Tyrosine Hydroxylase Deficiency due to a Compound-heterozygote Mutation with One Kwon Mutation and One Previously not Described Variant on the TH-Gen

Introduction: Tyrosine Hydroxylase Deficiency catalyzes the reaction from L-Tyrosine to L-Dopa and is a key enzyme in the catecholamine biosynthesis. When first described Tyrosine Hydroxylase Deficiency (OMIM #191290) was classified as L-dopa-responsive dystonia, but later followed descriptions of more complicated courses with L-dopa-non responsive-encephalopathy beginning from early age. We present a long-term follow-up of a case with L-dopa-responsive hyperkinesia originating from a novel, until now, not described mutation.

Initial Presentation: We report of a now 7 year old boy. The initial presentation was at the age of four month because of newly observed sterotype movements of all extremities. Those movements and the overall status worsened a week prior to hospital admission after a routine vaccination Prior to this he was a healthy boy born at 36+0 gestational weeks after a pregnancy complicated by premature contractions. Postpartal adaptation was normal. He is the oldest child of non-consanguineous parents of Caucasian decent.

Results: Neurologic Exam: choreatic movements of all extremities, mild generalized muscle hypotonia with normal deep tendon reflexes. No hyperkinesia during sleep. Normal Results for: Sonogram of head and abdomen, echocardiography, cMRI, EEG, pterine, amino acids, organic acids, very long chain fatty acids, beta-galactocerobrosidase, acetylcarinitine – profile Lumbar puncture: liquor status normal. Neurotransmitter: normal concentration for 5-HIAA (460nmol/l), reduced concentration of HVA (68nmol/l), slightly elevated BH2 concentration (38nmol/l), normal pterine. This led to the suspicion of a Tyrosine Hydroxylase Deficiency. Genetic Verification: compound-heterozygote mutation in the TH-Gene (exon 6 p.R233H and exon 8 p.Y274*)

Conclusion: Early on there was a high suspicion for Tyrosine Hydroxylase Deficiency which is why a L-dopa trial was performed. The patient’s hyperkinesia improved quickly. Genetic verification proofed the compound-heterozygote mutation in the TH-Gene with a novel, hitherto, not described mutation in exon 8 p.Y274*. The parents are each carrier for one mutation. The overall course of the disease was positive and we conclude L-dopa-responsiveness for the novel mutation. Adjustments of the L-dopa/carbidopa dose in the range form 4–8 mg/kg BW/d were decided by clinical state like infection, increased dystonia/hyperkinesia, aggressiveness, disturbed night sleep and disturbances of gait or eye movement. For monitoring we used prolactin in serum and dopamine degradation products in urine. During two hyperkinetic/dystonic crisis we performed lumbar puncture with analysis of neurotransmitters. In the meantime therapeutic trails with pramipexole and tetrahydrobiopterin did not lead to an improvement of the symptoms. Right now the patient is enrolled in the first year at a regular school.

Reference

1. Willemsen MA, Verbeek MM, Kamsteeg EJ, et al. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain 2010;133(Pt 6):1810–1822

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