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Introduction. Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the “lockdown”. The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic. Methods. We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials. Results. 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine. Conclusions. Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.

OBJECTIVES: To investigate, using resting state (RS) functional connectivity (FC), the selectivity of involvement of the sensorimotor network in patients with acquired (A) and with hereditary (H) peripheral neuropathies (PN) and the correlations of RS FC abnormalities with clinical impairment and structural brain damage. Temporal associations among RS networks were also explored. Experimental design: RS fMRI scans were acquired from 13 APN, 12 HPN, and 18 age‐ and sex‐matched healthy controls. Independent component analysis and functional network connectivity were used to investigate RS FC within and among RS networks with potential functional relevance. PRINCIPAL OBSERVATIONS: Compared to controls, patients had a decreased FC of the right precentral gyrus and an increased RS FC of the precuneus within the sensorimotor network. Both decreased and increased RS FC also involved the visual and auditory networks, which additionally had an increased coherence of function with the sensorimotor network (more pronounced in HPN). RS FC modifications in patients extended to several cognitive networks and were correlated with disease duration. In APN, they were also correlated with the severity of clinical impairment and corpus callosum atrophy. CONCLUSIONS: In PN, RS FC modifications extend beyond the sensorimotor network and involve other sensory and cognitive networks. The correlations between RS FC patterns and disease duration in patients as well as with clinical impairment in patients with APN suggest that modifications of FC might reflect an adaptive mechanism, which takes time to occur and helps to limit the clinical consequences of peripheral damage. Hum Brain Mapp 35:513–526, 2014. © 2012 Wiley Periodicals, Inc.

The neurotrophin system has a role in skeletal muscle biology. Conditional depletion of BDNF in mouse muscle precursor cells alters myogenesis and regeneration in vivo. However, the expression, localization and function of BDNF in human skeletal muscle tissue is not known, so the relevance of the rodent findings for human muscle are unknown. Here we address this by combining ex vivo histological investigations on human biopsies with in vitro analyses of human primary myocytes. We found that BDNF was expressed by precursor and differentiated cells both in vitro and in vivo. Differential analysis of BDNF receptors showed expression of p75NTR and not of TrkB in myocytes, suggesting that the BDNF-p75NTR axis is predominant in human skeletal muscle cells. Several in vitro functional experiments demonstrated that BDNF gene silencing or protein blockade in myoblast cultures hampered myogenesis. Finally, histological investigations of inflammatory myopathy biopsies revealed that infiltrating immune cells localized preferentially near p75NTR-positive regenerating fibres and that they produced BDNF. In conclusion, BDNF is an autocrine factor for skeletal muscle cells and may regulate human myogenesis. Furthermore, the preferential localization of BDNF-producing immune cells near p75NTR-positive regenerating myofibres suggests that immune cell-derived BDNF may sustain tissue repair in inflamed muscle.

INTRODUCTION: The aim of this international collaborative effort was to report 36-month longitudinal changes using the 6MWT in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. MATERIALS AND METHODS: Of the 92 patients included in the study, 24 had deletions amenable to skip exon 44, 27 exon 45, 18 exon 51, and 28 exon 53. Five patients with a single deletion of exon 52 were counted in both subgroups skipping exon 51 and 53. RESULTS: The difference between subgroups amenable to skip different exons was not significant at 12 months but became significant at both 24 (p≤0.05) and 36 months (p≤0.01). DISCUSSION: Mutations amenable to skip exon 53 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had better results both at baseline and at follow up. Deletions amenable to skip exon 45 were associated with a more variable pattern of progression. Single exon deletions were more often associated with less drastic changes but this was not always true in individual cases. CONCLUSION: Our results confirm that the progression of disease can differ between patients with different deletions, although the changes only become significant from 24 months onwards. This information is relevant because there are current clinical trials specifically targeting patients with these subgroups of mutations. ispartof: PLOS ONE vol:14 issue:6 ispartof: location:United States status: published

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. • Muscle MRI identifies a specific pattern of muscle involvement in FSHD patients. • Muscle MRI may predict FSHD in asymptomatic and severely affected patients. • Muscle MRI of upper girdle better predicts FSHD. • Muscle MRI may differentiate FSHD from other forms of muscular dystrophy. • Muscle MRI may show the involvement of non-clinical testable muscles.

Objective: To test the effect of the single nucleotide polymorphism −66 T>G (rs28357094) in the osteopontin gene ( SPP1 ) on functional measures over 12 months in Duchenne muscular dystrophy (DMD). Methods: This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the North Star Ambulatory Assessment (NSAA) and the 6-Minute Walk Test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups. Results: Eighty patients were selected (age 4.1–19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA ( p = 0.013) and 6MWT ( p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values. Conclusions: These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.

Nuclear envelope-related muscular dystrophies, in particular those referred to as laminopathies, are relatively novel and unclear diseases, also considering the increasing number of mutations identified so far in genes of the nuclear envelope. As regard LMNA gene, only tentative relations between phenotype, type and localization of the mutations have been established in striated muscle diseases, while laminopathies affecting adipose tissue, peripheral nerves or progerioid syndromes could be linked to specific genetic variants. This study describes the biochemical phenotype of neuromuscular laminopathies in samples derived from LMNA mutant patients. Since it has been reported that nuclear alterations, due to LMNA defects, are present also in fibroblasts from Emery–Dreifuss muscular dystrophy and familial partial lipodystrophy patients, we analyzed 2D-maps of skin fibroblasts of patients carrying 12 different LMNA mutations spread along the entire gene. To recognize distinctive proteins underlying affected biochemical pathways, we compared them with fibroblasts from healthy controls and, more importantly, fibroblasts from patients with non-lamin related neuromuscular disorders. We found less abundance of cytoskeletal/structural proteins, confirming a dominant role for Lamin A/C in structural support of nuclear architecture. Interestingly, we also established significant changes in the expression of proteins involved in cellular energy production and oxidative stress response. To our knowledge, this is the first report where proteomics was applied to characterize ex-vivo cells from LMNA patients, suggesting that this may represent a new approach to better understand the molecular mechanisms of these rare diseases and facilitate the development of novel therapeutic treatments.

Early differential diagnosis of motor neuropathies (MN) and lower motor neuron diseases (LMND) is important, as prognosis and therapeutic approaches are different. We evaluated the diagnostic contribution of the biopsy of the motor branch of the obturator nerve and gracilis muscle in 21 consecutive patients in which, after proper clinical and neurophysiological studies, the differential diagnosis was still open. At baseline, motor biopsy was performed; diagnostic confirmation was obtained by 2-year clinical follow-up. Our results support the usefulness of this diagnostic procedure for selected cases of MN and LMND.

Intra-arterial transplantation of mesoangioblasts proved safe and partially efficacious in preclinical models of muscular dystrophy. We now report the first-in-human, exploratory, non-randomized open-label phase I-IIa clinical trial of intra-arterial HLA-matched donor cell transplantation in 5 Duchenne patients. We administered escalating doses of donor-derived mesoangioblasts in limb arteries under immunosuppressive therapy (tacrolimus). Four consecutive infusions were performed at 2-month intervals, preceded and followed by clinical, laboratory, and muscular MRI analyses. Two months after the last infusion, a muscle biopsy was performed. Safety was the primary endpoint. The study was relatively safe: One patient developed a thalamic stroke with no clinical consequences and whose correlation with mesoangioblast infusion remained unclear. MRI documented the progression of the disease in 4/5 patients. Functional measures were transiently stabilized in 2/3 ambulant patients, but no functional improvements were observed. Low level of donor DNA was detected in muscle biopsies of 4/5 patients and donor-derived dystrophin in 1. Intra-arterial transplantation of donor mesoangioblasts in human proved to be feasible and relatively safe. Future implementation of the protocol, together with a younger age of patients, will be needed to approach efficacy.

Objectives: Our aim was to conduct a comparative study in a large cohort of myopathic patients carrying LMNA gene mutations to evaluate clinical and molecular features associated with different phenotypes. Methods: We performed a retrospective cohort study of 78 myopathic patients with LMNA mutation and 30 familial cases with LMNA mutation without muscle involvement. We analyzed features characterizing the various forms of LMNA -related myopathy through correlation statistics. Results: Of the 78 patients, 37 (47%) had limb-girdle muscular dystrophy 1B (LGMD1B), 18 (23%) congenital muscular dystrophy (MDCL), 17 (22%) autosomal dominant Emery-Dreifuss muscular dystrophy 2 (EDMD2), and 6 (8%) an atypical myopathy. The myopathic phenotypes shared a similar cardiac impairment. Cardioverter defibrillator or pacemaker was implanted in 41 (53%) myopathic patients compared to 7 (23%) familial cases without muscle involvement ( p = 0.005). Heart transplantation was performed in 8 (10.3%) myopathic patients and in none of the familial cases. Ten (12.8%) myopathic patients died; there were no deaths among the familial cases ( p = 0.032). Missense mutations were found in 14 patients (82%) with EDMD2 and 14 patients (78%) with MDCL compared to 17 patients (45%) with LGMD1B and 4 (67%) atypical patients. Frameshift mutations were detected in 17 (45%) LGMD1B compared to 3 (18%) EDMD2, 1 (6%) MDCL, and 2 (33%) with atypical myopathy ( p = 0.021). Furthermore, frameshift mutations were found in 30 of 73 patients (41%) with heart involvement compared to 4 of 35 (11%) without heart involvement ( p = 0.004). Conclusions: Our data provided new insights in LMNA -related myopathies, whose natural history appears to be dominated by cardiac involvement and related complications.

ObjectiveIn the last few years some of the therapeutical approaches for Duchenne muscular dystrophy (DMD) are specifically targeting distinct groups of mutations, such as deletions eligible for skipping of individual exons. The aim of this observational study was to establish whether patients with distinct groups of mutations have different profiles of changes on the 6 minute walk test (6MWT) over a 12 month period.MethodsThe 6MWT was performed in 191 ambulant DMD boys at baseline and 12 months later. The results were analysed using a test for heterogeneity in order to establish possible differences among different types of mutations (deletions, duplications, point mutations) and among subgroups of deletions eligible to skip individual exons.ResultsAt baseline the 6MWD ranged between 180 and 560,80 metres (mean 378,06, SD 74,13). The 12 month changes ranged between -325 and 175 (mean -10.8 meters, SD 69.2). Although boys with duplications had better results than those with the other types of mutations, the difference was not significant. Similarly, boys eligible for skipping of the exon 44 had better baseline results and less drastic changes than those eligible for skipping exon 45 or 53, but the difference was not significant.Conclusionseven if there are some differences among subgroups, the mean 12 month changes in each subgroup were all within a narrow Range: from the mean of the whole DMD cohort. This information will be of help at the time of designing clinical trials with small numbers of eligible patients.

Background Charcot-Marie-Tooth (CMT) neuropathies are very heterogeneous disorders from both a clinical and genetic point of view. The CMT genes identified so far encode different proteins that are variably involved in regulating Schwann cells and/or axonal functions. However, the function of most of these proteins still remains to be elucidated. Objective To characterize a large cohort of patients with demyelinating, axonal, and intermediate forms of CMT neuropathy. Design A cohort of 131 unrelated patients were screened for mutations in 12 genes responsible for CMT neuropathies. Demyelinating, axonal, and intermediate forms of CMT neuropathy were initially distinguished as usual on the basis of electrophysiological criteria and clinical evaluation. A sural nerve biopsy was also performed for selected cases. Accordingly, patients underwent first-level analysis of the genes most frequently mutated in each clinical form of CMT neuropathy. Results Although our cohort had a particularly high percentage of cases of rare axonal and intermediate CMT neuropathies, we found mutations in 40% of patients. Among identified changes, 7 represented new mutations occurring in the MPZ , GJB1 , EGR2 , MFN2 , NEFL , and HSBP1/HSP27 genes. Histopathological analysis performed in selected cases revealed morphological features, which correlated with the molecular diagnosis and provided evidence of the underlying pathogenetic mechanism. Conclusion Clinical and pathological analysis of patients with CMT neuropathies contributes to our understanding of the molecular mechanisms of CMT neuropathies.

Numerous transgenic and knockout mouse models of human hereditary neuropathies have become available over the past decade. We describe a simple, reproducible, and safe biopsy of mouse skin for histopathological evaluation of the peripheral nervous system (PNS) in models of hereditary neuropathies. We compared the diagnostic outcome between sciatic nerve and dermal nerves found in skin biopsy (SB) from the hind foot. A total of five animal models of different Charcot-Marie-Tooth neuropathies, and one model of congenital muscular dystrophy associated neuropathy were examined. In wild type mice, dermal nerve fibers were readily identified by immunohistochemistry, light, and electron microscopy and they appeared similar to myelinated fibers in sciatic nerve. In mutant mice, SB manifested myelin abnormalities similar to those observed in sciatic nerves, including hypomyelination, onion bulbs, myelin outfolding, redundant loops, and tomacula. In many strains, however, SB showed additional abnormalities—fiber loss, dense neurofilament packing with lower phosphorylation status, and axonal degeneration—undetected in sciatic nerve, possibly because SB samples distal nerves. SB, a reliable technique to investigate peripheral neuropathies in human beings, is also useful to investigate animal models of hereditary neuropathies. Our data indicate that SB may reveal distal axonal pathology in mouse models and permits sequential follow-up of the neuropathy in an individual mouse, thereby reducing the number of mice necessary to document pathology of the PNS. © 2010 Wiley-Liss, Inc.

Bridging the gap after a nerve transection has always been a top challenge in the field of neuroscience. The peripheral nervous system can regenerate after injury but to fill a gap needs to find a proper guide directing the axonal elongation. Many techniques and devices have been studied in order to promote nerve regeneration but are still inade- quate. The aim of this work is validating an innovative high porosity collagen tube (medical devices, MD) and comparing the nerve outgrowth through this MD to the already avail- able in clinical practice NeuroGen IntegraÒ collagen and the silicone tubes, as a standard control, in an animal model of traumatic injury. The conduits were implanted in a 10 mm- gap in rat sciatic nerve and retrieved at different time points for morphological and ultrastructural analysis. Nerve conduc- tion studies were also evaluated. Nerve outgrowth through the NeuroGen IntegraÒ devices appeared to be similar to the one in the silicone tubes, being characterized by mini- fascicles containing less small axons with thin myelin and without a well-organized blood vessels distribution in the en- doneurium. In contrast, our MD showed, in the regenerated mid-graft, a normal size and number of nerve fibers with a normal myelination (G-ratio), already evident at 60 days postoperatively. Moreover, perineurium and blood vessels appeared absolutely normal with tight junction by EM. At 90 days postoperatively a nerve action potential was recordable distally, at the paw, in the sciatic nerves of the rats implanted with our MD or with the NeuroGen ones whereas was absent in the silicon group. Overall the neurophysiologi- cal and neuropathological data demonstrate the terrific qual- ity of nerve regeneration using our MD. These results make us confident in proposing our MD in the clinical practice to treat injury of the PNS.

Leiomyomas are benign smooth muscle tumors, usually characterized by well-deWned Wbrous pseudocapsule and intersecting fascicles of spindle cells [3]. Few cases of leiomyomas in the peripheral nervous system (PNS) causing external nerve compression have been described [1, 7]. We report the case of a 71-year-old man who was referred for a 2 years history of burning pain and paresthesias associated with slowly progressive weakness of the lower limbs. He underwent total colectomy for diVuse polyposis 2 years before. Neurological examination and nerve conduction studies revealed symmetric sensorimotor axonal neuropathy of the lower limbs. Since all immunological, hematological and cerebrospinal Xuid examinations were negative, a sural nerve biopsy was performed. On semithin plastic sections, a mild degree of endoneurial Wbrosis, reduction of myelinated Wbers and signs of acute axonal degeneration were evident. Some fascicles had greater myelinated Wber loss than others, primarily in the center of the fascicles. Interestingly, paraYn-embedded, hematoxylin and eosinstained sections showed in epineurial and endoneurial perivascular spaces atypical large cells with abundant eosinophilic cytoplasm. Upon electron microscopy, these cells exhibited a basement membrane and prominent pinocytotic vesicles at the periphery (Fig. 1). The cytoplasm was Wlled with actin and myosin Wlaments, aggregates of glycogen particles and few organelles. Some cells showed oval and centrally located nuclei. Immunohistochemically, they were positive for smooth muscle actin, desmin and calponin (Fig. 2), but negative for CD31, cytokeratin and S-100 protein, demonstrating that they were smooth muscle cells (SMC). These cells did not show proliferative activity (negativity for Ki-67). Neither necrosis nor a deWnite capsule were present. The morphological and immunohistochemical data suggested a diagnosis of leiomyoma. This is the Wrst description of a diVuse SMC inWltrate of the PNS, both in the endoneurium and epineurium, whereas well circumscribed and encapsulated leiomyomas have occasionally been reported in the PNS. Other potential tumors such as leiomyosarcoma, schwannoma and hemangioma have to be considered in the diVerential diagnosis, but can be excluded based on immunoproWle [2]. Several hypotheses can be envisaged for the possible cellular origin of this unique tumor in the PNS, including pluripotential mesenchymal cells, perivascular connective tissue elements or SMC of blood vessels [6]. Epineurial proliferation of SMC in sural nerve biopsies indicating inXammatory or non-inXammatory angiopathy has been described before [5]. However, our patient’s sural nerve biopsy revealed SMC also in the endoneurium without signs of angiopathy, suggesting a diVerent origin of SMC. How this inWltrate caused damage of peripheral nerve Wbers remains unclear. Our patient’s clinical presentation suggests a diVuse damage of the PNS, while nerve biopsy Wndings associated with F. Cerri (&) Department of Neurology and INSPE, San RaVaele ScientiWc Institute, Via Olgettina, 6

Cold agglutinin disease (CAD) is characterized by the production of cold agglutinins (CAs), usually IgMk autoantibodies, causing chronic hemolytic anemia and cold induced acrocyanosis (reported in 90% of cases). CAD has traditionally been classified into a primary type (pCAD) and a secondary type accompanied by malignant disease, most often lymphoma. PCAD is considered a stable or slowly progressive disease with good prognosis (median survival: 12.5 years from onset). It has recently been shown that even pCAD frequently associates with an underlying lymphoproliferative disorder characterized by clonal expansion of B cells.1 Peripheral neuropathy (PN) is a rare complication of CAD, with isolated cases reported, but the pathogenetic mechanisms are still object of debate.2–4 ### Case report. A 58-year-old man was admitted to the hospital because of asymmetric motor and sensory impairment of limbs. Three years before he had developed cold-induced acrocyanosis and pCAD had been diagnosed. At that time, two bone marrow biopsies showed no evidence of lymphoma or plasma cell dyscrasia. Six months before admission, the patient developed progressive weakness, sensory loss, and paresthesias in the right foot; 3 months later, the same symptoms appeared in the left foot and the right hand. On admission, neurologic examination showed asymmetric (right>left) weakness in distal muscles of lower limbs and in the right hand, sensory loss with the same distribution, absent tendon reflexes at lower limbs, and hyporeflexia in the arms. Laboratory investigations showed mild anemia (hemoglobin 10 g/dL), …

Background: Mutations in the LMNA gene, encoding human lamin A/C, have been associated with an increasing number of disorders often involving skeletal and cardiac muscle, but no clear genotype/phenotype correlation could be established to date. Methods: We analyzed the LMNA gene in a large cohort of patients mainly affected by neuromuscular or cardiac disease and clustered mutated patients in two groups to unravel possible correlations. Results: We identified 28 variants, 9 of which reported for the first time. The two groups of patients were characterized by clinical and genetic differences: 1) patients with childhood onset displayed skeletal muscle involvement with predominant scapuloperoneal and facial weakness associated with missense mutations; 2) patients with adult onset mainly showed cardiac disorders or myopathy with limb girdle distribution, often associated with frameshift mutations presumably leading to a truncated protein. Conclusions: Our findings, supported by meta-analysis of previous literature, suggest the presence of two different pathogenetic mechanisms: late onset phenotypes may arise through loss of function secondary to haploinsufficiency, while dominant negative or toxic gain of function mechanisms may explain the severity of early phenotypes. This model of patient stratification may help patient management and facilitate future studies aimed at deciphering lamin A/C pathogenesis.

Axonal loss causes disabling and permanent deficits in many peripheral neuropathies, and may result from inefficient nerve regeneration due to a defective relationship between Schwann cells, axons and the extracellular matrix. These interactions are mediated by surface receptors and transduced by cytoskeletal molecules. We investigated whether peripheral nerve regeneration is perturbed in mice that lack glial fibrillary acidic protein (GFAP), a Schwann-cell-specific cytoskeleton constituent upregulated after damage. Peripheral nerves develop and function normally in GFAP-null mice. However, axonal regeneration after damage was delayed. Mutant Schwann cells maintained the ability to dedifferentiate but showed defective proliferation, a key event for successful nerve regeneration. We also showed that GFAP and the other Schwann-cell-intermediate filament vimentin physically interact in two distinct signaling pathways involved in proliferation and nerve regeneration. GFAP binds integrin αvβ8, which initiates mitotic signals soon after damage by interacting with fibrin. Consistently, ERK phosphorylation was reduced in crushed GFAP-null nerves. Vimentin instead binds integrin α5β1, which regulates proliferation and differentiation later in regeneration, and may compensate for the absence of GFAP in mutant mice. GFAP might contribute to form macro-complexes to initiate mitogenic and differentiating signaling for efficient nerve regeneration.

The coexistence of neurogenic and myogenic features in scapuloperoneal syndrome is rarely ascribed to a single gene. Defects in the nuclear envelope protein lamin A/C, encoded by the LMNA gene, have been shown to be associated with a variety of disorders affecting mainly the muscular and adipose tissues and, more recently, with autosomal recessive Charcot-Marie-Tooth type 2 neuropathy. This report is about a patient presenting features of myopathy and neuropathy due to a dominant LMNA mutation, suggesting that the peripheral nerve might be affected in primary LMNA myopathy. Our observations further support the marked intrafamilial and interfamilial phenotypic heterogeneity associated with lamin A/C defects.

Context: Hypokalemic periodic paralysis (HypoPP) is a rare disorder consisting of sudden episodes of muscle weakness with areflexia involving all four limbs, which spontaneously resolve within several hours or days. Primary HypoPP is genetically determined, while secondary acquired HypoPP has been described in association with thyreotoxycosis, hyperaldosteronism, kidney diseases, diuretics and liquorice abuse, gastrointestinal potassium loss, or cysplatinum therapy. Objective: To report a case of HypoPP associated with GH deficiency. Patient: A 33 yr-old man with hypopituitarism and diabetes insipidus secondary to pituitary stalk-localized sarcoidosis, and documented HypoPP episodes. Clinical Presentation: Neurologic exam outside HypoPP episodes was normal. Needle electromyography was normal without myotonia or other spontaneous electric activity. Muscle biopsy documented a vacuolar myopathy with tubular aggregates. However, genetic analysis ruled out common mutations of the voltage-gated calcium channel observed in primary HypoPP. Common causes of secondary HypoPP were also ruled out. The patient was diagnosed with severe GH deficiency with modest fasting hyperinsulinemia and insulin resistance and started on GH replacement therapy, an α-glucosidase inhibitor (acarbose) and a diet low in simple carbohydrates. Conclusions: GH replacement therapy, acarbose and a diet low in simple carbohydrates resulted in the complete long-term (>2 yr) remission of HypoPP episodes. This is consistent with the hypothesis that the hyperinsulinemia associated to GH deficiency may trigger HypoPP episodes by increasing Na+/K+ ATPase activity and K+ transport into the intracellular compartment with subsequent hypokalemia.