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Background: Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset muscle disorder, characterized by the presence of nemaline rods in muscle fibers. Phenotypic characterization in a large cohort and a comprehensive overview of SLONM are lacking., Methods: We studied the clinico-pathological features, treatment and outcome in a large cohort of 76 patients with SLONM, comprising 10 new patients and 66 cases derived from a literature meta-analysis (PubMed, 1966-2016), and compared these with 15 reported HIV-associated nemaline myopathy (HIV-NM) cases. In 6 SLONM patients, we performed a targeted next-generation sequencing (NGS) panel comprising 283 myopathy genes., Results: SLONM patients had a mean age at onset of 52 years. The predominant phenotype consisted of weakness and atrophy of proximal upper limbs in 84%, of proximal lower limbs in 80% and both in 67%. Other common symptoms included axial weakness in 68%, as well as dyspnea in 55% and dysphagia in 47% of the patients. In 53% a monoclonal gammopathy of unknown significance (MGUS) was detected in serum. The mean percentage of muscle fibers containing rods was 28% (range 1-63%). In 2 cases ultrastructural analysis was necessary to detect the rods. The most successful treatment in SLONM patients (all with MGUS) was autologous peripheral blood stem cell therapy. A targeted NGS gene panel in 6 SLONM patients (without MGUS) did not reveal causative pathogenic variants. In a comparison of SLONM patients with and without MGUS, the former comprised significantly more males, had more rapid disease progression, and more vacuolar changes in muscle fibers. Interestingly, the muscle biopsy of 2 SLONM patients with MGUS revealed intranuclear rods, whereas this feature was not seen in any of the biopsies from patients without paraproteinemia. Compared to the overall SLONM cohort, significantly more HIV-NM patients were male, with a lower age at onset (mean 34 years). In addition, immunosuppression was more frequently applied with more favorable outcome, and muscle biopsies revealed a significantly higher degree of inflammation and necrosis in this cohort. Similar to SLONM, MGUS was present in half of the HIV-NM patients., Conclusions: SLONM presents a challenging, but important differential diagnosis to other neuromuscular diseases of adult onset. Investigations for MGUS and HIV should be performed, as they require distinct but often effective therapeutic approaches. Even though SLONM and HIV-NM show some differences, there exists a large clinico-pathological overlap between the 2 entities.

Nerve conduction studies are an essential part of the work-up of peripheral neuropathies. Many neuropathic syndromes can be suspected on clinical grounds, but optimal use of nerve conduction study techniques (in combination with needle electromyography) allows diagnostic classification and is therefore crucial to understanding and separation of neuropathies. Multifocal motor neuropathy, for example, may clinically present as ALS. Detection of evidence of demyelination (conduction blocks) leads to the correct diagnosis and to proper treatment. Nerve conduction studies provide essential information on (1) the spatial pattern of neuropathy, (2) the pattern of abnormalities distinguishing between primarily axonal and demyelinating pathology, and (3) the severity of neuropathic damage. This information is very comprehensive since many nerves and long segments of individual nerves can be sampled. Moreover the information is extremely detailed to the extent that the cellular pathology of a patient's neuropathy is usually defined best by physiological testing rather than by biopsy. Neuropathies can be generalized, focal, or multifocal; they can be symmetric or asymmetric; they can be distally predominant or proximal and distal. Primarily axonal neuropathies mainly affect sensory nerve and compound muscle action potential amplitudes, whereas demyelinating neuropathies lead to slowing of nerve conductions, and to increased temporal dispersion or conduction block. Usually, the pattern of demyelination allows to distinguish hereditary (uniform demyelination) from acquired (segmental demyelination) neuropathies. Electrodiagnostic criteria for primary demyelination are helpful to identify acquired demyelinating neuropathies.

Rippling muscle disease (RMD) is a rare muscle disorder characterised by muscle stiffness, exercise induced myalgia, and cramp-like sensations. It is genetically heterogeneous and can be acquired, but most cases show autosomal dominant inheritance due to mutations in the caveolin-3 (CAV3) gene. We report a novel heterozygous missense mutation in CAV3 in a Belgian family with autosomal dominant RMD. A 40 year old woman complained of fatigue, exercise induced muscle pain, and muscle cramps since the age of 35. Neurological examination revealed percussion induced rapid muscle contractions (PIRCs) and localised muscle mounding on percussion; muscle rippling was not observed. Creatine kinase (CK) was elevated but electromyography and nerve conduction studies were normal. Fluorescence immunohistochemistry revealed reduced caveolin-3 and dysferlin staining in a quadriceps muscle biopsy. Western blot analysis confirmed severely reduced caveolin-3 levels, whereas dysferlin was normal. Sequence analysis of the two coding exons of CAV3 revealed a hitherto unreported heterozygous C82A transversion in the first exon, predicting a Pro28Thr amino acid exchange. Thr patient's first degree relatives did not present with neuromuscular complaints, but PIRCs, muscle mounding, and muscle rippling were found in the mother, who also carried the CAV3 mutation.

The inflammatory demyelinating neuropathies constitute a significant proportion of the acquired polyneuropathies. Major progress in finding the causes and in the treatment of these neuropathies has been made over the last decade. Early recognition is of paramount importance, because timely and appropriate treatment can largely reduce morbidity and disability. Electrodiagnosis plays a key role in the detection and characterization of the inflammatory demyelinating neuropathies. Electrodiagnostic criteria for primary demyelination have therefore been developed. They are empirically based on changes of nerve conduction parameters in populations of patients with a confirmed clinical and laboratory diagnosis of inflammatory demyelinating neuropathy. The challenge consists of defining criteria sets that are highly specific but also as sensitive as possible. Most of the hereditary demyelinating neuropathies are part of Charcot-Marie-Tooth disease type 1. The pattern of nerve conduction abnormalities usually provides valuable clues for the distinction from chronic inflammatory demyelinating neuropathies.

A 47-year-old female developed proximal limb weakness after hysterectomy for uterine fibromatosis. Muscle strength slowly improved, but relapse occurred at age 52. She presented with progressive gait difficulty, proximal limb weakness, and painful calves. Family history was not contributory. Cranial nerves, deep tendon reflexes, and sensation were normal. Serum creatine kinase was normal. An IgG kappa monoclonal protein was found. Nerve conduction studies were normal, but EMG showed brief small polyphasic motor unit action potentials with early recruitment in proximal muscles. Muscle biopsy showed abundant rods, atrophic muscle fibres, and type 1 fibre predominance. The sarcolemma was immunoreactive for IgG kappa. Plasmapheresis was unsuccessful, but methylprednisolone and azathioprine led to moderate improvement of muscle strength, associated with reduced monoclonal protein levels. This is the third case report, describing the association of monoclonal gammopathy and late-onset nemaline myopathy. Presence of a monoclonal protein at the sarcolemma and responsiveness to immunosuppressive treatment are suggestive of a dys-immune origin.