Biological follow‐up in amyotrophic lateral sclerosis: decrease in creatinine levels and increase in ferritin levels predict poor prognosis

Patin, Franck; Corcia, Philippe; Hounoum, Blandine Madji; Veyrat-Durebex, Charlotte; Respaud, E.; Piver, Éric; Bretagne, Isabelle Benz-de; Vourc’h, Patrick; Andres, Christian R.; Blasco, Hélène

doi:10.1111/ene.12754

Cited by 32 publications

(23 citation statements)

References 31 publications

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“…Serum creatinine levels have been reported to change significantly during the progression of other motor neuron diseases. 23,24 Radiological studies showed higher thigh muscle fat fraction and lower lean body mass. ALS4 patients have fatty infiltration in the muscles of their lower extremities.…”

Section: Discussionmentioning

confidence: 99%

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Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4

Patankar

Amaya

Watts

et al. 2020

Annals of Neurology

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Objective To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants. Methods Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual‐energy x‐ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. Results We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R2 = 0.35, p = 0.01; lower leg fat fraction R2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. Interpretation We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R‐loop levels in patient‐derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547–555

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Section: Discussionmentioning

confidence: 99%

“…Among our ALS4 cohort, the male patients had significantly lower creatinine levels, which reflects a greater disease burden in males. Serum creatinine levels have been reported to change significantly during the progression of other motor neuron diseases . Radiological studies showed higher thigh muscle fat fraction and lower lean body mass.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4

Patankar

Amaya

Watts

et al. 2020

Annals of Neurology

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“…Lipid metabolism was described as deeply involved in ALS pathophysiology [52,53]. In particular, several studies reported hyperlipidemia in patients with ALS [53][54][55][56][57], with a potential link with patient survival [53]. Close connections between IL-6 signaling and lipid metabolism exist [58,59].…”

Section: Moderate Effect On Metabolismmentioning

confidence: 99%

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

et al. 2016

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In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic impairment and neuroinflammation. Playing an important role in the regulation of both phenomena, interleukin (IL)-6, a major cytokine of the inflammatory response has been proposed as a target for management of ALS. Although a pilot clinical trial provided promising results in humans, another recent preclinical study showed that knocking out the IL-6 gene in mice carrying ALS did not improve clinical outcome. In this study, we aimed to determine the relevance of the IL-6 pathway blockade in a mouse model of ALS by using a pharmacological antagonist of IL-6, a murine surrogate of tocilizumab, namely MR16-1. We analyzed the immunological and metabolic effects of IL-6 blockade by cytokine measurement, blood cell immunophenotyping, targeted metabolomics, and transcriptomics. A deleterious clinical effect of MR16-1 was revealed, with a speeding up of weight loss (p = 0.0041) and decreasing body weight (p < 0.05). A significant increase in regulatory T-cell count (p = 0.0268) and a decrease in C-X-C ligand-1 concentrations in plasma (p = 0.0479) were observed. Metabolomic and transcriptomic analyses revealed that MR16-1 mainly affected branchedchain amino acid, lipid, arginine, and proline metabolism. IL-6 blockade negatively affected body weight, despite a moderated anti-inflammatory effect. Metabolic effects of IL-6 were mild compared with metabolic disturbances observed in ALS, but a modification of lipid metabolism by

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“…Creatinine concentrations are associated with disease severity as they are inversely correlated with ALSFRS-R scores and forced vital capacity [105][106][107]. The interpretation of this parameter remains very difficult as it depends on the muscle mass and on kidney function.…”

Section: Metabolites As Surrogate Endpointsmentioning

confidence: 99%

Further development of biomarkers in amyotrophic lateral sclerosis

Blasco

Vourc’h

et al. 2016

Expert Review of Molecular Diagnostics

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In this review, we specifically focus on biology and imaging markers. We detail the innovative field of 'omics' approach and imaging and explain their limits to be useful in routine practice. We describe the most relevant biomarkers and suggest some perspectives for biomarker research. Expert commentary: The successive failures of clinical trials in ALS underline the need for new strategy based on innovative tools to stratify patients and to evaluate their responses to treatment. Biomarker data may be useful to improve the designs of clinical trials. Biomarkers are also needed to better investigate disease pathophysiology, to identify new therapeutic targets, and to improve the performance of clinical assessments for diagnosis and prognosis in the clinical setting. A consensus on the best management of neuroimaging and 'omics' methods is necessary and a systematic independent validation of findings may add robustness to future studies.

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Biological follow‐up in amyotrophic lateral sclerosis: decrease in creatinine levels and increase in ferritin levels predict poor prognosis

Abstract: Changes to ferritin and creatinine levels with time are associated with ALS progression. This is the first study describing the changes to these biological variables during ALS progression.

Cited by 32 publications

References 31 publications

Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4

Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4

Combined Metabolomics and Transcriptomics Approaches to Assess the IL-6 Blockade as a Therapeutic of ALS: Deleterious Alteration of Lipid Metabolism

Further development of biomarkers in amyotrophic lateral sclerosis

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