X-linked Myotubular Myopathy Patients Research Articles

A healthcare claims analysis to identify and characterize patients with suspected X-Linked Myotubular Myopathy (XLMTM) in the Brazilian Healthcare System

BackgroundX-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital disease, which is not well-defined. To our knowledge, no studies characterizing the XLMTM disease burden have been conducted in Brazil. We identified and described patients with suspected XLMTM using administrative claims data from the Brazilian public healthcare system.MethodsData from 2015 to 2019 were extracted from the DATASUS database. As no XLMTM-specific ICD-10 code was available, a stepwise algorithm was applied to identify patients with suspected XLMTM by selecting male patients with a congenital myopathies code (G71.2), aged < 18 years at index date (first claim of G71.2), with an associated diagnostic procedure (muscle biopsy/genetic test) and without spinal muscular atrophy or Duchenne muscular dystrophy. We attempted to identify patients with suspected severe XLMTM based on use of both respiratory and feeding support, which are nearly universal in the care of XLMTM patients. Analyses were performed for the overall cohort and stratified by age at index date < 5 years old and ≥ 5 years old.ResultsOf 173 patients with suspected XLMTM identified, 39% were < 5 years old at index date. Nearly all (N = 166) patients (96%) were diagnosed by muscle biopsy (91% of patients < 5 years old and 99% of patients ≥ 5 years old), six (3.5%) were diagnosed by clinical evaluation (8% of patients < 5 years old and 1% of patients ≥ 5 years old), and one was diagnosed by a genetic test. Most patients lived in Brasilia (n = 55), São Paulo (n = 33) and Minas Gerais (n = 27). More than 85% of patients < 5 years old and approximately 75% of patients ≥ 5 years old had physiotherapy at the index date. In both age groups, nearly 50% of patients required hospitalization at some point and 25% required mobility support. Respiratory and feeding support were required for 3% and 12% of patients, respectively, suggesting that between 5 and 21 patients may have had severe XLMTM.ConclusionIn this real-world study, genetic testing for XLMTM appears to be underutilized in Brazil and may contribute to underdiagnosis of the disease. Access to diagnosis and care is limited outside of specific regions with specialized clinics and hospitals. Substantial use of healthcare resources included hospitalization, physiotherapy, mobility support, and, to a lesser extent, feeding support and respiratory support.

Prognostic Value of Genotype-Phenotype Correlations in X-Linked Myotubular Myopathy and the Use of the Face2Gene Application as an Effective Non-Invasive Diagnostic Tool.

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy resulting from dysfunction of the protein myotubularin encoded by the MTM1 gene. XLMTM has a high neonatal and infantile mortality rate due to a severe myopathic phenotype and respiratory failure. However, in a minority of XLMTM cases, patients present with milder phenotypes and achieve ambulation and adulthood. Notable facial dysmorphia is also present. We investigated the genotype-phenotype correlations in newly diagnosed XLMTM patients in a patients' cohort (previously published data plus three novel variants, n = 414). Based on the facial gestalt difference between XLMTM patients and unaffected controls, we investigated the use of the Face2Gene application. Significant associations between severe phenotype and truncating variants (p < 0.001), frameshift variants (p < 0.001), nonsense variants (p = 0.006), and in/del variants (p = 0.036) were present. Missense variants were significantly associated with the mild and moderate phenotype (p < 0.001). The Face2Gene application showed a significant difference between XLMTM patients and unaffected controls (p = 0.001). Using genotype-phenotype correlations could predict the disease course in most XLMTM patients, but still with limitations. The Face2Gene application seems to be a practical, non-invasive diagnostic approach in XLMTM using the correct algorithm.

Real-world analysis of healthcare resource utilization by patients with X-linked myotubular myopathy (XLMTM) in the United States

BackgroundX-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, often requiring invasive ventilator support, gastrostomy tube feeding, and wheelchair use. Understanding healthcare resource utilization in patients with XLMTM is important for development of targeted therapies but data are limited.MethodsWe analyzed individual medical codes as governed by Healthcare Common Procedure Coding System, Current Procedural Terminology, and International Classification of Diseases, 10th Revision (ICD-10) for a defined cohort of XLMTM patients within a US medical claims database. Using third-party tokenization software, we defined a cohort of XLMTM patient tokens from a de-identified dataset in a research registry of diagnostically confirmed XLMTM patients and de-identified data from a genetic testing company. After approval of an ICD-10 diagnosis code for XLMTM (G71.220) in October 2020, we identified additional patients.ResultsA total of 192 males with a diagnosis of XLMTM were included: 80 patient tokens and 112 patients with the new ICD-10 code. From 2016 to 2020, the annual number of patients with claims increased from 120 to 154 and the average number of claims per patient per year increased from 93 to 134. Of 146 patients coded with hospitalization claims, 80 patients (55%) were first hospitalized between 0 and 4 years of age. Across all patients, 31% were hospitalized 1–2 times, 32% 3–9 times, and 14% ≥ 10 times. Patients received care from multiple specialty practices: pulmonology (53%), pediatrics (47%), neurology (34%), and critical care medicine (31%). The most common conditions and procedures related to XLMTM were respiratory events (82%), ventilation management (82%), feeding difficulties (81%), feeding support (72%), gastrostomy (69%), and tracheostomy (64%). Nearly all patients with respiratory events had chronic respiratory claims (96%). The most frequent diagnostic codes were those investigating hepatobiliary abnormalities.ConclusionsThis innovative medical claims analysis shows substantial healthcare resource use in XLMTM patients that increased over the last 5 years. Most patients required respiratory and feeding support and experienced multiple hospitalizations throughout childhood and beyond for those that survived. This pattern delineation will inform outcome assessments with the emergence of novel therapies and supportive care measures.

Neuromuscular Features in XL-MTM Carriers: A Cross-sectional Study in an Unselected Cohort.

X-linked myotubular myopathy (XL-MTM) is an early-onset congenital myopathy characterized by mild to severe muscle weakness in male individuals. The objective was to characterize the clinical spectrum of neuromuscular features in X-linked myotubular myopathy (XL-MTM) carriers. We performed a nationwide cross-sectional study focusing on neuromuscular features in an unselected cohort of Dutch XL-MTM carriers. Participants were recruited from neuromuscular centers in the Netherlands and through the Dutch and European patient associations. Genetic results were collected. Carriers were classified based on ambulatory status and muscle weakness. We used a questionnaire focusing on medical and family history and neuromuscular symptoms. In addition, we performed a neurologic examination including manual muscle testing (MMT), timed up and go (TUG) test, and 6-minute walking test (6MWT). We included 21 carriers (20 genetically confirmed and 1 obligate), of whom 11 (52%) carriers were classified as manifesting, with severe (nonambulatory; n = 2), moderate (minimal independent ambulation/assisted ambulation; n = 2), mild (independent ambulation but with limb or axial muscle weakness; n = 3), and minimal (only facial muscle weakness, n = 4) phenotypes. Three of the manifesting carriers (2 severe and 1 moderate) were from families without genetically confirmed male XL-MTM patients. Furthermore, 7 manifesting carriers (1 moderate; 2 mild; and 4 minimal) were not classified as manifesting carriers before participation in our study. Three carriers reported a history of pneumothorax. The obstetric history revealed frequent polyhydramnios (50%) and reduced fetal movements (36%) in pregnancies of affected sons. Muscle weakness was most pronounced in proximal and limb girdle muscles. Other frequently reported signs included (asymmetric) facial weakness (73%), reduced or absent deep tendon reflexes (45%), scoliosis (40%), and ptosis (45%). Ten participants (48%) were classified as nonmanifesting. Manifesting carriers had lower functional testing scores on 6MWT and TUG compared with nonmanifesting carriers. This study showed that 52% of an unselected group of XL-MTM carriers has muscle weakness (3 of whom were previously unclassified as manifesting). This corresponds to findings of our recent questionnaire study on self-reported symptoms in XL-MTM carriers. These observations should raise awareness of the neuromuscular manifestations of the XL-MTM carrier state and provide important epidemiologic information required for future clinical trials.

P.07 Characterization of MRI brain abnormalities in X-linked myotubular myopathy

X linked myotubular myopathy (XLMTM) is a rare, typically severe, congenital myopathy that often results in significant weakness from birth, with a need for mechanical ventilation and wheelchair assistance. It is caused by a mutation in the myotubularin (<i>MTM1</i>) gene, whose gene product plays an important role in muscle cell differentiation. In addition to the important role of MTM1 in skeletal muscle, there is emerging evidence that patients with XLMTM can have multisystem abnormalities, including liver concerns and cognitive impairment. An organ system of particular interest for us is the Central Nervous System (CNS). Brain involvement has been described in different neuromuscular disorders, though not typically in congenital myopathies. In contrast to other congenital myopathies, there are a handful of case reports and informal observations of structural brain abnormalities in XLMTM. However, there has not yet been a comprehensive review of neuroimaging features in XLMTM. We have developed a multi-site study, aiming to retrospectively gather brain MRI and relevant clinical information for patients with XLMTM around the world. Our goals are to define the relative prevalence of CNS structural anomalies in XLMTM and to describe the common features of brain MRIs from XLMTM patients. In particular, we hope to elucidate unifying or common changes amongst many patients, and whether they correlate with birth-related injury, genotype, clinical phenotype, long-term outcome, or survival. We hypothesize that there is unrecognized brain involvement XLMTM, as will be reflected by brain MRI findings, and that these changes will correlate with both clinical outcomes and the degree of illness/adversity. In addition to study design, we will present our findings from the first cases collected for the study.

X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition

X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention.

OP018: ASPIRO gene therapy trial in X-Linked Myotubular Myopathy (XLMTM): Update on preliminary efficacy and safety findings

We present updated results from ASPIRO (NCT03199469), investigating gene replacement therapy with AT132 for XLMTM patients. XLMTM, an ultra-rare, life-threatening myopathy caused by variants in the MTM1 gene, leads to impaired neuromuscular and respiratory function, and early death.

POSA119 Medicaid Cost Analysis in Patients with X-Linked Myotubular Myopathy: A Retrospective Longitudinal Study

X-linked myotubular myopathy (XLMTM) is a rare genetic life-threatening disease characterized by early onset, severe muscle weakness and respiratory failure. Most children with XLMTM depend on permanent use of ventilation, feeding tubes, wheelchairs, and home health services. Medicaid provides coverage for XLMTM patients, but the costs paid by Medicaid for XLMTM patients have not been estimated.

Costs and health resource use in patients with X-linked myotubular myopathy: insights from US commercial claims.

BACKGROUND: In X-linked myotubular myopathy (XLMTM), mutations in the MTM1 gene result in absence or dysfunction of myotubularin, a protein required for normal development, maintenance, and function of skeletal muscle. Extreme muscle weakness results in severe respiratory failure that is fatal for approximately half of XLMTM-affected children by age 18 months. Most surviving patients require invasive mechanical ventilation, feeding tubes, and wheelchairs for mobility, due to profoundly impaired motor function. Little is known about the costs of care for this rare disease. Currently, there are no approved therapies for XLMTM. OBJECTIVE: To quantify the direct medical costs and health care resource utilization (HRU) incurred by XLMTM patients and paid by commercial insurers. METHODS: A retrospective, longitudinal study was conducted using the IQVIA PharMetrics Plus commercial database of adjudicated claims for more than 140 million individuals with commercial insurance coverage in the United States. An algorithm based on demographic information, diagnosis and procedure codes, and medications was used to identify XLMTM patients younger than aged 2 years during the study period from January 1, 2006, through September 30, 2018. All-cause direct medical costs and HRU during each month were calculated. Costs were grouped as inpatient hospital admissions (including the intensive care unit or neonatal intensive care unit [NICU]); emergency department visits; outpatient services (outpatient hospital visits, office visits, physician/provider office visits, ambulatory surgeries and procedures, laboratory tests, and imaging tests); and prescription medications. Monthly costs and HRU over time were stratified by age and use of mechanical ventilation. RESULTS: 49 patients met the study criteria. All had at least 1 inpatient hospital admission, and 36 (73%) had at least 1 NICU stay. All patients received ventilation at some time during the study period, including 40 (82%) treated with invasive ventilation. Mean monthly per patient direct medical costs were highest in the first year of life ($74,831), including costs for inpatient admissions ($69,025), outpatient services ($5,266), and prescription medication ($540). Mean monthly costs were lower in the second, third, and fourth years of life ($23,207, $13,044, and $9,440, respectively). When annualized, these all-cause monthly medical costs totaled $897,978 per patient in the first year of life and nearly $1.5 million total for patients who survived the first 4 years of life. Costs were consistently highest when patients were receiving invasive ventilation and lowest when they were not receiving ventilation (i.e., before they started on ventilator support). CONCLUSIONS: This direct health care cost and HRU analysis demonstrates the substantial economic burden associated with XLMTM. Costs are highest in the first year of life and are particularly significant for patients receiving invasive ventilation. DISCLOSURES: This study was funded by Audentes Therapeutics, an Astellas Company, and was conducted by PRECISIONheor with funding from Audentes Therapeutics, an Astellas Company. Slocomb is an employee of Audentes Therapeutics, an Astellas Company; James was an employee at the time of the study. Sacks, Healey, and Cyr are employees of PRECISIONheor. Graham participated in the medical/scientific advisory board for Audentes as part of a clinical trial design for XLMTM but declares no vested interest or holdings that would represent a conflict of interest. Beggs received consulting fees from Audentes Therapeutics, for work on this study, and has received grants from Alexion Pharmaceuticals, Audentes Therapeutics, Dynacure SAS, Pfizer Pharmaceuticals, along with personal fees from Asklepios Biopharmaceutical, Inc., Ballard Biologics, Biogen, F. Hoffmann-La Roche AG, GLG, Guidepoint Global, and Kate Therapeutics, unrelated to this study. In addition, Beggs has a patent (Patent number: 10736945) for systemic gene replacement therapy for treatment of X-linked myotubular myopathy (XLMTM) licensed to Audentes Therapeutics.

PMS57 Understanding the Impact of XLMTM on Parents and Caregivers in the US: An Analysis of Survey Results

X-linked myotubular myopathy (XLMTM), an ultra-rare, life-threatening congenital myopathy, is characterized by severe muscle weakness and respiratory failure often requiring ventilation. Most XLMTM patients never achieve independent ambulation and require lifelong respiratory support and extensive caregiving. This survey aimed to quantify the indirect medical cost, health resource use (HRU) and quality of life (QoL) impact of XLMTM on parents and caregivers. With the assistance of multiple XLMTM patient advocacy organizations, a web-based survey was provided to US parents and/or caregivers of children with XLMTM. The survey captured HRU, caregiver-reported out-of-pocket (OOP) costs, caregiver QoL data (via EQ-5D-5L tool) and the societal impact during the caregiving period. OOP costs did not include direct medical costs. Ventilation use was used to stratify results (i.e. non-invasive ventilation (NIV)<16hrs, invasive ventilation (IV) or NIV≥16hrs). There were 22 eligible survey respondents that cared for XLMTM patients with varying ventilation requirements (n= 3 NIV<16hrs; n= 19 IV or NIV≥16hrs) for 14 years, on average. Caregivers reported reduced QoL, primarily impacting the “usual activities” and “anxiety/depression” EQ-5D-5L domains, resulting in a disutility of -0.123 compared to the general population. On average, XLMTM patients required 2 unpaid caregivers, each providing >30 hours/week of care. Additionally, unpaid caregivers missed an average of 19.9 workdays/year, resulting in an estimated annual productivity loss of $73,836-$136,236/caregiver. Annual OOP costs for caregivers varied by patient ventilation use (NIV<16hrs=$2,667; IV or NIV≥16hrs =$10,568) and indirect costs were 2.9 times greater for patients requiring IV or NIV≥16hrs vs NIV<16hrs. 59% of XLMTM patients received SSDI aid. XLMTM has a major impact on family finances and caregiver quality of life. In addition to the substantial direct medical costs described elsewhere, unpaid caregivers of highly ventilated patients incur considerable OOP costs along with patient care demands similar to the time requirements of a full-time job.

PMS13 Hospital Costs for Xlmtm Patients - a German Perspective

X-linked Myotubular Myopathy (XLMTM) is an ultra-rare, life-threatening congenital myopathy characterized by profound muscle weakness, respiratory failure and early death. Due to limited local evidence, we examined inpatient costs, number of admissions and length of stay (LOS) for XLMTM patients admitted to German long-term ventilation (LTV) and acute care (AC) hospitals. Due to XLMTM ultra-rarity, a cross-sectional convenience sample of five XLMTM patients admitted to LTV and AC hospitals was evaluated, including records for three LTV patients and two AC patients admitted between April 2003 and February 2020. Age at admission for two of three LTV patients was >3.5 y.o. and was unknown for the other. AC patients were both < 1 y.o. upon first admission. Hospital costs, admissions, and total LOS were assessed. Costs for patients episodically admitted to AC hospitals were based on diagnosis-related groups whereas costs for LTV patients were based on negotiated per diems. Results were assessed for each patient and stratified by hospital type. The oldest LTV patient drove 71% of the total LOS (8,373 days) and 67% of the total cost (5,072,662€). Due to continuous admission, the LTV patients accounted for 97% of patient days and 90% of total costs. The average LTV per diem was 579.63€ (range 514.00-621.77€). The two patients admitted to ACs in their first year of life generated total hospital costs of 127,847€ and 376,894€ with a calculated average of 1,832€ per diem. The first had six admissions over 227 days with a cumulative LOS of 111 days and the second had 29 admissions over 2,042 days and a cumulative LOS of 150 days. XLMTM drives large clinical and economic burdens on patients affected and the overall German healthcare system. XLMTM patients admitted to LTVs potentially incur higher cumulative costs but lower per diems compared to those admitted to ACs.

MUSCLE FUNCTION & HOMEOSTASIS / MOLECULAR THERAPEUTIC APPROACHES: P.62 ASPIRO Gene therapy trial in X-linked myotubular myopathy (XLMTM): Update on preliminary safety and efficacy findings up to 72 weeks post-treatment

XLMTM, a rare monogenic disease caused by mutations in the MTM1 gene, is characterized by profound muscle weakness, respiratory failure, and early death. ASPIRO is an ongoing, open-label, randomized study (NCT03199469) evaluating safety/efficacy of AT132, an investigational gene therapy for delivery of functional MTM1 gene copies. XLMTM patients, ≤7 years old, were randomized to treatment or delayed-treatment control and enrolled into ascending dose cohorts to receive a single AT132 infusion. Safety/efficacy data are available for 12 patients with 4–72 weeks’ follow-up: 6, Cohort 1 (1 × 1014 vg/kg); 4, Cohort 2 (3 × 1014 vg/kg); 2, controls.

Use of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

P.106Mutation-specific therapy for X-linked myotubular myopathy

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy due to mutations in MTM1 encoding a 3-phosphoinositides phosphatase myotubularin. XLMTM patients display severe generalized hypotonia at birth accompanied by respiratory insufficiency and pathologically show small-size fibers with peripheral halo, centrally located nuclei, disorganized perinuclear organelles in the muscle. Among 78 patients with pathologically diagnosed as XLMTM in our cohort, causative mutations were not identified in 20 cases by targeted re-sequencing panel for congenital myopathy, MTM1 Sanger sequencing nor Whole-exome sequencing. In order to validate deep intronic mutations and aberrant splicing events, we performed RNA-seq analysis on 14 cases who had unreported variants or no-mutations in exonic regions of MTM1. Sashimi plot revealed retentions of intronic sequence in patient1 (between exon 5 and 6) and patient 2 (between exon 11 and 12), respectively. In patient 3, exon 4 skipping was observed due to a synonymous mutation in exon 4. These aberrant splicing were predicted to cause frameshift and subsequently create premature stop codon in these patients. The in vitro splicing experiments with artificial hybrid minigene constructs confirmed those mutations exclusively produced abnormal splicing products. Lastly, Myoblasts from patient 2 showed perinuclear distribution of mitochondria in addition to the abnormal splicing, and treatment with antisense morpholino oligonucleotides rescued those phenotypes. In conclusion, RNA-seq analysis can uncover deep intronic mutations and synonymous mutations which lead abnormal splicing events as the cause of muscle diseases such as XLMTM. We propose that antisense therapy is potentially practical for diseases arising from this type of mutation.

A multicenter, retrospective medical record review of X-linked myotubular myopathy: The recensus study.

ABSTRACT Introduction: X‐linked myotubular myopathy (XLMTM), characterized by severe hypotonia, weakness, respiratory distress, and early mortality, is rare and natural history studies are few. Methods: RECENSUS is a multicenter chart review of male XLMTM patients characterizing disease burden and unmet medical needs. Data were collected between September 2014 and June 2016. Results: Analysis included 112 patients at six clinical sites. Most recent patient age recorded was ≤18 months for 40 patients and >18 months for 72 patients. Mean (SD) age at diagnosis was 3.7 (3.7) months and 54.3 (77.1) months, respectively. Mortality was 44% (64% ≤18 months; 32% >18 months). Premature delivery occurred in 34/110 (31%) births. Nearly all patients (90%) required respiratory support at birth. In the first year of life, patients underwent an average of 3.7 surgeries and spent 35% of the year in the hospital. Discussion: XLMTM is associated with high mortality, disease burden, and healthcare utilization. Muscle Nerve 57: 550–560, 2018

Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs

X-linked myotubular myopathy (XLMTM) results from MTM1 gene mutations and myotubularin deficiency. Most XLMTM patients develop severe muscle weakness leading to respiratory failure and death, typically within 2 years of age. Our objective was to evaluate the efficacy and safety of systemic gene therapyin the p.N155K canine model of XLMTM by performing a dose escalation study. A recombinant adeno-associated virus serotype 8 (rAAV8) vector expressing canine myotubularin (cMTM1) under the muscle-specific desmin promoter (rAAV8-cMTM1) was administered by simple peripheral venous infusion in XLMTM dogs at 10weeks of age, when signsof the disease are already present. A comprehensive analysis of survival, limb strength, gait, respiratory function, neurological assessment, histology, vector biodistribution, transgene expression, and immune response was performed over a 9-month study period. Results indicate that systemic gene therapy was well tolerated, prolonged lifespan, and corrected the skeletal musculature throughout the body in a dose-dependent manner, defining an efficacious dose in this large-animal model of the disease. These results support the development of gene therapy clinical trials for XLMTM.

Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers

Mutations in the MTM1 gene cause X-linked myotubular myopathy (XLMTM), characterized by neonatal hypotonia and respiratory failure, and are responsible for a premature mortality in affected males. Female carriers are usually asymptomatic but they may present with muscular weakness because of a hypothesized skewed pattern of X-chromosome inactivation.By combining next generation sequencing (NGS) and CGH array approaches, we have investigated the role of MTM1 variants in a large cohort of undiagnosed patients with a wide spectrum of myopathies. Seven novel XLMTM patients have been identified, including two girls with an unremarkable family history for myotubular myopathy.Moreover, we have detected and finely mapped a large deletion causing a myotubular myopathy with abnormal genital development.Our data confirm that the severe neonatal onset of the disease in male infants is sufficient to address the direct molecular testing toward the MTM1 gene and, above all, suggest that the number of undiagnosed symptomatic female carriers is probably underestimated.

Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review With Cross-Species Comparisons

X-linked myotubular myopathy (XLMTM) is a devastating, rare, congenital myopathy caused by mutations in the MTM1 gene, resulting in a lack of or dysfunction of the enzyme myotubularin. This leads to severe perinatal weakness and distinctive muscle pathology. It was originally thought that XLMTM was related to developmental arrest in myotube maturation; however, the generation and characterization of several animal models have significantly improved our understanding of clinical and pathological aspects of this disorder. Myotubularin is now known to participate in numerous cellular processes including endosomal trafficking, excitation-contraction coupling, cytoskeletal organization, neuromuscular junction structure, autophagy, and satellite cell proliferation and survival. The available vertebrate models of XLMTM, which vary in severity from complete absence to reduced functional levels of myotubularin, recapitulate features of the human disease to a variable extent. Understanding how pathological endpoints in animals with XLMTM translate to human patients will be essential to interpret preclinical treatment trials and translate therapies into human clinical studies. This review summarizes the published animal models of XLMTM, including those of zebrafish, mice, and dogs, with a focus on their pathological features as compared to those seen in human XLMTM patients.

Mutation spectrum of the MTM1 gene in XLMTM patients: 10 years of experience in prenatal and postnatal diagnosis.

X-linked myotubular myopathy (XLMTM) is a congenital neuromuscular disorder defined by severe hypotonia, respiratory failure and histopathologic changes in muscle biopsy. The objective of this report is to inform about our experience of genetic analysis on a group of 25 unrelated XLMTM patients, clinically diagnosed by several Italian and European Medical Institutes from 2006 to 2015. The molecular strategy used for genotyping involved Sanger sequencing of coding and intron/exon regions and the Multiplex Ligation Probe Amplification method. A total of 13 different point variants (6 nonsense, 5 missense, 1 splicing and 1 small deletion) were found in 15 patients (60%). Three were new missense variants: c.185G>T p.(Arg62Ile), c.719T>A p.(Val240Glu), and c.1262G>T p.(Arg421Leu). No large duplications/deletions have been identified. We performed carrier testing of at-risk female relatives. Only one mutation was de novo. Successively, we offered XLMTM prenatal testing for seven pregnancies in five unrelated families. In this context, the aim to propose an effective molecular diagnostic service is to confirm clinical XLMTM diagnosis, to monitor the cause-disease mutation segregation in the family and to offer genetic counseling to have correct information regarding offspring risks and the prenatal testing.

G.P.40: Skeletal muscle MRI in an X-linked myotubular myopathy patient who became ambulatory

X-linked myotubular myopathy (XLMTM), one of the most severe forms of centronuclear myopathy Cis caused by mutations in the <i>MTM1</i> gene. XLMTM usually has a neonatal onset requiring respiratory support due to severe respiratory muscle weakness and patients remain bed-ridden. The few past reports on skeletal muscle imaging of the lower limbs in XLMTM patients showed involvement of the soleus muscles and of the posterior thigh. We present the magnetic resonance imaging (MRI) findings of both upper and lower limbs in an XLMTM patient, who survived with Non-invasive Positive Pressure Ventilation (NPPV) support and ultimately became ambulatory. The patient was a 12-year old boy. His older brother, who also had XLMTM, had died during infancy. The patient presented with reduction of fetal movements, and had needed artificial respirator support at birth. He was genetically diagnosed as having XLMTM. Although he suffered repeated exacerbations of respiratory failure due to infection, the frequency of mechanical ventilation decreased after the initiation of NPPV at the age of 21months. He obtained an independent gait at the age of 7years, and he also gained the ability to walk up the stairs while holding onto a railing. T1-weighted muscle MRI tended to show high intensity areas in the flexor group of both brachial muscles and muscles in the forearms. Whole muscles in the thighs were mildly affected, but the soleus muscles were preserved. We have presented a rare XLMTM case achieving satisfactory progress. Muscle imaging showed differences from past reports in terms of the affected muscles. The degree of muscle atrophy was milder, most notably, than previously thought. This is consistent with our patient's good clinical course. We speculate that skeletal muscle MRI shows specific muscle involvements also in the upper limbs. We advocate accumulating muscle imaging data not only for the lower but also for the upper limbs, to shed further light on the pathophysiology of XLMTM.