Isolated and combined genetic tremor syndromes: a critical appraisal based on the 2018 MDS criteria

Abstract

The 2018 consensus statement on the classification of tremors proposes a two-axis categorization scheme based on clinical features and etiology. It also defines "isolated" and "combined" tremor syndromes depending on whether tremor is the sole clinical manifestation or is associated with other neurological or systemic signs. This syndromic approach provides a guide to investigate the underlying etiology of tremors, either genetic or acquired.Several genetic defects have been proven to cause tremor disorders, including autosomal dominant and recessive, X-linked, and mitochondrial diseases, as well as chromosomal abnormalities. Furthermore, some tremor syndromes are recognized in individuals with a positive family history, but their genetic confirmation is pending. Although most genetic tremor disorders show a combined clinical picture, there are some distinctive conditions in which tremor may precede the appearance of other neurological signs by years or remain the prominent manifestation throughout the disease course, previously leading to misdiagnosis as essential tremor (ET). Advances in the knowledge of genetically determined tremors may have been hampered by the inclusion of heterogeneous entities in previous studies on ET. The recent classification of tremors therefore aims to provide more consistent clinical data for deconstructing the genetic basis of tremor syndromes in the next-generation and long-read sequencing era. This review outlines the wide spectrum of tremor disorders with defined or presumed genetic etiology, both isolated and combined, unraveling diagnostic clues of these conditions and focusing mainly on ET-like phenotypes. Furthermore, we suggest a phenotype-to-genotype algorithm to support clinicians in identifying tremor syndromes and guiding genetic investigations.

Essential Tremor

“…The presence of a family history of tremor along with additional neurologic signs/symptoms (dystonia, ataxia, parkinsonism, and cognitive impairment) should prompt appropriate genetic testing. 14…”

Analysis of Fine Motor Skills in Essential Tremor: Combining Neuroimaging and Handwriting Biomarkers for Early Management

“…Cases of overt tremors are generally easy to diagnose, although there are serious problems in reaching diagnostic certainty when the intensity of the tremor is small. By refining the diagnostic threshold in the early stages of ET, we may better conduct studies with oligosymptomatic subjects in two key areas: (i) research on the segregation of candidate genes in familial tremor, allowing assessment of the phenotype in doubtful cases, which is very common in patients, even from the same family (Magrinelli et al, 2020 ); and (ii) research study designs in therapeutic trials for patient selection of participants and for their follow-up assessment.…”

Rare tremors and tremors occurring in other neurological disorders

“…Covering all genetic disorders in which tremor might be present but is not the main movement disorder, or in which tremor is part of the motor phenomenology of another movement disorder such as dystonia and parkinsonism, is out of the scopes of this review and the interested readership is therefore referred elsewhere [128]. Beyond WD, which to us deserved a dedicated section (see above), there are few rare, genetic conditions to consider.…”