Objective: To characterize the myoclonus spectrum and related clinical burden in patients with autosomal dominant DHDDS deficiency.

Background: DHDDS deficiency is a neurometabolic disorder associated with a prominent cognitive and movement disorder (MD) phenotype. Myoclonus has been consistently associated with DHDDS deficiency, but so far it was characterized only in a few cases. Several other MDs such as tremor, ataxia, chorea, stereotypies, dystonia, and parkinsonism, have been described. However, misclassification of myoclonus with other MDs is possible, and this could lead to an overestimation of their frequency and severity.

Method: Three individuals with DHDDS deficiency underwent clinical and neurophysiological evaluation of myoclonus (EEG/EMG examination, jerk-locked back averaging (JLBA), and/or cortico-muscular coherence (CMC) analysis).

Results: Patients (1 M/ 2 F) aged from 14 to 22 years and suffered from mild to moderate intellectual disability. All cases had multifocal and irregular rest and action jerky movements of limbs and face. Different somatosensory triggers could evoke isolated or repetitive jerks. Patient 1 showed an irregular, high-frequency, jerky tremor and experienced falls due to lower limb jerks evoked by climbing/descending stairs. Patient 2 had falls caused by myoclonic/atonic epileptic seizures and had gait instability due to frequent lower limb jerks. No other MDs were observed on examination.

EMG polygraphy of jerks showed in all cases short EMG discharges (<30 milliseconds), with agonist-antagonist co-contraction, compatible with myoclonus. Tremor was found to be caused by slightly irregular high-frequency EMG myoclonic discharges.

JLBA demonstrated a positive-negative EEG waveform preceding the onset of EMG discharge in case 1 and 2, indicating a cortical origin of myoclonus. CMC analysis performed on myoclonic tremor in case 1 demonstrated a high level of coherence on the beta frequencies, compatible with cortical myoclonic tremor.

Conclusion: A broad spectrum of cortical myoclonus types (reflex, spontaneous, cortical myoclonic tremor, and myoclonic epilepsy) are associated with DHDDS. Myoclonus can result in severe motor impairment (gait instability, falls, difficulty in handling objects) and mimic other hyperkinetic MDs and/or ataxia. The correct characterization of MD in this condition is crucial to determine the nature of motor impairment and the possible therapeutic approaches.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cortical-myoclonus-in-dhdds-the-multifaced-presentation-of-a-single-movement-disorder/