A c.1775C > T Point Mutation of Sodium Channel Alfa Subunit Gene (SCN4A) in a Three-Generation Sardinian Family with Sodium Channel Myotonia.

Background: The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. Methods: Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro electrophysiology, site-directed mutagenesis and heterologous expression were collected. Results: A heterozygous point mutation (c.1775C >  T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude. Conclusions: The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia.

Efgartigimod in generalized myasthenia gravis: A real-life experience at a national reference center.

BACKGROUND AND PURPOSE: Inhibition of the neonatal Fc receptor (FcRn) for IgG is a promising new therapeutic strategy for antibody-mediated disorders. We report our real-life experience with efgartigimod (EFG) in 19 patients with generalized myasthenia gravis (gMG) along a clinical follow-up of 14 months. METHODS: EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of two treatment cycles [given 1 month apart] of four infusions at weekly intervals, followed by a Flexible period of re-cycling in case of worsening). Eight patients were positive for acetylcholine receptor antibody, four for muscle-specific tyrosine kinase antibody, and two for lipoprotein-related protein 4 antibody, and five were classified as triple negative. Efficacy of EFG was assessed by the Myasthenia Gravis Activities of Daily Living, Myasthenia Gravis Composite, and Quantitative Myasthenia Gravis scales. RESULTS: Fifty-three percent of patients needed three treatment cycles, 26% needed four, and 21% needed five along the 14-month clinical follow-up. Meaningful improvement was observed at the end of each cycle with the clinical scores adopted. EFG had a dramatic effect on disease course, as during the year before treatment eight of 19 patients (42%) were hospitalized, and 15 of 19 (79%) needed treatment with plasma exchange or immunoglobulins; three of 19 (16%) were admitted to the intensive care unit. During EFG, none of the patients was hospitalized and only one patient required plasma exchange and intravenous immunoglobulins. No major side effects or infusion-related reactions occurred. CONCLUSIONS: We observed that EFG was safe and modified significantly the course of the disease along a 14-month follow-up. Our experience strengthens the role of FcRn inhibition as an effective new tool for long-term treatment of gMG.

Physical activity practiced at a young age is associated with a less severe subsequent clinical presentation in facioscapulohumeral muscular dystrophy.

BACKGROUND: In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA). METHODS: People aged between 18 and 60 were recruited as being DRA carriers. Subcategory (classical phenotype, A; incomplete phenotype, B; asymptomatic carriers, C; complex phenotype, D) and FSHD score, which measures muscle functional impairment, were assessed for all participants. Information on PAs was retrieved by using an online survey dealing with the practice of sports at a young age. RESULTS: 368 participants were included in the study, average age 36.6 years (SD = 9.4), 47.6% male. The FSHD subcategory A was observed in 157 (42.7%) participants with average (± SD) FSHD score of 5.8 ± 3.0; the incomplete phenotype (category B) in 46 (12.5%) participants (average score 2.2 ± 1.7) and the D phenotype in 61 (16.6%, average score 6.5 ± 3.8). Asymptomatic carriers were 104 (subcategory C, 28.3%, score 0.0 ± 0.2). Time from symptoms onset was higher for patients with A (15.8 ± 11.1 years) and D phenotype (13.3 ± 11.9) than for patients with B phenotype (7.3 ± 9.0). The practice of sports was associated with lower FSHD score (-17%) in participants with A phenotype (MR = 0.83, 95% CI = 0.73-0.95, p = 0.007) and by 33% in participants with D phenotype (MR = 0.67, 95% CI = 0.51-0.89, p = 0.006). Conversely, no improvement was observed in participants with incomplete phenotype with mild severity (B). CONCLUSIONS: PAs at a young age are associated with a lower clinical score in the adult A and D FSHD subcategories. These results corroborate the need to consider PAs at the young age as a fundamental indicator for the correct clinical stratification of the disease and its possible evolution.

Respiratory function in a large cohort of treatment-naïve adult spinal muscular atrophy patients: a cross-sectional study.

Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72). Fifty-six (37 %) and 41 (31 %) patients had abnormal (<80 %) values of FVC and FEV1, respectively. Fourteen (14 %) patients needed NIV, started at median age of 21 (range 4-68). Motor function, measured by Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module as well as SMA2, loss of walking ability, surgery for scoliosis, use of NIV, and cough assisting device (CAD) were all significantly associated to lower FVC and FEV1 values, while no association with age at baseline, disease duration, gender or 6 min walking test was observed, except for a correlation between FVC and age in SMA3 walkers (p < 0.05). In conclusion, respiratory function in adult SMA patients is relatively frequently impaired, substantially stable, and significantly correlated with motor function and disease severity.

Diagnostics in skeletal muscle channelopathies.

INTRODUCTION: Skeletal muscle channelopathies (SMCs) are a heterogenous group of disorders, caused by mutations in skeletal ion channels leading to abnormal muscle excitability, resulting in either delayed muscle relaxation (myotonia) which characterizes non-dystrophic myotonias (NDMs), or membrane transient inactivation, causing episodic weakness, typical of periodic paralyses (PPs). AREAS COVERED: SMCs include myotonia congenita, paramyotonia congenita, and sodium-channel myotonia among NDMs, and hyper-normokalemic, hypokalemic, or late-onset periodic paralyses among PPs. When suspecting an SMC, a structured diagnostic approach is required. Detailed personal and family history and clinical examination are essential, while neurophysiological tests should confirm myotonia and rule out alternative diagnosis. Moreover, specific electrodiagnostic studies are important to further define the phenotype of de novo cases and drive molecular analyses together with clinical data. Definite diagnosis is achieved through genetic testing, either with Sanger sequencing or multigene next-generation sequencing panel. In still unsolved patients, more advanced techniques, as exome-variant sequencing or whole-genome sequencing, may be considered in expert centers. EXPERT OPINION: The diagnostic approach to SMC is still mainly based on clinical data; moreover, definite diagnosis is sometimes complicated by the difficulty to establish a proper genotype-phenotype correlation. Lastly, further studies are needed to allow the genetic characterization of unsolved patients.

Safety outcomes and patients' preferences for home-based intravenous enzyme replacement therapy (ERT) in pompe disease and mucopolysaccharidosis type I (MPS I) disorder: COVID-19 and beyond.

BACKGROUND: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting. RESULTS: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%). CONCLUSIONS: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.

Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

OBJECTIVE: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies. METHODS: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA). RESULTS: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow-up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross-sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43). INTERPRETATION: Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023;94:1126-1135.

Novel HSPG2 Gene Mutation Causing Schwartz-Jampel Syndrome in a Moroccan Family: A Literature Review.

Schwartz-Jampel syndrome type 1 (SJS1) is a rare autosomal recessive musculoskeletal disorder caused by various mutations in the HSPG2 gene encoding the protein perlecan, a major component of basement membranes. We report a novel splice mutation HSPG2(NM_005529.7):c.3888 + 1G > A and a known point mutation HSPG2(NM_005529.7):c.8464G > A, leading to the skipping of exon 31 and 64 in mRNA, respectively, in a Moroccan child with clinical features suggestive of SJS1 and carrying two compound heterozygous mutations in the HSPG2 gene detected by next-generation sequencing. Both parents harboured one mutation. Real-time and immunostaining analysis revealed down-regulation of the HSPG2 gene and a mild reduction in the protein in the muscle, respectively. We reviewed all genetically characterized SJS1 cases reported in literature, confirming the clinical hallmarks and unspecific instrumental data in our case. The genotype-phenotype correlation is very challenging in SJS1. Therapy is mainly focused on symptom management and several drugs have been administered with different efficacy.Here, we report the second case with spontaneous improvement.

Toll-like receptors and IL-7 as potential biomarkers for immune-mediated necrotizing myopathies.

We aimed to verify whether the immune system may represent a source of potential biomarkers for the stratification of immune-mediated necrotizing myopathies (IMNMs) subtypes. A group of 22 patients diagnosed with IMNM [7 with autoantibodies against signal recognition particle (SRP) and 15 against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR)] and 12 controls were included. A significant preponderance of M1 macrophages was observed in both SRP+ and HMGCR+ muscle samples (p < 0.0001 in SRP+ and p = 0.0316 for HMGCR+ ), with higher values for SRP+ (p = 0.01). Despite the significant increase observed in the expression of TLR4 and all endosomal Toll-like receptors (TLRs) at protein level in IMNM muscle tissue, only TLR7 has been shown considerably upregulated compared to controls at transcript level (p = 0.0026), whereas TLR9 was even decreased (p = 0.0223). Within IMNM subgroups, TLR4 (p = 0.0116) mRNA was significantly increased in SRP+ compared to HMGCR+ patients. Within IMNM group, only IL-7 was differentially expressed between SRP+ and HMGCR+ patients, with higher values in SRP+ patients (p = 0.0468). Overall, innate immunity represents a key player in pathological mechanisms of IMNM. TLR4 and the inflammatory cytokine IL-7 represent potential immune biomarkers able to differentiate between SRP+ and HMGCR+ patients.

NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia.

Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors.

Protein Aggregates and Aggrephagy in Myopathies.

A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about the direct involvement of aggrephagy and the activation of the key players, among others, p62, NBR1, Alfy, Tollip, Optineurin, TAX1BP1 and CCT2 in muscular diseases. In the first part of the review, we describe the aggrephagy pathway with the involved proteins; then, we illustrate the muscular disorder histologically characterized by protein aggregates, highlighting the role of aggrephagy pathway abnormalities in these muscular disorders.

Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD).

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Novel DPAGT1 Gene Mutation in Two Twins with Congenital Myasthenic Syndrome and a Review of the Literature.

Congenital myasthenic syndromes (CMS) are rare diseases caused by mutation in genes coding for proteins involved in neuromuscular junction structure and function. DPAGT1 gene mutations are a rare cause of CMS whose clinical evolution and pathophysiological mechanisms have not been clarified completely. We present the case of two twins displaying an infancy-onset predominant limb-girdle phenotype and carrying a novel DPAGT1 mutation associated with unusual histological and clinical findings. CMS can mimic paediatric and adult limb-girdle phenotype, hence neurophysiology plays a fundamental role in the differential diagnosis.

VCP-related myopathy: a case series and a review of literature.

The valosin-containing protein (VCP), a widely expressed protein, controls the ubiquitin-proteasome system, endolysosomal sorting, and autophagy to maintain cellular proteostasis. Frontotemporal dementia (FTD), inclusion body myopathy, and Paget's disease of the bone (PDB) are all caused by dominant missense mutations in the VCP gene, which interfere with these mechanisms and cause a multisystem proteinopathy. We describe phenotypic and genetic findings of five patients with four different mutations in VCP gene (NM_007126): c.278G > A (p.R93H), c.463C > T (p.R155C), c.410C > T (p.P137L), c.464G > A (p.R155H), c.410C > T (p.P137L). We analysed the patient' biopsies, all characterized by a muscular phenotype, and we executed immunofluorescence staining to evaluate the presence of proteins: p62, VCP, desmin, myotilin, TDP-43. Eventually we performed a brief literature review to compare our cases with those already reported. Our report strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement, as occasionally reported in the literature. Particularly, our patient with R93H shows only myopathic involvement while this mutation has been described once associated only to Hereditary Spastic Paraplegia. Further study will be necessary to understand such a broad and different clinical spectrum.

Anoctamin-5 related muscle disease: clinical and genetic findings in a large European cohort.

Anoctamin-5 related muscle disease is caused by biallelic pathogenic variants in the anoctamin-5 gene (ANO5) and shows variable clinical phenotypes: limb-girdle muscular dystrophy type 12 (LGMD-R12), distal muscular dystrophy type 3 (MMD3), pseudometabolic myopathy or asymptomatic hyperCKaemia. In this retrospective, observational, multicentre study we gathered a large European cohort of patients with ANO5-related muscle disease to study the clinical and genetic spectrum and genotype-phenotype correlations. We included 234 patients from 212 different families, contributed by 15 centres from 11 European countries. The largest subgroup was LGMD-R12 (52.6%), followed by pseudometabolic myopathy (20.5%), asymptomatic hyperCKaemia (13.7%) and MMD3 (13.2%). In all subgroups, there was a male predominance, except for pseudometabolic myopathy. Median age at symptom onset of all patients was 33 years (range 23-45 years). The most frequent symptoms at onset were myalgia (35.3%) and exercise intolerance (34.1%), while at last clinical evaluation most frequent symptoms and signs were proximal lower limb weakness (56.9%) and atrophy (38.1%), myalgia (45.1%) and atrophy of the medial gastrocnemius muscle (38.4%). Most patients remained ambulatory (79.4%). At last evaluation, 45.9% of patients with LGMD-R12 additionally had distal weakness in the lower limbs and 48.4% of patients with MMD3 also showed proximal lower limb weakness. Age at symptom onset did not differ significantly between males and females. However, males had a higher risk of using walking aids earlier (P = 0.035). No significant association was identified between sportive versus non-sportive lifestyle before symptom onset and age at symptom onset nor any of the motor outcomes. Cardiac and respiratory involvement that would require treatment occurred very rarely. Ninety-nine different pathogenic variants were identified in ANO5 of which 25 were novel. The most frequent variants were c.191dupA (p.Asn64Lysfs*15) (57.7%) and c.2272C>T (p.Arg758Cys) (11.1%). Patients with two loss-of function variants used walking aids at a significantly earlier age (P = 0.037). Patients homozygous for the c.2272C>T variant showed a later use of walking aids compared to patients with other variants (P = 0.043). We conclude that there was no correlation of the clinical phenotype with the specific genetic variants, and that LGMD-R12 and MMD3 predominantly affect males who have a significantly worse motor outcome. Our study provides useful information for clinical follow up of the patients and for the design of clinical trials with novel therapeutic agents.

Coexistence of SCN4A and CLCN1 mutations in a family with atypical myotonic features: A clinical and functional study.

Non-dystrophic myotonias include several entities with possible clinical overlap, i.e. myotonia congenita caused by CLCN1 gene mutations, as well as paramyotonia congenita and sodium channel myotonia caused by SCN4A gene mutations. Herein, we describe the clinical features of five relatives affected by clinical and neurophysiological myotonia, with an aspecific and mixed phenotype. Next-generation sequencing identified the novel p.K1302R variant in SCN4A and the p.H838P variant in CLCN1. Segregation of the two mutations with the disease was confirmed by genotyping affected and non-affected family members. Patch-clamp experiments showed that sodium currents generated by p.K1302R and WT hNav1.4 were very similar. Mutant channel showed a small negative shift (5 mV) in the voltage-dependence of activation, which increased the likelihood of the channel to open at more negative voltages. The p.H838P mutation caused a reduction in chloride current density and a small voltage-dependence shift towards less negative potentials, in agreement with its position into the CBS2 domain of the C-terminus. Our results demonstrated that the mild functional alterations induced by p.K1302R and p.H838P in combination may be responsible for the mixed myotonic phenotypes. The K1302R mutant was sensitive to mexiletine and lamotrigine, suggesting that both drugs might be useful for the K1302R carriers.

Opportunities for an early recognition of spinal muscular atrophy in primary care: a nationwide, population-based, study in Italy.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare genetic disease with a broad spectrum of severity. Although an early diagnosis of SMA is crucial to allow proper management of patients, the diagnostic delay is still an issue. Therefore, this study aimed to investigate the clinical correlates of SMA among primary care patients. METHODS: The Health Search Database (HSD) was adopted. To estimate the prevalence and incidence rate of SMA, a cohort study was conducted on the population (aged ≥6 years) being registered in HSD from 1 January 2000 up to 31 December 2019. To investigate the clinical correlates of SMA, a nested case-control study was performed. SMA cases have been classified according to a clinically based iterative process as "certain", "probable" or "possible". To test the association between clinical correlates and SMA cases a multivariate conditional logistic regression model was estimated. RESULTS: The SMA prevalence combining "certain", "probable" and "possible" cases was 5.1 per 100,000 in 2019 (i.e. 1.12 per 100,000 when limited to "certain" cases), while the yearly incidence rate ranged from 0.12 to 0.56 cases per 100,000. Comparing "certain" cases with matched controls, the presence of neurology visits (OR = 6.5; 95% CI: 1.6-25.6) and prescription of electromyography (OR = 4.6; 95% CI: 1.1-18.7) were associated with higher odds of SMA diagnosis. CONCLUSIONS: Our findings suggest that primary care databases may be used to enhance the early identification of SMA. Additional efforts are needed to exploit the electronic health records of general practitioners to allow early recognition of SMA.