Myogenic tremor - a novel tremor entity.

PURPOSE OF REVIEW: Tremor is a common neurological symptom with a plethora of potential etiologies. Apart from physiological tremor, the vast majority of tremor syndromes are linked to a pacemaker in the central nervous system (CNS) or, less common, in the peripheral nervous system. Myogenic tremor is a novel tremor entity, first reported in 2019 and believed to originate in the muscle itself. In this review, we describe the clinical properties of myogenic tremor and discuss its presumed pathogenesis on the basis of all of the patient cases published so far. RECENT FINDINGS: Myogenic tremor manifests itself as a high frequency, postural, and kinetic tremor with onset in infancy. To date, only myopathies affecting the contractile elements, in particular myosin and a myosin-associated protein, have been recognized to feature myogenic tremor. The generator of the tremor is believed to be located in the sarcomere, with propagation and amplification of sarcomeric oscillatory activity through CNS reflex loops, similar to neuropathic tremor. SUMMARY: True myogenic tremor must be distinguished from centrally mediated tremor due to myopathies with central nervous system involvement, i.e., mitochondrial myopathies or myotonic dystrophies. The presence of myogenic tremor strongly points toward a sarcomere-associated mutation and may thus be a valuable clinical tool for the differential diagnosis of myopathies.

Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy.

OBJECTIVE: To define a distinct, dominantly inherited, mild skeletal myopathy associated with prominent and consistent tremor in two unrelated, three-generation families. METHODS: Clinical evaluations as well as exome and panel sequencing analyses were performed in affected and nonaffected members of two families to identify genetic variants segregating with the phenotype. Histological assessment of a muscle biopsy specimen was performed in 1 patient, and quantitative tremor analysis was carried out in 2 patients. Molecular modeling studies and biochemical assays were performed for both mutations. RESULTS: Two novel missense mutations in MYBPC1 (p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy/tremor phenotype in the respective families. MYBPC1 encodes slow myosin binding protein-C (sMyBP-C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and myosin filaments. The Y247H and E248K mutations are located in the NH2 -terminal M-motif of sMyBP-C. Both mutations result in markedly increased binding of the NH2 terminus to myosin, possibly interfering with normal cross-bridge cycling as the first muscle-based step in tremor genesis. The clinical tremor features observed in all mutation carriers, together with the tremor physiology studies performed in family 2, suggest amplification by an additional central loop modulating the clinical tremor phenomenology. INTERPRETATION: Here, we link two novel missense mutations in MYBPC1 with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor. The molecular, genetic, and clinical studies are consistent with a unique sarcomeric origin of the tremor, which we classify as "myogenic tremor." ANN NEUROL 2019.

Serum Neurofilament Light Chain: A Marker of Nervous System Damage in Myopathies.

Purpose: Neurofilament light chain in serum (sNfL) has been suggested as a biomarker for the assessment of neuroaxonal damage. Since NfL are not expressed in muscle, elevated sNfL in patients with primary myopathies suggest additional nervous system involvement. To verify this hypothesis, we measured sNfL in a series of patients with myopathies. Methods: sNfL were determined in 62 patients with molecular proven primary myopathies in whom some nervous system involvement may be predicted: myotonic dystrophy type I and II (DM I, II) and mitochondrial disease. In addition, sNfL were measured in 8 patients with facioscapulohumeral muscular dystrophy (FSHD) and in a disease control group caused by genetic defects exclusively expressed in muscle. Results: sNfL values were significantly elevated in the DM I, the DM II and the mitochondrial group, with FSHD patients showing the lowest sNfL elevations. sNfL levels in the disease control group were not different from the healthy controls. A significant correlation between repeat length and sNfL levels was found in the DM I patients, but not in the DM II patients. Mitochondrial patients with encephalopathy showed significantly higher sNfL concentrations compared to patients with only muscular symptoms. Conclusion: sNfL levels are elevated in myopathies with, based on the underlying molecular defect or clinical features, established nervous system involvement, i.e., myotonic dystrophies and mitochondrial disorders. sNfL were also raised in FSHD, where involvement of the nervous system is not usually clinically apparent. Thus, sNfL concentrations may serve as a biomarker for additional neuronal damage in primary myopathies.