Clinical and genetic characteristics of Emery-Dreifuss muscular dystrophy patients from Turkey: 30 years longitudinal follow-up study.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare inherited disorder usually presenting in childhood with early contractures, slowly progressive scapulohumeroperoneal weakness/atrophy and potentially fatal dilated cardiomyopathy with conduction defects. We evaluated clinical and genetic findings of 32 patients with EDMD phenotype from 14 unrelated families, diagnosed at the Department of Neurology, Istanbul Faculty of Medicine between 1989 and 2022. Twenty-three patients from 8 unrelated families were diagnosed with EDMD1 (58%), 5 patients from 3 families with EDMD2 (21%), and 2 patients from 1 family with the rare EDMD3 (7%). Genetic diagnosis was achieved in 12 unrelated kinships with classical EDMD phenotype (86%) by applying panel testing, but no mutation could be determined in 2 patients with classical EDMD phenotype from 2 unrelated families (14%). Three novel pathogenic variants (c.19delC, c.416_417delTT, c.123C > G) in EMD, and a novel (c.1441dupT) heterozygous likely pathogenic variant in LMNA gene were found. This is the largest cohort from Turkey, expanding the genetic spectrum of EDMD, and providing clues for genetic testing of EDMD in Turkey.

Lumbar Spinal Stenosis: A Rare Presentation of Hereditary Transthyretin Amyloidosis.

Hereditary transthyretin amyloidosis (hATTR) is caused by the mutations of the transthyretin (TTR) gene. Length dependent sensory-motor neuropathy with autonomic involvement is the hallmark of the disease. However, it can manifest with unusual phenotypes. A 53-year-old man presented with progressive weakness in lower limbs and operated for lumbar spinal stenosis. The progression of weakness restarted after two years with the addition of symptoms related to polyneuropathy. Electrodiagnostic studies revealed sensorimotor polyneuropathy with autonomic involvement. Sural nerve biopsy disclosed amyloid deposits. Genetic testing of TTR gene identified Glu89Gln mutation. Two years after the diagnosis, he had another decompressive surgery for lumbar spinal stenosis. Histopathological examination of ligamentum flavum specimens revealed amyloid deposits. During the follow up, he was diagnosed with laryngeal amyloidosis, which is an unusual manifestation. Seven years after the diagnosis, he died due to cardiac complications. Our patient suggested that hATTR with Glu89Gln may present with atypical symptoms. Clinicians should carefully look for hATTR in recurrent lumbar stenosis.

Clinical course and outcome of an outpatient clinic population with myasthenia gravis and COVID-19.

INTRODUCTION/AIMS: Coronavirus disease-2019 (COVID-19) may have a more severe course in patients with myasthenia gravis (MG). We aimed to assess severity of the infection and factors contributing to its severity in a group of MG patients, most of whom were not hospitalized. METHODS: One hundred forty outpatients with MG followed between March 2020 and April 2021 were included in our study. Patients were asked to respond to a brief questionnaire in person, by telemedicine, or through electronic messages. RESULTS: Nineteen patients tested positive for COVID-19 by polymerase chain reaction. Two were asymptomatic. Of the 17 symptomatic patients, 11 had mild symptoms. They either had no treatment or received antivirals, antibiotics, and anticoagulants. Their myasthenia was well-controlled before infection and was unaffected by COVID-19. Three patients with moderate COVID-19 required hospitalization, but not intensive care, and had full recovery. Three other patients, the oldest in the cohort, had severe disease: One patient with a postsurgery myasthenic exacerbation before the infection needed intensive care without intubation, but recovered completely; two morbidly obese patients with comorbidities required intubation and died. Corticosteroids were increased in four of the six moderate/severely affected patients. Immunosuppressive (IS) agents were generally continued. Hydroxychloroquine (HCQ) for COVID-19 was used in one patient. DISCUSSION: Most patients had mild COVID-19 and all but two patients recovered. The design of the study made it possible to capture mild cases. Having well-controlled MG before infection and absence of comorbidities likely affected the course of the infection favorably. IS did not influence the progression.

History of Myasthenia Gravis Revisited.

The first description of myasthenia gravis (MG) was given by Thomas Willis in 1672. MG was the focus of attention after mid-nineteenth century and a great amount of information has been accumulated in a span of 150 years. The aim of this review is to convey this information according to a particular systematic and to briefly relate the experience of Istanbul University. MG history was examined in four periods: 1868-1930, 1930-1960, 1960-1990, and 1990-2020. In the first period (1868-1930), all the clinical characteristics of MG were defined. Physiological/pharmacological studies on the transmission at the neuromuscular junction were initiated, and the concept of repetitive nerve stimulation emerged. A toxic agent was believed to be the cause of MG which appeared to resemble curare intoxication. Association of MG with thymus was noticed. No noteworthy progress was made in its treatment. In the second period (1930-1960), acetylcholine was discovered to be the transmitter at the neuromuscular junction. Repetitive nerve stimulation was used as a diagnostic test. The autoimmune nature of MG was suspected and experiments to this end started to give results. The hallmark of this period was the use of anticholinesterases and thymectomy in the treatment of MG. The third period (1960-1990) can probably be considered a revolutionary era for MG. Important immunological mechanisms (acetylcholine receptor isolation, discovery of anti-acetylcholine receptor antibodies) were clarified and the autoimmune nature of MG was demonstrated. Treatment modalities which completely changed the prognosis of MG, including positive pressure mechanic ventilation and corticosteroids as well as plasma exchange/IVIg and azathioprine, were put to use. In the fourth period (1990-2020), more immunological progress, including the discovery of anti-MuSK antibodies, was achieved. Videothoracoscopic thymectomy reduced the morbidity and mortality rate associated with surgery. New drugs emerged and clinical trials were performed. Valuable guidelines were published. In the last part of the review, the experience in MG of Istanbul University, a pioneer in Turkey, is related.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

Rare slow channel congenital myasthenic syndromes without repetitive compound muscle action potential and dramatic response to low dose fluoxetine.

Congenital myasthenic syndromes are rare hereditary disorders caused by mutations associated with proteins of the neuromuscular junction. Abnormal ''gain of function'' mutations result in prolonged nicotinic acetylcholine receptor channel open state causing a rare subtype of CMS, slow-channel CMS (SCCMS). Mutations in the delta subunit encoding the gene, CHRND, resulting in SCCMS are extremely rare. An important clue to the diagnosis of SCCMS is repetitive CMAP's. Fluoxetine, usually at high doses, is used to treat SCCMS. The mutation, recently described in one patient, was identified by whole exome sequencing and validated, and its segregation with the disease was ascertained by Sanger sequencing. Here, we describe clinical and genetic findings of an early onset SCCMS patient carrying a very rare missense mutation c.880C > T in CHRND causing a highly conserved leucine to phenylalanine substitution in the M2 domain of CHRND. The patient had no repetitive CMAP. He had a dramatic response to fluoxetine at low-moderate doses (40 mg/day), increasing over months: Being wheelchair bound, he could walk independently after treatment. Rare cases may offer insight into the pathological gating mechanism leading to CMS. SCCMS should be suspected even without a repetitive CMAP. Fluoxetine at relatively low doses can be a very effective treatment.

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database.

The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well-established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome-wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease-associated candidates, points to a significant enrichment for cell cycle- and division-related genes. Within this network, literature text-mining highlights DECR1, ATL1, HDAC2, GEMIN4, and HNRNPA3 as important genes. Finally, information on ALS-related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (www.gendal.org).

Myasthenia gravis: MuSK MG, late-onset MG and ocular MG.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction which affects all striated muscles, resulting in fluctuating weakness. Approaching MG as a disease with subgroups having different clinical, serological and genetic features is crucial in predicting the progression and planning treatment. Three relatively less frequently seen subtypes of MG are the subject of this review: MG with anti-MuSK antibodies (MuSK MG), non-thymomatous late-onset MG (LOMG), and ocular MG (OMG). In addition to reviewing the literature, mainly from a clinical point of view, our experience in each of the subgroups, based on close to 600 patients seen over a 10 year period, is related. MuSK MG is a severe disease with predominant bulbar involvement. It is more common in women and in early-onset patients. With the use of high dose corticosteroids, azathioprine and more recently rituximab, outcome is favorable, though the patients usually require higher maintenance doses of immunosuppressives. LOMG with onset ≥ 50 years of age is more common in men and ocular onset is common. Frequency of anti-AChR and anti-titin antibodies are high. Although it can be severe in some patients, response to treatment is usually very good. OMG is reported to be more frequent in men in whom the disease has a later onset. Anti-AChR antibodies are present in about half of the patients. Generalization is less likely when symptoms remain confined to ocular muscles for 2 years. Low dose corticosteroids are usually sufficient. Thyroid disease is the most common autoimmune disease accompanying all three subgroups.

Late-onset generalized myasthenia gravis: clinical features, treatment, and outcome.

Late-onset myasthenia gravis (LOMG) is a unique MG subgroup. More information is needed on its subgroups such as non-thymomatous generalized LOMG. We evaluated the effect of demographic, clinical, and serological factors as well as different immunosuppressive modalities on outcome in generalized non-thymomatous LOMG with onset ≥ 50 years. Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, MGFA postintervention score (MGFA PIS) and MG Composite scores were obtained to define the severity of disease and clinical outcome. In 95 patients with generalized non-thymomatous LOMG, 60 (63%) were men, 45 (47%) had mild disease, 80 (84%) were anti-AChR, and 56 (61%) were anti-titin positive. In those who received immunosuppressives and provided the clinical scores (84 patients), 50 (60%) had favorable outcome (MGFA PIS categories of complete stable remission, pharmacological remission and minimal manifestations) at the end of 3 years. Use of prednisone + azathioprine had significantly positive effect on outcome. The presence of anti-titin antibodies had no significant effect on severity and outcome. Five anti-MuSK-positive patients had favorable outcome. In conclusion, the presence of neither anti-titin nor anti-MuSK antibodies points to unfavorable outcome. Prednisone and azathioprine combination has beneficial effects in non-thymomatous generalized LOMG.

Increased costimulatory molecule expression of thymic and peripheral B cells and a sensitivity to IL-21 in myasthenia gravis.

B cells may contribute to the pathogenesis of myasthenia gravis with anti-acetylcholine antibodies (AChR+ MG) by co-stimulation or selection of T cells. In this study, we investigated costimulatory molecules on B cells in the blood and in the thymus as well as by TLR9 and IL-21 stimulations in AChR+ MG patients with or without immunosuppressive treatment and controls. CD80 and CD86 expression on B cells was increased in the peripheral blood and in the thymus of untreated patients. CD86 was further amplified by IL-21. A role for activated B cells, active thymic environment and IL-21 is implicated in MG.

Electromyography in Pediatric Population.

INTRODUCTION: Electrodiagnostic evaluation provides an important extension to the neurological examination for the evaluation of pediatric neuromuscular disease. Many pediatric neuromuscular diseases are analogous to those seen in the adult. However, the relative frequency of these illnesses varies greatly when different age populations are compared. The purpose of the present study is to provide a retrospective analysis of children referred to our electromyography (EMG) laboratory for electrophysiological examinations. METHODS: We retrospectively reviewed electrodiagnostic records of patients aged between 0-15 years, from January 2004 to June 2013. Patients were classified as having plexopathy, nerve root lesions, polyneuropathy, myopathy, mononeuropathy, anterior horn cell disease, neuromuscular transmission disorder, facial nerve palsy, and other rare disorders. RESULTS: We reviewed totally 5563 pediatric records, which was on the average 578 studies per year. It was about 14% of the all EMG examinations performed in our laboratory. When we looked at all the procedures, 3271 of the records included needle EMGs, 170 of them were single fiber EMGs, 100 of them were repetitive nerve stimulations, and 52 of them were evoked potentials. The results were normal in 55% of the cases. As a result of electrophysiological examinations, the common diagnoses were: plexopathy (28.6%), polyneuropathy (7.4%), and myopathy (6.6%) in patients aged 0-5 years (41.2% of all records); myopathy (9.4%), PNP (8.5%), mononeuropathy (6.4%), and plexopathy (5.9%) in 6-10 years (28.2% of all records); PNP (11.3%), myopathy (6.6%), and mononeuropathy (5.6%) in 11-15 years (30.6% of all records). CONCLUSION: Infants and toddlers mostly suffered from brachial plexopathy which can be prevented by proper obstetrical management. Nerve conduction studies and EMG yielded diagnostic importance for demyelinating neuropathy and myopathy in patients older than 6 years of age.

Repetitive nerve stimulation and jitter measurement with disposable concentric needle electrode in newly diagnosed myasthenia gravis patients.

INTRODUCTION: The aim of this study was to define the diagnostic accuracy of concentric needle (CN)-jitter in newly diagnosed myasthenia gravis (MG) patients and to compare CN-jitter with repetitive nerve stimulation. METHODS: In 30 MG patients, repetitive nerve stimulation in 4 muscles (orbicularis oculi, nasalis, trapezius and abductor digiti minimi) and CN-jitter of extensor digitorum (ED) and frontalis muscles were evaluated. RESULTS: Twenty-eight of 30 patients (93%) had high jitter in at least one muscle. Repetitive nerve stimulation was abnormal in 23 of the patients (77%). Eighty-six percent of the patients in whom repetitive nerve stimulation test was negative could be diagnosed with CN-jitter. The most frequent muscle showing abnormal decrement was orbicularis oculi. The results of CN-jitter were similar between patients with different serological groups. Of 13 patients with generalized weakness, all had high jitter in both muscles studied whereas of 17 patients only with ocular weakness, 15 had high jitter in at least one muscle studied. CONCLUSION: Abnormal RNS was present in 77% of newly diagnosed MG patients, being less than CN-jitter (93%) but more than antibody positivity (73.3%).

Congenital myasthenic syndromes in Turkey: Clinical clues and prognosis with long term follow-up.

Congenital myasthenic syndromes (CMS) are a group of hereditary disorders affecting the neuromuscular junction. Here, we present clinical, electrophysiological and genetic findings of 69 patients from 51 unrelated kinships from Turkey. Genetic tests of 60 patients were performed at Mayo Clinic. Median follow-up time was 9.8 years (range 1-22 years). The most common CMS was primary acetylcholine receptor (AChR) deficiency (31/51) and the most common mutations in AChR were c.1219 + 2T > G (12/51) and c.1327delG (6/51) in CHRNE. Four of our 5 kinships with AChE deficiency carried p.W148X that truncates the collagen domain of COLQ, and was previously reported only in patients from Turkey. These were followed by GFPT1 deficiency (4/51), DOK7 deficiency (3/51), slow channel CMS (3/51), fast channel CMS (3/51), choline acetyltransferase deficiency (1/51) and a CMS associated with desmin deficiency (1/51). Distribution of muscle weakness was sometimes useful in giving a clue to the CMS subtype. Presence of repetitive compound muscle action potentials pointed to AChE deficiency or slow channel CMS. Our experience confirms that one needs to be cautious using pyridostigmine, since it can worsen some types of CMS. Ephedrine/salbutamol were very effective in AChE and DOK7 deficiencies and were useful as adjuncts in other types of CMS. Long follow-up gave us a chance to assess progression of the disease, and to witness 12 mainly uneventful pregnancies in 8 patients. In this study, we describe some new phenotypes and detail the clinical features of the well-known CMS.

Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ε-subunit.

We identify 2 homozygous mutations in the ε-subunit of the muscle acetylcholine receptor (AChR) in 3 patients with severe congenital myasthenia: εR218W in the pre-M1 region in 2 patients and εE184K in the ß8-ß9 linker in 1 patient. Arg218 is conserved in all eukaryotic members of the Cys-loop receptor superfamily, while Glu184 is conserved in the α-, δ-, and ε-subunits of AChRs from all species. εR218W reduces channel gating efficiency 338-fold and AChR expression on the cell surface 5-fold, whereas εE184K reduces channel gating efficiency 11-fold but does not alter AChR cell surface expression. Determinations of the effective channel gating rate constants, combined with mutant cycle analyses, demonstrate strong energetic coupling between εR218 and εE184, and between εR218 and εE45 from the ß1-ß2 linker, as also observed for equivalent residues in the principal coupling pathway of the α-subunit. Thus, efficient and rapid gating of the AChR channel is achieved not only by coupling between conserved residues within the principal coupling pathway of the α-subunit, but also between corresponding residues in the ε-subunit.

Myophosphorylase (PYGM) mutations determined by next generation sequencing in a cohort from Turkey with McArdle disease.

This study aimed to identify PYGM mutations in patients with McArdle disease from Turkey by next generation sequencing (NGS). Genomic DNA was extracted from the blood of the McArdle patients (n = 67) and unrelated healthy volunteers (n = 53). The PYGM gene was sequenced with NGS and the observed mutations were validated by direct Sanger sequencing. A diagnostic algorithm was developed for patients with suspected McArdle disease. A total of 16 deleterious PYGM mutations were identified, of which 5 were novel, including 1 splice-site donor, 1 frame-shift, and 3 non-synonymous variants. The p.Met1Val (27-patients/11-families) was the most common PYGM mutation, followed by p.Arg576* (6/4), c.1827+7A>G (5/4), c.772+2_3delTG (5/3), p.Phe710del (4/2), p.Lys754Asnfs (2/1), and p.Arg50* (1/1). A molecular diagnostic flowchart is proposed for the McArdle patients in Turkey, covering the 6 most common PYGM mutations found in Turkey as well as the most common mutation in Europe. The diagnostic algorithm may alleviate the need for muscle biopsies in 77.6% of future patients. A prevalence of any of the mutations to a geographical region in Turkey was not identified. Furthermore, the NGS approach to sequence the entire PYGM gene was successful in detecting a common missense mutation and discovering novel mutations in this population study.

Prompt Response to Prednisone Predicts Benign Course in MuSK-MG.

BACKGROUND: The difficult course of patients with myasthenia gravis (MG) with anti-muscle-specific tyrosine kinase antibodies (MuSK) has been emphasized. However, no clear information is available on patients who have a benign course. METHODS: This study was aimed at comparing patients with favorable (minimal manifestations [MM] or better) and unfavorable outcomes to determine whether excellent response to corticosteroid (CS) treatment within 3 months (good response-3 months) has any predictive effect on the prognosis. RESULTS: Forty-six percent of 46 patients had a favorable outcome at year 3 and 54% at final follow-up. The major finding of this study was its high predictive value with good response-3 months. Those with good response-3 months had significantly more favorable outcome as compared to those without at year 3. The positive predictive value of good response-3 months was high (89% at year 3 and 84% at final follow-up). The negative predictive value diminished from 85% at year 3 to 67% at final follow-up due to increasing number of patients improving in the long run. Overall, 33% of the patients had a benign course with good response-3 months and no major exacerbations until the end of follow-up. CONCLUSIONS: Excellent response to CSs within 3 months appears to predict a favorable outcome in MuSK-MG.

Turkish version of the Motor Function Measure Scale (MFM-32) forneuromuscular diseases: a cross-cultural adaptation, reliability, and validity study

Background/aim: The Motor Function Measure (MFM-32) is a classification system for ambulant and nonambulant patients with neuromuscular diseases (NMDs). We aimed to translate it into Turkish, culturally adapt it, and test its reliability and validity for Turkish patients with NMDs.Materials and methods: The translation of the 32 items assessing three functional areas: standing position and transfers (D1: 13), axial/proximal (D2: 12), and distal (D3: 7) motor functions was performed according to the established guidelines for cross-cultural adaptation. Totally 51 patients (12.56 ± 8.84 years; F/M 12/39) were tested. Vignos and Brooke scores for the lower and upper extremities, respectively, were used for the validity of the MFM-32-TR items, which were rated on a 4-point Likert scale. Results: The agreement coefficients for interrater reliability were excellent (0.72-0.93) for 10 items, good (0.58-0.77) for 16 items, and moderate (0.42-0.56) for 6 items of the MFM-32-TR. The intertester reliability varied from good to excellent and the intraclass correlation coefficient was 0.76-0.93. The MFM-32-TR positively correlated with Vignos and Brooke scores with coefficients 0.47 to 0.75, indicating concurrent validity.Conclusion: The MFM-32-TR is a reliable and valid outcome measure for the assessment of motor function of people with NMDs in our sociocultural context.

Muscle magnetic resonance imaging in spinal muscular atrophy type 3: Selective and progressive involvement.

INTRODUCTION: In this study we sought to identify magnetic resonance imaging (MRI) signs of selective muscle involvement and disease progression in patients with spinal muscular atrophy type 3b (SMA3b). METHODS: Twenty-five patients with genetically confirmed SMA3b underwent MRI on a 1.5-Tesla MR scanner. RESULTS: MRI showed significantly more severe involvement of the iliopsoas than of the gluteus maximus muscles, and more severe involvement of the triceps brachii than of the biceps brachii muscles. The quadriceps femoris muscles were severely involved. The deltoid, adductor longus, portions of the hamstrings, gracilis, sartorius, and rectus abdominis muscles were well preserved. We found a significant positive correlation between MRI changes and disease duration for gluteus maximus and triceps brachii. Follow-up MRIs of 4 patients showed disease progression. CONCLUSIONS: This study confirms the pattern of selective muscle involvement suggested by previous studies and further refines muscle MRI changes in SMA3b. Progressive muscle involvement is implicated. Muscle Nerve 55: 651-656, 2017.