Allan-Herndon-Dudley syndrome is a mutation in the SLC16A2 gene that alters the thyroid hormone transporter MCT8 and causes impaired iodothyronine uptake in muscle tissue and the central nervous system. Due to the mutation, affected individuals suffer from muscle weakness, as well as mobile and mental developmental delay. AHDS is incurable and has been treated exclusively with the administration of triiodothyroacetate.
What is Allan-Herndon-Dudley syndrome?
Allan-Herndon-Dudley syndrome is a mutation in the SLC16A2 gene that alters the thyroid hormone transporter MCT8 and causes impaired iodothyronine uptake in muscle tissue and central nervous system. Developmental delays or developmental retardations are summarized as delays in the physical, mental, or emotional development of adolescents and children. Developmental delays can have a variety of causes. For example, the trigger for delayed development may be in the central nervous system. This is the case, for example, with Allan-Herndon-Dudley syndrome (AHDS). In addition to a severe developmental delay in the mental area, the syndrome is characterized by disturbances in motor development. The first description of the syndrome dates back to 1944. The clinical picture they describe is a hereditary disease, i.e. a genetically determined disorder. The disease affects male infants in the majority of all cases documented to date. The developmental disorders and their consequences are clearly evident from birth in almost all cases. AHDS is an extremely rare disorder. For this reason, the state of research on Allan-Herndon-Dudley syndrome has been rather scanty.
Causes
AHDS is a genetic inherited disorder caused by a mutation in the SLC16A2 gene. This is the gene coding for the so-called thyroid hormone transporter MCT8. This transporter mediates the uptake of iodothyronines into muscle and nerve tissue. Due to the mutation, disturbances occur in the uptake of thyroid hormones, which throw the central nervous system out of balance and thus impair the cells of the nervous system in their development. Muscle tissue and brain become depleted of the active thyroid hormone they actually rely on due to the mutation-induced dysregulation. The syndrome is passed on in an X-linked recessive inheritance. Females can inherit the disease, but rarely become ill themselves due to their double X-chromosome structure. Affected males are unable to reproduce. Although the mutation is genetic, in addition to this internal factor, external factors probably play a role in the onset of the disease. Because of its rarity and such a limited research base, the role of these external factors has not yet been conclusively determined.
Symptoms, complaints, and signs
Allan-Herndon-Dudley syndrome is a congenital disorder that usually manifests in infants or young children. Affected individuals suffer from more or less severe muscle weakness. The children’s muscle tissue is conspicuously underdeveloped. The weakness of the musculature is soon accompanied by joint deformities. Contractures are also common accompanying symptoms. The children’s mobility is increasingly impaired by the contractures and deformities. For this reason, affected individuals often appear unnaturally static or even motionless. Due to the mutation-related undersupply of thyroid hormones, the affected individuals often additionally suffer from muscle spasms or perform involuntary movements with their arms and legs. Often, the affected persons are unable to move independently. In most cases, the motor impairments are associated with severe mental disorders. For example, a large proportion of patients are unable to speak. In individual cases, AHDS can be characterized by many other symptoms in the area of mental and physical development.
Diagnosis and course
The first suspicion of AHDS usually comes to the physician during the patient’s medical history. Laboratory chemistry reveals an elevated T3 level in the presence of normal FT4 and TSH levels, pointing to Allan-Herndon-Dudley syndrome. Imaging of the central nervous system is usually part of the diagnostic workup. Differentially, muscle weakness due to motoneuronal disease should be excluded. The prognosis for patients with Allan-Herndon-Dudley syndrome is relatively unfavorable.To date, the disease is incurable. Studies have suggested that the timing of diagnosis is likely to play a critical role in patients’ prognosis.
Complications
Like all chromosonally inherited disorders, Allan-Herndon-Dudley syndrome cannot be treated curatively. The most common complication of Allan-Herndon-Dudley syndrome – marked muscle weakness – can be treated with physical therapy. Such treatment, aimed at strengthening the muscles, can be painful for the patient. Young children in particular often refuse therapy because of the pain. Despite intensive training, physiotherapy does not always lead to the desired success. The situation is similar with speech therapy for the Allan-Herndon-Dudley patient. Although the reduction in speech ability can be improved with intensive training, treatment does not always lead to success due to the usually high degree of mental impairment of the affected person. Frustration in the patient himself as well as a high burden on the entire family is one of the most serious complications in the treatment of Allan-Herndon-Dudley syndrome. Muscle spasms and movements of the extremities that cannot be influenced can be treated with the administration of muscle relaxants. Complications are seen in the sometimes severe side effects of the drugs. Fatigue, a general feeling of exhaustion and malaise are to be mentioned in addition to a strain on the gastrointestinal tract. Long-term use of relanxants also damages the liver and kidneys. If treatment for Allan-Herndon-Dudley syndrome is omitted, affected individuals will not be able to make significant progress in terms of their mental or motor abilities.
When should you see a doctor?
In many cases, direct treatment of Allan-Herndon-Dudley syndrome is not possible. For this reason, treatment is primarily symptomatic, targeting individual symptoms and delays. As a rule, parents should consult a doctor if the child suffers from muscle weakness. This can become noticeable through fatigue or persistent tiredness. Furthermore, medical advice is also necessary if there is a delay in mental and motor development due to Allan-Herndon-Dudley syndrome. If treatment is not given in childhood, significant discomfort and limitations may result in adulthood. A doctor should be consulted especially if the patient is unable to speak. Treatment is also necessary for muscle spasms. If it is an acute emergency, the hospital can also be visited directly or an ambulance can be called. In most cases, Allan-Herndon-Dudley syndrome is treated by a general practitioner or by a pediatrician. However, the individual complaints must be examined and treated by the respective specialist or therapist.
Treatment and therapy
AHDS is a causally untreatable disorder. Because no therapies are available to correct the primary cause, the disease has not been curable to date. In the meantime, advances in the field of gene therapy suggest that gene therapy approaches will soon be approved for clinical use. The extent to which patients with the syndrome would benefit from approval has not yet been further clarified. At the present time, there is no established or standardized treatment option for patients with AHDS, even in the area of symptomatic therapy. Several years ago, researchers considered the administration of TRIAC to be a potentially suitable symptomatic treatment option. TRIAC is a non-classical thyroid hormone, triiodothyroacetate. Administration of the hormone has been performed in a clinical trial in affected children, but failed to produce visible results. The results of the study are not necessarily conclusive, as administration of the hormone was started relatively late. In 2014, TRIAC was still considered to be the best treatment option for this reason. In one case, a significant improvement in motor and mental development was documented in 2014 during therapy with TRIAC. The therapy was started on the affected person in early infancy. Thus, the study results to date indicate that the time of therapy initiation for patients with AHDS has an effect on therapy results that should not be underestimated.Supportive therapies such as occupational and physical therapy or early intervention can theoretically be used to improve the patient’s quality of life and abilities. However, little evidence exists regarding the efficacy of such an approach in the context of AHDS patients.
Outlook and prognosis
As a result of Allan-Herndon-Dudley syndrome, most patients experience a number of different complaints. First and foremost, affected individuals suffer from severe muscle weakness. This means that the affected person may no longer be able to perform ordinary activities or sports without difficulty. Likewise, there are severe delays in mental and mobile development. The patient’s concentration is significantly impaired and reduced. Severe cramps in the muscles continue to occur, often resulting in involuntary movements or twitching. As Allan-Herndon-Dudley syndrome progresses, the affected person is unable to speak. The patient’s daily life is thus significantly restricted by the syndrome and the quality of life is reduced. In some cases, patients are then dependent on the help of other people in their daily lives. It is usually not possible to treat Allan-Herndon-Dudley syndrome causally. For this reason, treatment is exclusively symptomatic. Those affected are dependent on various therapies, which, however, do not lead to a positive course of the disease in every case. In some cases, the life expectancy of the affected person is limited by Allan-Herndon-Dudley syndrome.
Prevention
AHDS can be prevented solely through genetic counseling. Mutation carriers, for example, can choose not to have children of their own.
Follow-up care
The need for follow-up in genetically caused Allan-Herndon-Dudley syndrome affects only male infants. The problem is that there is no appropriate treatment for this inherited disorder. The severe consequences caused by defects in thyroid hormone transmitters can hardly be improved. Attempts to provide relief for affected children by administering special thyroid hormones have failed. The problem is that the bases of the disease are usually already established in the mother’s body. They cause lasting damage to the unborn child. In this way, treatment comes too late, namely after birth. During postnatal care, only the damage that is already present can be treated. However, there is hope. In 2014, a case was reported in which an infant affected by Allan-Herndon-Dudley syndrome was successfully treated with TRIAC. Follow-up care still remained necessary because the child could not be cured. At least his symptoms were alleviated. One of the causes of Allan-Herndon-Dudley syndrome is a defective blood–brain barrier. That’s what studies at Cedars-Sinai Hospital suggest. The defective blood–brain barrier prevents thyroid hormones from working. This is also true of thyroid hormones administered after the child is born. It is possible that biotechnology or genetic research could provide a remedy after the fact. At the moment, all attempts at treatment are failing. This also affects aftercare for the severely damaged children.
What you can do yourself
Allan-Herndon-Dudley syndrome is a serious condition that cannot yet be treated effectively. However, parents can still take some steps to help with therapy. First, regular cognitive training and exercise are important. Comprehensive therapy, which can consist of speech and reading training, but also general brain exercises, depending on the severity of the syndrome, can also include exercises from physiotherapy. The training must be individually tailored to the symptom pattern. Parents of affected children should therefore ensure that the measures are optimally chosen and that the child is not overtaxed. In the case of severe mental disorders, the child may need permanent support in everyday life. An outpatient care service can provide important relief for the parents. Equally important is inpatient treatment, which can be supported at home by regular monitoring of symptoms. Parents should also seek psychological counseling and, if necessary, a self-help group, because contact with others affected by the disease makes it easier to cope with it.In addition, parents often receive important tips for dealing with a sick child.
