Differences in Drug Pharmacokinetics and Motor Fluctuation in DYT-GCH1

A 49-year-old lady, who is part of a previously reported large GCH1 mutation-positive family, complained of motor fluctuation. For 27 years, she was maintained on low-dose L-dopa/ carbidopa (Sinemet®) 100 mg twice daily and had been completely asymptomatic, without any reported treatment-related complications (Figure 1A). In 2019, Sinemet® was no longer available in Canada. Consequently, she resorted to taking a generic brand of L-dopa/carbidopa, with sub-optimal symptom relief, often complaining of pain, leg cramping, and fatigue. She tried another generic brand of L-dopa/carbidopa, but still with a sub-optimal response and a shortened duration of benefit; dose failures were also occasionally experienced. There was no benefit with taking higher individual doses of the generic L-dopa/carbidopa. Since then, she had to take the medication every 4 hours round-theclock as well as baclofen and zopiclone but still with poor symptom control and wearing-off throughout the day (Figure 1B). Coincidentally, she had a few tablets of Sinemet® kept in a different container; taking her previous low dose afforded complete symptom relief. On examination, she had right foot eversion despite being in a self-reported “on” state, 1 hour after taking a generic brand of L-dopa/carbidopa. There were no signs of bradykinesia. L-dopa/benserazide (Prolopa®) was then prescribed. At 100 mg thrice daily, she claimed to have complete symptom resolution (without additional baclofen and zopiclone), similar to the response she obtained with low dose Sinemet® (Figure 1C). The benefit has been sustained over the past 6 months, without any recurrence of the motor fluctuation. Foot eversion was no longer observed in the subsequent visits. Moreover, unaware of our patient’s experience, her son and one of her cousins had a similar experience with generic L-dopa/ carbidopa, but they improved with an increased dose of the drug and the addition of long-acting L-dopa/carbidopa at night in the latter. Dopa-responsive dystonia (DRD, DYT-GCH1) is a rare, genetic, highly treatable form of dystonia with an excellent, long-lasting response to low dose L-dopa. Motor fluctuation, a known complication of L-dopa therapy in advanced Parkinson’s disease (PD), is typically not a feature of DRD. Inadequate response to L-dopa is considered a diagnosis of exclusion, and the development of wearing-off and L-dopa-induced dyskinesia are deemed atypical of DRD. Subjective wearing-off has been reported in patients with DRD who missed taking a dose of L-dopa/carbidopa; however, on objective evaluation through an L-dopa withdrawal challenge, the dystonic symptoms recurred only after 29 hours. The wearing-off in these patients, which was considered non-motor in nature, was attributed to the effect of L-dopa on mood elevation. To date, all other reported cases of motor fluctuation in DRD have been attributed to the

• Publication year

  2020

• Venue

  Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques

• Publication date

  2020-11-16

• Fields of study

  Medicine

• Identifiers
  DOI 10.1017/cjn.2020.252PMID 33190650
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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