Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Late-onset facioscapulohumeral muscular dystrophy type 1 in previously undiagnosed families: Presenting clinical features in an often-misdiagnosed disorder.

INTRODUCTION/AIMS: In our experience, patients with late-onset facioscapulohumeral muscular dystrophy type 1 (FSHD1) are frequently misdiagnosed, some for many years. The aim of this report is to document this clinical experience including the presenting symptoms and misdiagnoses and to discuss the challenges in diagnosing patients with late-onset FSHD1. METHODS: We performed a retrospective medical record review and recorded clinical data on patients with a genetically confirmed diagnosis of FSHD1, who began to have symptoms at 50 years of age or older, and either had no family history of FSHD1 or had a history of an undiagnosed weakness in a family member. RESULTS: Thirteen patients, 7 men and 6 women, met the study inclusion criteria. Age of onset ranged from 52 to 74 (mean, 59.8) years, age of diagnosis ranged from 54 to 80 (mean, 66.5) years, and duration of symptoms from onset to diagnosis was 1 to 15 (mean, 6.7) years. Prior diagnoses included lumbosacral polyradiculopathy in five (38%); statin-related myopathy in two (15%); and one each of polymyositis, inclusion-body myositis, distal myopathy, limb-girdle muscular dystrophy, unspecific myopathy, and unspecified scapular winging. For eight patients (62%), family history was suspected in deceased members or if by confirmed DNA test postdiagnosis. DISCUSSION: The diagnosis of late-onset FSHD1 is often delayed by many years with patients frequently receiving misdiagnoses. FSHD1 may not be considered in the differential diagnosis of late-onset weakness due to its rarity and because its clinical features are subtler, nonspecific, and mimic other neuromuscular disorders.

Diagnostic yield of advanced genetic testing in patients with hereditary neuropathies: A retrospective single-site study.

INTRODUCTION/AIMS: Advanced genetic testing including next-generation sequencing (AGT/NGS) has facilitated DNA testing in the clinical setting and greatly expanded new gene discovery for the Charcot-Marie-Tooth neuropathies and other hereditary neuropathies (CMT/HN). Herein, we report AGT/NGS results, clinical findings, and diagnostic yield in a cohort of CMT/HN patients evaluated at our neuropathy care center. METHODS: We reviewed the medical records of all patients with suspected CMT/HN who underwent AGT/NGS at the Hospital for Special Care from January 2017 through January 2020. Patients with variants reported as pathogenic or likely pathogenic were included for further clinical review. RESULTS: We ordered AGT/NGS on 108 patients with suspected CMT/HN. Of these, pathogenic or likely pathogenic variants were identified in 17 patients (diagnostic yield, 15.7%), including 6 (35%) with PMP22 duplications; 3 (18%) with MPZ variants; 2 (12%) with MFN2 variants; and 1 each with NEFL, IGHMBP2, GJB1, BSCL2, DNM2, and TTR variants. Diagnostic yield increased to 31.0% for patients with a positive family history. DISCUSSION: AGT/NGS panels can provide specific genetic diagnoses for a subset of patients with CMT/HN disorders, which improves disease and genetic counseling and prepares patients for disease-focused therapies. Despite these advancements, many patients with known or suspected CMT/HN disorders remain without a specific genetic diagnosis. Continued advancements in genetic testing, such as multiomic technology and better understanding of genotype-phenotype correlation, will further improve detection rates for patients with suspected CMT/HN disorders.

Programmable Artificial Cells Using Histamine-Responsive Synthetic Riboswitch.

Artificial cells that encapsulate DNA-programmable protein expression machinery are emerging as an attractive platform for studying fundamental cellular properties and applications in synthetic biology. However, interfacing these artificial cells with the complex and dynamic chemical environment remains a major and urgent challenge. We demonstrate that the repertoire of molecules that artificial cells respond to can be expanded by synthetic RNA-based gene switches, or riboswitches. We isolated an RNA aptamer that binds histamine with high affinity and specificity and used it to design robust riboswitches that activate protein expression in the presence of histamine. Finally, the riboswitches were incorporated in artificial cells to achieve controlled release of an encapsulated small molecule and to implement a self-destructive kill-switch. Synthetic riboswitches should serve as modular and versatile interfaces to link artificial cell phenotypes with the complex chemical environment.

Fulminant lipid storage myopathy due to multiple acyl-coenzyme a dehydrogenase deficiency.

INTRODUCTION: The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells. METHODS: We describe a rapidly progressive myopathy in a previously healthy 33-year-old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death. RESULTS: Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene. CONCLUSIONS: This report illustrates a late-onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy.

Myotonic Muscular Dystrophy Type 2 in CT, USA: A Single-Center Experience With 50 Patients.

ABSTRACT: Myotonic dystrophy type 2 (DM2) is an autosomal dominant disorder due to a (CCTG)n repeat expansion in intron 1 of the CNBP gene. In this article, we report the clinicopathologic findings in 50 patients seen at a single site over a 27 year period. DM2 was the fifth most common type of muscular dystrophy seen at our center with a 5-fold lower frequency as compared to DM1. Age of symptom onset ranged from 15 to 72 years, and the mean duration between symptom onset and diagnosis was 7.4 years. Weakness referable to the proximal lower extremities was the presenting symptom in 62% of patients. The degree of generalized weakness varied from severe in 30% to no weakness in 20% of patients. Clinical myotonia was noted in 18% and myotonic discharges on electromyography in 97% of patients. Pain symptoms were uncommon in our cohort. A significant correlation was noted between limb weakness and degree of muscle pathologic changes. There was no correlation between CCTG repeat size and other clinicopathologic findings. Six patients (12%) had cardiac abnormalities including one who developed progressive nonischemic dilated cardiomyopathy ultimately leading to cardiac transplantation. In 21 patients followed for 2 or more years, we noted a mean rate of decline in total Medical Research Council score of about 1% per year.

Laing Myopathy: Report of 4 New Families With Novel MYH7 Mutations, Double Mutations, and Severe Phenotype.

Laing distal myopathy (LDM) is an autosomal dominant disorder caused by mutations in the slow skeletal muscle fiber myosin heavy chain (MYH7) gene on chromosome 14q11.2. The classic LDM phenotype-including early-onset, initial involvement of foot dorsiflexors and great toe extensors, followed by weakness of neck flexors and finger extensors-is well documented. Since the original report by Laing et al in 1995, the spectrum of MYH7-related myopathies has expanded to include congenital myopathies, late-onset myopathies, myosin storage myopathy, and scapuloperoneal myopathies. Most patients with LDM harbor mutations in the midrod domain of the MYH7 gene, but rare cases document disease-associated mutations in the globular head region. In this report, we add to the medical literature by describing the clinicopathological findings in 8 affected family members from 4 new LDM families-including 2 with novel MYH7 mutations (Y162D and A1438P), one with dual mutations (V39M and K1617del), and one family (E1508del) with severe early-onset weakness associated with contractures, respiratory insufficiency, and dilated cardiomyopathy. Our families highlight the ever-expanding clinical spectrum and genetic variation of the skeletal myopathies related to MYH7 gene mutations.

Whole exome sequencing discloses a pathogenic MTM1 gene mutation and ends the diagnostic odyssey in an older woman with a progressive and seemingly sporadic myopathy: Case report and literature review of MTM1 manifesting female carriers.

We report the case of a 58-year-old woman with a progressive and seemingly sporadic myopathy who, later through whole exome sequencing, was diagnosed as a manifesting carrier of a myotubularin 1 gene mutation (c.342_342 + 4delAGTAA). As the case was a diagnostic challenge for 7 years, we thought it would be helpful to report the patient and review the other 25 cases thus far described. The manifesting carrier state is a rare cause for myopathic weakness in a female but should be strongly considered in kindreds with known affected males with myotubularin 1 gene mutations, and families with history of gestational polyhydramnios or male infantile death. Although the clinical phenotype is quite variable, the findings of ptosis, ophthalmoparesis, facial weakness, and asymmetrical limb involvement should raise the suspicion of the manifesting carrier state. Necklace fibers appear to be a highly sensitive and specific pathologic finding in such cases.

Sensitivity and clinical utility of the anti-cytosolic 5'-nucleotidase 1A (cN1A) antibody test in sporadic inclusion body myositis: Report of 40 patients from a single neuromuscular center.

Sporadic inclusion body myositis (IBM) is the most common acquired myopathy affecting patients over age 50. The discovery of an autoantibody directed against a 43-44 kD protein (anti-cytosolic-5'-nucleotidase 1A or anti-cN1A) has provided support for the hypothesis of an immune-mediated pathogenesis. Previous studies have reported variable test sensitivity and specificity, and inconsistent results on the predictive value. In our cohort of 40 patients with clinico-pathologically or clinically defined IBM, we found the sensitivity of the anti-cN1A antibody test to be 50%. Comparing characteristics for test positive and test negative groups, we found that patients in our cohort testing positive for the anti-cN1A antibody were significantly more likely to be older than age 60 years at symptom onset. We found no positive association between anti-cN1A reactivity and other clinical, laboratory, and muscle histopathologic findings. Based on all clinical studies published to date including the present, the anti-cN1A antibody test shows high diagnostic specificity, moderate sensitivity, and a low predictive value in regards to age of onset, disease severity and other associated clinicopathological findings.

Benign calf amyotrophy: clinicopathologic study of 8 patients.

BACKGROUND: The benign focal amyotrophy disorders have been described since 1959 for the upper limbs and since 1981 for the lower limbs. The clinicopathologic features have pointed to a restricted and self-limiting form of motor neuron disease. OBJECTIVE: To describe the clinical, electromyographic, and muscle histopathologic features in 8 patients with benign calf amyotrophy. DESIGN: Retrospective review of patient charts, electromyograms, and muscle histopathology. PATIENTS AND RESULTS: Eight patients, aged 37 to 88 years, developed insidiously progressive calf muscle weakness and wasting during 1 to 5 years. The gastrocnemius weakness and wasting were bilateral in 4 patients. Initial progression of symptoms was followed by disease stabilization. None had a history of poliomyelitis or family history of neuromuscular disease. Creatine kinase values were mildly elevated in 5 patients. The electromyographic and muscle histopathologic findings were consistent with a chronic neuropathic disorder. Despite the restricted calf muscle involvement clinically, the electromyographic abnormalities suggested more diffuse lower limb involvement. Further studies, including DNA tests and muscle-based protein studies, excluded several types of inherited neuromuscular disorders. CONCLUSIONS: Benign calf amyotrophy is a variant of the benign focal amyotrophy disorders. The etiology for these disorders is unknown. Studies to exclude other causes of calf amyotrophy and careful follow-up examinations to document disease stabilization are necessary to diagnose this uncommon disorder.

Brachial plexopathy due to malignant peripheral nerve sheath tumor in neurofibromatosis type 1: case report and subject review.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome affecting approximately 1 in 4,000 persons. It is an autosomal-dominant disorder with half of the cases resulting from spontaneous mutations. This genetic defect leads to the formation of benign tumors or neurofibromas of the peripheral nervous system. Dermal neurofibromas may cause local discomfort and itching but are rarely associated with neurological deficit and do not undergo malignant change. The more extensive plexiform neurofibromas produce neurological complications in 27%-43% of patients with NF1 and may undergo malignant degeneration in 5% of cases. Patients with NF1 who develop pain or new neurological symptoms should have a rapid and thorough assessment for malignancy. In this report, we illustrate this point by presenting a patient who developed acute shoulder pain and weakness due to malignant degeneration of a plexiform neurofibroma involving the left brachial plexus, and review the literature on this subject.

The Clinical Features of Facioscapulohumeral Muscular Dystrophy Associated With Borderline (>/=35 kb) 4q35 EcoRI Fragments.

OBJECTIVES: : The objectives of this study were to characterize the clinical features of facioscapulohumeral muscular dystrophy (FSHD) in patients with borderline (>/=35 kb) EcoRI fragments and to compare patients with borderline EcoRI fragments with FSHD patients harboring fragments of <35 kb. BACKGROUND: : Most patients with FSHD harbor 4q35 EcoRI fragments of less than 35 kb. The clinical findings in patients with borderline fragments are not well known. METHODS: : The authors conducted a retrospective review of patients with FSHD followed at a regional neuromuscular center over a 12-year period. RESULTS: : Eleven patients with DNA-positive FSHD, found to harbor borderline (>/=35 kb) EcoRI fragments (group 1), were compared with 30 patients with fragments of <35 kb (group 2). Group 1 patients were less likely (18%) to present with the classic FSHD phenotype as compared with group 2 patients (63%). Statistically significant differences in clinical disease severity and manual muscle testing scores were noted between the 2 groups, with group 1 patients showing less severe weakness and disability at presentation. CONCLUSIONS: : Patients with borderline fragments are more likely to have a partial or less severe form of FSHD, probably resulting from a less disruptive DNA alteration at the 4q35 locus.

Apparent conduction block in patients with ulnar neuropathy at the elbow and proximal Martin-Gruber anastomosis.

A Martin-Gruber anastomosis (MGA) commonly results in an abnormal decline in amplitude across the forearm segment when ulnar motor nerve conduction studies are performed. A recent report described a proximal MGA resembling partial conduction block in a patient with ulnar neuropathy at the elbow (UNE). As a result, we screened patients with similar findings. We detected a proximal MGA in three patients over a period of 2 years, which suggests that this may be an under-recognized anomaly. We conclude that a proximal MGA must be excluded in all cases of UNE showing apparent partial conduction block across the elbow segment.

Multiple recurrences of diabetic muscle infarction: case report and literature review.

This is the report a case of diabetic muscle infarction (DMI) associated with multiple recurrences and a review of the literature on DMI from the first description in 1965 to the present. Specifically the review of the clinical, laboratory, and muscle histopathologic features of 86 reported cases of DMI.Patients with DMI usually present with acute or subacute focal lower extremity muscle pain or swelling. Elevations in the white blood cell count and erythrocyte sedimentation rate are common laboratory findings. Magnetic resonance imaging, a highly sensitive diagnostic test in DMI, shows increased T2-weighted signal and edema in affected muscles. Typical muscle histopathology includes muscle fiber necrosis and endomysial inflammation. Slow symptomatic improvement usually occurs over a period of 1 to 6 months. Conservative therapy and analgesics seem appropriate for most patients. Although self-limiting, DMI is often associated with recurrent muscle infarctions and multisystem diabetes-related complications. Diabetes-induced arteriosclerosis and microangiopathy are the suggested causes of DMI.It is concluded that DMI is an uncommon but probably underrecognized disorder causing focal muscle pain and swelling, usually of thigh or calf muscles, in patients with diabetes mellitus complicated by poorly controlled hyperglycemia and multiorgan complications.

Biopsy-proven alpha-glucosidase deficiency with normal lymphocyte enzyme activity.

Alpha-glucosidase deficiency is a rare cause of muscle disease in adults. The diagnosis relies on recognition of the salient clinical features and determination of significantly reduced alpha-glucosidase (GAA) activity. Lymphocytes are the usual tissue for diagnostic enzymology; discrepant results from analyses of different tissues are unusual. We report a patient with clinical, electromyographic, and biopsy findings indicative of alpha-glucosidase deficiency whose muscle and lymphocyte enzyme results were markedly discrepant on multiple analyses. As a result, we conclude that all patients with suspected alpha-glucosidase deficiency and a normal lymphocyte GAA assay should also have a determination of GAA activity in muscle or skin fibroblasts.