Wednesday, December 2, 2015

Diagnosing dopamine-responsive dystonias

Malek N, Fletcher N, Newman E. Diagnosing dopamine-responsive dystonias. Pract
Neurol. 2015 Oct;15(5):340-5.


The clinical spectrum of dopamine-responsive dystonias (DRDs) has expanded over the last decade to comprise several distinct disorders. At the milder end of the clinical spectrum is the autosomal-dominant guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), and at the more severe end is the much less common autosomal recessive tyrosine hydroxylase deficiency syndrome (TH-DRD), with intermediate forms in between. Understanding the pathophysiology of DRDs can help in their optimal diagnosis and management. These are conditions with the potential to be either underdiagnosed when not considered or overdiagnosed if there is an equivocal L-dopa (levo-3,4-dihydroxyphenylalanine) response. In this article, we discuss the clinical phenotypes of these disorders, and we outline how investigations can help in confirming the diagnosis.

From the article

In 1976, Segawa et al recognised levo-3,4-dihydroxyphenylalanine (l-dopa) responsiveness in a Japanese family and described 'hereditary progressive dystonia with marked diurnal fluctuation'. However, it was the 1980s before Nygaard et al coined the term 'dopa-responsive dystonia'...

When a child or adult presents with what appears to be a primary dystonia, mainly affecting the lower limbs, clinicians must consider and exclude a reversible or treatable DRD. This is the case even without an autosomal-dominant family history and/or diurnal variation (with symptoms worsening towards the end of the day). Such features suggest guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), but may be absent, and the diagnosis cannot rely on their presence. In contrast, tyrosine hydroxylase deficiency syndrome (TH-DRD) and sepiapterin reductase deficiency syndrome (SR-DRD)—considered to be 'DRD-plus' syndromes—usually present to paediatric neurologists in the first year of life with dystonia, hypotonia, hypersomnia, encephalopathy, oculogyric crisis or parkinsonism.

GTPCH and SR are enzymes required in the synthesis of tetrahydrobiopterin (BH4), which is an essential cofactor within the biosynthetic pathways for dopamine and serotonin. For dopamine synthesis, BH4 is a necessary cofactor for phenylalanine hydroxylase and TH enzymes.

Deficiency of any of these three enzymes (GTPCH, SR or TH) leads to dopamine depletion at the synaptic terminals within the basal ganglia, causing both motor and non-motor dysfunction (mood swings, depression, verbal memory deficits and concentration problems). There is pathological and biochemical evidence of striatal dopamine deficiency in DRDs to support this hypothesis.

The age of onset, clinical phenotype and response to treatment vary with the different DRD syndromes, although there is some overlap. Distinguishing between the DRD syndromes on clinical grounds alone may be difficult due to this phenotypic overlap, and diagnostic tests become valuable adjuncts in this setting. Identifying the specific molecular defect helps to inform accurate prognosis and obviates the risk of blind treatment....

In young people, it is easy to misdiagnose DRD as diplegic cerebral palsy or hereditary spastic paraplegia; brisk lower limb reflexes, increased lower limb tone and spurious 'striatal' plantar responses may contribute to this diagnostic error. It is even possible for dystonic spasms to be mistaken for seizures. Delays in diagnosis miss an opportunity to treat symptoms effectively, and can result in unnecessary orthopaedic interventions.

DRDs are potentially treatable disorders. Starting treatment with L-dopa early can give dramatic and sustained relief of symptoms, improving performance of activities of daily living and quality of life. It is important to give an adequate therapeutic trial of l-dopa—at least 300 mg daily for 3 months. This is usually decisive. Rarely, however, a limited or uncertain l-dopa response may not confirm or exclude the diagnosis of DRD. In this situation, identifying a biochemical defect or relevant genetic mutation may secure the diagnosis of a possible DRD syndrome.  We now suggest a protocol to investigate suspected DRD cases

Trial of L-dopa. In children, L-dopa (in combination with a dopa-decarboxylase inhibitor) should be started at 1 mg/kg/day in divided doses. This can be increased gradually according to tolerability and response, with most children requiring 4–5 mg/kg/day. For adult patients, L-dopa (with dopa-decarboxylase inhibitor) should be started at 100 mg/day in divided doses. L-dopa can be gradually increased, and most patients will respond to 300–400 mg/day.
In a case series of 58 patients with DRD, the average L-dopa requirement of 29 patients with identified GCH1 mutations was 166 mg/day (range 25–400 mg/day). L-dopa requirements in those without GCH1 mutations were higher at 232 mg/day (range 12.5–600 mg/day)...

There are over 200 different mutations described in the GCH1 gene located on chromosome 14q22.1–q22.2 that result in GTPCH-DRD. Whole gene sequencing should be performed due to the high number of pathogenic mutations described. In adults and children aged older than 1 year, this is the most likely gene to be mutated. In infancy, the causative genetic mutation most likely resides in either the SPR or TH genes. There are about 15 different known mutations in the SPR gene, which codes for the SR enzyme, located on chromosome 2p14–p12 and over 50 different known mutations in the TH gene located on chromosome 11p15.5. Several laboratories now offer multigene panel testing (using DNA microarray) for all three genes (GTPCH, SR and TH). Patients and their families should have access to appropriate prediagnostic and postdiagnostic genetic counselling... 

L-dopa helps the symptoms without altering the disease course. However, the non-motor manifestations within DRD-plus syndromes (eg, cognitive dysfunction) are not L-dopa responsive. The clinical assessment of the response to treatment is based on improvement in motor symptoms. However, there is no validated scale to measure this response reliably, and the clinical heterogeneity of DRD syndromes would make it challenging to develop such a scale.

The response to L-dopa in DRD is usually sustained and prolonged. It is very uncommon for patients to develop dyskinesia, but this occasionally happens. In one series of 20 patients with DRD, one-fifth of patients developed dyskinesias after a mean disease duration of 28.9±14.8 years (range 5–54 years) with a mean daily dose of 343 mg/day of L-dopa (range 100–600 mg/day). There was a relationship between the development of dyskinesias and the prescribed dose of L-dopa. In general, however, the appearance of motor fluctuations and/or significant dyskinesia should prompt a review of the diagnosis of DRD and consideration of early-onset Parkinson disease, in which lower limb dystonia can be a prominent and early feature.

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See:  It wasn't spastic diplegia  4/22/15

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