Tyrosine hydroxylase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Tyrosine hydroxylase (TH) deficiency is a disorder that primarily affects movement. There are three forms of tyrosine hydroxylase deficiency, and they are categorized based on the severity of their symptoms and their response to treatment. The three forms range in severity from mild to severe.

For those with the mild form of tyrosine hydroxylase deficiency (also called TH-deficient dopa-responsive dystonia), symptoms usually appear during childhood. Affected individuals may have difficulties walking and running, which can sometimes lead to falls. Some people with the disorder may walk on their toes because of stiffness in the leg muscles. Additional signs and symptoms may include involuntary muscle contractions (dystonia) that lead to abnormal repetitive movements in the legs, tremor when holding a position (postural tremor), or involuntary upward-rolling movements of the eyes. Symptoms tend to worsen later in the day for some people with TH-deficient dopa-responsive dystonia. Affected individuals may experience more pronounced movement difficulties as they age, but these symptoms almost always get better with medical treatment.

The more severe forms of tyrosine hydroxylase deficiency are often called TH-deficient infantile parkinsonism or TH-deficient progressive infantile encephalopathy. These forms of the disorder appear soon after birth and are more difficult to treat.

Signs and symptoms of TH-deficient infantile parkinsonism typically begin in the first year of life. Affected infants often have delayed development of motor skills such as sitting unsupported or reaching for a toy. Some signs and symptoms may resemble those seen in people with Parkinson disease: stiffness of the muscles in the arms and legs, slow or diminished movements (hypokinesia), and tremors. Additional signs and symptoms may include droopy eyelids (ptosis), involuntary upward-rolling eye movements, and intellectual disabilities. People with TH-deficient infantile parkinsonism may respond to treatment, though treatment may not work right away and may not resolve all of the symptoms of the condition.

The most severe form of tyrosine hydroxylase deficiency (also called TH-deficient progressive infantile encephalopathy) is characterized by brain dysfunction that leads to profound physical and intellectual disabilities. Signs and symptoms typically begin in the first six months of life. Babies with this form of tyrosine hydroxylase deficiency often have feeding difficulties and delayed growth. Additional features include hypokinesia and abnormal eye movements. This form of tyrosine hydroxylase deficiency is difficult to treat, as affected infants tend to be more likely to experience harmful side effects from the medicine.

ORPHANET DEFINITION A very rare neurometabolic disorder characterized by a spectrum of symptoms ranging from those seen in dopa-responsive dystonia (DRD) to progressive infantile encephalopathy.

Inheritance

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive

Frequency in the source

From: MedlinePlus Genetics, National Library of Medicine

Reported case(s): 50.0; Worldwide. This is a published case count, not prevalence. Point prevalence: 1-9 / 1 000 000; Europe; Class only.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of extrapyramidal motor function · Frequent (79-30%)

A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).

Ataxia · Frequent (79-30%)

Ataxia refers to impaired coordination of voluntary muscle movement. Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).

Babinski sign · Frequent (79-30%)

Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.

Bradykinesia · Frequent (79-30%)

Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).

Brisk reflexes · Frequent (79-30%)

Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.

Constipation · Frequent (79-30%)

Infrequent or difficult evacuation of feces.

Decreased CSF homovanillic acid concentration · Frequent (79-30%)

Decreased concentration of homovanillic acid (HVA) in the cerebrospinal fluid. HVA is a metabolite of dopamine.

Delayed speech and language development · Frequent (79-30%)

A degree of language development that is significantly below the norm for a child of a specified age.

Excessive salivation · Frequent (79-30%)

Excessive production of saliva.

Feeding difficulties · Frequent (79-30%)

Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.

Focal dystonia · Frequent (79-30%)

A type of dystonia that is localized to a specific part of the body.

Gait ataxia · Frequent (79-30%)

A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.

Hypokinesia · Frequent (79-30%)

Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.

Hypotonia · Frequent (79-30%)

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Other findings in the same source

From: Orphanet

Additional reported features include Irritability (Frequent (79-30%)); Lethargy (Frequent (79-30%)); Limb dystonia (Frequent (79-30%)); Lower limb hyperreflexia (Frequent (79-30%)); Motor delay (Frequent (79-30%)); Myoclonus (Frequent (79-30%)); Night sweats (Frequent (79-30%)); Oculogyric crisis (Frequent (79-30%)); Parkinsonism (Frequent (79-30%)); Pes cavus (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

When it may begin

From: MedlinePlus Genetics, National Library of Medicine

Infancy; Neonatal

Inheritance in the source

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive

Frequency and the population described

From: MedlinePlus Genetics, National Library of Medicine

Reported case(s): 50.0; Worldwide. This is a published case count, not prevalence. Point prevalence: 1-9 / 1 000 000; Europe; Class only.

Understanding the inheritance label

From: MedlinePlus Genetics

An autosomal recessive pattern usually involves disease-causing changes in both copies of a gene. Parents may each carry one altered copy without having the condition themselves. A genetic counsellor can explain carrier testing and reproductive implications using the actual laboratory findings, rather than the condition name alone.

Which doctor should you see?

The suggested department for discussing Tyrosine hydroxylase deficiency is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.