Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

OBJECTIVE: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year. METHODS: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis. RESULTS: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint. CONCLUSION: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials. CLINICALTRIALSGOV IDENTIFIER: NCT01676077.

Long term longitudinal study of muscle function in patients with glycogen storage disease type IIIa.

Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required. In this study we present preliminary longitudinal data of Motor Function Measure (MFM), timed tests, Purdue pegboard test, and handgrip strength collected over 5 to 9years of follow-up in 13 patients with GSDIII aged between 13 and 56years old. Follow-up for nine of the 13 patients was up to 9years. Similarly to our previous cross-sectional retrospective study, handgrip strength significantly decreased with age in patients older than 37years. MFM scores started to decline after the age of 35. The Purdue pegboard score also significantly reduced with increasing age (from 13years of age) but with large inter-visit variations. The time to stand up from a chair or to climb 4 stairs increased dramatically in some but not all patients older than 30years old. In conclusion, this preliminary longitudinal study suggests that MFM and handgrip strength are the most sensitive muscle function outcome measures in GSDIII patients from the end of their third decade. Sensitive muscle outcome measures remain to be identified in younger GSDIII patients but is challenging as muscle symptoms remain discrete and often present as accumulated fatigue.

The diagnostic value of hyperammonaemia induced by the non-ischaemic forearm exercise test.

AIMS: The non-ischaemic forearm exercise test (NIFET) is used as a diagnostic tool for the screening of patients with exercise intolerance and for the diagnosis of various metabolic muscle disorders. The production of lactate and ammonia are generally analysed to guide the diagnosis. The aim of this retrospective study was to determine the level of ammonia rise, which can be suggestive of a muscle disease. METHODS: This retrospective study involved 1440 patients who underwent NIFET. The clinical files of the patients with hyperammonaemia were methodically studied. Normal values were derived from 60 healthy controls. RESULTS: 110 patients with hyperammonaemia were detected. They were classified as either having mild (between 94 and 141 µmol/L) or severe (more than 141 µmol/L) hyperammonaemia. Their diagnosis was studied with respect to the increase in lactate induced by the NIFET. CONCLUSIONS: Severe postexercise hyperammonaemia, even in the presence of a normal lactate response, is strongly suggestive of a muscle glycogen storage disease. Mild hyperammonaemia in the absence of other abnormalities is most likely non-specific and not indicative of a muscle disease.

Relationships between grip strength, myotonia, and CTG expansion in myotonic dystrophy type 1.

In myotonic dystrophy type 1, several studies have suggested causal relationships between CTG repeat length and the severity of symptoms, such as weakness or myotonia. We aimed to explore these relationships in a large population of 144 DM1 patients. All patients underwent clinical and functional assessments using a standardized test for grip strength and myotonia assessment. Myotonia was assessed using a fully automatic software based on mathematical modeling of relaxation force curve. CTG repeat length was statistically correlated with both myotonia and grip strength, which are two major primary neuromuscular symptoms of DM1 patients. However, these relationships are not clinically meaningful and not predictive at the individual level.

Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III.

Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1.49, 1.10 and 0.70% of the predicted values (%pred), respectively. The MFM score and handgrip strength were also age-sensitive but only in patients older than 29 and 37 years old with annual losses of 1.42 and 1.84%pred, respectively. Muscle strength assessed by MMT and elbow extension measured by HHD demonstrated an annual loss of less than 0.50%pred and are thus unlikely to be promising outcome measures for future clinical trials. In conclusion, our results identified age-sensitive outcomes from retrospective data and may serve for future longitudinal studies in which an estimation of the minimal number of subjects is provided.

Relationship between muscle impairments, postural stability, and gait parameters assessed with lower-trunk accelerometry in myotonic dystrophy type 1.

This study evaluated gait using lower-trunk accelerometry and investigated relationships between gait abnormalities, postural instability, handgrip myotonia, and weakness in lower-limb and axial muscle groups commonly affected in myotonic dystrophy type 1 (DM1). Twenty-two patients (11 men, 11 women; age = 42 years (range: 26-51)) with DM1 and twenty healthy controls (9 men, 11 women; age = 44 years (range: 24-50)) participated in this study. Gait analysis using lower-trunk accelerometry was performed at self-selected walking pace. Postural stability was measured via center of pressure displacement analysis using a force platform during eyes-closed normal stance. Handgrip myotonia was quantified using force-relaxation curve modeling. Patients displayed lower walking speed, stride frequency, stride length, gait regularity, and gait symmetry. Strength of ankle plantar flexors, ankle dorsal flexors and neck flexors correlated with interstride regularity in the vertical direction (ρ = 0.57, ρ = 0.59, and ρ = 0.44, respectively; all P < 0.05). Knee extension strength correlated with gait symmetry in the anteroposterior direction (ρ = 0.45, P < 0.05). Center of pressure velocity was greater in patients and correlated with neck flexion and ankle plantar flexion weakness (ρ = -0.51 and ρ = -0.62, respectively; both P < 0.05), and with interstride regularity in the vertical direction (ρ = -0.58, P < 0.05). No correlation was found between handgrip myotonia and any other variable studied. Lower-trunk accelerometry allows the characterization of gait pattern abnormalities in patients with DM1. Further studies are required to determine the relevance of systematic gait analysis using lower-trunk accelerometry for patient follow-up and intervention planning.

Longitudinal functional and NMR assessment of upper limbs in Duchenne muscular dystrophy.

OBJECTIVE: To explore the value of nuclear magnetic resonance (NMR) and functional assessments for follow-up of ambulatory and nonambulatory patients with Duchenne muscular dystrophy (DMD). METHODS: Twenty-five 53-skippable patients with DMD were included in this study; 15 were nonambulatory at baseline. All patients underwent clinical and functional assessments every 6 months using the Motor Function Measure (MFM), hand grip and key pinch strength, MoviPlate, and NMR spectroscopy and imaging studies. RESULTS: Upper limb distal strength decreased in nonambulatory patients over the period of 1 year; ambulatory patients showed improvement during the same period. The same applied for several NMRS indices, such as phosphocreatine/adenosine triphosphate, which decreased in older patients but increased in younger ambulatory patients. Fat infiltration in the upper limbs increased linearly with age. Almost all NMR and functional assessment results correlated. CONCLUSIONS: Our results underscore complementarity of functional and NMR assessments in patients with DMD. Sensitivity to change of various indices may differ according to disease stage.

Wrist flexion and extension torques measured by highly sensitive dynamometer in healthy subjects from 5 to 80 years.

BACKGROUND: Wrist movements become impaired with disease progression in various neuromuscular disorders. With the development of new therapies, thorough measurement of muscle strength is crucial to document natural disease progression and to assess treatment efficacy. We developed a new dynamometer enabling wrist flexion and extension torque measurement with high sensitivity. The aims of the present study were to collect norms for healthy children and adults, to compute predictive equations, to assess the reliability of the measurements and to test the feasibility of using the device in patients with a neuromuscular disease. METHODS: The peak isometric torque of wrist flexion and extension was measured with the MyoWrist dynamometer in 345 healthy subjects aged between 5 and 80 years old and in 9 patients with limb girdle muscle dystrophy type 2 C (LGMD2C) aged between 16 and 38 years old. RESULTS: Predictive equations are proposed for the wrist flexion and extension strength in children and adults. Intra-rater and inter-rater reliability was good with ICCs higher than 0.9 for both wrist flexion and extension. However, retest values were significantly higher by 4% than test results. The dynamometer was applied with no difficulty to patients with LGMD2C and was sensitive enough to detect strength as weak as 0.82 N.m. From our models, we quantified the mean strength of wrist extension in LGMD2C patients to 39 ± 17% of their predicted values. CONCLUSIONS: The MyoWrist dynamometer provides reliable and sensitive measurement of both wrist flexion and extension torques. However, a training session is recommended before starting a study as a small but significant learning effect was observed. Strength deficit can be quantified from predictive equations that were computed from norms of healthy children and adults.

Four-year longitudinal study of clinical and functional endpoints in sporadic inclusion body myositis: implications for therapeutic trials.

Natural history studies in sporadic inclusion body myositis are of fundamental interest for future therapeutic trials. Previous works have demonstrated the particular relevance of knee extension strength in the follow-up of this disease. This work aimed to extend a preceding natural history over 9 months to a four year period. Thirteen patients were assessed using clinical and functional scales and dynamometry. Except wrist extension torque and manual muscle testing composite score, all the measurements presented a significant decline. The most important changes were observed for knee extension and ankle flexion and extension. The relative change in knee extension strength correlated with the level of strength at baseline. A non-linear correlation was found between 6-minute walk distance and knee extension strength. This study confirms that knee extension strength is particularly relevant to follow patients with sporadic inclusion body myositis. It also shows that a strength loss does not have linear consequences on motor ability. Finally strength and motor ability are complementing each other in the understanding of disease progression.

Effects of recombinant human growth hormone for 1 year on body composition and muscle strength in children on long-term steroid therapy: randomized controlled, delayed-start study.

CONTEXT: Recombinant human GH (rhGH) improves growth and body composition in glucocorticoid-treated children. Its effects on muscle strength are poorly evaluated. OBJECTIVES: Our objective was to evaluate rhGH effects on muscle strength in children receiving long-term glucocorticoid therapy; effects on height SD score (SDS) and body composition were assessed also. DESIGN AND SETTING: A randomized, controlled, delayed-start study of rhGH for 12 months was started after randomization (baseline) or 6 months later (M6). PATIENTS: Patients included 30 children with various diagnoses. INTERVENTION: rhGH was administered at 0.065 mg/kg/d for 6 months and then in the dosage maintaining serum IGF-I levels below +2 SDS for chronological age. MAIN OUTCOME MEASURES: The primary criterion was the between-group difference in composite index of muscle strength (CIMS) change at M6. Secondary criteria included between-group differences in CIMS SDS(height), lean mass (LM), thigh muscle area (MA), and height SDS changes at M6; these parameters were also assessed in the overall population after 1 year of rhGH therapy. RESULTS: At M6, rhGH therapy did not significantly affect changes in CIMS or CIMS SDS(height) (+17.6% vs +7.5% and +0.14 ± 0.38 vs +0.11 ± 0.62, respectively); the rhGH-treated group had significantly larger changes in height SDS (+0.2 [0.3] vs -0.2 [0.3]; P = 0.003), LM (+7.3% [+3.7%; +21.6%] vs 0% [-4.7%; +3.2%]; P = 0.002), and MA (+8.8% [+5%; +15.6%] vs. -0.6% [-6.3%; +7.7%]; P = 0.01) compared with the untreated group. After 1 year of rhGH, height SDS, LM, and MA increased significantly, CIMS increased by 24.7% (+5.8%; +34.2%), and CIMS SDS(height) remained within the normal range. CONCLUSIONS: rhGH increased height, LM, and MA. However, muscle strength did not improve significantly.

Ankle dorsi- and plantar-flexion torques measured by dynamometry in healthy subjects from 5 to 80 years.

BACKGROUND: Ankle strength is often impaired in some of the most common neuromuscular disorders. Consequently, strength generated around this joint is important to assess, because it has a great impact on balance and gait. The objectives of this study were to establish normative data and predictive equations for both ankle dorsi- and plantar-flexion strength from a population of healthy subjects (children and adults), to assess the reliability of the measurements and to study the feasibility of using a novel dynamometer on a group of patients with a neuromuscular disorder. METHODS: Measurements of maximal isometric torque for dorsi- and plantar-flexion were performed on 345 healthy subjects from 5 to 80 years of age. The feasibility of the method was tested on nine patients diagnosed with type 2A limb girdle muscular dystrophy. RESULTS: The results documented normal strength values depending on gender and age on ankle dorsi- and plantar-flexion. The reliability of the technique was good with no evaluator effect and a small learning effect. The dynamometer was found suitable in the group of patients, even very weak. CONCLUSIONS: The device developed was both reliable and accurate in assessing both ankle dorsi-flexion and plantar-flexion torque measurements from weak patients and children to strong healthy adults. Norms and predictive equations are provided for these two muscle functions.

Stature is an essential predictor of muscle strength in children.

BACKGROUND: Children with growth retardation or short stature generally present with lower strength than children of the same chronological age. The aim of the study was to establish if strength was dependent on variables related to stature in a population of healthy children and to propose practical predictive models for the muscle functions tested. A secondary aim was to test for any learning effects concerning strength measured at two successive visits by children. METHODS: Hand grip, elbow flexion and extension, and knee flexion and extension were measured by fixed dynamometry in 96 healthy subjects (47 girls and 49 boys, aged from 5 to 17 years). RESULTS: For the present paediatric population, muscle strength was highly dependent on height. Predictive models are proposed for the muscle functions tested. No learning effect between the first and the second visit was detected for any of the muscle functions tested. CONCLUSIONS: This work shows that strength measurements using fixed dynamometry are reliable in children when using appropriate standardization of operating procedures. It underlines the particular relationship between body stature and muscle strength. Predictive equations may help with assessing the neuromuscular involvement in children suffering from various disorders, particularly those affecting their stature.

Development of a French isometric strength normative database for adults using quantitative muscle testing.

OBJECTIVE: To establish a normative database for isometric strength measured by quantitative muscle testing (QMT) for a French adult population. DESIGN: Measurement of maximal voluntary isometric contraction. SETTING: Four clinical centers involved in neuromuscular disorders. PARTICIPANTS: A total of 315 healthy adults (147 men, 168 women) ages 20 to 80 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Isometric torque values of 14 muscle functions (13 bilaterally and neck). RESULTS: This study led to the development of a French isometric strength normative database for adults measured by QMT. For each muscle function, predictive regression models using age, sex, and weight are proposed. Some methodologic issues concerning strength measurement are discussed. CONCLUSIONS: This database can be used to compute relative deficits in muscle strength for 27 muscle functions and also to estimate composite scores for follow-up of patients either during the natural history of their disease or during a therapeutic trial.