Search Results (9)

Background: Point mutations in mitochondrial DNA (mtDNA) cause a range of neurometabolic disorders that currently have no curative treatments. The m.8993T>G mutation in the Homo sapiens MT-ATP6 gene leads to neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) when heteroplasmy exceeds approximately 70%. Methods: We engineered a split DddA-derived cytosine base editor (DdCBE), each half fused to programmable TALE DNA-binding domains and a mitochondrial targeting sequence, to correct the m.8993T>G mutation in patient-derived induced pluripotent stem cells (iPSCs). Seven days after plasmid delivery, deep amplicon sequencing showed 35 ± 3% on-target C•G→T•A conversion at position 8993, reducing mutant heteroplasmy from 80 ± 2% to 45 ± 3% with less than 0.5% editing at ten predicted off-target loci. Results: Edited cells exhibited a 25% increase in basal oxygen consumption rate, a 50% improvement in ATP-linked respiration, and a 2.3-fold restoration of ATP synthase activity. Directed neural differentiation yielded 85 ± 2% Nestin-positive progenitors compared to 60 ± 2% in unedited controls. Conclusions: Edits remained stable over 30 days in culture. These results establish mitochondrial base editing as a precise and durable strategy to ameliorate biochemical and cellular defects in NARP patient cells. Full article

Background/Objectives: Thoracic outlet syndrome (TOS) is a rare and difficult-to-diagnose condition in children, characterized by the compression of neurovascular structures in the thoracic outlet. Neurogenic TOS (nTOS) often presents with nonspecific symptoms such as paresthesia, weakness, and upper extremity discomfort. While anterior scalene muscle block (ASMB) has been used in adults as a diagnostic adjunct, its role in pediatric patients remains underreported. Methods: We present two adolescent female patients with suspected neurogenic thoracic outlet syndrome (nTOS) who were referred to the acute pain service for further evaluation. Both patients underwent ultrasound-guided ASMB. Results: Following the block, both patients experienced rapid and marked relief of symptoms. Subsequently, each underwent first rib resection with brachial plexus neurolysis. At follow-up, both patients reported a complete resolution of symptoms and a return to baseline function. Conclusions: These cases suggest that ASMB may serve as a functional diagnostic tool and short-term therapeutic test in pediatric nTOS patients. It also helps guide surgical decision-making for invasive treatment. However, as ASMB is not without risk, its role should be considered supportive rather than confirmatory. Further studies are needed to better define its utility and safety in the pediatric population. Full article

Flexural deformities (FDs) are a common condition in foals. Therapy is typically initiated without a precise diagnosis, and the etiopathogenesis often remains unknown. This study aimed (1) to investigate the clinical and pathological findings in congenital FD cases in foals and (2) to retrospectively describe the abnormalities detected in muscle biopsies of foals affected by CFDs. For these purposes, a retrospective study of the findings of muscle biopsies taken from foals with FDs referred to the Department of Veterinary Medicine and Animal Production at the University of Naples Federico II was performed from January 2005 to February 2024. Anamnesis, physical examination, hematological and biochemical data, along with the findings of histopathological muscle biopsy analysis and follow-up, were recorded. The clinical records of 15 cases of FDs were evaluated. The main clinical symptoms included flexural limb deformities associated with weakness, torticollis and scoliosis, mandibular prognathism, and inferior eyelid entropion. The evaluation of histopathological reports allowed us to observe the following muscle disorders: Core-like myopathy, mild nonspecific myopathy, mitochondrial myopathy, congenital fiber type disproportion, lipid storage myopathy, lipomatous dystrophy, myopathy with inclusion bodies, polysaccharide storage myopathy, and neurogenic myopathy. Even though many cases of FDs were diagnosed through clinical examination and successfully treated, we hypothesize that different underlying etiologies may present with similar flexural symptoms. A better understanding of these underlying causes is, therefore, desirable. These findings suggest that histopathological analysis may be a valuable tool for investigating FDs in foals, although further studies are needed to evaluate the significance of the observed alterations. Full article

Despite the efficacy of onabotulinumtoxinA, its safety profile remains a concern. This meta-analysis reviewed the major adverse events (AEs) associated with intravesical onabotulinumtoxinA treatment in patients with neurogenic detrusor overactivity (NDO) and idiopathic overactive bladder (iOAB). Randomized controlled trials (RCTs) conducted between January 2000 and December 2022 were searched for adult patients administered different onabotulinumtoxinA dosages or onabotulinumtoxinA vs. placebo. Quality assessment was performed using the Cochrane Collaboration tool, and statistical analysis was performed using Review Manager version 5.3. A total of 26 RCTs were included in the analysis, including 8 on NDO and 18 on iOAB. OnabotulinumtoxinA vs. placebo significantly increased the urinary tract infection (UTI) incidence in patients with NDO (relative risk, or RR, 1.54) and iOAB (RR, 2.53). No difference in the RR with different onabotulinumtoxinA dosages was noted. Urinary retention was frequent with onabotulinumtoxinA use in the NDO (RR, 6.56) and iOAB (RR, 7.32) groups. Similar observations were made regarding the risks of de novo clean intermittent catheterization (CIC). The risk of voiding difficulty increased with onabotulinumtoxinA use in patients with iOAB. Systemic AEs of onabotulinumtoxinA, including muscle weakness (RR, 2.79) and nausea (RR, 3.15), were noted in patients with NDO; most systemic AEs had a low incidence and were sporadic. Full article

Congenital myopathies (CMs) are a group of diseases that primarily affect the muscle fiber, especially the contractile apparatus and the different components that condition its normal functioning. They present as muscle weakness and hypotonia at birth or during the first year of life. Centronuclear CM is characterized by a high incidence of nuclei located centrally and internally in muscle fibers. Clinical case: a 22-year-old male patient with symptoms of muscle weakness since early childhood, with difficulty in performing physical activity according to his age, with the presence of a long face, a waddling gait, and a global decrease in muscle mass. Electromyography was performed, showing a neurogenic pattern and not the expected myopathic one, neuroconduction with reduced amplitude of the motor potential of the peroneal nerve and axonal and myelin damage of the posterior tibial nerves. The microscopic study of the studied striated muscle fragments stained with hematoxylin–eosin and Masson’s trichrome showed the presence of fibers with central nuclei, diagnosing CM. The patient meets most of the description for CM, with involvement of all striated muscles, although it is important to note the neurogenic pattern present in this case, due to the denervation of damaged muscle fibers, which contain terminal axonal segments. Neuroconduction shows the involvement of motor nerves, but with normal sensory studies, axonal polyneuropathy is unlikely, due to normal sensory potentials. Different pathological findings have been described depending on the mutated gene in this disease, but all coincide with the presence of fibers with central nuclei for diagnosis by this means, which is so important in institutions where it is not possible to carry out genetic studies, and allowing early specific treatment, according to the stage through which the patient passes. Full article

The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns–Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29. Full article

A 32-year-old man presented with complete third nerve palsy. Brain magnetic resonance imaging revealed a possible sporadic oculomotor nerve schwannoma in the left cavernous sinus. Interestingly, the patient’s ptosis was fluctuating and eased immediately after application of ice over his eyelid. The ice pack test (IPT) is a simple and fast method that can help diagnose myasthenia gravis (MG) in patients with ptosis. Additional diagnostic investigations (antibody assays and repetitive stimulation) excluded associated MG in the patient. Tumor treatment with Gamma Knife radiosurgery was planned. This case highlights the finding that IPT can also be positive in neurogenic (non-myasthenic) ptosis, but its usefulness in other disorders associated with muscle weakness and fatigability remains questionable. Full article

Our aim was to define clinical long-term outcome of surgery for neurogenic thoracic outlet syndrome without rib resection, and to find factors predicting long-term results. For the 94 patients, the main outcomes were pain, numbness, weakness, and upper-extremity function. The Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) survey, the Cervical-Brachial Symptom Questionnaire (CBSQ), and a numerical rating system served as functional outcome measures. Mean follow-up was 12.9 years. Preoperative pain diminished from 7.8 to 2.2, numbness from 7.4 to 4.0, and weakness from 7.3 to 3.8. Grip strength increased from 25.7 to 31.8 kg. QuickDASH averaged at follow-up 37.1 and CBSQ 51.5. No correlation appeared between smoking and long-term results regarding pain, numbness, weakness, or functioning. Positive TOS provocative tests or intraoperative anatomical findings like consistency of the scaleni muscles showed no correlation with outcome. 82% of female and 57% of male patients reported that aid from this surgery had been excellent or good; 69% reported that surgery helped considerably for at least a mean 9.9 years. The risk for worse self-reported long-term outcome was higher among men, but neither BMI nor age at surgery associated with self-reported outcome. Pain, numbness, and weakness significantly decreased and function improved after supraclavicular release without rib resection. We found no significant preoperative nor per-operative factors predicting long-term results. Full article

Introduction. The acquired muscle paralysis associated with modern critical care can be of neurogenic or myogenic origin, yet the distinction between these origins is hampered by the precision of current diagnostic methods. This has resulted in the pooling of all acquired muscle paralyses, independent of their origin, into the term Intensive Care Unit Acquired Muscle Weakness (ICUAW). This is unfortunate since the acquired neuropathy (critical illness polyneuropathy, CIP) has a slower recovery than the myopathy (critical illness myopathy, CIM); therapies need to target underlying mechanisms and every patient deserves as accurate a diagnosis as possible. This study aims at evaluating different diagnostic methods in the diagnosis of CIP and CIM in critically ill, immobilized and mechanically ventilated intensive care unit (ICU) patients. Methods. ICU patients with acquired quadriplegia in response to critical care were included in the study. A total of 142 patients were examined with routine electrophysiological methods, together with biochemical analyses of myosin:actin (M:A) ratios of muscle biopsies. In addition, comparisons of evoked electromyographic (EMG) responses in direct vs. indirect muscle stimulation and histopathological analyses of muscle biopsies were performed in a subset of the patients. Results. ICU patients with quadriplegia were stratified into five groups based on the hallmark of CIM, i.e., preferential myosin loss (myosin:actin ratio, M:A) and classified as severe (M:A < 0.5; n = 12), moderate (0.5 ≤ M:A < 1; n = 40), mildly moderate (1 ≤ M:A < 1.5; n = 49), mild (1.5 ≤ M:A < 1.7; n = 24) and normal (1.7 ≤ M:A; n = 19). Identical M:A ratios were obtained in the small (4–15 mg) muscle samples, using a disposable semiautomatic microbiopsy needle instrument, and the larger (>80 mg) samples, obtained with a conchotome instrument. Compound muscle action potential (CMAP) duration was increased and amplitude decreased in patients with preferential myosin loss, but deviations from this relationship were observed in numerous patients, resulting in only weak correlations between CMAP properties and M:A. Advanced electrophysiological methods measuring refractoriness and comparing CMAP amplitude after indirect nerve vs. direct muscle stimulation are time consuming and did not increase precision compared with conventional electrophysiological measurements in the diagnosis of CIM. Low CMAP amplitude upon indirect vs. direct stimulation strongly suggest a neurogenic lesion, i.e., CIP, but this was rarely observed among the patients in this study. Histopathological diagnosis of CIM/CIP based on enzyme histochemical mATPase stainings were hampered by poor quantitative precision of myosin loss and the impact of pathological findings unrelated to acute quadriplegia. Conclusion. Conventional electrophysiological methods are valuable in identifying the peripheral origin of quadriplegia in ICU patients, but do not reliably separate between neurogenic vs. myogenic origins of paralysis. The hallmark of CIM, preferential myosin loss, can be reliably evaluated in the small samples obtained with the microbiopsy instrument. The major advantage of this method is that it is less invasive than conventional muscle biopsies, reducing the risk of bleeding in ICU patients, who are frequently receiving anticoagulant treatment, and it can be repeated multiple times during follow up for monitoring purposes. Full article