Mehmet Ali Akalin

The distinct genetic pattern of ALS in Turkey and novel mutations

The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. In this study, we screened 477 ALS patients for mutations, including 116 familial ALS patients from 82 families and 361 sporadic ALS (sALS) cases. Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey. No SOD1 mutations were detected in sALS patients; however, C9orf72 (3.1%) and UBQLN2 (0.6%) explained 3.7% of sALS in the population. Exome sequencing revealed mutations in OPTN, SPG11, DJ1, PLEKHG5, SYNE1, TRPM7, and SQSTM1 genes, many of them novel. The spectrum of mutations reflect both the distinct genetic background and the heterogeneous nature of the Turkish ALS population.

Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis.

This study aims to investigate genetic susceptibility to early-onset and late-onset anti-acetylcholine receptor antibody positive myasthenia gravis (EOMG and LOMG) and anti-muscle specific kinase antibody positive MG (MuSK-MG) at genome-wide level in a single population. Using a custom-designed array and imputing additional variants and the classical HLA alleles in 398 patients, we detected distinct associations. In EOMG, rs113519545 in the HLA class I region (OR=5.71 [3.77-8.66], P=2.24×10(-16)), HLA-B*08:01 (OR=7.04 [3.95-12.52], P=3.34×10(-11)) and HLA-C*07:01 (OR=2.74 [1.97-3.81], P=2.07(-9)), in LOMG, rs111256513 in the HLA class II region (OR=2.22 [1.59-3.09], P=2.48×10(-6)) and in MuSK-MG, an intronic variant within HLA-DQB1 (rs68081734, OR=5.86, P=2.25×10(-14)) and HLA-DQB1*05:02 (OR=8.56, P=6.88×10(-13)) revealed the most significant associations for genome-wide significance. Differential genetic susceptibility within the HLA to EOMG, LOMG and MuSK-MG has been established in a population from Turkey.

Is diabetic dermopathy a sign for severe neuropathy in patients with diabetes mellitus? Nerve conduction studies and symptom analysis

OBJECTIVE To assess if diabetic dermopathy (DD) is a sign for severe polyneuropathy (PNP). METHODS We investigated the clinical and electrophysiological characteristics of 166 diabetic men (59.5+11.1 years) with different degrees of peripheral nerve involvement. RESULTS All of the clinical variables were more common in patients with diabetic foot ulcers (DF) than in patients with sole PNP (P<0.001). Only the loss of superficial and vibration sense was more common in the DF patients than the DD patients (P<0.02). Nerve conduction studies showed the mean compound muscle action potentials (CMAP) were smaller in the DD and DF patients than the PNP patients for peroneal, median and ulnar nerves (P<0.01). The mean nerve conduction velocities (NCV) of all nerves were slower in the DD and DF patients in compared to sole PNP patients (P<0.01). The mean distal latencies (DL) of the DD/DF patients were longer than the PNP group. CONCLUSIONS The DD and DF patients did not significantly differ in CMAP, NCV, and DL. SIGNIFICANCE Both clinical and electrophysiological features of DD and DF are similar, and significant different than PNP alone. These results suggest that DD is an important clinical sign for more severe neuropathic impairment.

Blink reflex in patients with postparalytic facial syndrome and blepharospasm: Trigeminal and auditory stimulation

OBJECTIVE The enhancement of blink reflex (BR) excitability was shown in patients with postparalytic facial syndrome (PFS) and essential blepharospasm (EB). We prospectively investigated patients with PFS and EB whether BR alterations demonstrated by trigeminal stimulation will similarly be observed upon auditory stimulation. METHODS Fifteen patients with PFS, 15 patients with EB, and 30 healthy volunteers were involved. Electrically stimulated trigeminal BR and auditory BR were studied bilaterally. RESULTS The mean R2 amplitude and duration values were highest in EB patients, being significantly higher than PFS patients (p < 0.05) and control group (p < 0.01). The mean R2 duration in PFS patients were also significantly longer in compared to control group (p = 0.025). EB patients showed a higher mean R (auditory) amplitude and duration than PFS patients (p < 0.05) and controls (p < 0.04). The mean R (auditory) duration was longer on symptomatic side of PFS patients in compared to controls (p = 0.05). CONCLUSIONS We observed that there is an enhanced excitability of BR circuit in postparalytic facial syndrome and essential blepharospasm, which could be evoked by auditory stimulation in addition to trigeminal stimulation. SIGNIFICANCE The enhanced excitability in patients with EB and PFS probably originates from the final common pathway of BR circuit, namely facial motor or premotor neurons.

Lambert-Eaton myasthenic syndrome associated with thymic neuroendocrine carcinoma.

decremental response, and the initial CMAP of the RNS train had improved (Fig. 1C). On discharge at day 44, her MG-ADL score was 2. Although respiratory infection is the most common cause of MG exacerbation, intravenous peramivir may have induced the respiratory failure in the patient described, because it developed within 20 minutes after drug administration and the symptoms recovered rapidly, with improvement in the RNS test. Her improvement may be a result of the discontinuation of peramivir, regardless of immunotherapy. Furthermore, the safety factor for neuromuscular transmission, which decreased subclinically, may have improved because of immunotherapy. MG exacerbation has been reported with various medications. A few neuraminidase inhibitors suppress respiratory function through mechanisms including ion channel/receptor inhibition. Therefore, we speculate that peramivir may inhibit ion channels/receptors in the neuromuscular junctions, leading to respiratory failure and MC. Further studies are necessary to understand the mechanism underlying MC induction by intravenous peramivir. Koji Hayashi, MD

A database for screening and registering late onset Pompe disease in Turkey

The aim of this study was to search for the frequency of late onset Pompe disease (LOPD) among patients who had a myopathy with unknown diagnosis registered in the pre-diagnostic part of a novel registry for LOPD within a collaborative study of neurologists working throughout Turkey. Included in the study were 350 patients older than 18 years who have a myopathic syndrome without a proven diagnosis by serum creatine kinase (CK) levels, electrodiagnostic studies, and/or muscle pathology, and/or genetic tests for myopathies other than LOPD. Acid alpha glucosidase (GAA) in dried blood spot was measured in each patient at two different university laboratories. LOPD was confirmed by mutation analysis in patients with decreased GAA levels from either both or one of the laboratories. Pre-diagnostic data, recorded by 45 investigators from 32 centers on 350 patients revealed low GAA levels in a total of 21 patients; from both laboratories in 6 and from either one of the laboratories in 15. Among them, genetic testing proved LOPD in 3 of 6 patients and 1 of 15 patients with decreased GAA levels from both or one of the laboratories respectively. Registry was transferred to Turkish Neurological Association after completion of the study for possible future use and development. Our collaborative study enabled collection of a considerable amount of data on the registry in a short time. GAA levels by dried blood spot even from two different laboratories in the same patient may not prove LOPD. LOPD seemed to be rarer in Turkey than in Europe.

Auditory evoked blink reflex in peripheral facial paresis.

Purpose: The auditory blink reflex (ABR) is a teleceptive reflex consisting of an early brief muscle contraction of the orbicularis oculi in response to sound stimuli. Constriction of the orbicularis oculi in response to auditory stimulation is accepted as a part of the startle reaction. The blink reflex and ABR might share a final common pathway, consisting of facial nerve nuclei and the facial nerve and may have common premotor neurons. Methods: In this study, the authors evaluated the value of the ABR in patients with peripheral facial palsy (PFP), cross-checking the results with commonly used blink reflex changes. Results: In total, 83 subjects with PFP and 34 age-matched healthy volunteers were included. Auditory blink reflex was elicited in all control subjects and in 36 PFP cases on the paralytic sides (43.3%), whereas it was asymmetric in 30.1% of the patients. Auditory blink reflex positivity was significantly lower in PFP cases with increasing severity. Blink reflex results were largely correlated with ABR positivity. Conclusions: Auditory blink reflex is a useful readily elicited and sensitive test in PFP cases, providing parallel results to blink reflex and being affected by disease severity.

Acute peripheral facial palsy: Is there a trigeminal nerve involvement?

The aim of this study was to investigate trigeminal nerve involvement in patients with peripheral facial palsy. In total, 25 patients with facial nerve palsy and 19 controls were tested by electrophysiological methods regarding their facial and trigeminal nerve functions within 1 month after disease onset. The presence of an abnormal blink reflex was determined in patients with peripheral facial palsy by comparing paralytic and non-paralytic sides (12.3+/-1.1 and 10.8+/-1.3, respectively; p=0.001). However, the average masseter inhibitory reflex difference between the paretic and non-paralytic sides of patients compared with the corresponding side-to-side comparison for controls was not statistically significant. The masseter inhibitory reflex response was abnormal in some cases. These findings suggest that the masseter inhibitory reflex, a trigemino-trigeminal reflex, was normal in most of our patients with peripheral facial palsy, but may be abnormal in individual cases. Our study showed that subclinical disorders affecting the trigeminal pathways occur in individual patients with idiopathic facial palsy, while the majority of patients have no trigeminal nerve involvement.

F27. Myoclonus in demyelinating polyneuropathies: Preliminary results

Introduction The reports on tremor and different types of polyneuropathies have been increasing and it was suggested to be associated with cerebellar involvement in chronic inflammatory demyelinating polyneuropathy (CIDP). Apart from specific syndromes, the co-existence of polyneuropathy and myoclonus is exceptional. We previously observed cortical myoclonus in cases with inflammatory polyneuropathy who were referred for tremor analysis and aimed to analyze presence of myoclonus and its relation with clinical features in demyelinating polyneuropathies. Methods We prospectively included all patients with inflammatory polyneuropathy who were admitted between January 2017 and June 2017 and had tremor-like, regular or irregular involuntary movements on clinical examination. All patients underwent neurological examination and multichannel surface electromyography which included upper extremity muscles as well as lower extremity and facial or neck muscles in selected cases. We also recorded long latency reflexes and somatosensory evoked potentials (SEPs) to categorize myoclonus. Results We identified eight patients with demyelinating polyneuropathy who matched the inclusion criteria: four patients with CIDP, three patients with Guillain–Barre syndrome and one patient with Charcot-Marie-Tooth disease. The mean age was 50.5 ± 19.6 years (range: 26–81 years) and there were seven male patients. Seven out of eight patients had myoclonus, two of which were in the form of polyminimyoclonus. Others had myoclonus on both proximal and distal parts of upper extremities. Negative myoclonus was observed in four of them. Duration of myoclonus was between 30 and 100 ms. only one had duration of 200 ms. Most patients (five out of seven) had cortical myoclonus (with high-amplitude C reflex or SEPs). Conclusion Myoclonus in the patients with polyneuropathy was irregular tremor-like, however, the electrophysiological characteristics was similar to a cortical subtype. Therefore, it would be interesting to investigate a bigger cohort of inflammatory polyneuropathies for the presence and subtypes of myoclonus and to determine associated clinical features.

Stiff Person Syndrome with Pyramidal Signs

Stiff person syndrome (SPS) is a rare disorder characterized by continuous muscle activity causing severe rigidity and episodic spasms in axial and limb muscles (1). According to the diagnostic criteria, normal motor and sensory examination is the rule. Hyperactive deep tendon reflexes may be observed, but extensor plantar reflexes are rare (1,2,3,4). Here, by presenting this case with atypical features like pyramidal signs, we aimed to review the clinical and electrophysiological signs of this rare syndrome.