NORD gratefully acknowledges Michèl Willemsen, MD, Pediatric Neurologist, Nijmegen, The Netherlands, for assistance in the preparation of this report.
Tyrosine hydroxylase deficiency is a rare genetic disorder characterized by a wide spectrum of disease ranging from a mild movement disorder at one end to a life-threatening, neurological disorder at the other. The symptoms of the disorder can vary widely from person to another, even among members of the same family. Common symptoms include an uncoordinated or clumsy manner of walking (abnormal gait) and dystonia. Dystonia is a general term for a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Dystonia in tyrosine hydroxylase deficiency usually affects the legs. Additional symptoms that may occur include tremors, eye abnormalities, and a tendency of affected children to walk on their tiptoes. The severe form of tyrosine hydroxylase deficiency causes symptoms at a very young age (first months of life). The symptoms generally do not resemble those of a movement disorder, but rather give the impression of a severe, diffuse brain disorder. Mild and moderate forms of tyrosine hydroxylase deficiency show dramatic improvement when treated with levodopa. Levodopa is an amino acid that is converted to dopamine. Dopamine is a brain chemical that serves as a neurotransmitter and is deficient in children with tyrosine hydroxylase deficiency. Treatment options for severe tyrosine hydroxylase deficiency have been less effective. Tyrosine hydroxylase deficiency occurs due to disruptions or changes (mutations) of the TH gene. The TH gene mutation is inherited as an autosomal recessive trait.
Tyrosine hydroxylase deficiency represents a spectrum of disease ranging from a mild form to a severe form. The symptoms of tyrosine hydroxylase deficiency 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 become apparent later during infancy or even during early childhood. The case reports of individuals with tyrosine hydroxylase deficiency in the medical literature are limited, making it difficult to determine an accurate picture of the disorder.
The mild form of tyrosine hydroxylase deficiency is characterized by an abnormal, awkward manner of walking (gait) that usually becomes apparent sometime early during childhood. Affected children may appear clumsy or uncoordinated when walking or running, but may not have any other obvious symptoms of the disorder.
Children with the mild form of the disorder may develop repetitive, involuntary movements of an affected arm or leg that force the body into abnormal, sometimes painful, movements and positions (limb dystonia). In some cases, an early sign of tyrosine hydroxylase deficiency may be the tendency of affected children to walk on their tiptoes because of tightness or stiffness of leg muscles. Prolonged exercise or fatigue may set off or worsen symptoms. In some cases, the symptoms may become worse or more pronounced in the afternoon and evening than in the morning (diurnal fluctuation).
Affected children may also experience tremors when attempting to hold certain poses or positions (postural tremors) or have abnormal, involuntary eye movements. The symptoms of mild tyrosine hydroxylase deficiency slowly become more pronounced (progressive) as affected children age. Without treatment all affected individuals will eventually depend on a wheelchair due to progressive motor disturbances.
Children with the moderate form of tyrosine hydroxylase deficiency have an abnormal manner of walking (abnormal gait), dystonic posturing especially when walking, and a tendency to walk on their tiptoes. In some cases, affected children may be unable to coordinate voluntary movements or have involuntary muscles 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.
Children with the tyrosine hydroxylase deficiency spectrum are sometimes referred to as having “infantile parkinsonism” because they may have symptoms that resemble Parkinson’s disease including 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 tyrosine hydroxylase deficiency are obvious early in infancy and include, poor control of voluntary muscles, delays in achieving motor milestones (e.g., sitting up unassisted, crawling), increased muscle tone (hypertonia), abnormal rigidity of the arms and legs (limbs), decreased motor function or activity (hypokinesia), and involuntary muscles spasms that result in slow, stiff movements of the limbs (spasticity).
In those individuals in whom the disorder presents within the first months of life, other symptoms complicate the picture: abnormal swallowing, inability to drink, temperature imbalance, crying, “discomfort” whether or not in episodes that come and go spontaneously, among others. 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, the production and release of certain hormones, and bowel or bladder control.
Some children may have diminished muscle tone (hypotonia or “floppy” baby), which can result in an inability to hold ones head up or sit up unassisted. Affected infants may also develop spasms of the neck muscles that result in involuntary rotation and tilting of the head and twisting of the neck (torticollis).
Additional findings may occur in children with severe tyrosine hydroxylase deficiency including abnormal eye movements, drooping of the upper eyelid (ptosis), and eyes that appear crossed (strabismus). 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. Affected infants may also experience difficulties chewing, swallowing and feeding. Constipation is also a common finding.
As affected infants age, they may experience behavioral problems including attention deficiency hyperactivity disorder, impulsivity, anxiety, depression and obsessive-compulsive disorder. In the most severe cases, affected children may experience delays in the developing speech or difficulties with articulation. Besides the neuropsychiatric features, affected children may have learning disabilities or even suffer from moderate to severe intellectual disability.
In some cases, the severe form of tyrosine hydroxylase deficiency 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, malaise, lethargy, irritability and excessive drooling. Infants usually do not show improvement of encephalopathy or motor abilities despite treatment with levodopa.
Tyrosine hydroxylase deficiency is caused by mutations of the tyrosine hydroxylase (TH) gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the TH gene is located on the short arm (p) of chromosome 11 (11p15.5). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p15.5” refers to band 15.5 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The TH gene contains instructions for creating (encoding) the enzyme tyrosine hydroxylase. This enzyme converts the amino acid tyrosine into dopamine. Amino acids are the chemical building blocks that form proteins in the body. Dopamine is a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Dopamine is also converted into two additional neurotransmitters called norepinephrine and epinephrine (adrenaline). Dopamine is critical for the proper function of certain processes of the brain especially those that control movement. Mutation of the TH gene results in deficient levels of tyrosine hydroxylase, which, in turn, results in a deficiency of dopamine, norepinephrine, and epinephrine.
Tyrosine hydroxylase deficiency may be classified as a form of dystonia, an inherited neurotransmitter disorder, and a metabolic disorder. Dystonia is a group neuromuscular disorders in which involuntary muscle contractions force the body into abnormal, sometimes painful, movements and positions (postures).
Pediatric inherited neurotransmitter disorders are an emerging group of rare disorders characterized by defects in the creation (synthesis) and metabolism of one or more neurotransmitters and result in a variety of neurological and neuromuscular symptoms. The disorders are differentiated by the specific neurotransmitter involved.
Tyrosine hydroxylase deficiency may also be classified as an inborn error of metabolism (metabolic disorder). “Metabolism” refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones (catabolism), usually with the release of energy, and processes in which complex substances are built up from simpler ones (anabolism), usually resulting in energy consumption. Inborn errors of metabolism result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body.
The exact incidence of tyrosine hydroxylase deficiency in the general population is unknown. Fewer than 50 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. Tyrosine hydroxylase deficiency and guanosine triphosphate cyclohydrolase I deficiency (autosomal dominant Segawa syndrome) account for approximately 5-10 percent of all cases of primary dystonia in childhood. Tyrosine hydroxylase deficiency was first described in the medical literature in the 1970s.
A diagnosis of tyrosine hydroxylase deficiency is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a variety of specialized tests. Such tests include examination of cerebrospinal fluid (CSF) to detect certain substances that are byproducts of metabolism (metabolites). Identification of certain metabolites at reduced or normal levels can help to distinguish tyrosine hydroxylase deficiency from 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 tyrosine hydroxylase deficiency can be confirmed through molecular genetic testing, which can reveal the characteristic mutation of the TH gene that causes the disorder. Molecular genetic testing is available on a clinical basis.
Tyrosine hydroxylase deficiency is treated with medications to restore normal dopamine levels in the brain. All infants are initially treated with low levels of an amino acid called levodopa (L-dopa). Dopamine cannot cross the blood-brain barrier (BBB), and thus cannot reach the place where it should act. L-dopa (which can cross the blood-brain barrier) is given as drug. In the body, L-dopa is easily converted to dopamine after uptake from the gut. To prevent or block this conversion, a second medication (usually carbidopa) is added, to ensure that enough L-dopa is available to effectively cross the blood-brain barrier. The blood-brain barrier is a protective network of blood vessels and cells that allow some materials to enter the brain, while keeping other materials out.
The response to L-dopa therapy varies among affected individuals. Some people respond quickly and completely to L-dopa 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 cases, mostly in individuals with the severe form of tyrosine hydroxylase deficiency, L-dopa therapy may prove ineffective initially. Such individuals may require prolonged treatment, which eventually lessens symptoms and leads to an overall improvement in motor skills.
Some individuals with the severe form of tyrosine hydroxylase deficiency are especially prone to the side effects of L-dopa therapy including difficulties in performing voluntary movements (dyskinesia), gastroesophageal reflux, vomiting and suppression of appetite. In some cases, the dose of L-dopa used to treat an affected individual may need to be adjusted until a dosage can be achieved that effectively treat the disorder, but is being well tolerated.
Genetic counseling may be of benefit for affected individuals and their families. Physical and speech therapy may be beneficial in some cases. Other treatment is symptomatic and supportive.
The drug selegiline has been used to treat individuals with tyrosine hydroxylase deficiency. Selegiline is a monoamine oxidase type B (MAO-B) inhibitor and slows down the breakdown (catabolism) of dopamine in the body. Selegiline is used in conjunction with L-dopa/carbidopa and has improved the effectiveness of these drugs in some individuals with tyrosine hydroxylase deficiency.
Anticholinergic drugs including trihexyphenidyl and amantidine have also been used to boost the effectiveness of L-dopa/carbidopa therapy with moderate success. Anticholinergic drugs lower the levels of the neurotransmitter acetylcholine. Acytylcholine must maintain a balance in relationship to dopamine within nerve cells.
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