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Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study.

ABSTRACT: Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognized (types I-III). All patients usually have 2-4 copies of a highly homologous gene (SMN2), which produces insufficient levels of functional survival motor neuron (SMN) protein due to the alternative splicing of exon 7. The availability of potential candidates to the treatment of SMA has raised a number of issues, including the availability of biomarkers. This study was aimed at evaluating whether the quantification of SMN2 products in peripheral blood is a suitable biomarker for SMA. Forty-five adult type III patients were evaluated by Manual Muscle Testing, North Star Ambulatory Assessment scale, 6-min walk test, myometry, forced vital capacity, and dual X-ray absorptiometry. Molecular assessments included SMN2 copy number, levels of full-length SMN2 (SMN2-fl) transcripts and those lacking exon 7 and SMN protein. Clinical outcome measures strongly correlated to each other. Lean body mass correlated inversely with years from diagnosis and with several aspects of motor performance. SMN2 copy number and SMN protein levels were not associated with motor performance or transcript levels. SMN2-fl levels correlated with motor performance in ambulant patients. Our results indicate that SMN2-fl levels correlate with motor performance only in patients preserving higher levels of motor function, whereas motor performance was strongly influenced by disease duration and lean body mass. If not taken into account, the confounding effect of disease duration may impair the identification of potential SMA biomarkers.

SUBMITTER: Tiziano FD

PROVIDER: S-EPMC3658179 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study.

Tiziano Francesco D FD Lomastro Rosa R Di Pietro Lorena L Barbara Pasanisi Maria M Fiori Stefania S Angelozzi Carla C Abiusi Emanuela E Angelini Corrado C Sorarù Gianni G Gaiani Alessandra A Mongini Tiziana T Vercelli Liliana L Vasco Gessica G Vita Giuseppe G Vita Giuseppe G Luca Vita Gian G Messina Sonia S Politano Luisa L Passamano Luigia L Di Gregorio Grazia G Montomoli Cristina C Orsi Chiara C Campanella Angela A Mantegazza Renato R Morandi Lucia L

European journal of human genetics : EJHG 20121017 6

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognized (types I-III). All patients usually have 2-4 copies of a highly homologous gene (SMN2), which produces insufficient levels of functional survival motor neuron (SMN) protein due to the alternative splicing of exon 7. The availability of potential candidates to the treatment of SMA has raised a number of issues, including ...[more]

PMID: 23073312

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Project description:ObjectiveSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by proximal muscle weakness and atrophy. The increasing availability of disease-modifying therapies has prompted the development of biomarkers to facilitate clinical assessments. We explored the association between disease severity and serum creatinine (Crn) levels in SMA patients undergoing up to two years of treatment with nusinersen.MethodsWe measured serum Crn levels and assessed function performance using the Hammersmith Functional Motor Scale-Expanded (HFMSE), Medical Research Council Scale (MRC), 6-Minute Walk Test (6MWT), ulnar Compound Muscle Action Potential (CMAP), and forced vital capacity (FVC) in a cohort comprising 28 adolescent and adult patients with SMA. The association between Crn and disease severity was investigated through partial rank correlation analysis and linear mixed models while accounting for age, gender, and BMI. Linear models were employed to predict functional performance.Results28 SMA patients and 28 gender- and age-matched healthy controls (HCs) were included, resulting in a dataset of 185 visits. Compared to HCs, SMA patients exhibited significantly lower Crn values (67.4 ± 14 vs. 23.7 ± 14.8 umol/L, p<0.0001). After adjusting for age, sex, and BMI, Crn showed positive correlations with the HFMSE (p<0.0001, r = 0.884), MRC (p<0.0001, r = 0.827), FVC (p = 0.002, r = 0.730), and ulnar CMAP (p<0.0001, r = 0.807). Patients with SMN2 copy number ≥ 4 had nearly twice as high Crn levels as those with SMN2 copy number < 4 (34.1 ± 3.75 vs. 17.2 ± 2.52 umol/L, p = 0.00145). Ambulant SMA patients had more than double the Crn levels compared to non-ambulant ones (32 ± 2.33 vs. 12.9 ± 2.38 umol/L, p<0.0001). Furthermore, Crn explained that up to 83.5% of the variance in functional performance measured by HFMSE, MRC, and 6MWT was significantly higher than that of traditional biomarkers.ConclusionsThese findings suggest that Crn may be a potential biomarker for assessing disease severity in adolescents and adults with SMA, demonstrating its promise in clinical applications.

Project description:ObjectiveSpinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by the degeneration of motor neurons in the spinal cord. It remains uncertain whether the cognitive performance of adult patients with SMA is impaired. The objective of this study was to assess the cognitive profile of adult Chinese patients with SMA and the association between clinical features and cognitive ability, particularly executive function.MethodsThis cross-sectional study included 22 untreated adult patients with type III SMA and 20 healthy subjects. The following variables were assessed: general intelligence, memory, attention, language, executive function, depression, anxiety, and other demographic and clinical parameters. In addition, physical function was evaluated using the Hammersmith Functional Motor Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM), and the 6-Minute Walk Test (6MWT).ResultsSMA patients had lower scores than healthy subjects in the Verbal Fluency Test, Stroop effect, Total Errors, Perseverative Responses, Perseverative Errors, and Non-perseverative Errors in the Wisconsin Card Sorting Test, showing impaired abilities of SMA patients in executive function. In the Attention Network Test (ANT), the results indicated that the SMA patients also had selective deficits in their executive control networks. Ambulant patients had better executive function test performance than non-ambulant ones. Compromised executive abilities in patients with SMA were correlated with a younger age at onset, poorer motor function, and higher levels of anxiety and depression.ConclusionOur study presented the distribution of cognitive impairment in a Chinese cohort with SMA. Patients with type III SMA showed selective deficits in executive function, which may be associated with disease severity, physical impairment, depression and anxiety. Future cognitive studies, accounting for motor and emotional impairment, are needed to evaluate if executive impairment is driven by specific brain changes or by those confounding factors.

Dataset Information

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study.

Publications

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study.

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