Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders. METHODS: Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel. RESULTS: Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS. DISCUSSION: Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes

Brody myopathy demonstrates a pseudo-increment on repetitive nerve stimulation.

Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM. We performed exercise tests and repetitive nerve stimulation (RNS; 10 supramaximal stimuli at 3 Hz) in 10 patients with BM. All participants showed incremental responses on RNS. Compound muscle action potential amplitude was increased and duration was decreased, especially in the ulnar nerve (+30.2 ± 7.1% and - 30.3 ± 2.8%, respectively; both P < .001). Easily accessible, this sign, referred to as the Arzel sign, could prove to be a very useful tool in BM diagnosis and in broadening its phenotype

Whole-Body Muscle Magnetic Resonance Imaging in Glycogen-Storage Disease Type III

Introduction: The main objective of this study was to describe muscle involvement on whole-body magnetic resonance imaging scans in adults at different stages of glycogen-storage disease type III (GSDIII). Methods: Fifteen patients, 16\u201359 years of age, were examined on a 3-T system. The examinations consisted of coronal and axial T1-weighted images or fat images with a Dixon technique, and were scored for 47 muscles using Mercuri's classification. Muscle changes consisted of internal bright signals of fatty replacement. Results: Distribution across muscles showed predominant signal alteration in the lower limbs and postural muscles. This finding is consistent with the overall clinical presentation of GSDIII and the results of heatmap scores. Review of the MRI scans provided new information regarding recurrent muscle changes, particularly in the soleus, gastrocnemius medial head, and thoracic extensor muscles. Discussion: Whole-body muscle imaging provides clinically relevant information regarding muscle involvement in GSDIII. A severity score may contribute to improved patient management. Muscle Nerve, 2019

VP429 Impaired skeletal muscle strength in adult patients with laminopathies

Muscle is one of the most frequently affected tissues in laminopathies with loss of strength with or without joint contractures. Impairments in range of motion, grip strength and walking endurance have recently been measured in Hutchinson-Gilford progeria syndrome (Malloy et al. 2023). Here, we quantify muscle strength, joint contractures and walking in adult laminopathies (LGMD1B, EDMD, isolated dilated cardiomyopathy (DCM-CD) or partial lipodystrophy (PLD)). Handgrip and elbow/knee flexion/extension maximum isometric strength was measured by specific dynamometers. Strength and distance covered during a 6-minute walk test (6MWD) were expressed as a percentage of predicted value (%pred). The median(min,max) of the %pred values are presented here. So far, 30 participants aged 53(24,76) years, 20% male, have been included. Most had an impaired elbow flexion strength with a median below 100%pred regardless of phenotype: 17(6,44) for EDMD (n=3), 19(2,90) for myopathy+PLD (n=3), 51(16,65) for LGMD1B (n=9), 75(59,112) for PLD (n=9), 68 for Myopathy+DCM-CD (n=1) and 59(41,99) for DCM-CD (n=5). Elbow extension and flexion strengths were strongly correlated (rS=0.864,P<0.001), but not with elbow contracture. Handgrip strength was impaired in all participants with EDMD (61(58,62)) or myopathy+PLD (58(48,89)) and in some individuals with other phenotypes. The 6MWD was most affected in EDMD (45(0,78)), followed by myopathy+PLD (55(0,81)), LGMD1B (67(50,93)), PLD (87(66,101)), Myopathy+DCM-CD (92), and DCM-CD (98(69,103)). For all participants, knee extension and flexion strengths were strongly correlated (rS=0.730,P<0.001). The 6MWD was correlated with knee extension (rS=0.719,P<0.001) and flexion (rS=0.717,P<0.001) strength. At this stage of inclusion, no age dependence was observed for muscle strength or 6MWD. In conclusion, skeletal muscle weakness has been observed in the major phenotypes of laminopathies. Longitudinal follow-up is underway

SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages.

Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C &gt; G, c.379G &gt; A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C &gt; A variant, and one patient carried a new homozygous c.786 + 5G &gt; A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications

Cardiac Outcomes in Adults With Mitochondrial Diseases

Background: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE). Objectives: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population. Methods: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases. Results: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction <50% (HR: 10.2; 95% CI: 4.6-22.3), and premature ventricular beats (HR: 4.1; 95% CI: 1.7-9.9). Independent predictors for arrhythmia were single, large-scale mtDNA deletions (HR: 4.3; 95% CI: 1.7-10.4), conduction defects (HR: 6.8; 95% CI: 3.0-15.4), and LV ejection fraction <50% (HR: 2.7; 95% CI: 1.1-7.1). C-indexes of the Cox regression models were 0.91 (95% CI: 0.88-0.95) and 0.80 (95% CI: 0.70-0.90) for the HF and arrhythmic MACE, respectively. Conclusions: We developed the first prediction models for HF and arrhythmic MACE in patients with mitochondrial diseases using genetic variant type and simple cardiac assessments

Cardiac Outcomes in Adults With Mitochondrial Diseases

International audienceBackground: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE). Objectives: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population. Methods: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases. Results: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction <50% (HR: 10.2; 95% CI: 4.6-22.3), and premature ventricular beats (HR: 4.1; 95% CI: 1.7-9.9). Independent predictors for arrhythmia were single, large-scale mtDNA deletions (HR: 4.3; 95% CI: 1.7-10.4), conduction defects (HR: 6.8; 95% CI: 3.0-15.4), and LV ejection fraction <50% (HR: 2.7; 95% CI: 1.1-7.1). C-indexes of the Cox regression models were 0.91 (95% CI: 0.88-0.95) and 0.80 (95% CI: 0.70-0.90) for the HF and arrhythmic MACE, respectively. Conclusions: We developed the first prediction models for HF and arrhythmic MACE in patients with mitochondrial diseases using genetic variant type and simple cardiac assessments