1H-NMR-based metabolic profiling identifies non-invasive diagnostic and predictive urinary fingerprints in 5q spinal muscular atrophy

Abstract

Background 5q spinal muscular atrophy (SMA) is a disabling and life-limiting neuromuscular disease. In recent years, novel therapies have shown to improve clinical outcomes. Yet, the absence of reliable biomarkers renders clinical assessment and prognosis of possibly already affected newborns with a positive newborn screening result for SMA imprecise and difficult. Therapeutic decisions and stratification of individualized therapies remain challenging, especially in symptomatic children. The aim of this proof-of-concept and feasibility study was to explore the value of 1H-nuclear magnetic resonance (NMR)-based metabolic profiling in identifying non-invasive diagnostic and prognostic urinary fingerprints in children and adolescents with SMA. Results Urine samples were collected from 29 treatment-naïve SMA patients (5 pre-symptomatic, 9 SMA 1, 8 SMA 2, 7 SMA 3), 18 patients with Duchenne muscular dystrophy (DMD) and 444 healthy controls. Using machine-learning algorithms, we propose a set of prediction models built on urinary fingerprints that showed potential diagnostic value in discriminating SMA patients from controls and DMD, as well as predictive properties in separating between SMA types, allowing predictions about phenotypic severity. Interestingly, preliminary results of the prediction models suggest additional value in determining biochemical onset of disease in pre-symptomatic infants with SMA identified by genetic newborn screening and furthermore as potential therapeutic monitoring tool. Conclusions This study provides preliminary evidence for the use of 1H-NMR-based urinary metabolic profiling as diagnostic and prognostic biomarker in spinal muscular atrophy.

Cathepsin D as biomarker in cerebrospinal fluid of nusinersen‐treated patients with spinal muscular atrophy

“…Apart from the SMN2 copy number and less frequent genetic modifiers [11,12], only few laboratory biomarkers such as neurofilaments (peripheral neurofilament light chain [pNF-L], peripheral neurofilament heavy chain [pNF-H]) are available for SMA with early onset [13]. No longitudinal changes under nusinersen treatment were identified by extensive analyses of the metabolome in urine, serum, and cerebrospinal fluid (CSF) [14,15]. Cathepsin D is a lysosomal aspartyl protease that is highly expressed in the central nervous system as well as skeletal and cardiac muscle (Figure S1) and is involved in lysosomal degeneration of proteins [16].…”

“…Apart from the SMN2 copy number and less frequent genetic modifiers [11,12], only few laboratory biomarkers such as neurofilaments (peripheral neurofilament light chain [pNF‐L], peripheral neurofilament heavy chain [pNF‐H]) are available for SMA with early onset [13]. No longitudinal changes under nusinersen treatment were identified by extensive analyses of the metabolome in urine, serum, and cerebrospinal fluid (CSF) [14,15].…”

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

“…Whole metabolome. Urinary metabolic profiles successfully differentiated SMA patients from HCs with 81% sensitivity and 98% specificity [55]. Another study showed that even 59 plasma metabolites and 44 urine metabolites correlated with the MHFMS scores [34].…”

Ex vivo proton spectroscopy (1H‐NMR) analysis of inborn errors of metabolism: Automatic and computer‐assisted analyses

“…43 In a more complex disease like spinal muscular atrophy SMA1 (OMIM 253300), 1 H-NMR-based metabolic profiling identifies biomarkers for diagnosis and treatment monitoring for an otherwise fatal neuromuscular disease, as shown recently. 44…”