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Background Endocrine dysfunctions are commonly associated with mitochondrial diseases. This study aimed to investigate clinical characteristics and outcomes of endocrine manifestations in patients with mitochondrial diseases. Methods This study included 54 patients from 47 families with mitochondrial diseases who were genetically confirmed; 49 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), four with Pearson syndrome, and one with Kearns–Sayre syndrome (KSS). Clinical and endocrine findings were retrospectively reviewed. Results The median age at diagnosis was 18.5 years (range, 0.1 − 49 years). In 49 patients with MELAS, the mean height and weight standard deviation scores were − 2.0 ± 1.3 and − 2.6 ± 1.6, respectively, with 44.9% ( n  = 22) of the patients exhibiting short stature at diagnosis. Twenty-three (46.9%) patients with MELAS were diagnosed with diabetes mellitus (DM) at a median age of 26 years (range, 12 − 50 years). Interestingly, papillary thyroid cancer was observed in 10.2% of patients ( n  = 5) with MELAS at a mean age of 34.1 ± 6.9 years. One patient with MELAS and one with KSS exhibited hypoparathyroidism. Patients with Pearson syndrome and KSS exhibited more severe short stature. Adrenal insufficiency was noted in 50% of the patients with Pearson syndrome. Conclusions In 20% of patients with MELAS, endocrine dysfunctions including having a short stature, DM, and hypoparathyroidism preceded the onset of neurological manifestations. Papillary thyroid cancer occurred in 10% of patients with MELAS. Patients with Pearson syndrome and KSS showed profound growth retardation and multisystem dysfunctions, such as chronic kidney disease and neurological defects, which contributed to increased mortality.

Background and objectives Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare genetic syndrome mostly associated with pathogenic variants in mitochondrial DNA. As there is limited research on the life experience of patients with MELAS, this study aimed to develop an understanding of the patient experience of MELAS through qualitative interviews to identify, describe, and substantiate important and relevant signs, symptoms, and health-related quality-of-life (HRQoL) impact (S/S/I) concepts. Methods Clinician and patient interviews were conducted virtually using semi-structured interview guides. During 60-minute interviews with five experts in the United States, clinicians were asked for their perspective on S/S/I of patients with MELAS, patient experience of fatigue and cognitive impairment, and whether patients would be able to accurately report and rate their symptoms and complete a 90-minute patient experience interview. During a 45-minute interview conducted with 16 adults with confirmed pathogenic variant and clinical diagnosis of MELAS, patients were asked about S/S/I. Interviews were recorded, transcribed, anonymized, coded, and analyzed for saturation and concept frequency and clarification (e.g., severity, frequency, duration). Results Experts reported 44 distinct S/S and 36 HRQoL impact concepts. All five experts confirmed that cognitive impairment would not inhibit a typical patient’s ability to report on their own experiences; three reported that patients with MELAS would not be able to complete a 90-minute interview. Sixteen patient interviews (mean age: 42.3 [11.1], n  = 10 women) were conducted. Interviews with patients with MELAS achieved saturation of concept and yielded 35 S/S concepts and 68 HRQoL impacts across 15 domains. The most frequently reported S/S concepts were physical fatigue ( n  = 15, 93.8%), hearing loss ( n  = 13, 81.3%), mental fatigue ( n  = 12, 75.0%), and exercise intolerance and memory problems ( n  = 11, 68.8% each). The most frequently reported impact domains were adaptive behaviors and work impacts ( n  = 14, 87.5% each) and emotional function ( n  = 13, 81.3%). Discussion Patients with MELAS can self-report on S/S/I. Results from both patient and clinician interviews demonstrate that symptoms related to fatigue and cognitive impairment are frequent, bothersome, and important to improve. Assessments of fatigue and cognitive function should therefore be considered key outcome measures in clinical trials enrolling patients with MELAS.

Background Systemic anesthetic management of patients with mitochondrial disease requires careful preoperative preparation to administer adequate anesthesia and address potential disease-related complications. The appropriate general anesthetic agents to use in these patients remain controversial. Case presentation A 54-year-old woman (height, 145 cm; weight, 43 kg) diagnosed with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes underwent elective cochlear implantation. Infusions of intravenous remimazolam and remifentanil guided by patient state index monitoring were used for anesthesia induction and maintenance. Neither lactic acidosis nor prolonged muscle relaxation occurred in the perioperative period. At the end of surgery, flumazenil was administered to antagonize sedation, which rapidly resulted in consciousness. Conclusions Remimazolam administration and reversal with flumazenil were successfully used for general anesthesia in a patient with mitochondrial disease.

Few cases of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) with an onset older than 60 years have been reported. Herein, we report a 63-year-old Chinese female initially suspected of ischemic infarction but was ultimately diagnosed with MELAS. Therefore, even in the elderly, a diagnosis of MELAS should be considered when encountering patients with recurrent stroke-like episodes, cognitive dysfunction, and psychotic symptoms. In order to achieve the correct diagnosis and launch the appropriate management in time, a detailed medical history together with appropriate diagnostic laboratory investigations should therefore be collected.

Previously, renal cell carcinoma tissues were reported to display a marked reduction of components of the respiratory chain. To elucidate a possible relationship between tumourigenesis and alterations of oxidative phosphorylation, we screened for mutations of the mitochondrial DNA (mtDNA) in renal carcinoma tissues and patient-matched normal kidney cortex. Seven of the 15 samples investigated revealed at least one somatic heteroplasmic mutation as determined by denaturating HPLC analysis (DHPLC). No homoplasmic somatic mutations were observed. Actually, half of the mutations presented a level of heteroplasmy below 25%, which could be easily overlooked by automated sequence analysis. The somatic mutations included four known D-loop mutations, four so far unreported mutations in ribosomal genes, one synonymous change in the ND4 gene and four nonsynonymous base changes in the ND2, COI, ND5 and ND4L genes. One renal cell carcinoma tissue showed a somatic A3243G mutation, which is a known frequent cause of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episode) and specific compensatory alterations of enzyme activities of the respiratory chain in the tumour tissue. No difference between histopathology and clinical progression compared to the other tumour tissues was observed. In conclusion, the low abundance as well as the frequently observed low level of heteroplasmy of somatic mtDNA mutations indicates that the decreased aerobic energy capacity in tumour tissue seems to be mediated by a general nuclear regulated mechanism.

A 67-year-old woman had frequent subacute ileus, hearing difficulty, muscle atrophy and stroke-like episodes. Computed tomography revealed multiple low-density areas, which did not correlate with the vascular supply, in the cerebral cortex. She had metabolic disturbance comprising lactic acidosis and elevated pyruvate level. Her skeletal muscle biopsy specimen showed ragged-red fibers, and mitochondrial DNA analysis revealed a point mutation at position 3243, findings consistent with MELAS. Examination of her small intestine revealed a necrotic zone and numerous abnormal large mitochondria in the smooth muscle cells, vascular media and endothelium, and intestinal ganglion cells. The cerebral cortex showed multiple microcystic necrotic foci in cerebral cortex. Cactus-like pathology resembling the changes associated with Menkes' kinky hair disease and torpedoes were observed in the cerebellar Purkinje cells. The intestinal dysmotility due to MELAS and cerebellar changes were presumed to be associated with a disturbance of copper metabolism.

The leukodystrophies are inherited disorders of brain white matter that are often associated with cognitive impairment. Although most classically affected individuals present in childhood, there are late‐onset cases wherein the diagnosis is often missed, particularly in the absence of a family history. Although cognitive and behavioral changes can be a presenting complaint and may arise at any stage, these problems are rarely the only manifestations. Leukodystrophies usually follow a slowly progressive course, rather than a relapsing–remitting one. Spasticity, motor weakness, and ataxia are common features, and the presence of peripheral neuropathy and/or autonomic dysfunction may be a valuable clue in the differential diagnoses. Biochemical and/or molecular confirmatory testing is available for a selected group of leukodystrophies, which should be distinguished from cases of multiple sclerosis, so patients are given proper counseling and treatment. Unfortunately, management of leukodystrophies is largely symptomatic, although a genetic diagnosis enables appropriate counseling regarding prognosis and reproductive risks, if applicable, and the provision of treatment, if available.

Movement disorders include a large number of diseases that clinically present as neurological conditions that affect the speed, quality, fluency or ease of movements. Clinically movement disorders can present with one or a combination of the following clinical conditions:

Strabismus (misalignment of the eyes; also known as “squint”) comprises a common heterogeneous group of disorders characterised by a constant or intermittent ocular deviation often associated with amblyopia (uniocular failure of normal visual development) and reduced or absent binocular vision. The associated poor cosmetic appearance may also interfere with social and psychological development. Extensive twin and family studies suggest a significant genetic component to the aetiology of strabismus. The complexity of the molecular basis of strabismus is now beginning to be elucidated with the identification of genetic loci and disease causing genes. Currently greater insights have been gained into the incomitant subtype (differing magnitude of ocular misalignment according to direction of gaze), whereas less is known about the pathogenesis of the more common childhood concomitant strabismus. It is hoped that a greater understanding of the molecular genetics of these disorders will lead to improved knowledge of disease mechanisms and ultimately to more effective treatment. The aim of this paper is to review current knowledge of the molecular genetics of both incomitant and concomitant strabismus.