Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4

Wel, Bram De; Goosens, Veerle; Sobota, Atka; Camp, Elke Van; Geukens, E I; Kerschaver, Griet Van; Jagut, Marlène; Claes, Kathleen; Claeys, Kristl G.

doi:10.1007/s00415-020-10223-9

Cited by 55 publications

(74 citation statements)

References 32 publications

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“…Our data show that both CK and Crn reflect the severity of SMA and might serve as useful and easily accessible biomarkers to predict treatment response and to monitor the disease course and could therefore be implemented effortless in the laboratory routine of the monitoring of patients with SMA. During nusinersen treatment, CK decreased and Crn slightly increased, while motor function ameliorated coincidently in adult patients with SMA type 2 and type 3 based on motor score improvements 5–8,10,49 . To what degree CK levels depend on muscle mass or muscle damage in SMA and whether a therapy decision could be made based on the dynamic of CK or/and Crn should be evaluated in further prospective studies.…”

Section: Discussionmentioning

confidence: 99%

“…During nusinersen treatment, CK decreased and Crn slightly increased, while motor function ameliorated coincidently in adult patients with SMA type 2 and type 3 based on motor score improvements. [5][6][7][8]10,49 To what degree CK levels depend on muscle mass or muscle damage in SMA and whether a therapy decision could be made based on the dynamic of CK or/and Crn should be evaluated in further prospective studies. We suggest monitoring CK and Crn as additional laboratory assessments.…”

Section: Discussionmentioning

confidence: 99%

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Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment

Freigang

Wurster

Hagenacker

et al. 2021

Ann Clin Transl Neurol

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Objective To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q‐associated spinal muscular atrophy (SMA). Methods Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months. Results CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = −17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05). Interpretation Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment

Freigang

Wurster

Hagenacker

et al. 2021

Ann Clin Transl Neurol

View full text Add to dashboard Cite

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“…The evolution of this score might also be crucial to prove the global efficiency of any therapeutic intervention in CS and would probably be a more relevant endpoint than any assessment of one single dimension of this multisystem syndrome. This scoring approach has been successfully used in ceroidlipofuscinosis [21,22] and very similar approaches based on functional scores are now routinely used in gene therapies for spinal muscular atrophy or Duchenne muscular dystrophy [23][24][25][26]. Recent experience in these disorders has shown that an accurate knowledge of the slope of the curves, of the interindividual variability and of the periods of plateauing is a prerequisite before using these scores in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and severity scores for Cockayne syndrome

Spitz

Séverac

Obringer

et al. 2021

Orphanet J Rare Dis

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Background Cockayne syndrome is a progressive multisystem genetic disorder linked to defective DNA repair and transcription. This rare condition encompasses a very wide spectrum of clinical severity levels ranging from severe prenatal onset to mild adult-onset subtypes. The rarity, complexity and variability of the disease make early diagnosis and severity assessment difficult. Based on similar approaches in other neurodegenerative disorders, we propose to validate diagnostic and severity scores for Cockayne syndrome. Methods Clinical, imaging and genetic data were retrospectively collected from 69 molecularly confirmed CS patients. A clinical diagnostic score and a clinical-radiological diagnostic score for CS were built using a multivariable logistic regression model with a stepwise variable selection procedure. A severity score for CS was designed on five items (head circumference, growth failure, neurosensorial signs, motor autonomy, communication skills) and validated by comparison with classical predefined severity subtypes of CS. Results Short stature, enophtalmos, hearing loss, cataracts, cutaneous photosensitivity, frequent dental caries, enamel hypoplasia, morphological abnormalities of the teeth, areflexia and spasticity were included in the clinical diagnostic score as being the most statistically relevant criteria. Appropriate weights and thresholds were assigned to obtain optimal sensitivity and specificity (95.7% and 86.4% respectively). The severity score was shown to be able to quantitatively differentiate classical predefined subtypes of CS and confirmed the continuous distribution of the clinical presentations in CS. Longitudinal follow-up of the severity score was able to reflect the natural course of the disease. Conclusion The diagnostic and severity scores for CS will facilitate early diagnosis and longitudinal evaluation of future therapeutic interventions. Prospective studies will be needed to confirm these findings.

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“…An autopsy analysis showed the uptake of nusinersen into motor neurons throughout the spinal cord and into neurons in the brainstem [18]. Increased motor function was manifested as an increased ability to sit or walk independently [19][20][21], increased bite force [22], and increased hand strength [23]. Although nusinersen is administered intrathecally, which requires a lot of expertise, it has been shown that such application is well tolerated and safe [24].…”

Section: Introductionmentioning

confidence: 99%

Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort

et al. 2021

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Spinal muscular atrophy (SMA) is a genetically heterogeneous group of rare neuromuscular diseases and was until recently the most common genetic cause of death in children. The effects of 2-month nusinersen therapy on urine, serum, and liquor 1H-NMR metabolomes in SMA males and females were not explored yet, especially not in comparison to the urine 1H-NMR metabolomes of matching male and female cohorts. In this prospective, single-centered study, urine, serum, and liquor samples were collected from 25 male and female pediatric patients with SMA before and after 2 months of nusinersen therapy and urine samples from a matching healthy cohort (n = 125). Nusinersen intrathecal application was the first therapy for the treatment of SMA by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Metabolomes were analyzed using targeted metabolomics utilizing 600 MHz 1H-NMR, parametric and nonparametric multivariate statistical analyses, machine learning, and modeling. Medical assessment before and after nusinersen therapy showed significant improvements of movement, posture, and strength according to various medical tests. No significant differences were found in metabolomes before and after nusinersen therapy in urine, serum, and liquor samples using an ensemble of statistical and machine learning approaches. In comparison to a healthy cohort, 1H-NMR metabolomes of SMA patients contained a reduced number and concentration of urine metabolites and differed significantly between males and females as well. Significantly larger data scatter was observed for SMA patients in comparison to matched healthy controls. Machine learning confirmed urinary creatinine as the most significant, distinguishing SMA patients from the healthy cohort. The positive effects of nusinersen therapy clearly preceded or took place devoid of significant rearrangements in the 1H-NMR metabolomic makeup of serum, urine, and liquor. Urine creatinine was successful at distinguishing SMA patients from the matched healthy cohort, which is a simple systemic novelty linking creatinine and SMA to the physiology of inactivity and diabetes, and it facilitates the monitoring of SMA disease in pediatric patients through non-invasive urine collection.

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Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4

Cited by 55 publications

References 32 publications

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment

Diagnostic and severity scores for Cockayne syndrome

Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort

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