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Impaired kidney structure and function in spinal muscular atrophy.

ABSTRACT: Objective:To determine changes in serum profiles and kidney tissues from patients with spinal muscular atrophy (SMA) type 1 compared with age- and sex-matched controls. Methods:In this cohort study, we investigated renal structure and function in infants and children with SMA type 1 in comparison with age- and sex-matched controls. Results:Patients with SMA had alterations in serum creatinine, cystatin C, sodium, glucose, and calcium concentrations, granular casts and crystals in urine, and nephrocalcinosis and fibrosis. Nephrotoxicity and polycystic kidney disease PCR arrays revealed multiple differentially expressed genes, and immunoblot analysis showed decreased calcium-sensing receptors and calbindin and increased insulin-like growth factor-binding proteins in kidneys from patients with SMA. Conclusions:These findings demonstrate that patients with SMA type 1, in the absence of disease-modifying therapies, frequently manifest impaired renal function as a primary or secondary consequence of their disease. This study provides new insights into systemic contributions to SMA disease pathogenesis and the need to identify coadjuvant therapies.

SUBMITTER: Nery FC

PROVIDER: S-EPMC6705648 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Impaired kidney structure and function in spinal muscular atrophy.

Nery Flávia C FC Siranosian Jennifer J JJ Rosales Ivy I Deguise Marc-Olivier MO Sharma Amita A Muhtaseb Abdurrahman W AW Nwe Pann P Johnstone Alec J AJ Zhang Ren R Fatouraei Maryam M Huemer Natassja N Alves Christiano R R CRR Kothary Rashmi R Swoboda Kathryn J KJ

Neurology. Genetics 20190812 5

<h4>Objective</h4>To determine changes in serum profiles and kidney tissues from patients with spinal muscular atrophy (SMA) type 1 compared with age- and sex-matched controls.<h4>Methods</h4>In this cohort study, we investigated renal structure and function in infants and children with SMA type 1 in comparison with age- and sex-matched controls.<h4>Results</h4>Patients with SMA had alterations in serum creatinine, cystatin C, sodium, glucose, and calcium concentrations, granular casts and cryst ...[more]

PMID: 31517062

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Project description:ImportanceThe important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively).ObjectiveTo investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA.Design, setting, and participantsWe studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015.ExposuresWe used histochemical, biochemical, and molecular techniques to examine the muscle samples.Main outcomes and measuresRespiratory chain activity and mitochondrial content.ResultsResults of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator-activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets, implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P = .004), COX2 (32.4%; P < .001), COX4 (26.6%; P < .001), and succinate dehydrogenase complex subunit A (65.8%; P = .03) as well as the structural outer membrane mitochondrial porin (33.1%; P < .001). Conversely, the levels of expression of 3 myogenic regulatory factors-muscle-specific myogenic factor 5, myoblast determination 1, and myogenin-were higher in muscles from patients with SMA compared with muscles from age-matched controls (P < .05).Conclusions and relevanceOur results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes.

Dataset Information

Impaired kidney structure and function in spinal muscular atrophy.

Publications

Impaired kidney structure and function in spinal muscular atrophy.

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