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A long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency constitutes a very rare autosomal recessive disease, affecting long fatty acids' metabolism. In the prenatal period, it is difficult to suspect this diagnosis in the absence of family history, as there are no specific sonographic signs of this disease. A 32-year-old pregnant woman was receiving follow-up care, as she was a carrier for Duchenne muscular dystrophy (DMD). The fetus was female, and the pregnancy progressed normally until 29th week of gestation. At that time, the fetal bowel had noted dilatation with mild hyperechogenicity. Fetal surveillance was conducted with sequential sonograms. Labor was induced at 36 weeks, due to pre-eclampsia. The newborn presented with poor weight gain and hypoglycemic episodes. Neonatal screening revealed the diagnosis of an LCHAD deficiency. Prenatal diagnosis of LCHAD is usually performed by genetic testing when there is a family history. However, only a few sonographic signs have been described in association with this disease, such as fetal bowel hyperechogenicity or cardiomyopathy. This is the first case study to report a prenatal sonographic finding of bowel dilatation in a fetus with LCHAD deficiency, and one of the few to report fetal bowel hyperechogenicity. [ABSTRACT FROM AUTHOR]

Mitochondrial diseases are rare, often go undiagnosed and can lead to devastating cascades of multisystem organ dysfunction. This report of a young woman with hearing loss and gestational diabetes illustrates a novel presentation of a cardiomyopathy caused by a previously described mutation in a mitochondrial gene, MT-TL1. She initially had biventricular heart dysfunction and ventricular arrhythmia that ultimately recovered with beta blockade and time. She continues to participate in sport without decline. It is important to keep mitochondrial diseases in the differential diagnosis and understand the testing and management strategies in order to provide the best patient care.

Background: Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness. Methods: Our method involved the description of three cases of CMS that were initially characterized as probable PMM. Results: All patients were male and presented with ptosis and/or external ophthalmoplegia at birth, with proximal muscle weakness and fatigue on physical exertion. After normal repetitive nerve stimulation (RNS) studies performed on facial muscles, a muscle biopsy (at a median age of 9) was performed to rule out congenital myopathies. In all three cases, the biopsy findings (COX-negative fibers or respiratory chain defects) pointed to PMM. They were referred to our neuromuscular unit in adulthood to establish a genetic diagnosis. However, at this time, fatigability was evident in the physical exams and RNS in the spinal accessory nerve showed a decremental response in all cases. Targeted genetic studies revealed pathogenic variants in the MUSK, DOK7, and RAPSN genes. The median diagnostic delay was 29 years. Treatment resulted in functional improvement in all cases. Conclusions: Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy. [ABSTRACT FROM AUTHOR]

Metabolic myopathies are rare inherited disorders that deserve more attention from neurologists and pediatricians. Pompe disease and McArdle disease represent some of the most common diseases in clinical practice; however, other less common diseases are now better-known. In general the pathophysiology of metabolic myopathies needs to be better understood. Thanks to the advent of next-generation sequencing (NGS), genetic testing has replaced more invasive investigations and sophisticated enzymatic assays to reach a final diagnosis in many cases. The current diagnostic algorithms for metabolic myopathies have integrated this paradigm shift and restrict invasive investigations for complicated cases. Moreover, NGS contributes to the discovery of novel genes and proteins, providing new insights into muscle metabolism and pathophysiology. More importantly, a growing number of these conditions are amenable to therapeutic approaches such as diets of different kinds, exercise training protocols, and enzyme replacement therapy or gene therapy. Prevention and management—notably of rhabdomyolysis—are key to avoiding serious and potentially life-threatening complications and improving patients' quality of life. Although not devoid of limitations, the newborn screening programs that are currently mushrooming across the globe show that early intervention in metabolic myopathies is a key factor for better therapeutic efficacy and long-term prognosis. As a whole NGS has largely increased the diagnostic yield of metabolic myopathies, but more invasive but classical investigations are still critical when the genetic diagnosis is unclear or when it comes to optimizing the follow-up and care of these muscular disorders. [ABSTRACT FROM AUTHOR]

Thymidine kinase (TK2) deficiency causes mitochondrial DNA depletion syndrome. We aimed to report the clinical, biochemical, genetic, histopathological, and ultrastructural features of a cohort of paediatric patients with TK2 deficiency. Mitochondrial DNA was isolated from muscle biopsies to assess depletions and deletions. The TK2 genes were sequenced using Sanger sequencing from genomic DNA. All muscle biopsies presented ragged red fibres (RRFs), and the prevalence was greater in younger ages, along with an increase in succinate dehydrogenase (SDH) activity and cytochrome c oxidase (COX)-negative fibres. An endomysial inflammatory infiltrate was observed in younger patients and was accompanied by an overexpression of major histocompatibility complex type I (MHC I). The immunofluorescence study for complex I and IV showed a greater number of fibres than those that were visualized by COX staining. In the ultrastructural analysis, we found three major types of mitochondrial alterations, consisting of concentrically arranged lamellar cristae, electrodense granules, and intramitochondrial vacuoles. The pathological features in the muscle showed substantial differences in the youngest patients when compared with those that had a later onset of the disease. Additional ultrastructural features are described in the muscle biopsy, such as sarcomeric de-structuration in the youngest patients with a more severe phenotype. [ABSTRACT FROM AUTHOR]

Significance: Reactive oxygen species (ROS) are highly reactive compounds that behave like a double-edged sword; they damage cellular structures and act as second messengers in signal transduction. Mitochondria and endoplasmic reticulum (ER) are interconnected organelles with a central role in ROS production, detoxification, and oxidative stress response. Skeletal muscle is the most abundant tissue in mammals and one of the most metabolically active ones and thus relies mainly on oxidative phosphorylation (OxPhos) to synthesize adenosine triphosphate. The impairment of OxPhos leads to myopathy and increased ROS production, thus affecting both redox poise and signaling. In addition, ROS enter the ER and trigger ER stress and its maladaptive response, which also lead to a myopathic phenotype with mitochondrial involvement. Here, we review the role of ROS signaling in myopathies due to either mitochondrial or ER dysfunction. Recent Advances: Relevant advances have been evolving over the last 10 years on the intricate ROS-dependent pathways that act as modifiers of the disease course in several myopathies. To this end, pathways related to mitochondrial biogenesis, satellite cell differentiation, and ER stress have been studied extensively in myopathies. Critical Issues: The analysis of the chemistry and the exact quantitation, as well as the localization of ROS, are still challenging due to the intrinsic labile nature of ROS and the technical limitations of their sensors. Future Directions: The mechanistic studies of the pathogenesis of mitochondrial and ER-related myopathies offer a unique possibility to discover novel ROS-dependent pathways. Antioxid. Redox Signal. 37, 301–323. [ABSTRACT FROM AUTHOR]

We present a case of a 36-years-old male patient with MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic acidosis, and Stroke-like episodes) underwent ureteroscopy, lithotripsy and indwelling double J stent exchange under neuraxial anesthesia. MELAS is a progressive mitochondrial myopathy that results in defects in respiratory enzyme complexes I and IV, which lead to defects in aerobic metabolism, thus endangering high-energy-dependent organs. MELAS causes a wide range of physiologic changes that present a variety of challenges to the anesthetists. In this case, we managed our patient safely with spinal/epidural anesthesia without any major complications. [ABSTRACT FROM AUTHOR]

Abstract Myopathies are common manifestations of mitochondrial diseases. To investigate whether gene replacement can be used as an effective strategy to treat or cure mitochondrial myopathies, we have generated a complex I conditional knockout mouse model lacking NDUFS3 subunit in skeletal muscle. NDUFS3 protein levels were undetectable in muscle of 15‐day‐old smKO mice, and myopathy symptoms could be detected by 2 months of age, worsening over time. rAAV9‐Ndufs3 delivered systemically into 15‐ to 18‐day‐old mice effectively restored NDUFS3 levels in skeletal muscle, precluding the development of the myopathy. To test the ability of rAAV9‐mediated gene replacement to revert muscle function after disease onset, we also treated post‐symptomatic, 2‐month‐old mice. The injected mice showed a remarkable improvement of the mitochondrial myopathy and biochemical parameters, which remained for the duration of the study. Our results showed that muscle pathology could be reversed after restoring complex I, which was absent for more than 2 months. These findings have far‐reaching implications for the ability of muscle to tolerate a mitochondrial defect and for the treatment of mitochondrial myopathies.

We report a 23‐year‐old‐female with MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke‐like episodes) syndrome with uncontrolled epilepsy due to massive gastric dilatation, immediate decompression and medical treatment was initiated; after it, she improved remarkably and has remained seizure free following hospitalization. This case illustrates massive gastric dilatation, an uncommon and underdiagnosed presentation of intestinal pseudo‐obstruction, as a potential cause of uncontrolled epilepsy in patients with MELAS syndrome. [ABSTRACT FROM AUTHOR]