April 01, 2022
Years published: 2011, 2014, 2022
NORD gratefully acknowledges Callan Russell, MS, Jacqueline Fung, BS, and MaryAnn Campion, EdD, MS, CGC, from the Stanford University MS Program in Human Genetics and Genetic Counseling for assistance in the preparation of this report.
Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder characterized by a wide spectrum of symptoms. These symptoms can vary widely in people who are affected, and even among members of the same family. Common symptoms include an uncoordinated manner of walking (abnormal gait) and dystonia. Dystonia is a general term describing involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). In THD, dystonia usually affects the legs, but can include other parts of the body (generalized dystonia). Additional symptoms may include a tendency to walk on tiptoes, difficulty walking, tremors, eye abnormalities, muscle weakness (hypotonia) and intellectual disability. However, there are fewer than 100 case reports of individuals with THD in the medical literature, so it is difficult to predict all the features of the disorder.
THD is caused by changes (mutations) in the TH gene. This gene is important for making the enzyme, or protein, that is necessary to produce dopamine. Dopamine is an important chemical signal (neurotransmitter) that plays a role in motor control and movement. Mutations in the TH gene cause symptoms of THD when inherited in an autosomal recessive pattern.
Symptoms can range in severity. Mild and moderate forms may resemble a movement disorder, but typically can be treated with a medication called levodopa. The most severe form of THD typically causes symptoms at a much younger age, with additional symptoms such as low muscle tone, decreased movement and intellectual disability. The severe form of THD often does not respond well to levodopa treatment. Historically, THD was characterized under two different subtypes (type A and B), but because there can be overlapping symptoms, the subtype designations are no longer widely used.
THD represents a spectrum of disease, and the symptoms can vary greatly from one person to another. In the severe form, symptoms may be obvious early in infancy. In more moderate or mild cases, symptoms may arise later during infancy or even during early childhood.
The mild form of THD is characterized by an abnormal manner of walking (gait) that usually becomes apparent sometime during early childhood. Affected children may appear clumsy or uncoordinated when walking or running. They also may or may not develop repetitive, involuntary movements of an arm or leg that force the body into abnormal, sometimes painful, movements and positions (limb dystonia). In some children, an early sign of THD may be the tendency to walk on tiptoes because of tightness or stiffness of leg muscles. Prolonged exercise or fatigue may trigger or worsen symptoms. In some children, symptoms may become worse or more pronounced in the afternoon and evening than in the morning after rest (diurnal fluctuation).
Affected children may also experience tremors when attempting to hold certain poses or positions (postural tremors), and they may have abnormal, involuntary eye movements. The symptoms of mild THD slowly become more pronounced (progressive) as affected children age. Without treatment, individuals eventually need wheelchairs due to progressive motor disturbances.
Children with the moderate form of THD have an abnormal manner of walking (abnormal gait), dystonic posturing especially when walking and a tendency to walk on their tiptoes. Some affected children may be unable to coordinate voluntary movements or have involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). Speech delays and abnormal eye movements may also occur. Abnormalities of eye movement may range from brief upward eye-rolling movements to oculogyric crisis, a condition characterized by eyes that roll upward for a sustained period of time. As opposed to the mild form of THD, children with the moderate form of THD typically display delays in achieving motor milestones (e.g., sitting up unassisted, crawling) and low muscle tone of the upper body (truncal hypotonia).
Children with the moderate form of THD are sometimes referred to as having “infantile Parkinsonism.” This is because their symptoms may resemble those of Parkinson disease: involuntary, rhythmic, quivering movements (tremors), abnormal slowness of movement (bradykinesia) and an inability to remain in a stable or balanced position (postural instability).
Symptoms of the severe form of THD are often obvious in the first six months of life and include poor control of voluntary muscles, delays in achieving motor milestones (e.g., sitting up unassisted, crawling), abnormal rigidity of the arms and legs, decreased motor function or activity (hypokinesia), and involuntary muscle spasms that result in slow, stiff movements of the limbs (spasticity). Some children may have diminished muscle tone (hypotonia), which can result in an inability to hold their head up or sit up unassisted. Affected infants may develop spasms of the neck muscles that lead to involuntary tilting of the head and twisting of the neck (torticollis). Additionally, children may have abnormal eye movements, drooping of the upper eyelids (ptosis) and eyes that appear crossed (strabismus).
Individuals with the severe form of THD sometimes have other symptoms such as abnormal chewing or swallowing, inability to drink or feed, temperature imbalance, crying and general feelings of discomfort. This is caused by dysfunction of the autonomic nervous system. The autonomic nervous system is the portion of the nervous system that controls or regulates certain involuntary body functions including heart rate, blood pressure, sweating, production and release of certain hormones and bowel or bladder control. Low levels of dopamine can prevent the body from making other neurotransmitters that play important roles in the autonomic nervous system.
As infants with severe THD age, they may experience behavioral problems including attention deficiency hyperactivity disorder (ADHD), impulsivity, anxiety, depression and obsessive-compulsive disorder (OCD). Affected children may experience delays in developing speech, learning disabilities or intellectual disability.
In some patients, the severe form of THD is characterized by abnormal brain function that develops during infancy and slowly gets worse (progressive infantile encephalopathy). Affected children may also experience episodes of profuse sweating, general feelings of discomfort, lack of energy, irritability and excessive drooling. Infants usually do not show improvement of encephalopathy or motor abilities despite treatment with levodopa. As opposed to mild and moderate forms of THD, individuals with the severe form of THD typically do not experience dystonia or diurnal fluctuation of symptoms.
THD is caused by mutations of the tyrosine hydroxylase (TH) gene and is inherited in an autosomal recessive pattern.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
The TH gene contains instructions for creating (encoding) the enzyme tyrosine hydroxylase. This enzyme converts the amino acid tyrosine into levodopa, which is then converted to dopamine. Dopamine is a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, allowing nerve cells to communicate. Dopamine is also converted into two additional neurotransmitters, norepinephrine and epinephrine (adrenaline), that are involved in the autonomic nervous system. Dopamine is critical for the proper function of certain processes of the brain, especially those that control movement. Mutations of the TH gene can result in deficient levels of tyrosine hydroxylase, which, in turn, causes a deficiency of levodopa, dopamine, norepinephrine and epinephrine, ultimately leading to the symptoms of THD.
THD may be classified as: (1) a form of dystonia, (2) an inherited neurotransmitter disorder or (3) a metabolic disorder.
1. Dystonia is a group of neuromuscular disorders in which involuntary muscle contractions force the body into abnormal, sometimes painful, movements and positions (postures).
2. Pediatric inherited neurotransmitter disorders are an emerging group of rare disorders characterized by defects in the creation (synthesis) or function of one or more
neurotransmitters, causing a variety of neurological and neuromuscular symptoms. The disorders are differentiated by the specific neurotransmitter involved (e.g., dopamine in THD).
3. Metabolism refers to the chemical processes in the body, including those in which complex substances are broken down into simpler ones (catabolism), and those in which complex
substances are built up from simpler ones (anabolism). Inborn errors of metabolism are metabolic disorders and result from abnormal functioning of a specific protein or enzyme that
accelerates particular chemical activities in the body (e.g., tyrosine hydroxylase in THD).
The exact incidence of THD in the general population is unknown. Approximately 100 cases have been reported in the medical literature. Researchers believe that the disorder is often misdiagnosed or goes undiagnosed, making it difficult to determine its true frequency in the general population.
THD is a type of dopa-responsive dystonia (DRD). DRD is a group of disorders that have childhood onset of limb dystonia and other symptoms. While the frequency of THD is difficult to determine, DRDs in general have an estimated prevalence of 0.5 to 1 per million worldwide. THD and guanosine triphosphate cyclohydrolase I deficiency (autosomal dominant Segawa syndrome) account for approximately 5-10% of all cases of primary dystonia in childhood.
A diagnosis of THD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests. These tests include examination of cerebrospinal fluid (CSF) to detect certain substances (metabolites) that are byproducts of metabolism. Identification of certain metabolites at specific levels can help to distinguish THD from other related neurotransmitter disorders. A sample of CSF is obtained through a procedure called a spinal tap (lumbar puncture) in which a needle is inserted into the spinal canal in the lower back.
A diagnosis of THD can be confirmed through molecular genetic testing, which can reveal the precise mutations in the TH gene causing the condition. Molecular genetic testing is available on a clinical basis.
THD is treated with medications to restore normal dopamine levels in the brain. All infants are initially treated with low levels of a medication called levodopa. Dopamine cannot cross the blood-brain barrier, a protective network of blood vessels and cells that allow some materials to enter the brain, while keeping other materials out. Therefore, dopamine would not be able to reach the brain if taken as a medication. Levodopa, however, can cross the blood-brain barrier, and can be given as a drug. In the body, levodopa is easily converted to dopamine after uptake from the gut. A second medication (usually carbidopa) is added to prevent the conversion of levodopa outside of the brain, ensuring that enough can effectively cross the blood-brain barrier.
The response to levodopa therapy varies among individuals with THD. Some people, particularly those with mild THD, respond quickly and completely to levodopa therapy, seeing a full reversal of symptoms. In others, the response may take time and improvement is seen slowly over a few months. In some people with the severe form of THD, levodopa therapy may not be effective initially. These patients may require prolonged treatment to eventually lessen symptoms and lead to an overall improvement in motor skills.
Some individuals with the severe form of THD are especially prone to the side effects of levodopa therapy including difficulties in performing voluntary movements (dyskinesia), gastroesophageal reflux, vomiting and suppression of appetite. In some patients, the dose of levodopa may need to be adjusted until the medication can effectively treat the disorder while being well tolerated.
Genetic counseling is recommended for affected individuals and their families. Physical and speech therapy may be beneficial in some patients. Other treatments are symptomatic and supportive.
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