State biomarkers for Machado Joseph disease: Validation, feasibility and responsiveness to change

Abstract

Machado-Joseph disease (SCA3/MJD) is the most common spinocerebellar ataxia worldwide, and particularly so in Southern Brazil. Due to an expanded polyglutamine at ataxin-3, SCA3/MJD presents a relentless course with no current disease modifying treatment. Clinical scales used to measure SCA3/MJD progression present moderate effect sizes, a major drawback for their use as main outcomes in clinical trials, given the rarity and slow progression of the disease. This limitation might be overcome by finding good surrogate markers. We present here a review of studies on peripheral and neurophysiological markers in SCA3/MJD that can be candidates for state biomarkers. Data on markers already studied were summarized, giving emphasis on validation against clinical scale, and responsiveness to change. While some biological fluid compounds and neurophysiological parameters showed poor responsiveness, others seemed to be good candidates. Some potential candidates that are waiting for responsiveness studies were serum levels of neuron specific enolase, vestibulo-ocular reflex and video-oculography. Candidates evaluated by RNA and microRNA expression levels need further studies to improve their measurements. Data on peripheral levels of Beclin-1 and DNAJB1 are promising but still incipient. We conclude that several potential candidates should follow onto validating studies for surrogate state biomarkers of SCA3/MJD.

Caracterização clínica e molecular de 211 pacientes brasileiros com a doença de Machado-Joseph

“…No presente estudo, a média da idade de início da AEC3/DMJ foi de 38, 13 No presente trabalho, esse viés foi reduzido, uma vez que os pacientes que apresentaram tempo de evolução da doença inferior a cinco anos foram excluídos de todas as análises estatísticas que envolvessem o subtipo clínico. Embora em percentual reduzido, os subtipos 4, 5 e 7 também foram encontrados em nossa série, sugerindo que os fenótipos de parkinsonismo, paraparesia espástica e ataxia mista não são raros e devem ser incluídos no rol de apresentação clínica da AEC3/DMJ, reduzindo assim, o número de subdiagnósticos.…”

A Meta-Analysis of Neuron-Specific Enolase Levels in Cerebrospinal Fluid and Serum in Children With Epilepsy

“…Serum and CSF levels of NSE, elevated within the first 48 h after a seizure episode, are correlated with patient outcomes and the duration of epilepsy (DeGiorgio et al, 1995;Correale et al, 1998). Neuron-specific enolase levels can also be useful for diagnosis, prognosis, and follow-up of a variety of tumors and other diseases such as neuroendocrine tumors, neuroblastoma in newborns, and small cell lung cancer (Isgro et al, 2015;Mjønes et al, 2017;Furtado et al, 2019;Park et al, 2019).…”