Step 1: Is It Myoclonus?

Myoclonus must be distinguished from other movement disorders, including dystonic jerks, tics, tremor, chorea, or functional movement disorders. A few principles can help to distinguish between the different types of jerky movement disorders. First, the speed of the movement is important. Movements in myoclonus are fast, whereas the movements in dystonia and chorea are usually relatively slower. Furthermore, rhythmicity may help to differentiate between tremor and myoclonus. Tics may be suppressed for a while, whereas this is not possible with myoclonus. Functional jerks are inconsistent, reduced with distraction, and may be influenced by entrainment. Finally, it is important to define whether the abnormal movements occur at rest, during action, or during both. Ataxia is per definition only present during action, while myoclonus can get worse during action, but may also be present during posture and rest. In practice, myoclonus is frequently misclassified as ataxia in IEMs [8]. In metabolic disorders in particular, the differentiation between myoclonus and other movement disorders can be difficult because multiple movement disorders can be present in one patient, and myoclonus can be subtle. Clinical classification can be difficult, and in these cases electrophysiological testing can help to define the anatomical subtype of myoclonus. The basic electrophysiological test is polymyography (multiple electromyography [EMG] channels) to detect myoclonus (both positive and negative myoclonus), and to register both the burst duration and the recruitment of muscles.

Step 2: What is the Anatomical Substrate?

Anatomical classification of the myoclonus subtype is important to diagnose the underlying cause of myoclonus and to guide tailored treatment. Although myoclonus is a complication of many IEMs, in only a few reports the myoclonus is actually described in the context of the anatomical classification. However, the clinical presentation of distal and action-induced myoclonus, often in combination with epilepsy, strongly points towards a cortical origin of the myoclonus in most patients. Cortical myoclonus is caused by abnormal firing of the sensorimotor cortex, leading to short-lasting, often multifocal myoclonus affecting the face, hands, and feet. Involvement of a network of the fronto-temporal cortex, hippocampus, thalamus, and cerebellum has been suggested based on neuropathological studies. Myoclonus can be both positive and negative. It can be evoked by voluntary movements or unexpected stimuli. Next to myoclonus originating from the cortex, myoclonus can have an origin between the cortex and spinal cord. Important areas include the basal ganglia and brainstem. This subtype is classified as subcortical (sometimes also called non-cortical) myoclonus. An important example of subcortical myoclonus is myoclonus-dystonia, which is characterized by multifocal myoclonus combined with dystonia predominantly affecting the upper limbs and neck. In about 50% of the patients, myoclonus-dystonia is due to a mutation in the SGCE gene, encoding epsilon-sarcoglycan [9]. The myoclonus-dystonia phenotype is infrequently caused by an IEM. Brainstem myoclonus is characterized by a generalized, predominantly axial, and often stimulus-sensitive myoclonus. The main example is the genetically determined hyperekplexia [10]. Spinal myoclonus is generated in the spinal cord. It can be divided into segmental myoclonus and propriospinal myoclonus. Segmental myoclonus is very rare and is usually based on a lesion in the spinal cord. Propiospinal myoclonus is characterized by a fixed pattern of muscle activation in the trunk and abdominal muscles. Although propiospinal myoclonus can have an organic substrate, it is often thought to be a functional movement disorder. Finally, myoclonus can have a peripheral origin, and is caused by damage of the peripheral nerve system. Clinically, this results in polyminimyoclonus.

EEG–EMG polygraphy can not only be used to determine whether jerks are myoclonus or not, but can also be used to define the anatomical substrate of the myoclonus. Burst duration in cortical myoclonus, but also in peripheral myoclonus, is shorter than 100 ms, whereas it is larger than 100 ms in the other subtypes of myoclonus. Other electrophysiological characteristics of cortical myoclonus include positive back-averaging, positive coherence, giant somatosensory evoked potentials, and a C-reflex.

Step 3: Is Myoclonus Induced by Medication or Toxic Agents?

Before considering a metabolic disorder as the cause of myoclonus, other causes of myoclonus must be excluded. The most common cause of myoclonus is medication-induced myoclonus. This is often related to the start of a new treatment, although patients who develop myoclonus after chronic use of a drug have been described. To complicate matters further, drugs that may cause myoclonus include many antiseizure drugs and serotonin reuptake inhibitors. After withdrawal of the drug, myoclonus usually disappears. For a complete overview of drugs and toxic agents see the review of Zutt et al. [3].

Step 4: Additional Tests to Rule Out Acquired Myoclonus

Step 5: Does the Patient’s Clinical Syndrome Suggest a Metabolic Disorder?

Once acquired myoclonus is determined unlikely, a genetic cause must be considered. Some combinations of clinical features point towards a metabolic disorder in patients with myoclonus. In particular, the combination of myoclonus with other movement disorders, other neurological features, or systemic symptoms may point to an underlying metabolic disorder. If a treatable metabolic disorder is suspected, metabolic testing can be performed before or in parallel with genetic testing in order to reduce diagnostic delay.

Step 6: Does the Inheritance Patterns Suggest an IEM or Another Genetic Disorder?

Many IEMs, including those that cause myoclonus, are autosomal-recessive disorders, so a positive family history, i.e. with multiple affected family members or reported consanguinity, are important clues. However, a few autosomal-dominant metabolic disorders can cause myoclonus as well, including several forms of NCL (Kufs disease), and glucose transporter type 1 (GLUT1) deficiency syndrome. If there is a strong suspicion of a specific IEM, it is sometimes possible to do a specific biochemical test. Metabolic testing can be performed in parallel with genetic testing, or can be performed afterwards, in order to confirm the metabolic disorder found with genetic testing.

Step 7: Next-Generation Sequencing

If there is no strong suspicion of a specific IEM, testing multiple genes at the same time is not only faster but also cost-effective [11, 12]. The costs of sequencing three individual genes are comparable to the costs of whole-exome sequencing (WES). However, there are a few pitfalls. First, large structural rearrangements can be missed due to technical reasons. Second, mitochondrial DNA (mtDNA) is not tested in these gene panels, and analysis of mtDNA should be requested separately. Third, it is sometimes difficult to interpret a variant, in particular because little information is available about clinical phenotypes of some late-onset IEMs, which may be different from the early-onset classic presentations. It is especially difficult to interpret heterozygous mutations that can cause classic IEMs in adults due to dominant negative effects of the mutations [13]. In this case, results of genetic testing need to be confirmed by a biochemical test.