Expanding Phenotype and Clinical Analysis of Tyrosine Hydroxylase Deficiency

Abstract

This study included 12 Chinese patients with a wide spectrum of phenotypes of tyrosine hydroxylase deficiency. Seven females and 5 males, aged 2.2 to 41 years, had phenotypes ranging from severe type with onset at infancy to mild type with onset after 3 years of age. Patients with the severe type had encephalopathy with poor treatment response or infantile parkinsonism with motor delay. Patients with the less common mild type had dopa-responsive dystonia or a newly recognized predominant symptom of myopathy. Female siblings had more severe phenotypes. The phenotype and treatment outcomes were strongly related to a homovanillic acid level and homovanillic acid/5-hydroxyindolacetic acid ratio of less than 1 in the cerebrospinal fluid. Hyperprolactinemia was found in 50% of the severe cases. Levodopa was the mainstay of treatment, and early addition of selegiline resulted in a remarkable response in some patients. Treatment response for mild-type patients is universally good even with a treatment delay of 10 years after onset of neurological symptoms.

Discovery of compounds that protect tyrosine hydroxylase activity through different mechanisms

“…THD is a very rare genetic disease, with about 70 patients reported worldwide [7,16,51], thus making it an ultra-orphan disease [52]. Research on drug development for these uncommon disorders is rather limited both in academia and in the pharmaceutical industry.…”

Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency

“…It has been already described that the phenotypes and treatment outcomes are related to the lowest HVA levels and a HVA/5-HIAA ratio of less than 1 in the CSF [7,9,10]. Clinical features compatible with dopa-responsive dystonia were the most salient features of the two other patients with A phenotype (9 and 10).…”

“…This enzymatic conversion is a rate-limiting step in the biosynthesis of catecholamines. Around sixty patients with TH deficiency have been reported worldwide [1][2][3][4][5][6][7][8][9][10][11]. TH deficiency causes a neurological disease with predominant extrapyramidal signs and a variable response to L-DOPA.…”

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“…Many different features of THD (hypokinesia, bradykinesia, rigidity, dystonia, tremor, chorea, ptosis, oculogyric crises and hyper salivation, among others) are caused by cerebral dopamine and nor epinephrine deficiency [1,4]. Based on the presenting neurological features, THD usually be divided in two phenotypes: an infantile onset, progressive, hypo kinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B) [3].…”

“…And the trials may be stopped after 6 weeks upon the dose of 450-600 mg/day, if no improvement can be observed [12] . It was reported that selegiline could be added to the treatment to increase the effection some cases [1,4,13].Besides, there is literature mentions that anticholinergics and dopamine agonists may also be effective in the disease [12]. The patient had a complete response to a very low dose of L-dopa within 3 days, so the other medicines were not added.…”