Fasting Dependent Paroxysmal Exercise Induced Dystonia as Presenting Symptom in PRKN Type of Parkinson's Disease.

Abstract

Paroxysmal exercise-induced dystonia (PED) can occur as a symptom of early-onset Parkinson's disease (EOPD), Dopa-responsive dystonia (DRD), or Glut1 deficiency syndrome (Glut1DS). Red flags of PED in Glut1DS include influence of diet, while diurnal fluctuations are characteristic for DRD.1 A 22-year-old White-European man presented with a 5-year history of paroxysmal involuntary movements of his left foot. Past medical history and family history were unremarkable without known consanguinity. At the age of 17 (BMI 38 kg/m2), he started a diet and regular physical exercise and lost 35 kg weight. After approximately 30 min of physical exercise, he occasionally noticed mild and involuntary abnormal posturing of his left foot. Symptoms only occurred in the evening or after fasting. Since then, symptoms have worsened, and abnormal movements started after 15 min of exercise in the morning and after 5 min in the evening or when fasting. Recently, he also noticed a mild tremor and clumsiness of his right hand. Physical examination revealed mild rigidity of neck and extremities, mild resting tremor of the right hand and mild bradykinesia of upper and lower limbs (right dominant). He had reduced arm swing, but otherwise walking was unremarkable (see Video 1). After 10 min of running, he developed dystonia of his left foot (see Video 2), which ceased shortly after resting. A 3-Tesla-MRI of the brain, CSF/serum fasting glucose ratio and a metabolic panel including blood/CSF amino acids and neurotransmitters were unremarkable. A (123)I-Ioflupane single-photon emission computed tomography was abnormal. A genetic panel including known genes causing EOPD, DRD and Glut1DS was ordered. Both next generation sequencing and exon-specific PCR detected a homozygous deletion of exons 2–4 of the PRKN gene. Levodopa/benserazide 50/12.5 mg QID led to marked improvement of parkinsonian symptoms and PED. To the best of our knowledge, this is the first reported case of the PRKN type of EOPD featuring PED with marked diurnal fluctuation and worsening with fasting as presenting symptom. In 16% of PRKN mutation carriers symptoms start in adolescence.2 Initial foot dystonia, in some cases induced by exercise,1, 3 and diurnal fluctuation are recognized features.4 However, symptom provocation by fasting is a novel finding. The products of several PD-associated genes including PRKN have important roles in mitochondrial biology and fasting induces an upregulation of protein markers of mitophagy. Our patient noticed remission of PED with regular carbohydrate intake. A low protein-to-carbohydrate ratio has been shown to increase lifespan, motor ability and mitochondrial function in a PRKN mutant Drosophila model of PD,5 providing a potential pathophysiological link to our finding. A deletion of exons represents the most common mutation of the PRKN gene; deletions of exons 2–4 are classified as definitely pathogenic.2 Another reported case presenting with juvenile-onset PED had a deletion of exon 4.3 Worsening with fasting was neither described in a published case series4 nor in patients with deletions of exons 2–4 of the PRKN gene within the MDS gene database. In conclusion, diurnally fluctuating PED that worsens with carbohydrate restriction may be the presenting symptom in the PRKN type of EOPD. We would like to thank our patient for giving us the opportunity to publish this case report. We also thank Johann Semmler-Bruckner for his assistance in genetic analyses and database research. 1. Research project: A. Conception, B. Organization, C. Execution; 2. Data Collection: A. Clinical Assessment, B. Genetic Analysis, C. Literature Review; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. L.G.: 1B, 1C, 2A, 2C, 3A C.W.: 1B, 1C, 2B, 3B P.K.W.: 1B, 1C, 2A, 3B P.S.: 1A, 1B, 1C, 2A, 2C, 3B Ethical Compliance Statement: No formal approval by an ethics committee was required; the Journal's Ethical Publication guidelines and the Declaration of Helsinki were followed. Informed written consent on video acquisition and case publication was obtained from the patient using our standardized patient's video consent form. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for Previous 12 Months: L. Gattermeyer, C. Windpassinger and P. Katschnig-Winter declare that there are no additional disclosures to report. P. Schwingenschuh reports personal fees from Bial.