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

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR 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.Motor neuron disease (MND) is a neurodegenerative disorder involving the loss of upper and/ or lower motor neurons, and it is characterized clinically by progressive weakness and death within a few years of onset; the most common clinical MND phenotype is amyotrophic lateral sclerosis (ALS NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript pathological protein of the motor neuron inclusions found in sporadic MND and also in frontotemporal lobar degeneration with ubiquitin-immunoreactive, tau-negative inclusions (FTLD-U), which can be associated with MND, but not in familial MND with Cu/Zn superoxide dismutase-1 (SOD1) mutation. [1][2][3][4] Although largely sporadic, about 10% of MND cases are familial, and of these about 20% have mutations in the SOD1 gene. 5 Evidence suggests that SOD1 mutations cause MND by a toxic gain of function. 6 The recent discovery that pathological TDP-43 inclusions are present in sporadic/non-SOD1 cases of MND, but absent from SOD1 cases and SOD1 transgenic mice, suggests that the sporadic form of the disease may have a different underlying pathophysiology. Therefore, new genetic insights into MND are needed to further the understanding of disease pathogenesis and to develop animal models representative of the sporadic form of the disease.

Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive IBM2.

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. Neurology ® 2012;78:1714-1720 GLOSSARY CMT ϭ Charcot-Marie-Tooth; gDNA ϭ genomic DNA; indels ϭ insertions/deletions; SDS-PAGE ϭ sodium dodecyl sulfate polyacrylamide gel electrophoresis; SMA ϭ spinal muscular atrophy; SMA-LED ϭ spinal muscular atrophy with lower extremity predominance; SNP ϭ single nucleotide polymorphism.Developmental and degenerative disorders affecting motor neurons or their axons produce a broad range of inherited human diseases, including spinal muscular atrophy (SMA), hereditary motor neuropathy, and amyotrophic lateral sclerosis. Many hypotheses regarding the pathophysiology of motor neuron loss (e.g., impaired axonal transport, aberrant protein aggregation, disrupted protein homeostasis, altered RNA metabolism 1,2 ) were first suggested by the identification of new genes producing hereditary motor neuron disease. To identify additional genes required for motor neuron survival, we studied a large pedigree with a rare form of dominantly inherited SMA with early childhood onset of weakness and disproportionate involvement of From the Department of Neurology

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.