An unusual presentation of tyrosine hydroxylase deficiency

Abstract

BackgroundDopa-responsive dystonia (DRD) has largely been associated with autosomal dominant mutations in the GCH1 gene leading to GTP cyclohydrolase 1 deficiency. More recently, a deficiency in tyrosine hydroxylase (TH) has been recognized to cause DRD. This is a rare disorder resulting from genetic mutations in the TH gene on chromosome 11. The phenotype ranges from DRD with complete resolution on levodopa to infantile parkinsonism and encephalopathy only partially responsive to levodopa. Here we discuss an adult with TH deficiency with a history of possible parkinsonism and dystonia responsive to levodopa, notable for a residual dynamic segmental dystonia.Case presentationOur patient grew up in rural Myanmar with limited medical care. Childhood was normal except for episodic illness with difficulty moving and speaking. At 18 years he developed difficulty writing. At 21 years he could not speak, walk, or write and was taken to a city hospital. Multiple medications were tried without benefit until he received carbidopa/levodopa, to which he had a miraculous response. Since then he has attempted to come off medication, however after several weeks his symptoms returned. On presentation to us at 31 years he was taking 450 mg levodopa/day and 4 mg trihexyphenidyl/day. He had a dynamic dystonia in his neck and trunk, subtle at rest and prominent with walking. He exhibited a sensory trick when touching his hand to his chin; improvement occurred to a lesser degree when he imagined touching his chin, and to an even lesser degree when the examiner touched his chin. He had no parkinsonism. He underwent genetic testing which revealed a homozygous variant mutation in the TH gene (p.Thr494Met) leading to a diagnosis of autosomal recessive tyrosine hydroxylase deficiency.ConclusionsTH deficiency can cause a broad range of clinical symptoms and severity. As more cases are discovered, the phenotype expands. Here we describe a unique case of DRD and possible parkinsonism due to TH deficiency with residual symptoms of dystonia that was task dependent and responded to a sensory trick. In addition, while the history is limited, it is possible he may have had episodes similar to “lethargy-irritability crises” seen in more severe cases. In large part he fits within the milder form of TH hydroxylase deficiency.Electronic supplementary materialThe online version of this article (10.1186/s40734-017-0065-z) contains supplementary material, which is available to authorized users.

Dopa-responsive dystonia caused by tyrosine hydroxylase deficiency

“…Our case 1 had hypokinesia, dystonia, tremor, dysarthria, and rigidity with a phenotype categorized as type A, whereas our cases 2 and 3 had encephalopathy, psychomotor retardation, and dystonia with a phenotype categorized as type B. Among the previously reported case, 38.7% had obvious diurnal fluctuation of symptoms, which has been noted in the literature [ 13 ] and was observed in our case 1. Among 43 cases for which cerebral MRI was performed, abnormal findings were reported for only 9 cases, including bilateral widening of the frontotemporal extracerebral space, ventriculomegaly, and other nonspecific changes, indicating that the pathogenesis of brain connectivity impairment in most cases was caused by dopamine deficiency rather than a defect in cerebral structure.…”

Mild dopa-responsive dystonia in heterozygous tyrosine hydroxylase mutation carrier: Evidence of symptomatic enzyme deficiency?

“…A 2010 study described 36 TH-DRD cases and reviewed all previously published cases: the oldest age of onset was 5 years [2]. Since then, others have reported onset at older ages (7, 12 and 18 years) [3][4][5]. If the present TH mutation is the cause of our patient's DRD, he has by far the oldest age of onset and is the only one with a mild phenotype of isolated dystonia resembling GCH1-DRD.…”

Dystonia: diagnosis and management

“…Isolated dystonia may be the presenting feature of combined syndromes that can remain isolated for a significant amount of time before another movement disorder appears. An isolated dystonia may be the long‐standing presenting feature of PARK2 parkinsonism (PARK‐Parkin) , of rapid‐onset dystonia parkinsonism (DYT12, DYT‐ATP1A3) , of Lubag disease (DYT3, DYT/PARK‐TAF1) and of dopa‐responsive dystonia (DYT5a, DYT‐GCH1 or DYT5b, DYT‐TH ). In most cases, a full‐house syndrome of combined dystonia will develop in time, whilst in some cases the phenotype will remain limited to isolated dystonia.…”