Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.

Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.

Inclusion body myositis triggerred with long-term imatinib use.

INTRODUCTION: Imatinib is an orally administered tyrosine kinase inhibitor with wide clinical use in different indications from solid tumors to hematologic malignancies. Inclusion body myositis (IBM) is an acquired myopathy of both inflammatory and degenerative nature. CASE REPORT: We present an 81 years old male with a history of gastrointestinal stromal tumor (GIST) operated 8 years ago and was evaluated for the progressive loss of weight and muscle strength leading to total immobilization in 6 months. He was under imatinib for 8 years despite the remission of GIST. Physical examination disclosed diffuse loss of muscle strength, most prominently involvement of distal upper and proximal lower extremity in an asymmetrical pattern with normal serum creatinine kinase level (CK). Further investigations including bilateral thigh MRI, electromyography (EMG), and PET/CT suggested myositis and degenerative myopathy and ruled out any malignancy. Quadriceps femoris biopsy proved the diagnosis of IBM and no trigger except for imatinib was displayed. MANAGEMENT AND OUTCOME: Clinical improvement in terms of weight loss and muscle weakness was achieved after the discontinuation of imatinib. DISCUSSION: This is the first case of IBM associated with prolonged use of imatinib not reported in the literature so far. Since imatinib is widely used in different conditions, it is important to be aware of even its rare adverse effects. Poor response of IBM to conventional immunosuppressive agents enhances the value of etiology identification to relieve symptoms in addition to supportive care.

Post-COVID-19 vaccination inflammatory syndrome: A case report.

A previously healthy 24-year-old male patient was referred to our clinic with bilateral lower extremity pain and dark urine, which were developed 2 weeks after receiving the second dose of the BNT162b2 vaccine against severe acute respiratory coronavirus 2. Laboratory tests indicated rhabdomyolysis. Lower extremity magnetic resonance imaging was compatible with myositis. Myositis-related antibodies were negative. Biopsy taken from gastrocnemius muscle revealed muscle necrosis and striking expression of major histocompatibility complex class I antigen. He was successfully treated, and his complaints were resolved. One week later at follow-up, he reported new-onset exertional dyspnoea with palpitations. ST-segment depressions were spotted on electrocardiography. Troponin T was found elevated as 0.595 ng/ml (normal <0.014 ng/ml). Echocardiography showed a hypokinetic left ventricle with an ejection fraction of 40% and pericardial effusion of 2 mm. An appropriate treatment plan was formulated for the diagnosis of myocarditis, eventually, the patient recovered within 10 days. The BNT162b2 messenger ribonucleic acid (mRNA) vaccine was felt to cause the aforementioned condition since no other aetiology could be identified. Although it is known that BNT162b2 may induce myocarditis, myositis concomitant myocarditis appears to be a very rare adverse effect of this vaccine.

Disease activity in chronic inflammatory demyelinating polyneuropathy: A comparative study of clinical and skin biopsy markers.

INTRODUCTION/AIMS: Epidermal nerve fiber involvement in chronic inflammatory demyelinating neuropathy (CIDP) has been reported in a limited number of patients. We quantified small-fiber involvement in a mixed cohort of patients with typical CIDP and CIDP variants to evaluate relationships with clinical outcome measures at different disease stages. METHODS: Intraepidermal nerve fiber densities (IENFDs) were evaluated by skin punch biopsies of 23 patients with CIDP and 13 healthy controls at the forearm, thigh, and distal leg. Skin sections were optimally interpreted in all three regions in 16 CIDP patients and 10 age- and sex-matched healthy controls. Statistical analysis was performed in these subjects. RESULTS: The IENFDs in forearm, thigh, and distal leg were similar among seven typical CIDP and nine CIDP variants. IENFDs in those regions were significantly reduced in CIDP compared with healthy controls, with a moderate negative correlation with scores on the International Neuropathy Cause and Treatment (INCAT) Upper Limb Functional Disability Scale. The reduction in IENFD compared with controls was more remarkable in the distal leg. In clinically unstable CIDP patients, the IENFDs of distal leg and forearm were significantly reduced compared with stable CIDP patients and controls. Stable CIDP patients had significantly reduced IENFDs in distal leg and forearm compared with controls. DISCUSSION: In this exploratory study, we confirm that small fibers are also affected in CIDP. Larger studies are needed to explore longitudinal changes of IENFD in CIDP and its relation to disease stage.

Further clinical and genetic evidence of ASC-1 complex dysfunction in congenital neuromuscular disease.

Transcriptional coregulators modulate the efficiency of transcription factors. Bi-allelic variants in TRIP4 and ASCC1, two genes that encode members of the tetrameric coregulator ASC-1, have recently been associated with congenital bone fractures, hypotonia, and muscular dystrophy in a total of 22 unrelated families. Upon exome sequencing and data repository mining, we identified six new patients with pathogenic homozygous variants in either TRIP4 (n = 4, two novel variants) or ASCC1 (n = 2, one novel variant). The associated clinical findings confirm and extend previous descriptions. Considering all patients reported to date, we provide supporting evidence suggesting that ASCC1-related disease has a more severe phenotype compared to TRIP4-related disorder regarding higher incidence of perinatal bone fractures and shorter survival.

Effects of Collagen- and Arginine-Fortified Osteokine Supplementation on Fracture Healing.

Introduction Delayed union or nonunion is an important clinical challenge for orthopedic surgeons. In addition to the main treatment algorithms, the use of nutritional supplements is increasingly common. In this study, we investigated the effects of nutritional supplements fortified with arginine and collagen on fracture healing. Materials and methods Twenty-four rats with femur fractures were divided into experimental and control groups. Intramedullary fixation was performed in both groups. 20 ml/kg nutritional supplement was given to the experimental group. Radiological examination was performed at third and sixth weeks, and histopathological examination was performed at the sixth week. Results No statistically significant difference was found between the radiological scores of the groups at the third and sixth weeks. Nutritional supplement affected the histological properties of callus. Histological evidence of bone healing was observed by the sixth week in both groups but the score was higher in nutritional supplement group. A statistically significant difference was found between the histopathological scores of the groups at the sixth week. Conclusion Arginine- and type two collagen-augmented traditional nutritional supplements may help to achieve more successful results in fracture healing.

Effects of different molecular subtypes and tumor biology on the prognosis of medulloblastoma.

PURPOSE: Medulloblastoma is one of the most common malignant brain tumors in the pediatric population. Recent studies identified four distinct medulloblastoma subgroups with different molecular alterations and pathways, and natural courses and outcomes. To evaluate the results of surgical and medical treatments of patients with medulloblastoma and compare them among the medulloblastoma subgroups. METHODS: The clinical and radiological features, medical and surgical management and treatment outcomes and their correlation with molecular subgroups of 58 patients treated for medulloblastoma in the last 20 years were evaluated. RESULTS: Fifty-eight patients, of whom 35 were male and 23 were female, were evaluated. The median age was 6 years (range, 1-19 years). The most common symptoms were nausea and vomiting (60%). Forty-three percent of the patients had headache and 40% had ataxia. Previous pathology reports revealed that 43 (74%), eight (14%), five (8%), and two (3%) had classic, desmoplastic, desmoplastic/nodular, and anaplastic morphologies, respectively. After the subgroup analyses, five patients (12%) were attributed to the wingless subgroup (WNT) group; 14 (32.5%), to the sonic hedgehog subgroup (SHH) group; and 24 (56%), to the non-WNT non-SHH group. On the basis of immunohistochemical analysis results, 15 patients could not be attributed to any subgroups. The clinical risk groups (average vs high-risk) and age at diagnosis (≥ 3 years vs < 3 years of age) were significant for 5-year event free survival (86% vs 43%, p:0.011 and 59% vs 36%, p:0.039). There was no significant difference in survival or event free survival according to molecular subtypes in this cohort. CONCLUSION: In corporation of molecular features to the clinicopathologic classification leads to risk-adapted treatment. Although the molecular subgroups did not affect outcome significantly in this study, more studies with larger numbers of patients are needed to understand the tumor pathophysiology of medulloblastoma and design the future medical practice.

Late-Onset Lipid Storage Myopathy with Fatal Hepatosteatosis.

Hepatosteatosis, a common condition, is increasing in prevalence. It is typically associated with diet, alcohol consumption and obesity. In some cases, a rare genetic disease may be the underlying defect. Lipid storage myopathy (LSM) is a genetic disease caused by lipid metabolism defects. LSM often affects the muscles, heart and liver. Coenzyme Q, riboflavin or carnitine replacement can be beneficial in some cases. We describe a patient who presented with liver failure and was unresponsive to treatment. LEARNING POINTS: Hepatosteatosis can be associated with genetic disease and not just diet.Lipid storage disease should be considered in patients presenting with liver disease with hypoglycaemia, muscle weakness and a family history.Lipid storage disease is a rare heterogeneous genetic condition that has no specific treatment and requires further research.

Follow-up of patients with epilepsy harboring antiglycine receptor antibodies.

OBJECTIVE: The long-term follow-up of patients with epilepsy harboring autoantibodies against the glycine receptor (also glycine receptor antibodies or GlyR-Ab) is not well-known. Our aim was to investigate the 5-year prognosis and treatment response of patients with epilepsy who were seropositive for GlyR-Ab. METHODS: Clinical features; electroencephalogram (EEG), neuroradiological, and neuropathological findings; and treatment responses of patients with epilepsy with GlyR-Ab seropositivity were investigated. RESULTS: Thirteen (5.46%) of 238 patients with epilepsy were GlyR-Ab positive: focal epilepsy of unknown cause (FEoUC) was diagnosed in four (7.27%) out of 55 patients, mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) in five (4.5%) out of 111 patients, epileptic encephalopathy (EE) in two (4%) out of 50 patients, and status epilepticus (SE) in two (9.09%) out of 22 patients. None of the patients developed any other neurological symptoms or cancer during the 5-year follow-up. Seven of them had seizures that were resistant to antiepileptic drug (AED). Immunotherapy was used in two patients (with FEoUC and EE) improving seizure control. Three patients with MTLE-HS benefited from epilepsy surgery, and another patient with EE showed spontaneous remission. CONCLUSION: Glycine receptor antibodies are detected in a wide spectrum of epileptic disorders with unclear pathogenic significance. Two GlyR-Ab seropositive patients with AED-resistant epilepsy treated with intravenous immunoglobulin (IVIg) showed clear benefit from immunotherapy. Future studies will be valuable in determining the role of screening patients with drug-resistant epilepsy for GlyR-Ab in order to identify patients who may benefit or respond to immunotherapy.

Brain Infiltration of Immune Cells in CASPR2-Antibody Associated Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis.

INTRODUCTION: Antibodies directed against neuronal surface antigens have recently been identified in patients with focal temporal lobe epilepsy (TLE) of unknown cause and mesial TLE with hippocampal sclerosis (MTLE-HS), thereby emphasizing the role of autoimmunity in TLE. Antibodies to contactin-associated protein-like 2 (CASPR2) are prevalent in MTLE-HS patients. We aimed to find out whether anti-neuronal autoimmunity might be involved in CASPR2 antibody-related MTLE-HS. METHODS: Surgically resected medial temporal lobe specimens of seropositive and seronegative MTLE-HS patients were examined with hematoxylin and eosin and immunohistochemical staining using specific immune cell markers. RESULTS: Two of 5 CASPR2 antibody-positive MTLE-HS patients showed polymorphonuclear and mononuclear cells infiltrating the subarachnoidal region. One of these patients also showed mononuclear cell infiltration in the parenchyma of the temporal lobe cortex. Subarachnoidal and parenchymal infiltrates contained CD3+, CD8+, and CD68+ cells. None of the 13 seronegative MTLE-HS patients displayed cellular infiltrates in their brain samples, and all MTLE-HS patients showed marked neuronal cell loss but no immune cell infiltration in their hippocampi. CONCLUSION: Our results show that CASPR2 antibody-associated MTLE-HS can present with central nervous system inflammation; thus, this subtype of MTLE-HS might have an autoimmune origin.