Slow Nerve Conduction Velocity Research Articles

PAK2 is necessary for myelination in the peripheral nervous system.

Myelination enables electrical impulses to propagate on axons at the highest speed, encoding essential life functions. The Rho family GTPases, RAC1 and CDC42, have been shown to critically regulate Schwann cell myelination. P21-activated kinase 2 (PAK2) is an effector of RAC1/CDC42, but its specific role in myelination remains undetermined. We produced a Schwann cell-specific knockout mouse of Pak2 (scPak2-/-) to evaluate PAK2's role in myelination. Deletion of Pak2, specifically in mouse Schwann cells, resulted in severe hypomyelination, slowed nerve conduction velocity and behaviour dysfunctions in the scPak2-/- peripheral nerve. Many Schwann cells in scPak2-/- sciatic nerves were arrested at the stage of axonal sorting. These abnormalities were rescued by reintroducing Pak2, but not the kinase-dead mutation of Pak2, via lentivirus delivery to scPak2-/- Schwann cells in vivo. Moreover, ablation of Pak2 in Schwann cells blocked the promyelinating effect driven by neuregulin-1, prion protein and inactivated RAC1/CDC42. Conversely, the ablation of Pak2 in neurons exhibited no phenotype. Such PAK2 activity can also be either enhanced or inhibited by different myelin lipids. We have identified a novel promyelinating factor, PAK2, that acts as a critical convergence point for multiple promyelinating signalling pathways. The promyelination by PAK2 is Schwann cell-autonomous. Myelin lipids, identified as inhibitors or activators of PAK2, may be utilized to develop therapies for repairing abnormal myelin in peripheral neuropathies.

Slowing of Peripheral Nerve Conduction Velocity in Children and Adolescents With Type 1 Diabetes Is Predicted by Glucose Fluctuations.

There is a strong need for the better identification of early subclinical manifestations of microvascular complications, such as diabetic peripheral neuropathy, in young individuals with diabetes. To identify peripheral neuropathy and contributing factors at an asymptomatic disease stage, and to exclude height as a known modifying factor, we performed association studies of height-adjusted nerve conduction velocity. We identified high glucose variability, especially the SD of mean glucose, as an unexpectedly strong predictor of slowed nerve conduction velocity. More attention should be paid to the goal of low glucose variability in the care of individuals with diabetes.

Disruption of Endosomal Sorting in Schwann Cells Leads to Defective Myelination and Endosomal Abnormalities Observed in Charcot-Marie-Tooth Disease.

Endosomal sorting plays a fundamental role in directing neural development. By altering the temporal and spatial distribution of membrane receptors, endosomes regulate signaling pathways that control the differentiation and function of neural cells. Several genes linked to inherited demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth (CMT) disease, encode proteins that directly interact with components of the endosomal sorting complex required for transport (ESCRT). Our previous studies demonstrated that a point mutation in the ESCRT component hepatocyte growth-factor-regulated tyrosine kinase substrate (HGS), an endosomal scaffolding protein that identifies internalized cargo to be sorted by the endosome, causes a peripheral neuropathy in the neurodevelopmentally impaired teetering mice. Here, we constructed a Schwann cell-specific deletion of Hgs to determine the role of endosomal sorting during myelination. Inactivation of HGS in Schwann cells resulted in motor and sensory deficits, slowed nerve conduction velocities, delayed myelination and hypomyelinated axons, all of which occur in demyelinating forms of CMT. Consistent with a delay in Schwann cell maturation, HGS-deficient sciatic nerves displayed increased mRNA levels for several promyelinating genes and decreased mRNA levels for genes that serve as markers of myelinating Schwann cells. Loss of HGS also altered the abundance and activation of the ERBB2/3 receptors, which are essential for Schwann cell development. We therefore hypothesize that HGS plays a critical role in endosomal sorting of the ERBB2/3 receptors during Schwann cell maturation, which further implicates endosomal dysfunction in inherited peripheral neuropathies.SIGNIFICANCE STATEMENT Schwann cells myelinate peripheral axons, and defects in Schwann cell function cause inherited demyelinating peripheral neuropathies known as CMT. Although many CMT-linked mutations are in genes that encode putative endosomal proteins, little is known about the requirements of endosomal sorting during myelination. In this study, we demonstrate that loss of HGS disrupts the endosomal sorting pathway in Schwann cells, resulting in hypomyelination, aberrant myelin sheaths, and impairment of the ERBB2/3 receptor pathway. These findings suggest that defective endosomal trafficking of internalized cell surface receptors may be a common mechanism contributing to demyelinating CMT.

Associations of Lower Extremity Peripheral Nerve Impairment and Risk of Dementia in Black and White Older Adults.

Peripheral nerve impairments and dementia are common among older adults and share risk factors. However, few studies have examined whether peripheral nerve function and dementia are associated. We evaluated whether lower extremity peripheral nerve impairments were associated with higher incidence of dementia and whether associations differed by comorbidity subgroups (diabetes, low vitamin B12, and APOE ε4 allele carriers). We studied Black and White Health, Aging, and Body Composition Study participants 70 to 79 years of age and without dementia at enrollment. Lower extremity sensory and motor peripheral nerve function was measured at year 4 (the analytic baseline of this study). Sensory nerve impairments were measured with monofilament (1.4 g, 10 g) and vibration threshold of the toe. Monofilament insensitivity was defined as unable to detect monofilament (3 of 4 touches), and vibration detection impairment was defined as >130 μm. Fibular motor impairments were defined as <1 mV compound motor action potential (CMAP) amplitude and slow nerve conduction velocity <40 m/s. Incident dementia over the following 11 years was determined from medical records, cognitive scores, and medications. Cox proportional hazard models adjusted for demographics and health conditions assessed associations of nerve impairments with incident dementia. Among 2,174 participants (52% women, 35% Black), 45% could not detect monofilament 1.4 g, 9% could not detect monofilament 10 g, 6% could not feel vibration, 10% had low CMAP amplitude, and 24% had slow conduction velocity. Monofilament 10 g (hazard ratio [HR] 1.35, 95% CI 0.99-1.84) and vibration detection insensitivity (HR 1.73, 95% CI 1.24-2.40) were associated/borderline associated with a higher risk of dementia after covariate adjustment. Estimates were elevated but not significant for monofilament 1.4 g, CMAP amplitude, and conduction velocity (p > 0.05). Increasing number of peripheral nerve impairments was associated with higher risk of dementia in a graded fashion; for ≥3 impairments, the HR was 2.37 (95% CI 1.29-4.38). In subgroup analyses, effect estimates were generally higher among those with diabetes, low vitamin B12, and APOE ε4 allele except for vibration detection. Peripheral nerve impairments, especially sensory, were associated with a higher risk of dementia even after adjustment for age and other health factors. These associations may represent a shared susceptibility to nervous system degeneration.

HP39: PMP22 neuropathies: Charcot-Marie-Tooth disease type 1A in a boy and changes in electroneuromyography

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, affecting 1/1500 to 1/10000 (60%-70% of all CMT and is caused by a duplication on chromosome 17p11.2 leading to an overexpression of the Peripheral Myelin Protein 22 (PMP22)). CMT1A characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. Early diagnosis is necessary for further prognosis and management of the patient. At the boy from 9 years parents noticed gait disturbances: it was difficult to step on a heel. Within a few years, the symptoms progressed and there was a sensitivity disorder. According to the neurological status, the knee reflexes were reduced and there were no Achilles. We performed electroneuromyography and recorded a significant decrease in motor and sensory responses (less than 1 μV). Needle myography showed secondary denervation changes in the muscles. We sent the patient's blood for genetic analysis (Comprehensive Neuropathies Panel). We received a Pathogenic variant, Gain (Entire coding sequence), was identified in PMP22. This variant is a gross duplication of the genomic region encompassing exons 2-5 of the PMP22 gene. Therefore, it is assumed that the entire gene is duplicated. Duplications of the region on chromosome 17p11.2 which contain the PMP22 gene cause Charcot-Marie-Tooth type 1A (CMT1A). The patient was also found to have mutations of uncertain significance: in SCN11A (associated with autosomal dominant hereditary sensory and autonomic neuropathy type 7) and SCN9A. After the diagnosis, we also provided him with recommendations for multidisciplinary management together with rehabilitation specialists and orthopedists.

Exogenous neuritin treatment improves survivability and functions of Schwann cells with improved outgrowth of neurons in rat diabetic neuropathy.

Pathogenesis and treatment for diabetic neuropathy are still complex. A deficit of neurotrophic factors affecting Schwann cells is a very important cause of diabetic neuropathy. Neuritin is a newly discovered potential neurotrophic factor. In this study, we explored the effect of exogenous neuritin on survivability and functions of diabetic Schwann cells of rats with experimental diabetic neuropathy. Diabetic neuropathy was induced in rats. 12‐week diabetic rats contrasted with non‐diabetic normal rats had decreased levels of serum neuritin and slowed nerve conduction velocities (NCVs). Schwann cells isolated from these diabetic rats and cultured in high glucose showed reduced cell neuritin mRNA and protein and supernatant neuritin protein, increased apoptosis rates, increased caspase‐3 activities and progressively reduced viability. In contrast, exogenous neuritin treatment reduced apoptosis and improved viability, with elevated Bcl‐2 levels (not Bax) and decreased caspase‐3 activities. Co‐cultured with diabetic Schwann cells pre‐treated with exogenous neuritin in high glucose media, and diabetic DRG neurons showed lessened decreased neurite outgrowth and supernatant NGF concentration occurring in co‐culture of diabetic cells. Exogenous neuritin treatment ameliorated survivability and functions of diabetic Schwann cells of rats with diabetic neuropathy. Our study may provide a new mechanism and potential treatment for diabetic neuropathy.

Clinical, neuroelectrophysiological and muscular pathological analysis of chronic progressive external ophthalmoplegia.

The aim of the present study was to explore the clinical, neuroelectrophysiological and muscular pathological characteristics of chronic progressive external ophthalmoplegia (CPEO) and to improve the understanding of CPEO. Clinical manifestations, neuroelectrophysiology and pathological features of muscle biopsies from 12 patients with CPEO were retrospectively analyzed. The average age of onset for the 12 patients (6 males and 6 females) was 17.2 years. All patients had different degrees of blepharoptosis. A total of 11 patients experienced ocular dyskinesia, but diplopia was rare. Electrophysiological testing in 12 patients revealed abnormal changes in 6 patients, including 4 patients with a myogenic lesion, 1 patient with a neurogenic lesion, and 1 patient with mixed myogenic/neurogenic lesions. Two patients had slow sensory nerve conduction velocity. Muscle biopsies in 12 patients demonstrated ragged-red, irregular and broken fibers in 11 patients through Gomori trichrome and hematoxylin and eosin (H&E) staining, increased lipid levels in some muscle fibers in 4 patients through Οil Ρed O staining and abnormal distribution of type I and II muscle fibers in 3 patients through ATPase staining. Electron microscopy in 5 patients showed an increased number of mitochondria and abnormal mitochondrial aggregation between submucosa and myofibrils in 4 patients. These findings suggest that the possibility of CPEO should be considered if patients present with obvious extraocular muscle paralysis without diplopia. Furthermore, the identification of ragged-red fibers by Gomori trichrome and H&E staining of muscle biopsies from patients is an important basis for the diagnosis of CPEO.

Disruption of dystonin in Schwann cells results in late-onset neuropathy and sensory ataxia.

Dystonin (Dst) is a causative gene for Dystonia musculorum (dt) mice, which is an inherited disorder exhibiting dystonia-like movement and ataxia with sensory degeneration. Dst is expressed in a variety of tissues, including the central nervous system and the peripheral nervous system (PNS), muscles, and skin. However, the Dst-expressing cell type(s) for dt phenotypes have not been well characterized. To address the questions whether the disruption of Dst in Schwann cells induces movement disorders and how much impact does it have on dt phenotypes, we generated Dst conditional knockout (cKO) mice using P0-Cre transgenic mice and Dst gene trap mice. First, we assessed the P0-Cre transgene-dependent Cre recombination using tdTomato reporter mice and then confirmed the preferential tdTomato expression in Schwann cells. In the Dst cKO mice, Dst mRNA expression was significantly decreased in Schwann cells, but it was intact in most of the sensory neurons in the dorsal root ganglion. Next, we analyzed the phenotype of Dst cKO mice. They exhibited a normal motor phenotype during juvenile periods, and thereafter, started exhibiting an ataxia. Behavioral tests and electrophysiological analyses demonstrated impaired motor abilities and slowed motor nerve conduction velocity in Dst cKO mice, but these mice did not manifest dystonic movements. Electron microscopic observation of the PNS of Dst cKO mice revealed significant numbers of hypomyelinated axons and numerous infiltrating macrophages engulfing myelin debris. These results indicate that Dst is important for normal PNS myelin organization and Dst disruption in Schwann cells induces late-onset neuropathy and sensory ataxia. MAIN POINTS: Dystonin (Dst) disruption in Schwann cells results in late-onset neuropathy and sensory ataxia. Dst in Schwann cells is important for normal myelin organization in the peripheral nervous system.

Swallowing impairment in older adults: association with sensorimotor peripheral nerve function from the Health, Aging and Body Composition study.

The purpose of this study was to examine whether impairments in sensorimotor peripheral nerve function are associated with a higher likelihood of swallowing impairment in older adults. Health, Aging and Body Composition participants (n = 607, age = 75.8 ± 2.7years, 55.8% women, 32.3% black) underwent peripheral nerve testing at Year 4 and 11 with swallowing difficulty assessed at Year 4 and 15. Nerve conduction amplitude and velocity were measured at the peroneal motor nerve. Sensory nerve function was assessed with the vibration detection threshold and monofilament (1.4-g/10-g) testing at the big toe. Symptoms of lower extremity peripheral neuropathy and difficulty swallowing were collected by self-report. Data analysis was performed using a hierarchical approach. Odds ratios (ORs) were estimated using non-conditional logistic regression. At Year 15 108 (17.8%) participants had swallowing impairments. In fully adjusted models, the peripheral nerve impairments associated with swallowing impairment were numbness (OR 4.67; 95%CI 2.24-9.75) and poor motor nerve conduction velocity (OR 2.26; 95%CI 1.08-4.70). Other peripheral nerve impairments were not related to swallowing. The association between slow motor nerve conduction velocity and numbness and a higher likelihood of swallowing difficulties a decade later in our prospective study identifies an important area for further investigation in older adults.

Potential Risk of Developing Peripheral Neuropathy in Heavy Motor Vehicle Driving: A Cross-sectional Study

Introduction: There is a growing concern regarding increasing road traffic accidents due to overburdened drivers, which also affect their general health. Drivers maintain the extreme position of arm, forearm, and legs which during distant journeys may put increased constraint on nerves passing in forearm and legs in addition to the vibrations transmission i.e., Hand Arm Vibration Syndrome (HAVS) and Foot Transmitted Vibration (FTV). Aim: To find out if chronic repeated movements at wrist and foot along with vibration transmitted from steering wheel and pedals influence the nerve conduction parameters and to find out which nerves are more prone to neurological conduction defects. Materials and Methods: A cross-sectional study was conducted over a period of two years in Neurophysiology Lab, Department of Physiology, JN Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. Mean peak sensory and motor latency, mean motor and sensory Nerve Conduction Velocity (NCV), Sensory Nerve Action Potential (SNAP) and Compound Muscle Action Potential (CMAP) of median, ulnar and common peroneal nerve in Professional Heavy Vehicle Drivers (PHVD) was compared with non-drivers using Medicaid System’s (Electromyography) EMG/ (Nerve Conduction Velocity) NCV equipment with Neuroperfect Software. Student’s unpaired t-test was used to assess the significance of difference in nerve conduction study findings. Results: Heavy vehicle drivers showed slow Sensory Nerve Conduction Velocity (SNCV) (drivers: 51.40±3.30, non-drivers: 53.66±3.60 in right hand p-value 0.0001) and (drivers: 52.51±3.78, non-drivers: 53.87±3.61 in left hand p-value=0.0145) and increase in sensory latency (drivers: 3.71±0.72, non-drivers: 2.89±0.56 in right hand p-value&lt;0.0001 and drivers: 3.4±0.81 non-drivers: 2.76±0.70 in left hand p-value &lt;0.0001) of median nerve. Ulnar nerve sensory latency was prolonged (drivers: 2.98±0.52, non-drivers: 2.76±0.42 in right hand p-value 0.0021 and drivers: 2.97±0.42, non-drivers: 2.80±0.65 in left hand p-value 0.0386) and sural nerve sensory latency was prolonged (drivers: 3.05±0.55, non-drivers: 2.78±0.54 in right leg p-value=0.0011 and drivers: 2.92±0.45, non-drivers: 2.69±0.40 in left leg p-value 0.0004).There was no significant difference in Motor Nerve Conduction Velocity (MNCV), motor latency, SNAP and CMAP of median, ulnar and common peroneal nerve among heavy vehicle drivers in comparison to non-drivers. Conclusion: We conclude that pressure and vibrations transmitted at hand and foot along with repeated movements at forearm wrist and pedals leads to more neurological conduction defects in median nerve than in ulnar and sural nerve. Flexibility in delivery time, incorporating judicious breaks in duty, better ergonomics design may help in improving work conditions of drivers.

Ultrasound-Guided Steroid Injections for Lateral Antebrachial Cutaneous Nerve Entrapment Within Post-Surgical Scar

A 26-yr-old man experienced a motorbike accident and underwent open reduction and internal fixation of a right humerus and radio-ulnar shaft fractures the next day. Nerve conduction studies were performed 3 mos later because of sensorimotor symptoms in his right upper limb and confirmed axillary, musculocutaneous, and radial neuropathies at the level of the axilla. Because of persistent elbow flexion weakness (manual muscle testing grade 3), surgical excision and advance flap of a longitudinal hypertrophic scar extending from the shoulder to the upper arm were performed. He also eventually underwent removal of the orthopedic implants. He then started rehabilitation focused on range of motion and strengthening exercises of his right upper limb. Function and strength improved gradually, and he returned to work after 1 yr. However, right lateral forearm tightness and numbness were interfering with his daily activities and with sleep. Ultrasonographic (US) tracking of his lateral antebrachial cutaneous nerve (LABCN) showed focal swelling within the forearm scar. Ultrasound-guided hydrodissection of the LABCN with 5 mL of 5% dextrose water was attempted. The symptoms improved by 50% after the procedure but recurred 1 mo later. Therefore, the same procedure was performed a second time 2 mos later, and the symptoms were relieved completely for 1 mo. A third US-guided hydrodissection of the LABCN was performed, but the injectate was changed to triamcinolone 10 mg and 5 mL of lidocaine 1% (Video 1). The patient remained symptom free at the 6-mo follow-up. The LABCN is a terminal branch of musculocutaneous nerve, which is responsible for sensation of the lateral aspect of the forearm. It lies adjacent to the cephalic vein and the distal biceps brachii tendon within the antebrachial region of the elbow, and compression of the LABCN typically presents as pain and dysesthesia along the lateral forearm.1 Common causes of LABCN neuropathy include cephalic venipuncture, distal biceps brachii tendon tears and repair, and pull-up exercises during military training camp.1 This is the first reported case in the literature of LABCN entrapment within a surgical scar. Although electrophysiological studies can determine the level and type of nerve lesion, US nerve tracking may be used to evaluate the cause, severity, and etiology of the entrapment.2 In this case, nerve conduction studies showed slowed sensory nerve conduction velocity and reduced sensory nerve action potential amplitude in the right LABCN. Ultrasound further identified entrapment level and confirmed the cause, which provided a path for potential treatments. Ultrasound-guided nerve hydrodissection is commonly used in pain management although high-quality evidence of its effects is still lacking.3 In this case, the entrapped site was close to the radial artery. Ultrasound guidance prevented unintended injury to the artery. For safety concern, dextrose water is advocated as the primary regimen by more and more physicians for perineural injections. In this case, dextrose was initially used but the effect lasted only for 1 mo. In those whose nerve is entrapped within a scar, corticosteroid may be an alternative if dextrose fails. In conclusion, US is a useful tool to identify morphological changes of peripheral nerves and surrounding structures and is helpful to guide procedures.

Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders

ObjectivesTo describe the clinical and genetic features of a Chinese peroxisome biogenesis disorder 6B patient with PEX10 mutations and review PEX10–related peroxisomal disorders. Patients and methodsThe proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus. An extensive clinical and laboratory evaluation including molecular genetic studies was performed. Genomic DNA was extracted from peripheral blood using the standardized phenol/chloroform extraction method, and the coding region of the PEX10 gene was sequenced in three family members. ResultsCerebral MRI showed cerebellar atrophy. Magnetic resonance spectroscopy revealed a decreased N-acetyl aspartate peak in the cerebellum. Nerve conduction velocity examination found prolonged motor and sensory nerve potential latencies (proximal obvious), decreased potential amplitude, and slow nerve conduction velocity. Routine blood tests and biochemistries were abnormal. The PEX10 gene test showed compound heterozygous mutations (c.209 G > A, p. G70E and c.830 T > C, p. L277 P). The mutation c.830 T > C, p. L277 P has been previously reported, whereas c.209 G > A, p. G70E is novel. ConclusionWe identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene. Peroxisome biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia, especially cases with early onset.

Morphological intelligence counters foot slipping in the desert locust and dynamic robots

During dynamic terrestrial locomotion, animals use complex multifunctional feet to extract friction from the environment. However, whether roboticists assume sufficient surface friction for locomotion or actively compensate for slipping, they use relatively simple point-contact feet. We seek to understand and extract the morphological adaptations of animal feet that contribute to enhancing friction on diverse surfaces, such as the desert locust (Schistocerca gregaria) [Bennet-Clark HC (1975) J Exp Biol 63:53-83], which has both wet adhesive pads and spines. A buckling region in their knee to accommodate slipping [Bayley TG, Sutton GP, Burrows M (2012) J Exp Biol 215:1151-1161], slow nerve conduction velocity (0.5-3 m/s) [Pearson KG, Stein RB, Malhotra SK (1970) J Exp Biol 53:299-316], and an ecological pressure to enhance jumping performance for survival [Hawlena D, Kress H, Dufresne ER, Schmitz OJ (2011) Funct Ecol 25:279-288] further suggest that the locust operates near the limits of its surface friction, but without sufficient time to actively control its feet. Therefore, all surface adaptation must be through passive mechanics (morphological intelligence), which are unknown. Here, we report the slipping behavior, dynamic attachment, passive mechanics, and interplay between the spines and adhesive pads, studied through both biological and robotic experiments, which contribute to the locust's ability to jump robustly from diverse surfaces. We found slipping to be surface-dependent and common (e.g., wood 1.32 ± 1.19 slips per jump), yet the morphological intelligence of the feet produces a significant chance to reengage the surface (e.g., wood 1.10 ± 1.13 reengagements per jump). Additionally, a discovered noncontact-type jump, further studied robotically, broadens the applicability of the morphological adaptations to both static and dynamic attachment.

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease. Here, we show that antisense oligonucleotides (ASOs) effectively suppress PMP22 mRNA in affected nerves in 2 murine CMT1A models. Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals. In addition to disease-associated gene expression networks that were restored with ASO treatment, we also identified potential disease biomarkers through transcriptomic profiling. Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy. These results support the use of ASOs as a potential treatment for CMT1A and elucidate potential disease and target engagement biomarkers for use in future clinical trials.

Diagnostic value of the near-nerve needle sensory nerve conduction in sensory inflammatory demyelinating polyneuropathy.

In this study we report the diagnostic value of the near-nerve needle sensory nerve conduction study (NNN-SNCS) in sensory inflammatory demyelinating polyneuropathy (IDP) in which the routine nerve conduction study was normal or non-diagnostic. The NNN-SNCS was performed to identify demyelination in the plantar nerves in 14 patients and in the median or ulnar nerve in 2 patients with sensory IDP. In 16 patients with sensory IDP, routine NCSs were either normal or non-diagnostic for demyelination. Demyelination was identified by NNN-SNCS by dispersion and/or slow nerve conduction velocity (NCV) below the demyelination marker. Immunotherapy was initiated in 11 patients, 10 of whom improved or remained stable. NNN-SNCS played an essential role in identifying demyelinaton in 16 patients with sensory IDP, leading to proper treatment. Muscle Nerve 57: 414-418, 2018.

Neuropathy genetics

Charcot-Marie-Tooth disease (CMT) is the most frequent form of hereditary neuropathy. Three genes commonly causing CMT encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). PMP22 duplication causes mainly demyelinating phenotype, known as CMT1A, with slowed motor nerve conduction velocity (MCV). Two distinctive phenotypic subgroups are present in patients with MPZ mutations: one shows preserved MCV and exclusively axonal pathological features, while the other is exclusively demyelinating. Patients with Cx32 mutations show intermediate slowing of MCV. Hereditary neuropathy with liability to pressure palsies (HNPP) usually is associated with a deletion of PMP22, which represents a reciprocal product of CMT1A. Focal thickening of the myelin sheath, known as tomacula, is a characteristic pathological feature in HNPP. Motor conduction studies show age-associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve, suggesting that irreversible axonal damage occurs at entrapment sites in motor nerves in HNPP patients. Familial amyloid polyneuropathy (FAP) is also an important hereditary neuropathy. Although FAP was originally reported in endemic foci of Portugal, Japan, and Sweden, recent progress in diagnostic techniques has revealed that late-onset form of this disease is widely prevalent beyond these conventional endemic foci. Clinicians should consider the possibility of FAP in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis.

P 38 Vestibular Schwannoma associated with hypertrophic neuropathy – An unusual manifestation of NF2 or not?

We report a case of generalized hypertrophic neuropathy, which was first noted with pressure palsy after surgery of a vestibular nerve schwannoma. A 46-year-old caucasian female presented with incomplete left radial nerve palsy and incomplete left ulnar nerve palsy with loss of muscle mass between the thumb and forefinger and additional slight hypaesthesia oft he fingertips dig. 1–2. Two weeks ago she underwent surgery for a left vestibular nerve schwannoma (see picture 1). One year before neurosurgery carpal tunnel syndrome was diagnosed bilaterally. In the first interview no family history of nerve diseases was reported. Neurography of median, ulnar, tibial and peroneal nerves showed very slow nerve conduction velocities (NCV) less than 30 m/s and diminished compound motor action potentials (CMAP) with prolonged duration. Electromyography showed no signs of acute denervation. High resolution nerve sonography (HRUS) showed markedly enlarged fascicles resulting in up to 6-fold nerve cross sectional areas (see picture 2, ulnar nerve oft he right upper arm) without vascularisation. This was present in all examined nerves in different expression. Family history was complemented by the patient: Her father suffered on a “disease of muscles” (has died at the age of 45 years) and her sister, too. No signs of neurofibromatosis (1 or 2) were reported. Genetic testing on mutations typically in neurofibromatosis 1 and 2 and schwannomatosis (“NF 3”) was negative. Because of demyelinating neuropathy (suspicious Charcot-Marie-Tooth disease) duplication of PMP22 gene was examined, but it was negative. At last heterozygous MPZ-Mutation was detected. This accounts for CMT1B neuropathy. The diagnosis of CMT1B is in accordance to the neurographic and sonographic findings of peripheral nerves. The focal enlargement of some fascicles is observed in schwannomas or neurofibromas, but usually they shows vascularisation, which was not present in this case. To date an association of CMT with vestibular schwannoma is not reported in the literature. Kwon et al. (2009) described a family with CMT1A caused by duplication of the PMP22 gene. Two family members had schwannomas of the spinal cord and median nerve. The authors argue that the co-occurrence of CMT1A and schwannomas in this family would be the result of independent events, but one could not completely ignore the possibility that the coincidence of two diseases might be due to a shared genetic background. Despite the missing association of CMT with vestibular schwannoma in the literature hearing loss seems not to be rare in CMT. Sanmaneechai et al. (2015) referred to patients with CMT disease caused by MPZ gene mutations. 21 of 103 patients had hearing loss, but tests like MRI or BAER (brainstem auditory evoked response) are not given in the paper. Grider et al. (2015) found in 25 CMT patients that BAER waveforms were robust even in the absence of acoustic reflexes, except for two patients with CMT1B who had abnormal BAER recordings that were not consistent with hearing thresholds. These observations supports for the neural nature of the hearing loss in CMT1B and should improve further investigations with MRI in those patients.

P 43 A novel deletion in two exons of the SH3TC2 gene with mutation in the DPYD gene in Charcot-Marie-Tooth disease type 4C

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating neuropathy associated with SH3TC2 mutations. More than 60 variants including nonsense, frameshift, and splice site variants have been reported in families of different ethnic origins as well as in sporadic patients. CMT4C is clinically characterised by early onset neuropathy, cranial nerve involvement and spine deformities. We present a family from Kuwait with a novel deletion of exons 13 and 14 in the SH3TC2 gene combined with a novel homozygous mutation in the DPYD gene. The 40 year-old male patient had foot deformities in infancy and delayed walking after the age of two. He first required walking aids when ten years old and became wheelchair-bound since the age of 18. He had progressive hearing loss over five years. Walking difficulties and wheelchair-dependency were reported in his father as well as a cousin of his mother while there were no symptoms reported in his own siblings and child. Clinical examination showed hypoacusis requiring the use of hearing aids, marked widespread symmetric muscular atrophies with weakness, and areflexia. He could walk a few steps with bilateral support. He had sensory neuropathy with skin atrophy and loss of hair on the lower legs. Spinal examination and X-ray showed slight hyperkyphosis of the thoracic spine but no signs of kyphoscoliosis. Electrophysiological studies showed severe motor and sensory neuropathy with very low amplitudes, markedly prolonged distal motor latencies and very slow motor nerve conduction velocities in the ulnar nerve. Needle electromyography detected fibrillations, positive sharp waves and complex repetitive discharges. High resolution sonography of the median nerve at the wrist showed a few enlarged fascicles with only moderately raised cross sectional area. Creatin kinase levels were constantly and significantly raised. Genetic testing revealed a homozygous large deletion in the SH3TC2 gene comprising exons 13 and 14 that had not been described before. Furthermore a second homozygous novel mutation (c.680+1G>T;p.?) was found in the DPYD gene. The same combination in heterozygous form was detected in the asymptomatic eight year old daughter. This newly described family with CMT4C broadens the spectrum of genetic causes and underlines the clinical variability of phenotypes as the absence of scoliosis does not exclude mutations in the SH3TC2 gene even in patients with severe disabling Azzedine et al., 2006 , Azzedine et al., 2016 , Varley et al., 2015 , Inherited Peripheral Neuropathies Mutation Database, 2016 .

P 37 Rare treatable cause of ulnar nerve paresis after critical illness detected by nerve ultrasound

We report a case of neuropathy of the right ulnar nerve first diagnosed after intensive care unit treatment including ventilation and hemodialysis due to a status epilepticus. A 37-year-old caucasian male presented with convulsive status epilepticus. Since he underwent surgical treatment of a left cerebral arteriovenous malformation 11 years ago he suffered on symptomatic epilepsy. Some weeks before he decide to stop his antiepileptic drugs. Following admission to the intensive care unit (ICU), the antiepileptic medication (valproate, phenytoin) was without successfully alleviating seizures. The patient was finally anaesthetized and intubated to secure airway. Medication of propofol and midazolam resulted in a burst supression pattern on EEG. Finally a combination of levetiracetam and phenytoin was given. EEG was than without epileptic activity. Unfortunately patient suffered pneumonia, consecutive sepsis with renal failure and required hemodialysis for 13 days. ICU treatment was successfull and weaning of mechanical ventilation was achieved after 4 weeks. When patient was awake he noted weakness and paraesthesias of his right hand. Because of general weakness following severe disease it was thought to be a symptom of a critical illness neuropathy. After admission to rehabilitation clinic general weakness improved rapidly, but a sensorimotor ulnar paresis persisted. All muscles of the right hand supplied by the ulnar nerve showed weakness and atrophy equally. Electromyography of the right abductor digiti minimi muscle (ABDM) showed fibrillation potentials and positive sharp waves. Neurography showed slow nerve conduction velocity (NCV) oft he right ulnar nerve of the foream (36 m/s; left: 51 m/s), but normal NCV oft he upper arm. Compound motor action potential (CMAP) oft he right ABDM was strongly diminished (0,3 mV; left 6 mV) on all sites of stimulation. There were neither sensory nerve action potential nor F-waves obtainable oft he right ulnar nerve. Left ulnar nerve and median nerve bilaterally showed normal findings. There were no clinical signs of involvement of other peripheral nerves. Nerve sonography was performed to rule out local compression, for example caused by synovial cyst. Ulnar nerve showed a 3-4-fold thickening of the cross sectional area (CSA) beginning in the distal forearm up to the distal upperarm. Nearly all fascicles showed discontinuous hypoechoic hyperthrophy. Neither other nerves nor brachial plexus showed abnormal findings on nerve sonography. Laboratory investigations did not reveal any pathology concerning focal hypertrophic neuropathy. Despite the monofocal pattern diagnosis of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) was made. At that time the symptoms of the ulnar paresis remained unchanged since 3 month. We introduced IVIG treatment and patient responded well. This case demonstrates the diagnostic power of nerve sonography in addition to routine investigations in the detection of a curable focal neuropathy. It should be used in any case of focal neuropathy if no other diagnosis can be made safely.

Hereditary neuropathy with liability to pressure palsy in patients under 30 years old: Neurophysiological data and proposed electrodiagnostic criteria.

In young patients with mononeuropathy who lack family history and precipitating factors, hereditary neuropathy with liability to pressure palsy (HNPP) may be a possibility. Our objective is to propose neurophysiological criteria for HNPP in patients <30 years of age. We conducted a national multicenter retrospective clinical and neurophysiological study in patients under 30 with genetically confirmed HNPP. All of the 51 patients included in the study had at least 1 demyelinating pattern in 2 asymptomatic nerves, and 3 abnormalities were found in almost 90%, including slowed motor nerve conduction velocity across the elbow in at least 1 ulnar nerve (97.5%), increased distal motor latency (DML) in at least 1 fibular nerve (95.8%), and increased DML in both median nerves (89%). Age influenced DML slightly only in the fibular nerve. Dissemination of nerve involvement in HNPP incites to perform a complete nerve conduction study. including bilateral ulnar, fibular, and median nerves. Muscle Nerve 57: 217-221, 2018.