Genetic mouse models of essential tremor: are they essential?

Abstract

The causative genes for essential tremor (ET), one of the most common genetic neurological disorders, have eluded scientists despite intensive search. Two gene loci linked to ET, one on chromosome 3q13 and another on chromosome 2p24.1, have been identified, and a missense mutation in the HS1-BP3 gene on the 2p has been suggested as the cause of the disorder in about 10% of American ET patients. Therefore, the genetic basis for the vast majority of familial ET is still unknown. In this issue of the JCI, the gene coding for the γ-aminobutyric acid A (GABA A ) receptor α1 subunit is suggested as a potential candidate gene for ET, as mice lacking the gene express a phenotype that overlaps with some clinical characteristics of the human condition (see the related article beginning on page 774).

REVIEW: Movement disorders and alcohol misuse

“…These mice exhibit a limb predominant tremor which is absent with relaxation, and is ameliorated by propranolol and primidone, as well as alcohol, hence mimicking ET. However, tremor in these mice appears earlier in life and has a higher mean frequency (19.3 Hz) than the tremor seen in ET patients, and is also accompanied by considerable incoordination, which is not typical for ET (Jankovic & Noebels 2005). The tremor is attributed to the demonstrated loss of GABA‐ergic inhibition of Purkinje cells in the cerebellum and the global reduction of GABA A binding sites in the brain.…”

Voxel-based morphometry shows no decreases in cerebellar gray matter volume in essential tremor

“…21,22 The first hypothesis is supported by two independent proton MR spectroscopy (MRS) studies that reported a reduced N-acetylaspartate/creatine ratio in patients with ET vs control subjects. 23,24 The latter hypothesis is supported by two lines of evidence.…”

“…25 Second, a knockout model, mice lacking the gene for the ␣1 subunit of the ␥-aminobutyrate receptors show generalized alcohol-sensitive trembling, like ET. 21,22 Histopathologic data are inconclusive. Qualitative postmortem examinations have revealed no consistent histopathologic abnormalities in small groups of patients with ET, 26,27 yet a quantitative histologic assessment of the cerebellum is still lacking.…”

Effects of unilateral stereotactic posterior striatotomy on harmaline-induced tremor in rats

“…V C 2013 Wiley Periodicals, Inc. Key words: harmaline; tremor; essential tremor; striatum; electrolytic lesion Essential tremor (ET) is the most frequent movement disorder. Its prevalence varies between 0.4% and 5.6%, although it can affect up to 14% of the population aged 65 years (Elble, 2000;Jankovic and Noebels, 2005). Despite its high prevalence and the fact that it was first described by Most 176 years ago (Most, 1836[see Findley, 2000), there is still a great deal of speculation over the pathophysiological substrate of ET.…”