Proximal Weakness Research Articles

Autosomal recessive VWA1-related disorder: comprehensive analysis of phenotypic variability and genetic mutations

Abstract A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain containing 1 (VWA1). This study further delineates the disease characteristics in a cohort of 20 individuals diagnosed through genome or exome sequencing, incorporating neurophysiological, laboratory, and imaging data, along with data from previously reported cases across three different studies. Newly reported clinical features include hypermobility/hyperlaxity, axial weakness, dysmorphic signs, asymmetric presentation, dystonic features, and, notably, upper motor neuron signs. Foot drop, foot deformities, and distal leg weakness followed by early proximal leg weakness are confirmed to be initial manifestations. Additionally, this study identified 11 novel VWA1 variants, reaffirming the 10bp insertion-induced p.Gly25ArgfsTer74 as the most prevalent disease-causing allele, with a carrier frequency of ∼1 in 441 in the UK and Western European population. Importantly, VWA1-related pathology may mimic various neuromuscular conditions, advocating for its inclusion in diverse gene panels spanning hereditary neuropathies to muscular dystrophies. The study highlights the potential of lower quality control filters in exome analysis to enhance diagnostic yield of VWA1-disease that may account for up to 1% of unexplained hereditary neuropathies.

Clinical characteristics of idiopathic inflammatory myopathies related to anti-SRP: a single center experience

Idiopathic inflammatory myopathy (IIM) with autoantibodies recognizing the signal recognition particle (SRP) is characterized by prominent proximal weakness, infrequent extramuscular involvement, dramatically elevated creatine kinase levels, and myofiber necrosis with few inflammatory cell infiltrates in muscle tissue. To enhance understanding of the clinically used diagnosis and treatment of this disease, this study presents a single-center experience and analysis of a Chinese cohort with anti-SRP IIM. The most recent European Neuromuscular Center criteria were used to include Anti-SRP IIM patients from September 2016 to November 2019. Prior to treatment initiation, all sera were collected for the detection of anti-SRP autoantibodies and other myositis-related autoantibodies. Muscle strength, concurrent autoimmune conditions, comorbidities like interstitial lung disease (ILD), treatment outcomes, and follow-up results were also documented. Univariate logistic regression was employed to determine factors affecting prognosis. Among 271 patients with IIM, we identified 23 (8.5%) patients with anti-SRP IIM. Lower limb muscle weakness was frequently more severe. Interstitial lung disease (ILD) was observed in 50% of anti-SRP IIM patients. The presence of ILD may serve as a predictor of a poor prognosis, as revealed by univariate logistic regression analysis (odds ratio, 3.8, 95% CI: 1.0-6.8, p = 0.05).This Chinese Anti-SRP IIM cohort from Hunan province seems to have higher incidences of ILD, and associated ILD may be a risk factor for a poor prognosis. To fully understand the specific role of the anti-SRP autoantibody in this unique subset with ILD, further research is necessary.

Comment on: Critically ill neuropathy alone is sufficient to explain proximal limb weakness and femoral nerve damage in severe SARS-CoV-2 infection.

Comment on: Critically ill neuropathy alone is sufficient to explain proximal limb weakness and femoral nerve damage in severe SARS-CoV-2 infection.

Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease.

Pathogenic variants in the titin gene (TTN) are known to cause a wide range of cardiac and musculoskeletal disorders, with skeletal myopathy mostly attributed to biallelic variants. We identified monoallelic truncating variants (TTNtv), splice site or internal deletions in TTN in probands with mild, progressive axial and proximal weakness, with dilated cardiomyopathy frequently developing with age. These variants segregated in an autosomal dominant pattern in 7 out of 8 studied families. We investigated the impact of these variants on mRNA, protein levels, and skeletal muscle structure and function. Results reveal that nonsense-mediated decay likely prevents accumulation of harmful truncated protein in skeletal muscle in patients with TTNtvs. Splice variants and an out-of-frame deletion induce aberrant exon skipping, while an in-frame deletion produces shortened titin with intact N- and C-termini, resulting in disrupted sarcomeric structure. All variant types were associated with genome-wide changes in splicing patterns, which represent a hallmark of disease progression. Lastly, RNA-seq studies revealed that GDF11, a member of the TGF-β superfamily, is upregulated in diseased tissue, indicating that it might be a useful therapeutic target in skeletal muscle titinopathies.

Further insights into anti-IgLON5 disease: a case with complex clinical presentation

BackgroundAnti-IgLON5 disease is an autoimmune encephalitis overlapping with neurodegenerative disorders due to pathological accumulation of hyperphosphorylated tau. It is characterized by several clinical manifestations determined by involvement of different brain areas, and mild response to first-line immunotherapies. We report a case of anti-IgLON5 disease with a multifaceted semiology and an unusually good response to glucocorticoid monotherapy.Case presentationA 68-year-old man with type 2 diabetes was evaluated for an 8-month history of progressive gait disorder causing frequent falls. He also suffered from obstructive sleep apneas and complained of dysphonia, dysarthria, occasional dysphagia, urinary incontinence, and upper limb action tremor. Neurological examination demonstrated bilateral eyelid ptosis, limitation of ocular horizontal smooth pursuit movements, slow horizontal saccades, and lack of inhibition of the vestibulo-ocular reflex during rapid horizontal head torsions. The patient also displayed involuntary, slow, rhythmic movements of the left periorbital and perioral muscles, spreading to the ipsilateral hemipalate and hemitongue, along with bilateral negative upper limb myoclonus. There were proximal muscle wasting in the upper limbs, proximal weakness of the four limbs, and diffuse fasciculations. Ataxia of stance and gait and of the four limbs was noted. MRI of the brain and spine was unremarkable; nerve conduction studies revealed a chronic, predominantly demyelinating, sensory-motor polyneuropathy, probably due to diabetes. Routine CSF examination was unrevealing and serum GFAP level was 89.6 pg/mL; however, the autoimmunity tests revealed a high-titer positivity for anti-IgLON5 autoantibodies in both CSF and serum, leading to the diagnosis of anti-IgLON5 disease. Symptoms improved significantly after intravenous methylprednisolone.ConclusionsHemifacial and hemiorolingual myorhythmia along with peculiar oculomotor abnormalities characterizes the multifaceted clinical picture of our case. The complex semiology of our patient may reflect multifocal targeting of the autoimmune process or sequential spreading of tau inclusions in different brain areas. Our patient’s optimal response to glucocorticoid monotherapy could be underpinned by a slightly different phenotype in which autoimmunity plays a greater pathogenic role than tauopathy, with a lower burden of tau deposition. In such patients, neurodegeneration and tau accumulation could be merely secondary to immune-mediated neuronal dysfunction, supporting the existence of a group of glucocorticoid-responsive patients.

Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.

Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes. Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells. We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands' fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies. Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes with coexisting nemaline myopathy: a case report

BackgroundMitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and nemaline myopathy are two rare genetic conditions. We report the first case reported in world literature with coexistence of both these rare disorders.Case presentationA 11-year-old previously healthy Sri Lankan male child, product of a nonconsanguineous marriage with normal development presented with acute onset short lasting recurring episodes of right-sided eye deviation with impaired consciousness. In between episodes he regained consciousness. Family history revealed a similar presentation in the mother at 36 years of age. Examination was significant for short stature and proximal upper and lower limb weakness. His plasma and cerebrospinal fluid lactate were elevated. Magnetic resonance imaging brain had evidence of an acute infarction in the right occipital territory. Sanger sequencing for common mitochondrial variants of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes confirmed this diagnosis. Whole exome sequencing revealed pathogenic compound heterozygous variants in NEB gene implicating in coexisting nemaline myopathy. Acute presentation was managed with supportive care, antiepileptics, and mitochondrial supplementation. Currently he is stable on daily supplementation of arginine and limb-strengthening physiotherapy. He is being monitored closely clinically and with serum lactate level.ConclusionGenetic diseases are rare. Coexistence of two genetic conditions is even rarer. Genetic confirmation of diagnosis is imperative for prediction of complications, accurate management, and genetic counseling.

Absence of Pathogenic Mutations and Strong Association With HLA-DRB1*11:01 in Statin-Naïve Early-Onset Anti-HMGCR Necrotizing Myopathy.

Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype. Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed. Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls. WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy.

Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 genes implicated in LGMD. The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes (CAPN3, COL6A1, COL6A2, and COL6A3) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1, though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. The expert-reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case-level data that help clarify disputed or novel LGMD associations.

Approach to gait disorders and orthotic management in adult onset neuromuscular diseases.

In order to understand abnormal gait, this article will first review normal gait, discuss how neuromuscular diseases disturb gait patterns and review orthotic interventions. In normal gait, concentric contractions accelerate and eccentric contractions decelerate the limb. Neuromuscular gait disorders can be grouped into (1) proximal weakness, (2) distal weakness, (3) nonlength-dependent or generalized weakness, (4) asymmetric weakness, and (5) sensory disorders. Identification of gait disturbance type in neuromuscular diseases leads to the appropriate orthotic prescription since orthotic strategies are grouped into (1) proximal weakness, (2) distal weakness, and (3) sensory disturbances. Orthotics is not indicated in all types of gait disturbance. Weakness in proximal hip musculature can be managed with gait aids such as walkers. In contrast, distal muscle weakness can be managed with orthotics. Preservation of gait assists in maintenance of daily function and integration in society.

Investigating the trajectory of functional disability in systemic sclerosis: group-based trajectory modelling of the Health Assessment Questionnaire-Disability Index.

To identify the trajectories and clinical associations of functional disability in systemic sclerosis (SSc). Australian Scleroderma Cohort Study (ASCS) participants meeting ACR/EULAR criteria for SSc recruited within 5 years of disease onset, with ≥2 Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were included. Group based trajectory modelling (GBTM) was used to identify the number and shape of HAQ-DI trajectories. Between group comparisons were made using the chi-squared test, two-sample t-test or Wilcoxon rank-sum test as appropriate. Multiple logistic regression was used to identify features associated with trajectory group membership. Survival analyses were performed using Kaplan Meier and Cox proportional hazard modelling. We identified two HAQ-DI trajectory groups within 426 ASCS participants with incident SSc: low-stable disability (n=221, 52%), and high-increasing disability (n=205, 48%). Participants with high-increasing disability were older at disease onset, more likely to have diffuse SSc (dcSSc), cardiopulmonary disease, multimorbidity, digital ulcers, and gastrointestinal involvement (all p≤0.01), as was use of immunosuppression (p<0.01). Multimorbidity was associated with high-increasing trajectory group membership (OR3.1, 95%CI1.1-8.8, p=0.04); independently, multiple SSc features were also strongly associated including dcSSc (OR2.3, 95%CI1.3-4.2, p<0.01), proximal weakness (OR7.3, 95%CI2.0-27.1, p<0.01) and joint contractures (OR2.7, 95%CI1.3-5.3, p<0.01). High-increasing physical disability was associated with an almost two-fold increased risk of mortality (HR1.9, 95%CI1.0-3.8, p=0.05), and higher symptom burden. Two trajectories of functional disability in SSc were identified. Those with high-increasing functional disability had a distinct clinical phenotype and worse survival compared to those with low-stable functional disability. These data highlight the pervasive nature of physical disability in SSc, and its prognostic importance.

Anti-HMGCR myopathy: Diversity of clinical presentations in a national cohort in New Zealand

AimsWe describe the varied clinical presentations, barriers in diagnosis and outcomes of anti-HMGCR myopathy in a large national cohort. MethodsAdults found positive for serum anti-HMGCR autoantibodies via line blot or enzyme-immunoassay followed by immunoprecipitation were included in the study. ResultsOf 75 patients identified, the records of 72 (96 %) described weakness as the presenting symptom. The records of 65 gave a reliable description of proximal weakness. In 22/65 (33.8 %) the weakness was described as predominantly or solely lower limb weakness. Forty-five of 75 (60 %) presented with a subacute onset (duration of symptoms >4 weeks -≤6 months), whilst 22/75 (29.3 %) presented with a more indolent chronic onset (duration of symptoms >6 months). Eighteen of 75 (24 %) suffered falls and 2/75 (2.7 %) had “general decline”. In three patients no weakness was described: two presented with myalgia and one with a skin rash characterized as Jessner lymphocytic skin rash. Median creatine kinase at presentation was 7337 U/L (range 1050–25,500). Muscle biopsy was performed in 38 (50.7 %). Associated malignancy was infrequent. Four patients recovered without immunosuppression. Five-year and 10-year survival was 92.7 % (95 % CI 80.6–97.4 %), and 82.5 % (95 % CI 61.2–92.8 %) respectively. ConclusionRecurrent falls, a long prodrome and dominant lower limb proximal weakness were common in this anti-HMGCR myopathy cohort. These features overlap with frailty syndrome and sporadic inclusion body myositis emphasizing the importance of considering anti-HMGCR myopathy in that clinical context. A minority of patients recover after statin withdrawal alone.

Spinal muscular atrophy caused by compound heterozygous SMN1 mutations: two cases and literature review.

Spinal muscular atrophy (SMA) is a rare neuromuscular disease, which is characterized by the degeneration of motor neurons, leading to symmetrical muscle weakness and atrophy.Description of two novel SMN1 mutations (patient1: c.683T > A, p.Leu228Ter; patient2: c.347 T > C, p.Ile116 Thr).We reported two patients with SMN1 mutations with the clinical features, and provided a literature review of the previously reported 22 cases.Two SMA patients showed progressive proximal lower limb weakness and milder clinical symptom. In a total of 22 cases, the most commonly observed SMN1 gene alteration was missense mutation (55%), followed by splicing defect (27%), nonsense (9%) and frameshift (9%).We discuss the possible decisive role of these intragenic mutations in the phenotypic results, which enriched the SMN 1 fine mutation database.

The first reported familial case of statin-induced immune-mediated necrotizing myopathy associated with anti-hydroxy-3-methylglutaryl-CoA reductase autoantibodies and HLA DRB1*11:01

ABSTRACT Immune-mediated necrotizing myopathy (IMNM) is a rare type of auto-immune myositis, characterized by symmetric muscle pain, proximal weakness, elevated serum CK levels and pathologic findings of necrotized muscle fibers. IMNM may be seronegative, associated with anti-signal recognition particle (SRP) antibodies or anti-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies, the last widely related with statin use. This last entity affects only 2 to 3 of 100,000 patients under statins. Recently, patients carrying the class II human leukocyte antigen (HLA) DRB1*11:01 were identified to be more at risk to present IMNM with anti-HMGCR antibodies. We describe the case of a daughter and father diagnosed with HMGCR-IMNM and both carrying HLA DRB1*11:01. To our knowledge, it is the first familial case reported in the literature.

ExoBand, A Passive Wearable Device as a Walking Aid in Neuromuscular Patients: First Quantitative Assessment.

Exoband (by Moveo, Padova, Italy) functions as a walking brace, comprising a belt and two leg loops connected by a mechanism that stores energy during the initial phase of the gait cycle and releases it in the subsequent phase. This enhances hip flexor thrust, leading to functional improvement in walking for individuals with conditions characterized by proximal weakness. It has been approved as a passive wearable device for individuals with impaired walking abilities. Objective of this study was to establish a protocol to assess the use of Exoband in patients with various neuromuscular disorders. This exploratory retrospective study includes consecutive patients diagnosed with neuromuscular disorders (CIDP, motor polyneuropathy, MND), exhibiting a proximal involvement and gait abnormalities. The evaluation protocol incorporated specific walking-related outcome measures, the 10-meter walk test (10mWT), Time-up-and-go test (TUG), and 2-minute walking test (2MWT). The assessments were conducted both with and without the Exoband under standard conditions. Eight patients (6 males, aged 60-78 years) were tested. An increase in velocity was observed in the 10mWT (median 13.4 sec, IQR 12.0-15.7 vs. 12.2 sec, IQR 11.3-14.2 seconds, p < 0.05) and the TUG (14.0 sec, IQR 13-16.2 vs 13.35 sec, IQR 11-13.8; p < 0.05, by non-parametric Wilcoxon test), and a trend of increase in 2MWT (median 88.2 vs 92.6 m, n.s.). Six out of 8 patients reported subjective benefits from the very first use, including improved walking stability, speed, confidence, and reduced fatigue. Our protocol provides a quantitative assessment of Exoband usefulness for patients affected by neuropathies with gait abnormalities. Further investigations are warranted to assess the long-term effects of its regular Exoband use, its efficacy in specific neuromuscular diseases, and its potential role as a rehabilitation device.

LMNA‐related muscular dystrophy presenting as an inflammatory myopathy

AbstractIntroductionThere are overlapping features between inflammatory myopathies and muscular dystrophies, particularly laminopathies. Key features that characterize laminopathies include axial and proximal weakness, contractures, and cardiac abnormalities.Methods/ResultsA 12‐year‐old girl diagnosed with juvenile dermatomyositis as a child presented with cardiac failure and was found to have an LMNA likely pathogenic variant, with a phenotype most consistent with Emery–Dreifuss muscular dystrophy type 2.DiscussionThe spectrum of clinical features of LMNA‐related muscular dystrophies can mimic or present with inflammatory myopathy‐like features. Early identification of LMNA‐related muscular dystrophies is crucial to ensure appropriate cardiac screening and prevent devastating cardiac complications.

From how many Angles Should Immune-Mediated Necrotizing Myopathy be Observed?

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of autoimmune diseases characterized by inflammation of skeletal muscle causing proximal weakness. The clinical case describes a 72-year-old male patient with proximal quadriparesis for 3 months, associated with constitutional syndrome. Analyzes with rhabdomyolysis and positive anti-SRP antibody. Biopsy findings compatible with immune-mediated necrotizing myopathy. The complementary study revealed a laryngeal neoplasia. The patient refused treatment and died 6 months after diagnosis.

Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

P.064 A case of late onset Pompe Disease presenting in 6th decade

Background: Late onset Pompe disease (LOPD), rare autosomal recessive lysosomal storage disease, resulting from mutation in alpha glucosidase enzyme (GAA) can present even in 6th decade of life. Slowly progressive, subtle, limb girdle pattern of weakness (LGPW), with auxiliary features such as ptosis, enlarged tongue, axial rigidity, facial diplegia, variable degree of respiratory weakness is not uncommon. Hypertrophic and electrical cardiac abnormalities are well described in LOPD. Methods: We present a case of 67-year-old male presenting with proximal weakness, subtle ptosis, bilateral quadriceps and shoulder girdle atrophy, and left toe numbness. PMHx: CABG, NSTEMI. Statin use. FMHx: noncontributory. Results: EMG: L5 radiculopathy, with unexpected myopathic units in hip/pelvic/ shoulder girdle muscles with active denervation and muscle irritability. CK, CRP, SPEP, ANA, LFTs, HMG-CoA reductase: normal. GAA enzymatic activity=0.96µmol/L/hr (low), genetics: pathogenic variants in GAA gene: c.-32-13T&gt;G and c.1194+3G&gt;C. ECHO: severe diastolic dysfunction, restrictive left ventricular filling. PFTs: normal. Diagnosed with LOPD, started on therapy. Conclusions: LOPD remains a differential for LGPW especially in older patient population with history of cardiopulmonary features. Age-appropriate conconminant pathologies may confound the diagnostic process.Symptoms may preceed diagnosis for years.GAA enzymatic activity followed by genetic testing remains readily available and can confirm diagnosis, preventing delay of approved therapy.

P.042 Anti-HMG Coenzyme A reductase antibody (anti-HMGCR) myopathy: case review of two pediatric patients from a single center

Background: Necrotizing anti-HMGCR myopathy is rare in children. Pediatric cases are not typically associated with statin use or malignancy. Methods: Retrospective chart review (January 2009 to December 2023) identified cases of anti-HMGCR myopathy at our hospital. Results: Two patients were identified. Patient A, presented at 8 yo with a 2 year history of proximal muscle weakness. His CK was 4,840 U/L (normal &lt;205 U/L) with a high anti-HMGCR antibody titre. His Childhood Myositis Assessment Scale (CMAS) score was 33/52. Monthly IVIG was started and his muscle strength and CK improved. Two years later, weekly methotrexate was started for persistent mild CK elevation (602 to 869 U/L). At 11 years old, 3 years after diagnosis, his CMAS score was 47 and he could participate in soccer with mild fatigue. Patient B, presented at 8 yo with acute proximal weakness, rash and CMAS 13/52. His CK was 20,185 U/L with elevated anti-HMGCR antibody titre. He received oral corticosteroids, weekly methotrexate and monthly IVIG. At 10 yo, 2 years after diagnosis, he is asymptomatic with CMAS 51. He is maintained on methotrexate monotherapy. Conclusions: Anti-HMGCR antibody myopathy requires prompt diagnosis to obviate muscle necrosis and long-term complications. Our patients showed clinical and CMAS improvement with treatment.