Muhammad Al-Lozi

TDP-43 A315T mutation in familial motor neuron disease

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA‐binding protein 43 (TDP‐43) proteinopathies to investigate TDP‐43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP‐43 gene led to the identification of a novel missense mutation, Ala‐315‐Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP‐43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP‐43 function and neurodegeneration. Ann Neurol 2008

Myopathy with antibodies to the signal recognition particle: clinical and pathological features

Objectives: To study myopathies with serum antibodies to the signal recognition particle (SRP), an unusual, myositis specific antibody associated syndrome that has not been well characterised pathologically. Methods: Clinical, laboratory, and myopathological features were evaluated in seven consecutive patients with a myopathy and serum anti-SRP antibodies, identified over three years. The anti-SRP myopathy was compared with myopathology in other types of inflammatory and immune myopathies. Results: The patients with anti-SRP antibodies developed weakness at ages ranging from 32 to 70 years. Onset was seasonal (August to January). Weakness became severe and disability developed rapidly over a period of months. Muscle pain and fatigue were present in some patients. No patient had a dermatomyositis-like rash. Serum creatine kinase was very high (3000 to 25 000 IU/l). Muscle biopsies showed an active myopathy, including muscle fibre necrosis and regeneration. There was prominent endomysial fibrosis, but little or no inflammation. Endomysial capillaries were enlarged, reduced in number, and associated with deposits of the terminal components of complement (C5b-9, membrane attack complex). Strength improved in several patients after corticosteroid treatment. Conclusions: Myopathies associated with anti-SRP antibodies may produce severe and rapidly progressive weakness and disability. Muscle biopsies show active myopathy with pathological changes in endomysial capillaries but little inflammation. Corticosteroid treatment early in the course of the illness is often followed by improvement in strength. In patients with rapidly progressive myopathies and a high serum creatine kinase but little inflammation on muscle biopsy, measurement of anti-SRP antibodies and pathological examination of muscle, including evaluation of endomysial capillaries, may provide useful information on diagnosis and treatment.

Efavirenz concentrations in CSF exceed IC50 for wild-type HIV

OBJECTIVES HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This studys objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF. METHODS CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF). RESULTS Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV. CONCLUSIONS Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.

Human Immunodeficiency Virus Protease Inhibitors and Risk for Peripheral Neuropathy

Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long‐term use in highly active ARV therapy.

Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods: Patients with a phenotype suggestive of a motor, non–length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion: Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.

Peripheral neuropathy in an outpatient cohort of patients with Sjögren's syndrome

Peripheral neuropathy is common in patients with Sjögrens syndrome (SS), but its precise prevalence is unknown. Most prior studies were conducted at neurology or rheumatology specialty clinics and likely selected for a more severely affected population. We evaluated 22 SS patients and 10 controls for evidence of neuropathy in an outpatient setting at a regional meeting of the Sjögrens Syndrome Foundation. We performed neurological examinations and nerve conduction studies (NCSs) and measured serum antinuclear antibody (ANA) and SS‐A and SS‐B antibody levels. Participants filled out a questionnaire pertaining to symptoms, diagnosis, and treatment. We found that signs and symptoms related to small axons were more common in patients with SS than in controls. Complaints of painful distal paresthesias in the feet were noted in 59% of patients but in only 10% of controls, and of abnormal sweating in 41% and 0%, respectively. Examination revealed decreased pinprick sensation in 64% of patients with SS, but in only 30% of controls. Overall, 45% of the patients but none of the controls were thought to have an isolated small‐fiber neuropathy. Large‐fiber dysfunction (as measured by testing vibration, deep tendon reflexes, and NCSs) was similar between the two groups. We conclude that small‐fiber neuropathy is common in patients with SS. Muscle Nerve 2006

Organ-specific autoantibodies with muscle weakness.

The motor unit includes the anterior horn cell, the motor axon and the muscle fibers it innervates, and the neuromuscular junction. Diseases of the motor unit usually present with weakness. Diagnosis of motor unit disorders involves the history, physical examination, electrophysiologic studies of nerve and muscle, and blood testing for creatine kinase, genetic disorders, and autoantibodies. Antibody testing is often useful for the identification of specific immune-mediated motor unit disorders. Identification of these disorders is important because they are often treatable. Antibodies with disease specificity include those directed against autoantigens with and without organ specificity. Several autoantibodies to non-organ-specific antigens are associated with subgroups of immune myopathies. Organ-specific autoantibodies in motor unit disorders with weakness occur in myasthenia gravis, especially with thymoma, a myopathy associated with Waldenstroms macroglobulinemia, Lambert-Eaton myasthenic syndrome, and multifocal motor neuropathy.

Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy

&NA; Sensory neuropathy (HIV‐SN) is a common cause of pain in HIV‐infected people. Establishing a diagnosis of HIV‐SN is important, especially when contemplating opioid use in high‐risk populations. However physical findings of HIV‐SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self‐report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV‐SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV‐SN were measured by a modified Total Neuropathy Score (TNS), composed of six objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self‐report of DNPP was associated with all six TNS items in univariate analysis and with four TNS items in multivariate analysis. The sensitivity and specificity of self‐report of DNPP in detecting the presence of a sensory abnormality were 52% and 92%, respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV‐infected patients reporting symptoms consistent with HIV‐SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV‐SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history.

Familial ALS with extreme phenotypic variability due to the I113T SOD1 mutation

We describe a large family with amyotrophic lateral sclerosis (ALS) caused by an I113T mutation in superoxide dismuatse type 1 (SOD1). The proband developed symptoms typical for ALS at age 39 years and is still walking five years later. Marked phenotypic variability is manifested by her mother with onset of gait difficulty and decision-making problems at age 67 years and a five-year course marked by progressive mild upper motor neuron weakness, frontotemporal dementia and chorea. An aunts initial symptoms included foot numbness and an uncle with the mutation is asymptomatic. Penetrance is only 50% at age 60 years and 88% at age 80 years with an 86-year-old woman harboring the mutation and having a normal neurologic examination. This family highlights the extreme variability in age of onset, clinical manifestations, disease progression and penetrance due to the I113T SOD1 mutation.

Sensory neuropathy with monoclonal IgM binding to a trisulfated heparin disaccharide.

We studied clinical and serological features of five patients with polyneuropathy and serum immunoglobulin M (IgM) binding to the trisulfated disaccharide IdoA2S‐GlcNS‐6S (TS‐HDS), the most abundant disaccharide component of heparin oligosaccharides. The patients all had painful, predominantly sensory polyneuropathies. Sensory loss was distal and panmodal. Electrophysiological and pathological studies were consistent with axonal loss, especially of unmyelinated axons. Immunohistochemistry showed IgM and κ light chains deposited around the rim of intermediate‐sized veins in the perimysium and epineurium. Serum IgM binding to TS‐HDS was selective, present in high titer (>12,000), and limited to κ light chains. We conclude that TS‐HDS is a newly identified target carbohydrate antigen of some IgM M‐proteins. Monoclonal IgM binding to TS‐HDS is associated with a painful, predominantly sensory, polyneuropathy syndrome with axonal loss and deposition of IgM in veins. The role of IgM binding to TS‐HDS in the pathogenesis of the neuropathy remains to be determined. Muscle Nerve 27: 188–195, 2003