Reply: Pentameric repeat expansions: cortical myoclonus or cortical tremor? and Cortical tremor: a tantalizing conundrum between cortex and cerebellum Free

We are thankful for van Rootselaar et al’s and Striano et al’s interest in our work, and for sharing their considerations on the subject (Striano et al., 2020; van Rootselaar et al., 2020). The rare and poorly understood disorder that is familial cortical myoclonic tremor and epilepsy (FCMTE) captivates the curiosity of movement disorder and epilepsy specialists, because of its complex phenomenology and its intriguing genetic and pathophysiological underpinnings. We agree that the mechanisms whereby expansions in non-coding regions contribute to disease, regardless of the gene involved, could potentially be ‘textbook material’ as van Rootselaar et al. propose. Indeed, recent genetic discoveries (i.e. intronic pentanucleotide repeat expansions in different genes) have paved the way for the understanding the pathogenesis of FCMTE and potentially of other expansion disorders and opened new possible treatment considerations (Ishiura et al., 2018; Corbett et al., 2019; Florian et al., 2019; Yeetong et al., 2019). In this regard, our attention was drawn to one peculiar aspect of this heterogeneous disease, namely that most of the genes involved are highly expressed in the cerebellum (Latorre et al., 2020). This interesting finding helped us in closing the loop of a story begun in 1985, when the concept of ‘cortical myoclonus spectrum’ was proposed (Obeso et al., 1985), or even before, when Greenfield first observed cerebellar degeneration in a patient with cortical myoclonic jerks (Marsden et al., 1972). Presuming that cortical tremor as described in FCMTE, given its electrophysiological features, is part of this spectrum, we proposed the cerebellum as a possible common denominator, speculating on how it could represent the link in the continuum. In both letters, the authors agree on the role of the cerebello-thalamo-cortical connections in the pathogenesis of cortical myoclonus, supporting the hypothesis that cortical sensorimotor hyperexcitability might be a consequence of the loss of cerebellar inhibitory control. It is worth adding further evidence to this theory, nicely detailed by Striano and co-workers in their letter. Wang and colleagues have recently investigated functional MRI brain alterations in a relatively large group of genetically confirmed FCMTE1 patients with a heterozygous pathogenic (TTTCA)n insertion in SAMD12 (Wang et al., 2020). The authors found abnormal fluctuations in spontaneous brain activity, represented by increased ultra-low-frequency oscillations in the cerebellum and decreased higher-frequency ones in the motor cortex, suggesting that poor inhibitory output from Purkinje cells may lead to increased cortical hyperexcitability. Additionally, a positive correlation was noted between the abnormal spontaneous activity in the cerebellum and cortical tremor duration, revealing an important association between deranged cerebellar function and motor symptoms in FCMTE1.

One of the reasons why, in our Update paper (Latorre et al., 2020), we proposed that the cerebellum might contribute to the regularity of muscle discharges observed in cortical tremor, is that cerebellar dysfunction often results in rhythmic activity, which is thought to synchronize motor unit activation in several forms of tremor. In this regard, we note that van Rootselaar and colleagues questioned the rhythmicity of the muscle jerks overserved in FCMTE patients, rejecting the definition of ‘cortical tremor’ in favour of ‘cortical myoclonic tremor’, i.e. a high frequency continuous myoclonus that might be mistaken with tremor. As we pointed out in our Update (Latorre et al., 2020), by definition, the distinction between tremor and myoclonus is based on the rhythmicity of the jerks. In practice, this distinction is made by recording the tremor with EMG and transforming the signal from the time domain to the frequency domain. In tremor caused by oscillation generated in the nervous system, motor unit activity is synchronous at a specific frequency, so as to produce a clear peak in the EMG power spectrum; by contrast, myoclonus is normally characterized by arrhythmic bursts with no predominant frequency. Most of the studies that investigated the involuntary movements observed in FCMTE with EMG described rhythmic discharges compatible with tremor, with a frequency range of 8–15 Hz (Ikeda et al., 1990; Oguni et al., 1995; Terada et al., 1997; Okuma et al., 1998; Guerrini et al., 2001). To our knowledge, in only one case report frequency decomposition was applied to the EMG, demonstrating a peak at 7.4 Hz (Oguni et al., 1995). Van Rootselaar and colleagues performed frequency analysis in seven patients with FCMTE and found that the involuntary EMG activity could be described as a ‘frequency band rather than a frequency peak’ (van Rootselaar et al., 2006), which is not supportive of tremor. However, looking at the illustrations provided in their manuscript (Figure 2 in van Rootselaar et al., 2006), a 16 Hz peak in the power spectrum of the EMG recorded from the forearm extensor is visible; this is present also in the EMG recorded from the first dorsal interosseous muscle, although somewhat confounded by further, lower frequency peaks. Interestingly, the authors also found significant cortico-muscular coherence at the same frequency of 16 Hz (van Rootselaar et al., 2006). In our view, this might indicate a rhythmicity of muscle discharges, possibly driven by cortical oscillations. A similar high frequency cortico-muscular coherence (range 8–25 Hz) was also found in the thorough electrophysiological study by Guerrini and colleagues, who observed regular EMG bursting with a mean frequency of 12 Hz (SEM ± 0.4, range 8–15 Hz) (Guerrini et al., 2001). This evidence suggests that rhythmicity, albeit at a variable frequency, is common in cortical tremor. The theory we proposed in our Update (Latorre et al., 2020) includes the possibility that the degree of EMG synchronization in FCMTE can vary, which implies that the involuntary muscle activity is more regular in some subjects than others. This fits well with the two fold role of the cerebellum we described: from deranged gain control in the sensorimotor cortex, involved in reflex and spontaneous myoclonus, to regular activation of the cortical focus, leading to synchronous muscle jerks. That said, we agree that EMG frequency peaks in the power spectrum of cortical tremor might be less neat and at a more variable frequency than other forms of tremor, for example essential tremor. However, it might still be possible that, as we proposed in our Update, a deranged cerebellar function might synchronize EMG burst and give rise to rhythmic discharges in cortical tremor.

What clearly emerges from the present discussion is that FCMTE is clinically heterogeneous, with some patients showing rhythmic and others arrhythmic muscle activity, at a variable frequency. This might be due to the genetic heterogeneity of this disorder and to its incompletely understood genotype-phenotype correlation. In this regard, we would like to point out that the TTTTA/TTTCA repeat expansions found in MARCH6 (5p15.2-FCMTE3 locus) and described by Florian et al. (2019) was mentioned in our text, as well as in Table 1 (Latorre et al., 2020).

Nevertheless, it is important to highlight that the lack of standardized electrophysiological procedures to define and diagnose tremor, as well as cortical myoclonus (Latorre et al., 2018), makes comparison of results across different studies difficult. We therefore hope that this encourages experts to find a consensus on electrophysiological diagnostic criteria for these diseases.

Data availability

Data availability is not applicable to this article as no new data were created or analysed in this study.

Funding

F.M. is supported by the European Academy of Neurology (EAN) Research Fellowship 2020. This research study was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the Edmond J. Safra Philanthropic Foundation.

Competing interests

The authors report no competing interests.

References