Neuropathological features in brainstem, cerebellum and spinal cord. In addition to cerebellar, vestibullar nuclei and spinal cord posterior columns involvement, a moderate reduction of motor neurons ...in hypoglossal nucleus and anterior horn of the thoracic spinal cord was present.
Background and purpose
Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only ...15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%.
Methods
In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next‐generation sequencing and subsequent Sanger sequencing of SORD.
Results
Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals.
Conclusions
This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.
Distal hereditary motor neuropathies (dHMNs) are rare and genetically heterogeneous diseases. In this study, the diagnosis rate is 47.8%, and the calculated minimum prevalence is at least 2.3 per 100,000 individuals. The most frequent genetic causes of dHMN in our population are mutations in the HSPB1, GARS1, BICD2, and DNAJB2 genes, whereas 3.1% of patients carry biallelic mutations in SORD.
Objective
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a frequent autoimmune neuropathy with a heterogeneous clinical spectrum. Clinical and experimental evidence suggests that ...autoantibodies may be involved in its pathogenesis, but the target antigens are unknown. Axoglial junction proteins have been proposed as candidate antigens. We examined the reactivity of CIDP patients' sera against neuronal antigens and used immunoprecipitation for antigen unraveling.
Methods
Primary cultures of hippocampal neurons were used to select patients' sera that showed robust reactivity with the cell surface of neurons. The identity of the antigens was established by immunoprecipitation and mass spectrometry, and subsequently confirmed with cell‐based assays, immunohistochemistry with teased rat sciatic nerve, and immunoabsorption experiments.
Results
Four of 46 sera from patients with CIDP reacted strongly against hippocampal neurons (8.6%) and paranodal structures on peripheral nerve. Two patients' sera precipitated contactin‐1 (CNTN1), and 1 precipitated both CNTN1 and contactin‐associated protein 1 (CASPR1). Reactivity against CNTN1 was confirmed in 2 cases, whereas the third reacted only when CNTN1 and CASPR1 were cotransfected. No other CIDP patient or any of the 104 controls with other neurological diseases tested positive. All 3 patients shared common clinical features, including advanced age, predominantly motor involvement, aggressive symptom onset, early axonal involvement, and poor response to intravenous immunoglobulin.
Interpretation
Antibodies against the CNTN1/CASPR1 complex occur in a subset of patients with CIDP who share common clinical features. The finding of this biomarker may help to explain the symptoms of these patients and the heterogeneous response to therapy in CIDP. ANN NEUROL 2013;73:370–380
The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the ...disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed. These discoveries have enlarged an extense list of genes implicated in different cellular processes such as RNA processing or autophagia among others and have broaden the putative molecular targets of the disease. Some of ALS-related genes such as TARDBP or SOD1 among others have important roles in the regulation of glucose and fatty acids metabolism, so that an impairment of fatty acids (FA) consumption and ketogenic deficits during exercise in ALS patients would connect the physiopathology with some of the more intriguing epidemiological traits of the disease. The current understanding of ALS as part of a continuum with other neurodegenerative diseases and a crossroads between genetic, neurometabolic and environmental factors represent a fascinating model of interaction that could be translated to other neurodegenerative diseases. In this review we summarize the most relevant data obtained in the ten last years and the key lines for future research in ALS.
Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP‐43 pathology is ...currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP‐43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP‐43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non‐FTLD related findings can influence the cognitive status, particularly in older age groups.
We report the case of a patient with a clinical phenotype characterized by distal lower limb weakness and pes cavus. The electrophysiological study showed slightly reduced or normal amplitude of ...motor potentials, a decremental response to repetitive nerve stimulation and post‐exercise facilitation. Muscle biopsy showed only mild neurogenic features. Genetic analysis included a clinical exome sequencing, followed by Sanger analysis. Three‐dimensional (3D) models were generated with a SwissModel (https://swissmodel.expasy.org/) to explain the clinical observations and reinforce the pathogenic nature of the genetic variant identified. Genetic analysis demonstrated a new de novo heterozygous in frame deletion of the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing, which removes five aminoacids in the C2B domain of synaptotagmin‐2 protein, that cause a profound effect on the structure and function of this synaptic vesicle protein. We identified a de novo genetic variant in the SYT2 gene, further supporting its association with a highly stereotyped clinical and electrophysiological phenotype. Our case showed electrophysiological features consistent with a presynaptic dysfunction in the neuromuscular junction with normal post‐exercise amplitudes, not supporting the presence of predominant axonal damage. Although the analysis of SYT2 gene should be included in genetic analysis of patients presenting with this clinical phenotype that mimics motor neuropathy, clinicians have to consider the study of neuromuscular transmission to early identify this potentially treatable condition.
Abstract Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness, fatigability, and autoantibodies against protein antigens of the muscle endplate. Antibodies against ...acetylcholine receptor (AChR), and less frequently against muscle-Specific Kinase (MuSK) or lipoprotein related protein 4 (LRP4) occur in patients with seropositive MG (SPMG). However, about 10% of patients do not have detectable autoantibodies despite evidence suggesting that the disorder is immune mediated; this disorder is known as seronegative MG (SNMG). Using a protein array approach we identified cortactin (a protein that acts downstream from agrin/MuSK promoting AChR clustering) as potential new target antigen in SNMG. We set up an ELISA assay and screened sera from patients with SPMG, SNMG, other autoimmune diseases and controls. Results were validated by immunoblot. We found that 19.7% of patients with SNMG had antibodies against cortactin whereas only 4.8% of patients with SPMG were positive. Cortactin antibodies were also found in 12.5% of patients with other autoimmune disorders but only in 5.2% of healthy controls. We conclude that the finding of cortactin antibodies in patients with SNMG, suggests an underlying autoimmune mechanism, supporting the use of immune therapy.
OBJECTIVETo characterize the cortical macrostructure and microstructure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS)–frontotemporal dementia (FTD) continuum.
...METHODSWe prospectively recruited 88 participants with a 3T MRI structural and diffusion-weighted imaging sequences31 with ALS, 20 with the behavioral variant of FTD (bvFTD), and 37 cognitively normal controls. Participants with ALS underwent a comprehensive cognitive and behavioral assessment and were dichotomized into ALS without cognitive or behavioral impairment (ALSno-cbi; n = 12) and ALS with cognitive or behavioral impairment (ALScbi; n = 19). We computed cortical thickness and cortical mean diffusivity using a surface-based approach and explored the cortical correlates of cognitive impairment with the Edinburgh Cognitive and Behavioral ALS Screen.
RESULTSThe ALSno-cbi and ALScbi groups showed different patterns of reduced cortical thickness and increased cortical mean diffusivity. In the ALSno-cbi group, cortical thinning was restricted mainly to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on frontoinsular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum. Participants with ALS with either cognitive or behavioral impairment showed increased cortical mean diffusivity in the prefrontal cortex in the absence of cortical thickness.
CONCLUSIONSCortical mean diffusivity might be a useful biomarker for the study of extramotor cortical neurodegeneration in the ALS-FTD clinical spectrum.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that the cortical microstructure correlates with cognitive impairment in the ALS-FTD continuum.
Antibodies against myelin-associated glycoprotein (MAG) almost invariably appear in the context of an IgM monoclonal gammopathy associated neuropathy. Very few cases of anti-MAG neuropathy lacking ...IgM-monoclonal gammopathy have been reported. We investigated the presence of anti-MAG antibodies in 69 patients fulfilling diagnostic criteria for CIDP. Anti-MAG antibodies were tested by ELISA and confirmed by immunohistochemistry. We identified four (5.8%) anti-MAG positive patients without detectable IgM-monoclonal gammopathy. In two of them, IgM-monoclonal gammopathy was detected at 3 and 4-year follow-up coinciding with an increase in anti-MAG antibodies titers. In conclusion, anti-MAG antibody testing should be considered in chronic demyelinating neuropathies, even if IgM-monoclonal gammopathy is not detectable.
Objective
Several patients with previously reported titin gene (TTN) mutations causing tibial muscular dystrophy (TMD) have more complex, severe, or unusual phenotypes. This study aimed to clarify ...the molecular cause of the variant phenotypes in 8 patients of 7 European families.
Methods
Clinical, histopathological, and muscle imaging data of patients and family members were reanalyzed. The titin protein was analyzed by Western blotting and TTN gene by reverse transcription polymerase chain reaction (RT‐PCR) and Sanger sequencing.
Results
Western blotting showed more pronounced C‐terminal titin abnormality than expected for heterozygous probands, suggesting the existence of additional TTN mutations. RT‐PCR indicated unequal mRNA expression of the TTN alleles in biopsies of 6 patients, 3 with an limb‐girdle muscular dystrophy type 2J (LGMD2J) phenotype. Novel frameshift mutations were identified in 5 patients. A novel A‐band titin mutation, c.92167C>T (p.P30723S), was found in 1 patient, and 1 Portuguese patient with a severe TMD phenotype proved to be homozygous for the previously reported Iberian TMD mutation.
Interpretation
The unequal expression levels of TTN transcripts in 5 probands suggested severely reduced expression of the frameshift mutated allele, probably through nonsense‐mediated decay, explaining the more severe phenotypes. The Iberian TMD mutation may cause a more severe TMD rather than LGMD2J when homozygous. The Finnish patient compound heterozygous for the FINmaj TMD mutation and the novel A‐band titin missense mutation showed a phenotype completely different from previously described titinopathies. Our results further expand the complexity of muscular dystrophies caused by TTN mutations and suggest that the coexistence of second mutations may constitute a more common general mechanism explaining phenotype variability. Ann Neurol 2014;75:230–240
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