutation in the SLC16A2 gene.

What Is the Differential Diagnosis of Allan-Herndon-Dudley Syndrome?

The differential diagnosis of Allan-Herndon-Dudley syndrome induces:

• Pelizaeus-Merzbacher Disease: A rare genetic degenerative disorder of the brain that causes movement, cognition, and coordination problems. Individuals with this condition have normal T3 and T4 levels.

• Non-Goitrous Congenital Hypothyroidism 6: A rare genetic condition due to a mutation in the THRA (thyroid hormone receptor alpha) gene. Individuals with this condition have no problem with brain MRI and show improvement with L-Thyroxine therapy.

What Is the Treatment for Allan-Herndon-Dudley Syndrome?

There is no cure for Allan-Herndon-Dudley syndrome, but the management includes a multidisciplinary team of pediatricians, a neurologist, an endocrinologist, and a geneticist (a person who is well-versed in genetic disorders along with their inheritance). The affected individuals may benefit from occupational, social, physical, and speech therapy. The management includes:

• Use gastrostomy tube placement (a feeding tube) in case of feeding difficulties.

• Use of laxatives, transanal irrigation, or enemas in case of constipation.

• Use of Glycopyrrolate or Scopolamine in case of severe drooling.

• Use of anticholinergics, or Carbamazepine for dystonia.

• Orthopedic surgery in case of musculoskeletal problems such as kyphoscoliosis or hip dislocation.

• Use anti-seizure medications such as Phenytoin, Carbamazepine, Valproic acid, and Phenobarbital.

• Use of Melatonin or Hydroxyzine dichlorhydrate in case of sleep disorder.

• Recent drugs such as Tiratricol, Teatrois, or Emcitate (TRIAC) that do not use MCT8 protein to enter the nerve cells have shown success. But this can be used only during the first trimester of pregnancy when the brain development starts.

Conclusion:

Allan-Herndon-Dudley syndrome is a rare disorder with no cure, and individuals with this syndrome and family members should receive genetic counseling as this is inherited in an X-linked recessive manner where the female carriers can pass down the condition and have a 50 % risk of sons being affected by this condition and 50 % risk of daughters becoming carriers.