Mohamed Kazamel

Epidemiological features of amyotrophic lateral sclerosis in a large clinic-based African American population

Abstract Our objective was to identify the main clinical and epidemiological features of ALS in a large cohort of African American (AA) patients and compare them to Caucasian (CA) patients in a clinic-based population. We retrospectively identified 207 patients who were diagnosed with ALS based on the revised El Escorial criteria (60 AA and 147 CA subjects). Patients were seen in the Neuromuscular Division at the University Medical Center. We compared epidemiological and clinical features of these two groups, focusing on age of onset and diagnosis, clinical presentation and survival. Results showed that AA patients had a significantly younger age of disease onset (55 years vs. 61 years for CA, p = 0.011) and were diagnosed at an earlier age (56 years vs. 62 years, p = 0.012). In younger ALS patients (< 45 years of age), there was a significant difference in gender frequency, with females predominating in the AA population and males in the CA population (p = 0.025). In a multivariable Cox proportional hazard model, survival rates were not different between the groups. In both groups, survival significantly increased with younger age. In conclusion, AA patients presented at an earlier age, but there was no difference in survival compared to CA patients. A gender reversal occurred in younger ALS patients, with AA patients more likely to be female and CA patients more likely to be male.

Transforming Growth Factor Beta (TGF-β) Is a Muscle Biomarker of Disease Progression in ALS and Correlates with Smad Expression.

We recently identified Smads1, 5 and 8 as muscle biomarkers in human ALS. In the ALS mouse, these markers are elevated and track disease progression. Smads are signal transducers and become activated upon receptor engagement of ligands from the TGF-β superfamily. Here, we sought to characterize ligands linked to activation of Smads in ALS muscle and their role as biomarkers of disease progression. RNA sequencing data of ALS muscle samples were mined for TGF-β superfamily ligands. Candidate targets were validated by qRT-PCR in a large cohort of human ALS muscle biopsy samples and in the G93A SOD1 mouse. Protein expression was evaluated by Western blot, ELISA and immunohistochemistry. C2C12 muscle cells were used to assess Smad activation and induction. TGF-β1, 2 and 3 mRNAs were increased in ALS muscle samples compared to controls and correlated with muscle strength and Smads1, 2, 5 and 8. In the G93A SOD1 mouse, the temporal pattern of TGF-β expression paralleled the Smads and increased with disease progression. TGF-β1 immunoreactivity was detected in mononuclear cells surrounding muscle fibers in ALS samples. In muscle cells, TGF-β ligands were capable of activating Smads. In conclusion, TGF-β1, 2 and 3 are novel biomarkers of ALS in skeletal muscle. Their correlation with weakness in human ALS and their progressive increase with advancing disease in the ALS mouse suggest that they, as with the Smads, can track disease progression. These ligands are capable of upregulating and activating Smads and thus may contribute to the Smad signaling pathway in ALS muscle.

Clinical spectrum of valosin containing protein (VCP)‐opathy

Introduction: Valosin containing protein (VCP) mutations cause a rare disorder characterized by hereditary inclusion body myopathy, Paget disease of bone (PDB), and frontotemporal dementia (FTD) with variable penetrance. VCP mutations have also been linked to amyotrophic lateral sclerosis and Charcot‐Marie‐Tooth disease type 2. Methods: Review of clinical, serological, electrophysiological, and myopathological findings of 6 VCP‐opathy patients from 4 unrelated families. Results: Patients manifested muscle weakness between ages 40 and 53 years and developed predominant asymmetric limb girdle weakness. One patient had distal weakness at onset and co‐existing peripheral neuropathy. Another patient had PDB, 1 had mild cognitive deficits, and 1 had FTD. All patients had myopathic and neurogenic electromyographic findings with predominant neurogenic changes in 2. Rimmed vacuoles were infrequent, while neurogenic changes were prominent in muscle biopsies. Conclusions: VCP‐opathy is a multifaceted disorder in which myopathy and peripheral neuropathy can coexist. The electrophysiological and pathological neurogenic changes raise the possibility of coexisting motor neuron involvement. Muscle Nerve, 2015 Muscle Nerve 54: 94–99, 2016 Muscle Nerve 54: 94–99, 2016

Smads as muscle biomarkers in amyotrophic lateral sclerosis.

To identify molecular signatures in muscle from patients with amyotrophic lateral sclerosis (ALS) that could provide insight into the disease process and serve as biomarkers.

Sensory manifestations of diabetic neuropathies: anatomical and clinical correlations.

Background: Diabetes mellitus is among the most common causes of peripheral neuropathy worldwide. Sensory impairment in diabetics is a major risk factor of plantar ulcers and neurogenic arthropathy (Charcot joints) causing severe morbidity and high health-care costs. Objective: To discuss the different patterns of sensory alterations in diabetic neuropathies and their anatomical basis. Study design: Literature review. Methods: Review of the literature discussing different patterns of sensory impairment in diabetic neuropathies. Results: The different varieties of diabetic neuropathies include typical sensorimotor polyneuropathy (lower extremity predominant, length-dependent, symmetric, sensorimotor polyneuropathy presumably related to chronic hyperglycemic exposure, and related metabolic events), entrapment mononeuropathies, radiculoplexus neuropathies related to immune inflammatory ischemic events, cranial neuropathies, and treatment-related neuropathies (e.g. insulin neuritis). None of these patterns are unique for diabetes, and they can occur in nondiabetics. Sensory alterations are different among these prototypic varieties and are vital in diagnosis, following course, treatment options, and follow-up of treatment effects. Conclusions: Diabetic neuropathies can involve any segment of peripheral nerves from nerve roots to the nerve endings giving different patterns of abnormal sensation. It is the involvement of small fibers that causes positive sensory symptoms like pain early during the course of disease, bringing subjects to physician’s care. Clinical Relevance This article emphasizes on the fact that diabetic neuropathies are not a single entity. They are rather different varieties of conditions with more or less separate pathophysiological mechanisms and anatomical localization. Clinicians should keep this in mind when assessing patients with diabetes on the first visit or follow-up.

Charcot Marie Tooth disease (CMT): historical perspectives and evolution

Prior to Charcot and Marie’s and Tooth’s reports, patients with peroneal muscular atrophy had been described by Virchow, Eulenburg, Friedreich, Osler, and others. In February 1886, Charcot and Marie published their original description of five patients who had what they called Progressive Muscular Atrophy. They surmised that the lesion could be in the spinal cord. Three months later, Tooth presented his M.D. degree thesis entitled “Peroneal Type of Progressive Muscular Atrophy”, to the University of Cambridge, UK. Tooth localized the pathology to the peripheral nerves. Dyck and Lambert (Arch Neurol 18:619–625, 1968) classified several CMT kinships based on differences in modes of inheritance, natural history, biochemical features, nerve conduction velocity, and pathologic characteristics. This article will focus on historical landmarks and major discoveries pertinent to the disease since its original description through the second half of the twentieth century.

Subacute demyelinating polyradiculoneuropathy complicating Epstein-Barr virus infection in GATA2 haploinsufficiency

Introduction: Autosomal dominant haploinsufficiency of GATA2 causes monocytopenia and natural killer cell lymphopenia, resulting in predisposition to mycobacterial, fungal, and viral infections. Methods: Herein we report on the clinical, serologic, electrophysiologic, and pathologic evaluations of a 29‐year‐old woman with GATA2 haploinsufficiency and active Epstein–Barr virus (EBV) infection complicated by subacute painful neuropathy. Results: Nerve conduction and electromyography studies showed predominantly demyelinating sensorimotor polyradiculoneuropathy. Lumbar spine MRI showed thickening and enhancement of the cauda equina nerve roots. Serum and cerebrospinal fluid anti‐IgG and IgM EBV capsid and nucleic acid antibodies were positive. Sural nerve biopsy showed microvasculitis and an increased frequency of fibers with segmental demyelination. Intravenous immunoglobulin and steroids improved the patients neuropathy. Conclusion: GATA2 mutation–related immunodeficiency may predispose to EBV‐associated subacute demyelinating polyradiculoneuropathy by both viral susceptibility and immune dysregulation. In patients who present in this manner, immunodeficiency syndromes should be considered when lymphomatous infiltration is excluded. Immunotherapy can be helpful. Muscle Nerve 57: 150–156, 2018

Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis

ALS is a fatal neurodegenerative disorder of motor neurons leading to progressive atrophy and weakness of muscles. Some of the earliest pathophysiological changes occur at the level of skeletal muscle and the neuromuscular junction. We previously identified distinct mRNA patterns, including members of the Smad and TGF-β family, that emerge in muscle tissue at the earliest (pre-clinical) stages. These patterns track disease progression in the mutant SOD1 mouse and are present in human ALS muscle. Because miRNAs play a direct regulatory role in mRNA expression, we hypothesized in this study that there would be distinct miRNA patterns in ALS muscle appearing in early stages that could track disease progression. We performed next-generation miRNA sequencing on muscle samples from G93A SOD1 mice at early (pre-clinical) and late (symptomatic) stages, and identified distinct miRNA patterns at both stages with some overlap. An Ingenuity Pathway Analysis predicted effects on a number of pathways relevant to ALS including TGF-β signaling, axon guidance signaling, and mitochondrial function. A subset of miRNAs was validated in the G93A SOD1 mouse at four stages of disease, and several appeared to track disease progression, including miR-206. We assessed these miRNAs in a large cohort of human ALS and disease control samples and found that some had similar changes but were not specific for ALS. Surprisingly, miR-206 levels did not change overall compared to normal controls, but did correlate with changes in strength of the muscle biopsied. In summary, we identified distinct miRNA patterns in ALS muscle that reflected disease stage which could potentially be used as biomarkers of disease activity.

History of electromyography and nerve conduction studies: A tribute to the founding fathers

The early development of nerve conduction studies (NCS) and electromyography (EMG) was linked to the discovery of electricity. This relationship had been concluded by observing the effect of applying electricity to the body of an animal and discovering that nerves and muscles themselves could produce electricity. We attempt to review the historical evolution of NCS and EMG over the last three centuries by reviewing the landmark publications of Galvani, Adrian, Denny-Brown, Larrabee, and Lambert. In 1771, Galvani showed that electrical stimulation of animal muscle tissue produced contraction and, thereby, the concept of animal electricity was born. In 1929, Adrian devised a method to record a single motor unit potential by connecting concentric needle electrodes to an amplifier and a loud speaker. In 1938, Denny-Brown described the fasciculation potentials and separated them from fibrillations. Toward the end of World War II, Larrabee began measuring the compound muscle action potential in healthy and injured nerves of war victims. In 1957, Lambert and Eaton described the electrophysiologic features of a new myasthenic syndrome associated with lung carcinoma. Overall, research on this topic was previously undertaken by neurophysiologists and then later by neurologists, with Adrian most likely being the first neurologist to be involved. The field greatly benefited from the invention of equipment that was capable of amplifying small bioelectrical currents by the beginning of the 20th century. Significant scientific and technical advances were later made during and after World War II which provided a large patient population with nerve injuries to study.

Clinical and Electrophysiological Findings in Hereditary Inclusion Body Myopathy Compared With Sporadic Inclusion Body Myositis.

Objective: To compare the clinical and electrophysiological findings in hereditary inclusion body myopathy (hIBM) and sporadic inclusion body myositis (sIBM) patients. Methods: We retrospectively identified 8 genetically proven hIBM patients and 1 DNAJB6 myopathy with pathological features of hIBM, and compared their clinical, electromyographic, and serological data with a group of 51 pathologically proven sIBM patients. Results: hIBM patients had a younger mean age of onset (36 vs. 60 years, P = 0.0001). Diagnostic delay was shorter in sIBM (6 vs. 15 years, P = 0.0003). Wrist flexors (P = 0.02), digit flexors (P = 0.01), digit extensors (P = 0.02), and quadriceps (P = 0.008) muscles were more frequently affected in sIBM. Fibrillation potentials were more common in sIBM patients (P = 0.03). Electrical myotonia was found in 4 hIBM patients, not significantly different from sIBM patients (P = 0.45). Creatinine kinase was higher in sIBM patients (799 vs 232, P = 0.03). Conclusions: sIBM and hIBM seem to have similar electromyographic changes. The combination of clinical, serological, and histopathological findings can guide genetic testing to the final diagnosis.