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  • Writer's pictureThe Rare360 Editorial Team

Allan-Herndon-Dudley Syndrome (AHDS): Unraveling Genetics, Symptoms, Diagnosis, and Treatment Option

Updated: Jan 16

Female research team studying DNA mutations. Computer screens with DNA helix in foreground stock photo.

Understanding the Genetic Basis and Prevalence of Allan-Herndon-Dudley Syndrome (AHDS)

Allan-Herndon-Dudley syndrome (AHDS), also recognized as MCT8 deficiency, is a rare genetic disorder that impacts a child’s brain development and causes intellectual and mobility disabilities. This condition is caused by a genetic mutation in the SLC16A2 gene, also known as the MCT8 gene. This gene encodes a protein called monocarboxylate transporter 8 (MCT8) that transports thyroid hormones from the bloodstream into the nerve cells of the brain. The MCT8 protein allows thyroid hormones to enter nerve cells, where they can stimulate the activity of other genes and regulate processes necessary for normal development. Thyroid hormones play a crucial role in the development and function of the nervous system and are particularly important for proper brain development during pregnancy and early childhood.


AHDS is an X-linked recessive neurogenerative disorder. This means that the defective gene responsible for a disorder is located on the X chromosome, and it predominantly affects males. There is a 50% chance that male babies will have the disorder if their mother is a carrier of the abnormal gene that codes for the MCT8 thyroid hormone transporter protein. Although not well described female carriers of the MCT8 gene may also have symptoms, often milder than males. The disorder may also develop spontaneously during fetal development, where the baby is the first person in the family to have AHDS.


AHDS is an ultra-rare disorder. At least 132 families with 320 affected individuals have been reported in the literature to date. Although the prevalence of this ultra-rare disorder is unknown; the identification of more than 132 affected families in approximately 15 years suggests that the syndrome is more common than previously thought.


Signs and Symptoms of AHDS

AHDS/MCT8 deficiency starts showing signs shortly after birth or in the first few weeks or months of life. Babies affected by it often have weak muscles, making it hard for them to support their heads and reach motor milestones like rolling over or sitting up. As they grow, their muscles become stiff and they might have abnormal reflexes, making movements difficult. These difficulties continue into childhood, making it hard for them to learn and move like other children their age. People with this condition often have unique facial features, like an open mouth, droopy eyelids, and unusual ear shapes. Their feet might be long and thin with the toes pointing outward. Some individuals might also have seizures and struggle with gaining weight. Occasionally, they might develop a sunken chest or a curved spine due to their weak muscles.

Here are some common signs of AHDS:

  • Appearance: Patients might have a longer, narrower face and spine or chest abnormalities like scoliosis and pectus excavatum.

  • Developmental delay/severe intellectual disability: This can lead to difficulties in speaking, walking, and other developmental milestones.

  • Muscle issues: Patients often experience hypotonia (low muscle strength) along with stiffness to the legs (spasticity). They may also have disorganized, involuntary and abnormal muscle movements that can become more intense with physical contact. In adulthood, muscle problems can lead to contractures (joint deformities) and limited joint motion, which often results in the need for a wheelchair for mobility.

  • Growth and heart problems: Failure to thrive, poor weight gain, malnutrition, an increased heart rate (tachycardia), and abnormal heart rhythms (arrhythmia) can occur.

  • Additional symptoms: It is estimated that 80–99% of people with AHDS may also exhibit biparietal narrowing (narrowing of the skull), ataxia, neck abnormalities, absent speech development and aphasia.


Recognizing the Clinical Symptoms and Characteristics of AHDS

Diagnosing Allan-Herndon-Dudley syndrome (AHDS) typically involves a combination of clinical evaluation, genetic testing, and sometimes other diagnostic procedures. Below is the breakdown of the diagnostic process. It’s important to note that while these are the typical methods for diagnosing AHDS, the exact process may vary and should be overseen by a healthcare professional.

  • Clinical Evaluation: A healthcare provider, often a pediatrician or a geneticist, will assess the patient's medical history and conduct a thorough physical examination. They will look for characteristic signs and symptoms of AHDS, such as developmental delays, muscle weakness, spasticity, and other physical abnormalities. Below are some of the clinical characteristics:

​Prenatal/Neonatal Stage

​Week fetal movements

Fetal arrhythmia

Neonatal hypotonia

Premature birth

Neonatal hypotrophy

Congenital microcephaly

Congenital macrocephaly

Hydramnios

Neonatal jaundice

Growth

​Weight gain deficiency

Low weight

Short stature

Microcephaly

DD/ID

ID

Severe-to-profound ID

Mild-to-moderate ID

Speech

Walking

Neuromuscular

Axial hypotonia Amyotrophy Spasticity/hyperreflexia Dystonia Choreoathetosis Paroxysms or kinesigenic dyskinesias Ataxia Seizures Nystagmus

​Skeletal

Pectus excavatum

Kyphoscoliosis

Flat feet with valgus

Other

Narrow/elongated myopathic face Cryptorchidism

Peripheral dysthyroidism

  • Genetic Testing: Genetic testing, such as DNA sequencing or molecular genetic testing, can identify mutations in the SLC16A2 gene. A blood sample is usually taken from the patient for genetic analysis. If a mutation in the SLC16A2 gene is detected, it strongly supports the diagnosis of AHDS.

  • Hormone Testing: AHDS is associated with impaired thyroid hormone transport, leading to low levels of thyroid hormones in the brain. Blood tests can measure levels of thyroid hormones (T3 and T4) and thyroid-stimulating hormone (TSH). While these tests can indicate thyroid dysfunction, they alone are not sufficient to diagnose AHDS.

  • Brain Imaging: In some cases, brain imaging studies such as magnetic resonance imaging (MRI) or computed tomography (CT) scans may be performed. These imaging studies can help identify any structural abnormalities in the brain that may be contributing to the symptoms.

  • Electromyography (EMG) and Nerve Conduction Studies: These tests may be used to assess muscle function and nerve conduction. They can help in evaluating muscle weakness and spasticity.

  • Additional Testing: Depending on the patient's specific symptoms and clinical findings, other tests may be conducted to rule out other potential causes of similar symptoms.

Genetic testing is typically the most definitive method for diagnosing AHDS, as it can identify specific mutations in the MCT8 gene. However, the clinical evaluation and other tests play a crucial role in supporting the diagnosis and ruling out other conditions with similar features.


Comprehensive Care and Management Strategies for AHDS

Currently, there is no cure for Allan-Herndon-Dudley syndrome (AHDS), and treatment is symptomatic and supportive. This means that the treatment focuses on managing the symptoms and improving the quality of life for individuals with AHDS. The treatment plan may include:

  • Physical Therapy: People with AHDS often experience muscle weakness, which can impact their ability to move and perform daily activities. Physical therapy is a crucial part of the treatment plan because it helps individuals build strength, improve their mobility, and maintain as much independence as possible. Physical therapists create customized exercise routines and strategies to address the specific muscle weaknesses and physical challenges that each person with AHDS faces.

  • Speech Therapy: AHDS can affect not only physical abilities but also communication skills. Speech therapy is beneficial for individuals who experience difficulties with speech and language development. Speech therapists work with patients to improve their ability to communicate effectively, which can significantly enhance their overall quality of life and social interactions.

  • Nutritional Support: Some individuals with AHDS may have trouble with eating or gaining weight. Nutritional support may include dietary adjustments, special feeding techniques, or even the use of feeding tubes to ensure that individuals receive adequate nutrition and maintain a healthy weight. Proper nutrition is vital for overall health and energy levels.

  • Regular Monitoring: AHDS can lead to abnormal thyroid hormone levels, which can affect various aspects of health. Regular monitoring is essential to identify any imbalances and provide timely treatment if necessary.


Recommended Monitoring for Individuals with Allan-Herndon-Dudley Syndrome

​Concern/Aspect

​Evaluation

Frequency

Developmental Progress & Educational Needs

Monitor developmental progress and educational requirements

Every 6 months until age 4 years, then annually

Neurological Issues

Monitor individuals with seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, and movement disorders

Every 6 months for those with epileptic seizures; Every 6 months until age 4 years, then annually

Poor Weight Gain/Failure to Thrive

Measure growth parameters, evaluate nutritional status, and assess the safety of oral intake.

Perform evaluations every 3 months in case of poor weight gain, otherwise every 6 months until age 4 years, then annually

Musculoskeletal Concerns

​Monitor for scoliosis and joint problems. Assess mobility and self-help skills through physical medicine, occupational therapy, and physical therapy

Conduct assessments every 6 months until age 4 years, then annually or as needed.

Bone Health

Perform osteodensitometry (DXA) and assess phospho-calcic equilibrium

Conduct assessments annually in nonambulatory patients

Thyroid Abnormalities

No specific follow-up required if not being treated with thyroid analogs

Dysthyroidism Signs

Conduct history and physical exams to check for tachycardia, high blood pressure, and intestinal problems.

​Perform assessments every 6 months until age 4 years, then annually or as needed

Family/Community Support

Assess family needs for social work support, palliative/respite care, home nursing, and other local resources.

Provide care coordination as requested and needed

It’s important to note that the treatment plan can vary greatly depending on the individual’s symptoms and needs. Therefore, it should be developed in consultation with a team of healthcare professionals who are familiar with AHDS.


Advancements and Potential Therapies for AHDS

At present, there are no registered therapeutic approaches for addressing AHDS. Given the severity of this syndrome, its profound impact on patients' quality of life, and the high infant mortality rate, the urgent need for effective treatments is evident. Since the initial identification of MCT8 deficiency in patients, substantial research efforts have been directed toward designing and developing potential therapies.


The ideal therapy should aim to prevent the neurocognitive symptoms associated with the condition and alleviate peripheral thyrotoxicosis. It is generally recognized that the most promising effects on neurocognitive symptoms are achieved when treatment is initiated early in life, with limited benefits observed in older patients, similar to congenital hypothyroidism.


Research efforts have centred on thyroid hormone analogues, which can penetrate cell membranes independently of MCT8, with intracellular effects similar to T3. Preclinical studies in mice demonstrated that the thyroid hormone analogue diiodothyropropionic acid (DITPA) could normalize serum TSH concentrations and markers of peripheral thyrotoxicosis. However, DITPA treatment did not significantly improve neurocognitive symptoms in patients.


Triiodothyroacetic acid (Triac), another thyroid hormone analogue, showed promise in improving brain development and peripheral symptoms when administered directly after birth. Triac effectively reduced high serum T3 concentrations and improved clinical and biochemical features of thyrotoxicosis in a phase II trial involving MCT8 deficiency patients. Some patients treated early in life showed a trend toward improved neurodevelopment. Transplacental passage of Triac has also been observed, making it a potential candidate for prenatal treatment.


Additionally, the thyroid hormone analogue sobetirome has been explored, although its effects on peripheral symptoms and safety profile remain unclear.


Efforts to restore MCT8 function have involved gene therapy using adeno-associated virus 9 (AAV9) vectors containing human MCT8 cDNA, which increased cerebral thyroid hormone signalling in mice. Similar approaches have shown promising results in zebrafish models. However, the effects of these therapies on peripheral symptoms and their safety profiles require further exploration.


In addition, chemical chaperones have been investigated to enhance the stability and trafficking of mutant MCT8, potentially increasing thyroid hormone transport across cell membranes. These chaperones have shown varying effects in different cell models, but their impact on the overall clinical and neurocognitive phenotype remains unclear and largely untested in animal models.


Conclusion

In summary, Allan-Herndon-Dudley syndrome (AHDS) is an exceptionally rare genetic disorder that profoundly affects both the nervous system and peripheral functions of those affected. The condition arises due to mutations in the SLC16A2 /MCT8 gene, which impairs the transport of crucial thyroid hormones into brain cells. Given its rarity, AHDS poses unique challenges in terms of diagnosis and treatment.


The diagnostic process typically involves a combination of clinical evaluation, genetic testing to identify SLC16A2 gene mutations and assessments of thyroid hormone levels. Genetic testing is especially crucial for confirming an AHDS diagnosis.


Presently, there is no cure for AHDS, and treatment primarily revolves around symptom management and enhancing the overall quality of life. This involves a multifaceted approach encompassing physical and speech therapy, nutritional support, and ongoing monitoring of thyroid function.


Recent research initiatives have explored various potential treatments, such as thyroid hormone analogues, gene therapy, and chemical chaperones. While some of these approaches have shown promise in mitigating peripheral symptoms, their effectiveness in addressing the neurocognitive deficits associated with AHDS remains uncertain. It is clear that further research is essential to develop effective therapies for this complex condition.

AHDS represents a medical challenge due to its limited prevalence and intricate nature.


Consequently, ongoing research efforts and collaboration among healthcare professionals are crucial to advancing our understanding and improving the lives of individuals grappling with this disorder.

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