Lower limb tremor in Machado-Joseph disease

Ishida, Chiho; Sakajiri, Kenichi; Yoshikawa, Hiroaki; Sakashita, Yoshiharu; Okino, Shinichi; Yamaguchi, Koichi; Takamori, M

doi:10.1212/wnl.51.4.1225

Cited by 10 publications

(7 citation statements)

References 2 publications

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“…We also observed a slight improvement of the tremors, which is in agreement with our previous result using LiCl alone in these mice (Duarte-Silva et al, 2014), suggesting that this improvement might be due to that component of the treatment regimen. The presence of tremors in human patients is a rare event and can be treated with levodopa (Coutinho and Sequeiros, 1981;Ishida et al, 1998;Nandagopal and Moorthy, 2004;Bettencourt et al, 2011), so this improvement may not be very relevant in the disease context.…”

Section: Discussionmentioning

confidence: 99%

Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado–Joseph disease

et al. 2016

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A major pathological hallmark in several neurodegenerative disorders, like polyglutamine disorders (polyQ), including Machado-Joseph disease (MJD), is the formation of protein aggregates. MJD is caused by a CAG repeat expansion in the ATXN3 gene, resulting in an abnormal protein, which is prone to misfolding and forms cytoplasmic and nuclear aggregates within neurons, ultimately inducing neurodegeneration. Treatment of proteinopathies with drugs that up-regulate autophagy has shown promising results in models of polyQ diseases. Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (m-TOR), while lithium chloride (LiCl) acts by inhibiting inositol monophosphatase, both being able to induce autophagy. We have previously shown that chronic treatment with LiCl (10.4 mg/kg) had limited effects in a transgenic MJD mouse model. Also, others have shown that CCI-779 had mild positive effects in a different mouse model of the disease. It has been suggested that the combination of mTOR-dependent and -independent autophagy inducers could be a more effective therapeutic approach. To further explore this avenue toward therapy, we treated CMVMJD135 transgenic mice with a conjugation of CCI-779 and LiCl, both at concentrations known to induce autophagy and not to be toxic. Surprisingly, this combined treatment proved to be deleterious to both wild-type (wt) and transgenic animals, failing to rescue their neurological symptoms and actually exerting neurotoxic effects. These results highlight the possible dangers of manipulating autophagy in the nervous system and suggest that a better understanding of the potential disruption in the autophagy pathway in MJD is required before successful long-term autophagy modulating therapies can be developed.

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Section: Discussionmentioning

confidence: 99%

Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado–Joseph disease

et al. 2016

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“…Among hereditary ataxic disorders, patients with SCA10 7,8 or fragile X-associated tremor/ataxia syndrome 9 have prominent postural tremor as the disease hallmark. Postural tremor has been reported to be present in other forms of SCA patients in several case reports, [10][11][12][13][14][15][16][17][18][19] and can also be a prominent feature in CAG-repeat SCAs, 20-23 especially in SCA2. 23 However, the sample size in these studies is moderate (n 5 22-85), and there is no systemic comparison between SCA patients with and without postural tremor in terms of genetics and rate of clinical progression.…”

Section: Introductionmentioning

confidence: 99%

Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias

Gan

Wang

Figueroa

et al. 2017

Tremor and Other Hyperkinetic Movements

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Background: Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known. Methods: We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012. Results: Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p 5 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ¡ 3.12 vs. 70.42 ¡ 3.96, p 5 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, b 5-0.91, p , 0.001; SCA6, b 5-1.28, p 5 0.025), while SCA2 patients with postural tremor had a faster rate of ataxia progression (b 5 1.54, p 5 0.034). We also found that the presence of postural tremor in SCA2 patients could be influenced by repeat expansions of ATXN1 (b 5-1.53, p 5 0.037) and ATXN3 (b 5 0.57, p 5 0.018), whereas postural tremor in SCA3 was associated with repeat lengths in TBP (b 5 0.63, p 5 0.041) and PPP2R2B (b 5-0.40, p 5 0.032). Discussion: Postural tremor could be a clinical feature of SCAs, and the presence of postural tremor could be associated with different rates of ataxia progression. Genetic interactions between ataxia genes might influence the brain circuitry and thus affect the clinical presentation of postural tremor.

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“…SCA3 patients presenting initially with ET have yet to be reported. Interestingly our literature review found a report of a Japanese SCA3 patient who presented with prominent posture‐related lower limb tremor, together with ataxia 11. Unlike SCA2, reports of prominent postural tremor associated with ataxia is lacking in SCA3.…”

Section: Discussionmentioning

confidence: 94%

Genetic analysis of SCA 2 and 3 repeat expansions in essential tremor and atypical Parkinsonism

et al. 2007

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Anecdotal reports suggest that patients with spinocerebellar ataxia (SCA 2) patients can present with postural tremor with ataxia. We determined the prevalence of SCA2 and SCA3 mutations in a cohort of ET and atypical Parkinsonism patients. A total of 277 subjects comprising of 177 ET and 100 atypical Parkinsonism were examined. We identified one positive case of SCA3 among those who were diagnosed with ET, yielding a prevalence of 0.5%, but a zero prevalence among our atypical Parkinsonism patients. No study subjects carried an abnormal SCA2 repeat expansion. Our study highlights that SCA3 can present initially with ET symptoms, expanding the spectrum of genetic diseases that can be associated with ET-like phenotype. Routine screening for SCA2 and SCA3 in ET and atypical Parkinsonism patients may not be cost effective. However, in the long-term follow-up of patients who present with an ET phenotype, clinicians should be vigilant for other neurological signs, which may be point to an alternate diagnosis.

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Lower limb tremor in Machado-Joseph disease

Cited by 10 publications

References 2 publications

Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado–Joseph disease

Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado–Joseph disease

Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias

Genetic analysis of SCA 2 and 3 repeat expansions in essential tremor and atypical Parkinsonism

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