[Polyneuropathies in vasculitis and connective tissue diseases : Clinical manifestations and diagnostic recommendations]. / Polyneuropathien bei Vaskulitiden und Kollagenosen : Klinische Manifestationen und diagnostische Empfehlungen.

Vasculitic neuropathies result from inflammation of the vasa nervorum followed by ischemia and destruction of the peripheral nerve. The inflammation can be systemic or localized, i.e. non-systemic. Systemic vasculitis can be divided into primary and secondary forms. The latter is associated with, e.g. connective tissue diseases, infections, cancer or induced by certain drugs. Around two thirds of patients with systemic vasculitis develop vasculitic neuropathy presenting as characteristic painful, multifocal mononeuropathy of acute onset. The group of non-systemic neuropathies has grown in recent years with the addition of diabetic and non-diabetic lumbosacral radiculoplexus neuropathies, among others. Within the group of connective tissue diseases, other non-vasculitic neuropathies can occur as nerve-entrapment syndromes and sensory ataxic neuropathy. The aim of this article is to present a condensed overview of neuropathies associated with vasculitis and connective tissue diseases and to communicate characteristic clinical symptoms supporting rapid diagnostic and therapeutic procedures.

Novel SBF2 mutations and clinical spectrum of Charcot-Marie-Tooth neuropathy type 4B2.

Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.

Early-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany.

BACKGROUND: Early-onset myopathies are a heterogeneous group of neuromuscular diseases with broad clinical, genetic and histopathological overlap. The diagnostic approach has considerably changed since high throughput genetic methods (next generation sequencing, NGS) became available. OBJECTIVE: We present diagnostic subgroups in a single neuromuscular referral center and describe an algorithm for the diagnostic work-up. METHODS: The diagnostic approach of 98 index patients was retrospectively analysed. In 56 cases targeted sequencing of a known gene was performed, in 44 patients NGS was performed using large muscle specific panels, and in 12 individuals whole exome sequencing (WES) was undertaken. One patient was diagnosed via array CGH. Clinical features of all patients are provided. RESULTS: The final diagnosis could be found in 63 out of 98 patients (64%) with molecular genetic analysis. In 55% targeted gene sequencing could establish the genetic diagnosis. However, this rate largely depended on the presence of distinct histological or clinical features. NGS (large myopathy-related panels and WES) revealed genetic diagnosis in 58.5% (52% and 67%, respectively). The genes detected by WES in our cohort of patients were all covered by the panels. Based on our findings we propose an algorithm for a practical diagnostic approach.Prevalences:MTM1- and LAMA2-patients are the two biggest subgroups, followed by SEPN1-, RYR1- and Collagen VI-related diseases. 31% of genetically confirmed cases represents a group with overlap between "congenital myopathies (CM)" and "congenital muscular dystrophies (CMD)". In 36% of the patients a specific genetic diagnosis could not be assigned. CONCLUSIONS: A final diagnosis can be confirmed by high throughput genetic analysis in 58.5% of the cases, which is a higher rate than reported in the literature for muscle biopsy and should in many cases be considered as a first diagnostic tool. NGS cannot replace neuromuscular expertise and a close discussion with the geneticists on NGS is mandatory. Targeted candidate gene sequencing still plays a role in selected cases with highly suspicious clinical or histological features. There is a relevant clinical and genetic overlap between the entities CM and CMD.

Respiratory insufficiency as a presenting symptom of LGMD2D in adulthood.

Several forms of recessive limb girdle muscular dystrophy (LGMD2C-F) are due to mutations in genes coding for sarcoglycans. Clinically, most sarcoglycanopathies present in childhood with skeletal muscle wasting and early loss of ambulation; respiratory insufficiency is rare. However, some cases of LGMD2D with a late onset and a milder course have been reported. In this study, two adult brothers, compound heterozygous for two missense mutations of the SGCA gene (Arg77Cys, Val247Met), presented with respiratory insufficiency while they were still ambulatory.

Successful treatment of muscle sarcoidosis with thalidomide.

A 36-year-old male patient suffered from therapy resistant sarcoidosis with long-standing contractures, myopathy, skin lesions and pulmonary changes. Low-dose therapy with thalidomide (50 mg/day) was well tolerated, and the patient rapidly improved. Thalidomide was effective for muscular, cutaneous, and pulmonary involvement in our patient. This is the first report on the efficacy of thalidomide in muscle sarcoidosis. Therefore, thalidomide may become a second-line agent in patients with severe muscle and skin involvement, but further studies are warranted.

Characterization of neuronal nicotinic acetylcholine receptors in the membrane of unmyelinated human C-fiber axons by in vitro studies.

Application of acetylcholine to peripheral nerve terminals in the skin is a widely used test in studies of human small-fiber functions. However, a detailed pharmacological profile and the subunit composition of nicotinic acetylcholine receptors in human C-fiber axons are not known. In the present study, we recorded acetylcholine-induced changes of the excitability and of the intracellular Ca2+ concentration in C-fiber axons of isolated human nerve segments. In addition, using immunohistochemistry, an antibody of a subtype of nicotinic acetylcholine receptor was tested. Acetylcholine and agonists reduced the current necessary for the generation of action potentials in C fibers by > 5-Iodo-A-85380 > 1,1-dimethyl-4-phenylpiperazinium iodide > nicotine > cytisine > acetylcholine; choline had no effect. The epibatidine-induced increase in axonal excitability was blocked by mecamylamine and, less efficiently, by methyllycacontine and dihydro-beta-erythroidine. Many C-fiber axons were labeled by an antibody that recognizes the alpha5 subunit of nicotinic acetylcholine receptors. In summary, electrophysiological and immunohistochemical data indicate the functional expression of nicotinic acetylcholine receptors composed of alpha3, alpha5, and beta4 but not of alpha4/beta2 or of alpha7 subunits in the axonal membrane of unmyelinated human C fibers. In addition, the observations suggest that the axonal membrane of C fibers in isolated segments of human sural nerve can be used as a model for presumed cholinergic chemosensitivity of axonal terminals.

[Diagnosis and therapy of vasculitic neuropathy. Consensus statement of the German Centers for Neuromuscular Disease]. / Klinik, Diagnostik und Therapie der vaskulitischen Neuropathie. Bundeseinheitliche Konsensuspapiere der Muskelzentren im Auftrag der Deutschen Gesellschaft für Muskelkranke e. V. (DGM).

Vasculitic neuropathies are immune mediated diseases of the peripheral nervous system, in which inflammation of the blood vessels causes damage to the nerves. We distinguish neuropathies associated with primary and secondary systemic vasculitis, with rheumatic diseases, with malignant disorders, drug-induced vasculitis and the non-systemic vasculitic neuropathies (NSVN). The typical clinical picture consists in an asymmetric or multifocal, painful sensorimotor neuropathy with an acute, subacute or chronic course and acute relapses. Neurophysiology reveals an active, asymmetric, axonal sensorimotor neuropathy. The disorders usually respond to immunosuppressive treatment. A diagnosis of definite vasculitis can be made with evidence of vasculitis in a biopsy specimen. The absence of positive morphological evidence, however, does not exclude the diagnosis. There is no single laboratory test that can prove or exclude vasculitis, in NSVN even an elaborate panel of blood tests can show normal findings. Systemic vasculitis has an incidence of 4/100,000 per year and, untreated, has a poor prognosis, which is greatly improved by the use of immunosuppressive treatment. The prognosis of NSVN is generally better, although many patients need long term immunosuppression. Current treatment recommendations for vasculitic neuropathies are presented.