Tyrosine Hydroxylase (TH) Deficiency
Tyrosine hydroxylase deficiency, sometimes referred to as “autosomal recessive Segawa's disease," displays a diverse phenotype, ranging from exercise-induced dystonia to progressive gait disturbance and tremor in childhood to severe infantile parkinsonism. A wide range of symptoms can be associated with TH deficiency, associated with mild, moderate and severe phenotypes.
In the mildest cases, walking or running may be clumsy but little else may be noticed, at least initially. Abnormal posturing may be evident when the child is stressed, or later in the day. These symptoms may progress slowly as the child gets older. Sometimes, one side of the body may seem weaker, or the child may begin to toe-walk due to hamstring or heel-cord tightness. Sometimes these children are diagnosed with cerebral palsy; other times they are simply considered clumsy or uncoordinated. Some children demonstrate attentional difficulties or mild speech articulation difficulties or delay. Children with mild symptoms generally respond quite well to treatment with medication.
In moderately affected cases, children demonstrate an abnormal gait (an abnormal walking pattern). Children may demonstrate dystonic posturing (involuntary twisting arm or foot movements) while walking, especially when attempting to walk on their heels or toes. Some children are incoordinated or have poor balance, or have tight leg muscles (referred to in medical terms as spasticity). Speech delay may be present. Many of these children are diagnosed with cerebral palsy. Some demonstrate involuntary eye movement problems, characterized either by brief upward eye-rolling movements when tired or stressed, or frank oculogyric crises, where the eyes roll up and seem to get “stuck” for variable periods of time. The majority of these children have an excellent response to treatment, but full benefit may take many months and close monitoring for adjustment of medications and dosing.
In the most severe cases, children are severely disabled and affected from early infancy. This is referred to as the infantile Parkinson’s disease variant. Infants may demonstrate muscle tightness and rigidity, arching, tremor and poor muscle control, and involuntary eye movements. They may have ptosis. They usually have speech delay, and often demonstrate difficulties feeding, chewing or swallowing. Constipation is common. While most children tend toward increased muscle tone and even rigidity, there are children who have generalized low muscle tone, with poor head control and inability to sit unsupported. Oftentimes they demonstrate torticollis. They may have difficulty directing their hands to a toy, generating a flinging hand motion. Occasional children suffer from intermittent color changes, unexplained low body temperature or fevers, low blood sugar, and difficulty regulating blood pressure. These symptoms are more likely to occur during another illness the child may be experiencing. Children in the more severely affected group of patients are more difficult to treat, and several medications may be needed to modulate symptoms. They are unusually vulnerable to side effects of dopaminergic agonists or precursors, which can result in excessive movement and irritability. Response may be slow, with some continued benefit over months to years, but may not result in the complete resolution of all symptoms. Some children have had persistent mental retardation, encephalopathy, and motor disability in spite of directed treatment of their underlying dopamine deficiency state.
Low tyrosine hydroxylase activity results in significant CSF catecholamine deficiency as demonstrated by low HVA concentrations; CSF concentrations of 5-HIAA, neopterin, and biopterin are normal. It is more difficult to distinguish these children from secondary neurotransmitter deficiency states, since phenylalanine loading studies are normal, and enzymatic assays for confirmation of a suspected diagnosis are not presently available. Thus, confirmation via molecular testing is extremely helpful, particularly in providing adequate counseling for parents regarding recurrence risks with future pregnancies. Children reported to date seem to have a paucity of autonomic features, suggesting a compensatory peripheral mechanism, except in children with . In four patients whom the author has observed, including one patient with the severe infantile parkinsonism variant, peripheral plasma catecholamine levels have been normal, although reduced urine HVA levels have been noted.
Patients variably respond to L-dopa/carbidopa, and some have complete reversal of symptoms. The exception to this is the patient with the severe infantile parkinsonism form. These patients sometimes tolerate L-dopa poorly, with excessive dyskinesia, irritability, reflux or have incomplete or inadequate response with regard to their motor manifestations of the disorder. Slow institution of small doses of L-dopa/carbidopa, along with selegiline (MAO-B inhibitor) and an anticholinergic agent such as trihexyphenidyl, may be more beneficial than L-dopa/carbidopa alone. When diagnosis occurs late in such patients, motor development must be recapitulated, and continued slow improvement over months is to be expected. Typical features in the one infant affected by the severe infantile parkinsonism variant included rigidity, tremor, bradykinesia, oculogyric crises, and severe psychomotor delay.
Treatment with L-dopa/carbidopa alone may lead to severe dyskinesias with marked on-off effects in such patients. Addition of dopamine agonists such as selegiline, or anticholinergic agents like trihexyphenidyl can provide significant benefit and help promote the gradual ongoing attainment of motor skills and ability to ambulate independently, but such achievements may occur over years, rather than months or weeks, in the most severely affected patients. Patients with a mild form of the disorder, such as an isolated gait disorder or exercise-induced dystonia, respond well to monotherapy with L-dopa/carbide and rarely develop dyskinesia. Although inheritance to date in most families seems to be recessive, at least one family has been described in which the father of the affected proband had mild exercise-induced dystonia responsive to therapy, raising the possibility that tyrosine hydroxylase deficiency could present in an autosomal dominant fashion in some families with a milder phenotype.
