Tyrosine hydroxylase deficiency

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Tyrosine hydroxylase deficiency
Synonyms	N/A
Pronounce	N/A
Specialty	N/A
Symptoms	Dystonia, parkinsonism, autonomic dysfunction, developmental delay
Complications	N/A
Onset	Infancy or early childhood
Duration	Lifelong
Types	N/A
Causes	Mutations in the TH gene
Risks	Family history of the condition
Diagnosis	Genetic testing, clinical evaluation
Differential diagnosis	Dopa-responsive dystonia, Parkinson's disease, cerebral palsy
Prevention	N/A
Treatment	Levodopa, dopamine agonists, physical therapy
Medication	N/A
Prognosis	Variable; can be improved with treatment
Frequency	Rare
Deaths	N/A

Alternate names

Parkinsonism, infantile, autosomal recessive; Dystonia, DOPA responsive, autosomal recessive; DOPA responsive dystonia, autosomal recessive; Segawa syndrome, autosomal recessive; DYT/PARK-TH; Tyrosine hydroxylase-deficient dopa-responsive dystonia; DYT5b; TH-deficient DRD

Definition

Tyrosine hydroxylase (TH) deficiency is a rare inherited condition that affects the nervous system.

Cause

• Tyrosine hydroxylase (TH) deficiency is caused by changes (mutations) in the TH gene.
• This gene encodes an enzyme that helps convert certain amino acids (building blocks of protein) to dopamine.
• Dopamine is a chemical that is important to the function of the nervous system.
• For example, it helps the brain control movement by acting as a messenger to the other parts of the body.
• Dopamine can also be made into other chemicals that play an important role in the functioning of the autonomic nervous system.

Gene muttaions

Mutations in the TH gene result in reduced levels of dopamine, which leads to the many signs and symptoms associated with TH deficiency.

Inheritance

• Tyrosine hydroxylase deficiency is inherited in an autosomal recessive manner.
• This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell.
• The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers.
• Carriers typically do not show signs or symptoms of the condition.
• When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Types

• There are three different forms of the condition that vary in severity.
• The mild form is called TH-deficient dopa-responsive dystonia and typically develops between age twelve months and six years.
• The two severe forms, which are called infantile parkinsonism and progressive infantile encephalopathy, often begin shortly after birth or during early infancy.
• Although there is some overlap of features among the three forms, each is associated with unique signs and symptoms.

Signs and symptoms

Mild form

• The mild form of the condition is called TH-deficient dopa-responsive dystonia.
• Children affected by this form typically develop features of the condition between age twelve months and six years.
• Symptoms may include an abnormal gait (manner of walking); lack of coordination when walking or running; repetitive, involuntary movements of the arms and/or legs; unusual positioning of limbs; postural tremor (shaking when holding a position); and abnormal, involuntary eye movements.
• The features of TH-deficient dopa-responsive dystonia tend to get worse over time but are generally responsive to treatment.

Severe form The severe form of TH deficiency is called infantile parkinsonism. Children affected by this form generally begin developing features of the condition between age three to twelve months. Signs and symptoms of infantile parkinsonism may include:

• Delayed motor milestones (i.e. sitting up, crawling, walking)
• Intellectual disability
• Speech problems
• Muscle stiffness, especially in the arms and legs
• Unusual positioning of body
• Ptosis
• Abnormal, involuntary eye movements
• Constipation
• Gastroesophageal reflux
• Difficulty regulating body temperature, blood sugar and blood pressure
• Mental health conditions (i.e. depression, anxiety, or obsessive-compulsive behaviors)

Very severe form

• The very severe form of TH deficiency which is called progressive infantile encephalopathy, generally develops before age three to six months.
• Early symptoms may include fetal distress; feeding difficulties; low muscle tone; and small head circumference, height and/or weight from birth.
• Babies affected by this form generally have severe physical and intellectual disability due to underlying brain dysfunction and structural abnormalities.
• Other signs and symptoms include severe delay in motor milestones; rigidity and/or spasticity of arms and legs; ptosis of both eye lids; and episodes of profuse sweating, lethargy, irritability and/or excessive drooling.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 30%-79% of people have these symptoms

• Babinski sign
• Bradykinesia(Slow movements)
• Brisk reflexes
• Central hypotonia
• Constipation
• Decreased CSF homovanillic acid
• Delayed speech and language development (Deficiency of speech development)
• Excessive salivation(Mouth watering)
• Feeding difficulties(Feeding problems)
• Focal dystonia
• Gait ataxia(Inability to coordinate movements when walking)
• Hypokinesia(Decreased muscle movement)
• Irritability(Irritable)
• Lethargy
• Limb dystonia
• Lower limb hyperreflexia(Overactive lower leg reflex)
• Motor delay
• Myoclonus
• Night sweats
• Oculogyric crisis
• Parkinsonism
• Pes cavus(High-arched foot)
• Postural tremor
• Ptosis(Drooping upper eyelid)
• Rigidity(Muscle rigidity)
• Talipes equinovarus(Club feet)

5%-29% of people have these symptoms

• Fever
• Generalized dystonia
• Intellectual disability, mild(Mental retardation, borderline-mild)

1%-4% of people have these symptoms

• Generalized hypotonia(Decreased muscle tone)
• Progressive encephalopathy

Diagnosis

• A diagnosis of tyrosine hydroxylase (TH) deficiency is typically suspected based on the presence of characteristic signs and symptoms.
• Analysis of a small sample of cerebrospinal fluid may be recommended to support the diagnosis and to rule out other conditions associated with similar features.
• Identification of a disease-causing change (mutation) in each copy of the TH gene confirms a diagnosis of TH deficiency.

Treatment

• People affected by tyrosine hydroxylase (TH) deficiency are generally treated with a medication called levodopa.
• The effectiveness of levodopa therapy varies significantly depending on the severity of the condition.
• People affected by the mild form of TH deficiency (TH-deficient dopa-responsive dystonia) generally respond well to treatment.
• In most cases, this medication is able to drastically improve or even completely alleviate associated symptoms.
• Unfortunately, children with infantile parkinsonism or progressive infantile encephalopathy (the two severe forms of TH deficiency) may have an incomplete response to levodopa, or it may take several months to several years to see an improvement in symptoms.
• In many cases, affected children are also extremely sensitive to the drug and may experience negative side affects such as difficulties in performing voluntary movements (dyskinesia), vomiting and appetite suppression of appetite.<ref>Furukawa Y, Kish S. Tyrosine Hydroxylase Deficiency. 2008 Feb 8 [Updated 2017 May 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews¬Æ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1437/</ref>[1].

Prognosis

• The long-term outlook (prognosis) for people with tyrosine hydroxylase (TH) deficiency varies based on the severity of the condition.
• The mild form of TH deficiency (TH-deficient dopa-responsive dystonia) is generally associated with a good prognosis.
• People affected by this form usually respond quickly and completely to treatment with levodopa, often seeing a full reversal of symptoms.
• Unfortunately, babies affected by infantile parkinsonism or progressive infantile encephalopathy generally experience more severe signs and symptoms than those affected by TH-deficient dopa-responsive dystonia.
• These severe forms of TH deficiency are also more difficult to effectively treat and therefore, tend to have a worse prognosis.

References

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NIH genetic and rare disease info

• NIH info on Tyrosine hydroxylase deficiency

Tyrosine hydroxylase deficiency is a rare disease.

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