Progressive Proximal Weakness Research Articles

Case report: Rapid clinical improvement of anti-HMGCR immune-mediated necrotizing myopathy treated with efgartigimod

Immune-mediated necrotizing myopathy (IMNM) with anti-HMGCR antibody positivity is characterized by proximal extremity weakness, increased creatine kinase, and extensive muscle edema. There is an urgent need to find more appropriate treatment options for anti-HMGCR IMNM patients who do not respond well to conventional therapy in the acute phase. With the advent of targeted biologics, new treatment options are available. We report on a 66-year-old anti-HMGCR IMNM patient who initially presented with a 1-month history of progressive proximal extremity weakness and dysphagia with markedly elevated creatine kinase. The patient did not respond to conventional high-dose glucocorticoid and intravenous immunoglobulin therapy, and his symptoms rapidly deteriorated over the 2 weeks after this treatment, with worsening limb weakness that prevented walking, marked proximal muscle atrophy, and weight loss. After one cycle (four infusions) of efgartigimod, the patient’s symptoms improved markedly and he has since (for several months) remained in a good clinical state.

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.

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.

Sporadic Late-Onset Nemaline Myopathy: Current Landscape.

Sporadic late-onset nemaline myopathy (SLONM) is a rare adult-onset, acquired, muscle disease that can be associated with monoclonal gammopathy or HIV infection. The pathological hallmark of SLONM is the accumulation of nemaline rods in muscle fibers. We review here current knowledge about its presentation, pathophysiology, and management. SLONM usually manifests with subacutely progressive proximal and axial weakness, but it can also present with chronic progressive weakness mimicking muscular dystrophy. The pathophysiology of the disease remains poorly understood, with evidence pointing to both autoimmune mechanisms and hematological neoplasia. Recent studies have identified histological, proteomic, and transcriptomic alterations that shed light on disease mechanisms and distinguish SLONM from inherited nemaline myopathies. A majority of SLONM patients respond to intravenous immunoglobulins, chemotherapy, or hematopoietic stem cell transplant. SLONM is a treatable myopathy, although its underlying etiology and pathomechanisms remain unclear. A high degree of suspicion should be maintained for this disease to reduce diagnostic delay and treatment in SLONM and facilitate its distinction from inherited nemaline myopathies.

Family and literature analysis demonstrates phenotypic effect of two variants in the calpain-3 gene

Both, recessive (LGMD R1) and dominant (LGMD D4) inheritance occur in calpain 3-related muscular dystrophy. We report a family with calpain-related muscular dystrophy caused by two known variants in the calpain 3 gene (CAPN3, NM_000070.3; (I) c.700G>A, p.Gly234Arg and (II) c.1746-20C>G, p.?). Three family members are compound heterozygous and exhibit a relatively homogeneous phenotype characterized by progressive proximal weakness starting in the third to fourth decade of life in the shoulder girdle and spreading to the legs. Two family members affected only by the p.Gly234Arg heterozygous missense variants show a different phenotype characterized by severe exertional myalgia without overt pareses. We conclude that in our family, the missense variant causes a severe myalgic phenotype without pareses that is aggravated by the second intronic variant and put these findings in the context of previous studies of the same variants.

Clinical spectrum, biochemical profile and disease progression of Kennedy disease in an Indian cohort.

Kennedy disease (KD) is a slowly progressive lower motor neuron degenerative disease. The prevalence of KD is unknown in India. To describe the phenotypic and laboratory features of an Indian cohort of KD patients. A retrospective study was done on seven genetically confirmed KD patients based on demographic, clinical and laboratory details. Mean age at onset and presentation was 37 ± 11.9 and 44.6 ± 13.5 years respectively. Progressive asymmetric proximal and distal limb weakness was the commonest symptom (57.1%). All patients had motor symptoms along with non-specific symptoms such as cramps from the onset. Easy fatigability, decremental response along with ptosis were noted in two patients, which was a novel finding. Gynaecomastia and tongue wasting with fasciculations were universal findings. All five patients with nerve conduction studies showed sensorimotor neuropathy. Magnetic resonance imaging muscle done in two patients showed a prominent moth-eaten appearance in the thigh and posterior leg compartment in one patient. The mean cytosine-adenine-guanine repeats were 44 ± 3.7, and there was no association between age of onset or severity with repeat length. Only one patient required an assistive device for ambulation after 15 years of symptom onset. This study showed phenotypic heterogeneity in the Indian cohort. The age of onset was earlier with a slowly progressive indolent course as compared with other ethnic cohorts. This highlights the importance of considering the KD diagnosis in patients with the indolent course and suspected ALS diagnosis even with ptosis and fatigability in an appropriate clinical context.

A Case of Smoldering Anti-HMGCR antibody Myopathy (P9-8.015)

<h3>Objective:</h3> NA <h3>Background:</h3> Adult onset anti-HMGCR necrotizing myopathy is classically described as having a subacute but fulminant onset involving CK elevations in the 1–20,000 IU/L range with progressive proximal weakness following statin exposure despite statin cessation. Additional phenotypes have been described presenting as chronic limb girdle muscular dystrophy or in pediatric populations without statin exposure. <h3>Design/Methods:</h3> NA <h3>Results:</h3> 69 year-old woman with a history of diabetes, hyperlipidemia on atorvastatin for three years, morbid obesity, and congestive heart failure, presented with several months of pain and cramping in both calves. She denied associated back pain, numbness, tingling, or weakness. Neurologic exam showed isolated inability to toe-walk, limited by pain. She had normal strength, sensation, and reflexes. CK at the time of symptom onset was 510 U/L (&lt;170 U/L). Atorvastatin was stopped and symptoms improved but did not resolve. One week and one month after atorvastatin cessation, CK was 809 and 604 U/L and aldolase was 17 and 8.1 U/L (&lt;7.7 U/L), respectively. HMGCR Ab returned positive at 4000 (&lt;2500). Due to her mild and improving symptoms, we planned to monitor without immunotherapy. She was lost to follow up. She returned one year later with severe proximal weakness requiring a wheelchair and CK of 10,074 U/L. Repeat HMGCR Ab was 545.4 (&lt;20.0 CU). EMG was consistent with irritative proximal myopathy. Muscle biopsy was consistent with necrotizing myopathy. She was started on prednisone 60mg daily, IVIG 2g/kg every 2 weeks and Cellcept 1000mg twice daily with improvement. Two years later, she can stand and transfer independently but remains primarily wheelchair bound. <h3>Conclusions:</h3> This case highlights the potential for HMGCR myopathy to present with a period of calf pain and mild CK elevation (&lt;1000 U/L). In patients with a smoldering onset, there may be a treatment window to prevent transformation into a more disabling classical phenotype. <b>Disclosure:</b> Dr. Lin has nothing to disclose.

Atypical Overlapping Features Complicating Diagnoses of Dysferlinopathy and Immune-Mediated Necrotizing Myopathy. (P6-8.006)

<h3>Objective:</h3> To present overlapping features and atypical characteristics of dysferlinopathy and immune-mediated necrotizing myopathy (IMNM). <h3>Background:</h3> Dysferlinopathy typically presents with early onset progressive muscle weakness that can be proximal or distal. Definitive diagnosis is made with DYSF gene testing. Treatment is supportive. IMNM is an autoimmune inflammatory myopathy that affects older individuals and is often associated with occult malignancy. Aggressive immunotherapy improves outcomes. Muscle biopsy (MBx) reveals inflammatory infiltrates in both conditions. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> <h3>Case 1:</h3> A 35-year-old man presented with subacute progressive limb weakness and elevated creatine phosphokinase (CPK) &gt;8,000 units/L. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining; dystrophy stains were omitted due to the patient’s age and subacute symptoms. Anti-signal recognition peptide (SRP) and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies and malignancy screen were negative. The patient was initially diagnosed with seronegative IMNM and treated with steroids, methotrexate and IVIG without improvement. He was subsequently diagnosed with dysferlinopathy based on genetic testing showing double heterozygous pathogenic DYSF gene mutations. <h3>Case 2:</h3> An 18-year-old man presented with 3-years of progressive proximal limb weakness associated with Gower’s sign and elevated CPK &gt;10,000 units/L. Broad muscular dystrophy genetic testing was negative. MBx showed necrotizing myopathy and sarcolemmal C5b-9 staining suggestive of IMNM. Anti-SRP and anti-HMGCR antibodies, serum paraneoplastic panel, and malignancy screening with tumor markers, contrasted CT imaging, and scrotal ultrasound were negative. The patient was diagnosed with early-onset seronegative IMNM. CPK improved and symptoms stabilized with prednisone, methotrexate and IVIG therapy. <h3>Conclusions:</h3> Dysferlinopathy and IMNM can have overlapping clinical features and MBx findings. Heightened awareness of atypical features aids in timely diagnosis. Accurate diagnosis of dysferlinopathy based on genetic testing limits further invasive workup and the side effects of ineffective empiric therapy, whereas early diagnosis of IMNM allows for prompt immunotherapy which is shown to improve prognosis. <b>Disclosure:</b> Dr. Stout has nothing to disclose. Dr. Su has nothing to disclose.

The Association of Hepatitis B and Polymyositis: Rare but Real

Aims: Hepatitis B virus infection is a global health concern. Although Hepatitis B virus primarily affects hepatocytes, it sometimes develops disease manifestations outside the liver and can present as full fledged proximal myopathy. &#x0D; Presentation of Case: We report a 68-year-old man presenting with progressive proximal bilateral lower limb weakness for the last 14 days. The weakness was associated with pain and one episode of fever. Examination revealed 3/5 power in the shoulder and hip joint without any sensory deficit. Biochemical investigation showed elevated CPK levels (1102 IU/L) and liver enzymes (AST – 625 IU/L, ALT – 356 IU/L). HBsAg and HBeAg came out to be positive with HBV DNA of 73000 copies/mL. MRI shoulder and hip joints revealed diffuse intramuscular and myofascial edema suggesting inflammatory myositis. Muscle biopsy was suggestive of Necrotizing Autoimmune Myopathy.&#x0D; Discussion: Patient symptoms improved after starting IV Prednisolone and Entecavir therapy suggesting a close association between Hepatitis B infection and myopathy.&#x0D; Conclusion: Although Hepatitis B virus primarily affects hepatocytes, it sometimes develops disease manifestations outside the liver, such as Polymyositis. Therefore, it is imperative to screen for Viral markers in these patients.

An atypical presentation of dermatomyositis sine dermatitis

Dermatomyositis (DM) is a rare autoimmune disorder. This idiopathic inflammatory myopathy (IIM) is characterized by overexpression of major histocompatibility complex I and the formation of autoantibodies. Apart from muscle weakness, dermatological involvement is classically seen in DM. Recently, a few articles have been published documenting a subset of DM with no skin involvement – DM sine dermatitis. Here, we present a 37-year-old male with progressive proximal weakness with no skin involvement. Unlike classical DM, neither muscle enzymes (creatinine phosphokinase and aldolase) were elevated nor myositis-specific autoantibodies were detected. Muscle biopsy, however, was characteristic for DM with positivity for CD3, CD4, CD8, CD20, and CD68. The patient improved with initiation of immunosuppressants. Screening for malignancy and interstitial lung disease was unremarkable.

Povezanost mijastenije gravis i imunski-posredovanih miopatija

Introduction/Aim: Myasthenia gravis (MG) is a chronic autoimmune disease of the neuromuscular junction, characterized by muscle weakness and fatigability. Idiopathic inflammatory myopathies (IIM) are an immune-mediated group of diseases characterized by progressive painful proximal weakness of the extremities. The coexistence of these two diseases is extremely rare and so far, only about fifty cases have been reported worldwide. The aim of this study was to analyze the frequency of coexistence of IIM and patients with de novo MG. Material and Methods: The study is retrospective in nature and was conducted at the "Neurology Clinic", University Clinical Center of Serbia. It included 97 patients diagnosed with myasthenia gravis between January 1, 2014 and December 31, 2018. Results: The average age of the MG patients was 54.1±18.9 years. At the time of diagnosis, 19 (19.6%) participants had at least one of the anamnestic data observed as potential indicators for the existence of immune-mediated myopathy. Finally, one patient clinically presented with generalized seropositive (anti-AchR positive) myasthenia gravis associated with the diagnosis of antisynthetase syndrome. In addition, the main characteristics of patients with combined occurrence of de novo MG and antisynthetase syndrome are presented. Conclusion: Although the simultaneous occurrence of MG and IIM is a very rare phenomenon, we need to think about the possibility of combined occurrence of these two autoimmune diseases, with the aim of early recognition and adequate treatment, and thus a better prognosis of both diseases.

Delayed Diagnosis in a Patient With Progressive Proximal Weakness: A Clinical Vignette.

Delayed Diagnosis in a Patient With Progressive Proximal Weakness: A Clinical Vignette.

Osteitis Fibrosa Cystica; A Forgotten Manifestation of Secondary Hyperparathyroidism Due to End-Stage Renal Disease: A Case Report

IntroductionOsteitis fibrosa cystica is a rare complication of secondary hyperparathyroidism. Even though it is thought to be a disease of the past, it still continues to be seen in this modern era in the setting of undiagnosed or untreated chronic kidney disease.Case PresentationA 26-year-old married Ethiopian women presented with 4 year history of progressive proximal weakness of extremities and diffuse bone pain. Physical examination revealed diffuse bone tenderness and features consistent with myopathy. Blood work up showed raised creatinine, markedly elevated PTH, borderline low calcium, and vitamin D in severe deficiency range. X-Ray findings were consistent with classical skeletal lesion of severe secondary hyperparathyroidism.ConclusionOsteitis fibrosa cystica is a rare but still frequent complication of secondary hyperparathyroidism, which may be the initial presentation of chronic kidney disease. This case report emphasizes the importance of considering secondary hyperparathyroidism in patients presenting with weakness and bone pain to allow for early diagnosis, treatment, and improvement of overall prognosis.

GFPT1-Associated Congenital Myasthenic Syndrome Mimicking a Glycogen Storage Disease - Diagnostic Pitfalls in Myopathology Solved by Next-Generation-Sequencing.

GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1: the previously reported missense variant c.41G > A (p.Arg14Gln) and the novel truncating variant c.1265_1268del (p.Phe422TrpfsTer26). Patients showed progressive proximal atrophic muscular weakness with respiratory involvement, and a lethal disease course in adulthood. In the diagnostic workup at that time, muscle biopsy suggested a glycogen storage disease. Initially, Pompe disease was suspected. However, enzymatic activity of acid alpha-glucosidase was normal, and gene panel analysis including 38 genes associated with limb-girdle weakness (GAA included) remained unevocative. Hence, a non-specified glycogen storage myopathy was diagnosed. A decade later, the diagnosis of GFPT1-related CMS was established by genome sequencing. Myopathological reexamination showed pronounced glycogen accumulations, that were exclusively found in denervated muscle fibers. Only single fibers showed very small tubular aggregates, identified in evaluation of serial sections. This family demonstrates how diagnostic pitfalls can be addressed by an integrative approach including broad genetic analysis and re-evaluation of clinical as well as myopathological findings.

1057 A CASE OF AUTOIMMUNE NECROTISING MYOSITIS

IntroductionAn 88-year-old previously independent lady presented with progressive proximal weakness of all limbs and multiple falls for 10 months. Her swallowing got difficult lately. She lost weight gradually in that duration but denied any other symptoms suggestive of malignancy. PMH—Hypothyroid, Mild cognitive impairment Drg History—Atorvastatin for years. Stopped in this admission.On examination, she showed signs of proximal muscle weakness and areflexia in both upper and lower limbs without muscle tenderness. She had no facial nor eye muscle weakness. Sensory functions were intact. There were no rashes.Investigations CK 2000 TSH 24 Inflammatory markers, white cell counts—non-significant Vitamin D—18 CT-Chest Abdomen Pelvis, CT-colonography—No evidence of malignancy Paraneoplastic antibodies—Negative Anti-OJ and anti-Ro52 Antibodies—positive ENA profile—negative Anti-RNP—equivocal HMG-CoA reductase antibodies (HMCR)—Positive.ProgressPrednisolone was commenced and gradually increased to 60 mg once a day but there is no significant improvement clinically though creatinine kinase level had improved. She was unfortunately infected with COVID-19 infection in the stay which delayed the plan for muscle biopsy and EMG. It affected the plan for Intravenous Immunoglobulins and was later decided to be non-beneficial due to high risks of thromboembolic events and superimposed infections. Steroid was later switched to methotrexate. She was discharged to a rehab unit.ConclusionNecrotising Autoimmune Myopathy is a rare form of idiopathic inflammatory myopathy. Risk factors include statins, cancer, connective tissue diseases, autoimmune diseases, and infections such as HIV2. Diagnosis includes clinical features, serum creatine kinase, HMG CoA reductase antibody (HMGCR-Ab), electromyography, and muscle biopsy. The first-line treatment options are steroids and immunosuppressive agents. Early use of immunoglobulin achieves good outcome. It is still under investigation for the recommended choice for immunosuppressive therapy and the duration of the therapy.

P.043 Plasmapheresis for treatment of light chain amyloidosis related myopathy

Background: Light chain (AL) amyloidosis is a plasma cell disorder characterized by abnormal fibrillary light chain deposition causing cardiac, renal, hepatic, gastrointestinal and peripheral nervous system dysfunction. Muscle disease occurs in 1.5% of individuals causing progressive proximal weakness thus far considered untreatable. Methods: We reviewed two cases of AL amyloidosis associated myopathy at our institution who had robust response to plasmapheresis. Both were at stringent clinical response following CyBorME therapy during peak severity of their myopathy. Results: In case 1, a 70-year-old male with recently diagnosed kappa light chain multiple myeloma and cardiac/renal amyloidosis developed severe subacute proximal weakness preventing ambulation. CK was normal and electromyography was consistent with irritable myopathy. Deltoid biopsy showed perimysial and endomysial amyloidosis. A trial of plasmapheresis in a tapering schedule resulted in robust recovery of strength. In case 2, a 67-year-old female with recently diagnosed kappa light chain multiple myeloma with amyloidosis on fat pad aspirate developed severe subacute proximal weakness requiring prolonged hospital admission. CK was normal and electromyography demonstrated non-irritable myopathy. Bicep biopsy showed perivascular amyloidosis. A trial of plasmapheresis in a tapering schedule resulted in robust recovery of strength. Conclusions: Plasmapheresis is a novel and potentially effective treatment for patients with AL amyloidosis associated myopathy.

P.044 GMPPB mutation causes a muscular dystrophy-myasthenic spectrum

Background: Mutations in GDP-Mannose Pyrophosphorylase B (GMPPB) cause a spectrum of disease ranging from muscular dystrophy to congenital myasthenic syndrome (CMS). Recognition of neuromuscular junction dysfunction has important treatment implications. Methods: We describe a person with GMPPB mutation causing an overlapping limb girdle muscular dystrophy - myasthenic syndrome with robust response to acetylcholinesterase inhibitors. We review the literature on the muscular dystrophy - CMS and explore the phenotypic features that aid in recognizing neuromuscular junction dysfunction. Results: A 35-year-old woman presented with a 10-year history of debilitating myalgias, symmetrical limb girdle and neck weakness, and chronic CK elevation. Electromyography showed a non-irritable myopathy. Biopsies were consistent with muscular dystrophy. Whole genome sequencing revealed two heterozygous pathogenic mutations in the GMPPB gene, giving a diagnosis of genetically confirmed limb girdle muscular dystrophy. Subsequently, repetitive nerve stimulation revealed decrement in the trapezius muscle suggestive of an overlap myasthenic syndrome. She was started on pyridostigmine resulting in recovery of full motor power with significant functional improvement. Conclusions: Identification and treatment of neuromuscular junction dysfunction caused by GMPPB mutations can significantly improve motor power and function. Early onset of progressive fatigable proximal weakness, spared ocular and facial muscles, and pyridostigmine responsiveness are important features of GMPPB-related CMS.

EP243: A novel variant in MORC2 associated with pigmentary retinopathy, short stature, microcephaly and white matter abnormalities

MORC2 encodes Microrchidia CW-type zinc finger protein 2, an ATPase involved in transcriptional regulation of chromatin condensation in DNA damage, transcriptional repression and axonal transport. Variants in MORC2 have been associated with autosomal dominant Charcot-Marie-Tooth Disease Type 2Z characterized by progressive upper and proximal weakness in an asymmetric pattern and axonal neuropathy with a spinal-muscular atrophy (SMA)-like presentation. More recently, de novo missense variants in MORC2 variants have been implicated in an emerging phenotype including global developmental delay, growth delay and variable facial anomalies.

Characterizing oxiodoreductase Pyrox-D1

PYROX-D1 (pyridine oxidoreductase domain 1) is a human enzyme involved with intracellular oxidation management. Natural mutations in this protein have been identified and implicated with causing a newly defined form of limb-girdle muscular dystrophy. Pedigree analysis reveals an autosomal recessive inheritance pattern (requiring a mutated allele from both parents). The disease manifests with bulk muscle wasting, atypical connective tissue elasticity, progressive proximal and distal weakness, nasal speech, elevated creatine kinase, flat feet, and ambulation issues usually beginning between 20-30 years of age.

Knee Strength and Ankle Range of Motion Impacts on Timed Function Tests in Duchenne Muscular Dystrophy: In the Era of Glucocorticoids.

Duchenne Muscular Dystrophy (DMD) is a neuromuscular disorder that presents in childhood and is characterized by slowly progressive proximal weakness and lower extremity contractures that limit ambulatory ability [1, 2]. Contractures develop in the ankles, knees, and hips due to muscle imbalances, fibrotic changes, loss of strength, and static positioning [2, 5]. Currently, standards of care guidelines emphasize the importance of maintaining good musculoskeletal alignment through stretching, bracing, and glucocorticoid (GC) therapy to preserve strength and function. This is a retrospective analysis of prospectively collected data through the CINRG Duchenne Natural history study (DNHS). The objectives of this analysis are to understand the progression of ankle contractures for individuals with DMD and to investigate the relationship between progressive lower limb contractures, knee strength, and Timed Function Tests.A collection of TFTs including supine to stand (STS), 10 meter walk test (10MWT), and timed stair climbing (4SC) have been used to monitor disease progression and are predictive of loss of ambulation in these patients [4]. Multiple factors contribute to loss of ambulation, including progressive loss of strength and contracture development that leads to changing biomechanical demands for ambulation. A better understanding of the changes in strength and range of motion (ROM) that contribute to loss of function is important in a more individualized rehabilitation management plan. In this longitudinal study, we measured strength using quantitative muscle testing (QMT) with the CINRG Quantitative Measurement System (CQMS)), ROM was measuresed with a goniometer and TFTs were measured using a standard stopwatch and methodology. We enrolled 440 participants; mean baseline age was 8.9 (2.1, 28.0) years with 1321 observations used for analysis. GC use was stratified based on duration on drug with 18.7%at < 6 months or naïve; 4.3%<1 year; 58.0%1 < 10 years; and 19.3%between 10-25 years of GC use. Ankle ROM was better for those on GC compared to GC naive but did not significantly influence long-term progression rates. QMT, ROM, age and GCs contribute to speed of TFTs. Knee extension (KE) strength and Dorsiflexion (DF) ROM are significant predictors of speed for all TFTs (p < 0.001). Of the variables used in this analysis, KE strength is the primary predictor of walking speed, estimating that every pound increase in KE results in a 0.042 m/s improvement in 10MWT, and a smaller similar increase of 0.009 m/s with every degree of ankle DF ROM. GC use provides an improvement in strength and ROM but does not affect rate of change. Knee strength has a greater influence on speed of TFTs than DF ROM, although both are statistically significant predictors of speed. Results show that retaining knee strength [1, 2], along with joint flexibility, may be important factors in the ability to perform walking, climbing and supine to stand activities.