M. T. Al-Lozi

Treatment of IgM antibody associated polyneuropathies using rituximab

Objectives: Polyneuropathies with associated serum IgM antibodies are often difficult to treat. Rituximab is a monoclonal antibody directed against the B cell surface membrane marker CD20. Rituximab eliminates B cells from the circulation, and, over time, could reduce cells producing autoantibodies. This study tested the ability of rituximab to produce changes in serum antibody titres, and improvement in strength, in patients with neuromuscular disorders and IgM autoantibodies. Methods: Over a period of two years, the authors evaluated changes in strength, measured by quantitative dynamometry, and concentrations of several types of serum antibodies in patients with polyneuropathies and serum IgM autoantibodies. Twenty one patients treated with rituximab were compared with 13 untreated controls. Results: Treatment with rituximab was followed by improved strength (an increase of mean (SEM) 23% (2%)of normal levels of strength), a reduction in serum IgM autoantibodies (to 43% (4%) of initial values), and a reduction in total levels of IgM (to 55% (4%) of initial values). There was no change in levels of serum IgG antibodies. There were no major side effects, even though B cells were virtually eliminated from the circulation for periods up to two years. Conclusions: In patients with IgM autoantibody associated peripheral neuropathies, rituximab treatment is followed by reduced serum concentrations of IgM, but not IgG, antibodies, and by improvement in strength. Additional studies, with placebo controls and blinded outcome measures, are warranted to further test the efficacy of rituximab treatment of IgM associated polyneuropathies.

Paraneoplastic necrotizing myopathy : Clinical and pathologic features

Objective: To characterize the clinical features and muscle pathology of paraneoplastic necrotizing myopathy. Background: Paraneoplastic syndromes involving many levels of the nervous system are well described, but there are only rare case reports of a necrotizing myopathy associated with cancer. Design: Case series. Results: We identified four patients with paraneoplastic necrotizing myopathy from muscle biopsies done at Washington University over a 10-year period. The patients (aged 38 to 76 years) presented with subacutely evolving, symmetric, proximal weakness. Tumor types included gastrointestinal adenocarcinoma (2 of 4), transitional cell carcinoma, prostatic carcinoma, and non-small cell lung carcinoma. Two patients died. Two others improved after treatment that included corticosteroids and tumor resection. Muscle pathology showed numerous necrotic fibers (8 to 100%) and intense alkaline phosphatase staining of the muscle connective tissue, but little inflammation. Conclusions: Paraneoplastic necrotizing myopathy is characterized by a rapidly progressive, symmetric, predominantly proximal weakness that produces severe disability. Muscle pathology demonstrates prominent necrosis with alkaline phosphatase staining of connective tissue and little inflammation. Evaluation for cancer is indicated in patients with these clinical and pathologic findings.

Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy

Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed. Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state—a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance.

Sensory exam with a quantitative tuning fork Rapid, sensitive and predictive of SNAP amplitude

Background: In the standard neurologic examination, outcome measures of sensation testing are typically qualitative and subjective. The authors compared the outcome of vibratory sense evaluation using a quantitative Rydel-Seiffer 64 Hz tuning fork with qualitative vibration testing, and two other features of the neurologic evaluation, deep tendon reflexes and sensory nerve conduction studies. Methods: The authors studied 184 subjects, including 126 with Waldenström’s macroglobulinemia and 58 controls, over the course of a weekend. Standard neurologic examinations and quantitative vibratory testing were performed. Sensory nerve action potentials (SNAP) were tested as a measure of sensory nerve function. Tests were carried out by different examiners who were blinded to the results of other testing and to clinical information other than the diagnosis of Waldenström’s macroglobulinemia. Results: Quantitative vibration measurements in all body regions correlated with sural SNAP amplitudes. Quantitative vibration outcomes were more strongly related to sural SNAP results than qualitative evaluations of vibration. Quantitative vibration testing also detected a loss of sensation with increased age in all body regions tested. Conclusions: Quantitative vibratory evaluation with Rydel-Seiffer tuning fork is rapid, has high inter- and intrarater reliability, and provides measures for evaluating changes in sensory function over time. Examinations with the quantitative tuning fork are also more sensitive and specific than qualitative vibration testing for detecting changes in sensory nerve function. Use of the quantitative tuning fork takes no more time, provides more objective information, and should replace the qualitative vibratory testing method that is now commonly used in the standard neurologic examination.

Peripheral neuropathies in Waldenström’s macroglobulinaemia

Objective: We sought to determine the prevalence, clinical features, and laboratory characteristics of polyneuropathies in Waldenström’s macroglobulinaemia (WM), a malignant bone marrow disorder with lymphocytes that produce monoclonal IgM. Methods: We prospectively studied 119 patients with WM and 58 controls. Medical history was taken, and neurological examinations, electrodiagnostic tests, and serum studies were performed by different examiners who were blinded to results except the diagnosis of WM. Results: Polyneuropathy symptoms, including discomfort and sensory loss in the legs, occurred more frequently (p<0.001) in patients with WM (47%) than in controls (9%). Patients with WM had 35% lower quantitative vibration scores, and more frequent pin loss (3.4 times) and gait disorders (5.5 times) than controls (all p<0.001). Patients with IgM binding to sulphatide (5% of WM) had sensory axon loss; those with IgM binding to myelin associated glycoprotein (MAG) (4% of WM) had sensorimotor axon loss and demyelination. Patients with WM with IgM binding to sulphatide (p<0.005) or MAG (p<0.001) had more severe sensory axon loss than other patients with WM. Demyelination occurred in 4% of patients with WM with no IgM binding to MAG. Age related reductions in vibration sense and sural SNAP amplitudes were similar (∼30%) in WM and controls. Conclusions: Peripheral nerve symptoms and signs occur more frequently in patients with WM than controls, involve sensory modalities, and are often associated with gait disorders. IgM binding to MAG or sulphatide is associated with a further increase in the frequency and severity of peripheral nerve involvement. Age related changes, similar to those in controls, add to the degree of reduced nerve function in patients with WM.

Dominant spinal muscular atrophy with lower extremity predominance Linkage to 14q32

Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. Results: Ten affected individuals (ages 7–58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (θ = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765–106,368,585. No segregating copy number variations were found within the disease interval. Conclusions: We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy–lower extremity, dominant.

Primary α‐sarcoglycan deficiency responsive to immunosuppression over three years

An 8‐year‐old girl developed weakness over 2 years and an elevated creatine kinase. The biopsy was most consistent with an active dystrophy with many inflammatory cells present. A trial of immunosuppression was started. In the first 2 months of treatment with prednisone, she had functionally and quantitatively significant improvement in her proximal strength. Over 3 years of treatment she maintained stable strength. Subsequent genetic studies showed that she had primary α‐sarcoglycan deficiency. The timing and the degree of benefit in strength were similar to that seen in boys with Duchenne muscular dystrophy who are treated with prednisone.

Frequency of spinal arteriovenous malformations in patients with unexplained myelopathy

The authors reviewed charts of 78 myelopathy patients who underwent spinal angiography for possible arteriovenous malformations (AVMs). Twenty-two patients had an AVM. No neurologic complications from angiography were observed. MRI findings of increased T2 signal or flow voids were strongly associated with AVMs. Spinal angiography should be performed in all patients with unexplained myelopathy after neurologic evaluation and an MRI demonstrating increased T2 signal or flow voids.

A skeletal muscle-specific from of decorin is a target antigen for a serum IgM M-protein in a patient with a proximal myopathy

We described a myopathy in a patient, B.J., with Waldenströms macroglobulinemia and a serum IgM M-protein that binds to a glycoprotein located in skeletal muscle endomysium. The objective of this study was to identify and characterize the endomysial antigen. The antigenic protein was purified using sequential differential solubility steps, size exclusion chromatography, and anion exchange chromatography. We subjected the deglycosylated protein and several proteolytic fragments to sequence analysis. We used immunohistochemistry, Western blot, and ELISA to study the binding of the IgM monoclonal and the anti-decorin core protein antibodies to the muscle antigen before and after deglycosylation. Sequence analysis revealed amino acid residues with 100% homology to human decorin. The anti-decorin core protein antibody bound to the purified antigen by ELISA and Western blot methods and bound to skeletal muscle endomysium in a histologic pattern similar to the human IgM M-protein from the patient B.J. Deglycosylation experiments revealed that the human IgM M-protein from B.J. serum recognized a carbohydrate epitope on decorin, probably containing chondroitin sulfate. A skeletal muscle-specific form of the proteoglycan decorin, with a chondroitin sulfate-like epitope, is a target antigen for the IgM M-protein in our patient with Waldenströms macroglobulinemia and a myopathy. These results are the first demonstration of the binding of a human IgM M-protein to an endomysial antigen. The anti-decorin IgM may be relevant to disease pathogenesis because the patient studied had a myopathy with IgM monoclonal antibodies deposited in the muscle endomysium.

Steroid‐responsive myopathy with deficient chondroitin sulfate C in skeletal muscle connective tissue

A 71-year-old man developed severe limb, bulbar, and respiratory weakness over 18 months. A muscle biopsy showed only a moderate degree of type 2 atrophy, but immunocytochemistry showed absence of chondroitin sulfate C glycosaminoglycan in the endomysium. Prednisone produced a marked increase in strength. Diffuse loss of endomysial chondroitin sulfate C was a feature of this treatable myopathy with severe weakness, but few pathologic changes.