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Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments.

The aim of this case-control study was to evaluate the ability of digital health technology (DHT) to detect and quantify mobility alterations in late-onset Pompe Disease. The study enrolled eight subjects with Pompe Disease, including three young mildly affected/asymptomatic subjects, who underwent an extensive DHT mobility assessment and were contrasted to 52 matched controls. DHT enabled the detection of subtle mobility alterations, indicating a lower speed in walking, and worse performances in postural transition and turning in patients compared to controls. Interestingly, in the three mildly affected/asymptomatic cases, step time variability and step length showed detectable alterations compared to controls, despite scores within the normal range on clinical scales and timed tests.

Background SELENON -related myopathy is a rare autosomal recessive congenital neuromuscular disorder linked to defects in the selenoprotein N. The clinical onset typically occurs in infancy and axial weakness, rigid spine, and respiratory involvement are almost invariably present at early stages. Case presentation We report the case of a 44-year-old Italian woman who underwent intubation for acute respiratory failure, followed by weaning from invasive ventilation within 6 months. Her medical history was not significant, but a detailed medical history collection revealed slight motor limitations since childhood such as slow running, difficulty climbing high steps, early muscle exhaustion, and fatigue. The neurological examination showed a waddling gait and axial and proximal limb muscle weakness without rigid spine. The right quadriceps muscle biopsy showed nonspecific myopathic abnormalities. Clinical exome sequencing revealed the presence of the two heterozygous variants c.713DupA and c.803G > A in the SELENON gene. Conclusion This report focused on the clinical heterogeneity of SELENON -related myopathy. While we highlight that the absence of spinal rigidity and core pathology on muscle biopsy should not exclude the diagnostic suspicion, overall we stress the importance of respiratory failure as a possible late manifestation of the disease, even in middle-aged individuals.

Background: Revised El Escorial (rEEC) and Awaji criteria are currently used for diagnosing and categorizing amyotrophic lateral sclerosis (ALS). However, they are complex; their sensitivity is still not optimal for research purposes, and they present high inter-rater variability in clinical practice. To address these points, in 2019, a new set of diagnostic criteria was proposed, namely the Gold Coast criteria (GCC), characterized by a dichotomous diagnostic categorization, i.e., ALS or not ALS. Methods: In order to investigate the sensitivity, specificity, and clinical usefulness of GCC in a practical clinical setting, we retrospectively evaluated 131 patients diagnosed with ALS and 104 control subjects. ALSFRS-R score, electrophysiological tests, neuroradiological investigations, and CSF analysis were obtained. rEEC, Awaji, and GCC were applied at the first and last evaluations. Results: The sensitivity of GCC (93.1%; 96.1%) was greater than rEEC (71.8%; 87%) and Awaji criteria (77.8%; 89.3%) both at the first visit and last follow-up. The GCC’s specificity (28.8%) is lower than that of the other two criteria (rEEC 45.2%; Awaji 43.3%). Conclusions: Our study suggests that in a real-world setting, the GCC are more sensitive and have substantially lower risk of false negative diagnoses than rEEC and Awaji criteria. Although rEEC had the highest specificity, they may delay the diagnosis. Systematically using the GCC could help to achieve an earlier diagnosis and quickly refer patients to the correct management. The low specificity of GCC is likely to not significantly impact patient recruitment in clinical trials; therefore, its use might allow a faster and earlier enrollment.

Background Facioscapulohumeral dystrophy (FSHD) is a myopathy characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). The assessment of DNA methylation at two regions ( DUX4 -PAS and DR1) of D4Z4 locus proved to be an effective method to detect epigenetic signatures compatible with FSHD. The present study aims at validating the employment of this method into clinical practice and improving the protocol by refining the classification thresholds of 4qA/4qA patients. To this purpose, 218 subjects with clinical suspicion of FSHD collected in 2022–2023 were analyzed. Each participant underwent in parallel the traditional FSHD molecular testing ( D4Z4 sizing) and the proposed methylation assay. The results provided by both analyses were compared to evaluate the concordance and calculate the performance metrics of the methylation test. Results Among the 218 subjects, the 4q variant type distribution was 54% 4qA/4qA, 43% 4qA/4qB and 3% 4qB/4qB. The methylation analysis was performed only on carriers of at least one 4qA allele. After refining the classification threshold, the test reached the following performance metrics: sensitivity = 0.90, specificity = 1.00 and accuracy = 0.93. These results confirmed the effectiveness of the methylation assay in identifying patients with genetic signature compatible with FSHD1 and FSHD2 based on their DUX4 -PAS and DR1 profile, respectively. The methylation data were also evaluated with respect to the clinical information. Conclusions The study confirmed the ability of the method to accurately identify methylation profiles compatible with FSHD genetic signatures considering the 4q genotype. Moreover, the test allows the detection of hypomethylated profiles in asymptomatic patients, suggesting its potential application in identifying preclinical conditions in patients with positive family history and FSHD genetic signatures. Furthermore, the present work emphasizes the importance of interpreting methylation profiles considering the patients’ clinical data.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder caused by mutations in the ACADVL gene. The myopathic form presents with exercise intolerance, exercise-related rhabdomyolysis, and muscle pain, usually starting during adolescence or adulthood. We report on a 17-year-old boy who has presented with exercise-induced muscle pain and fatigue since childhood. In recent clinical history, episodes of exercise-related severe hyperCKemia and myoglobinuria were reported. Electromyography was normal, and a muscle biopsy showed only “moth-eaten” fibers, and a mild increase in lipid storage in muscle fibers. NGS analysis displayed the already known heterozygote c.1769G>A variant and the unreported heterozygote c.523G>C change in ACADVL both having disease-causing predictions. Plasma acylcarnitine profiles revealed high long-chain acylcarnitine species levels, especially C14:1. Clinical, histopathological, biochemical, and genetic tests supported the diagnosis of VLCAD deficiency. Our report of a novel pathogenic missense variant in ACADVL expands the allelic heterogeneity of the disease. Since dietary treatment is the only therapy available for treating VLCAD deficiency and it is more useful the earlier it is started, prompt diagnosis is essential in order to minimize muscle damage and slow the disease progression.

The extent of nerve involvement in leprosy is highly variable in distribution and clinical presentation. Mononeuropathies, multiple mononeuropathies, and polyneuropathies can present both in the context of a cutaneous and/or systemic picture and in the form of pure neuritic leprosy (PNL). The differential diagnosis of leprosy neuropathy remains challenging because it is a very rare condition and, especially in Western countries, is often overlooked. We report one case of the polyneuropathic form of PNL (P-PNL) and one case of multiple mononeuropathy in paucibacillary leprosy. In both cases, the diagnosis was achieved by performing a sural nerve biopsy, which showed subverted structure, severe infiltration of inflammatory cells in nerve fascicles, granulomatous abnormalities, and the presence of alcohol-acid-resistant, Ziehl–Neelsen-positive bacilli inside the nerve bundles. Leprosy remains an endemic disease in many areas of the world, and globalization has led to the spread of cases in previously disease-free countries. In this perspective, our report emphasizes that the diagnostic possibility of leprosy neuropathy should always be taken into account, even in Western countries, in the differential diagnostic process of an acquired sensory polyneuropathy or multineuropathy and confirms that nerve biopsy remains a useful procedure in working up neuropathies with unknown etiology.

Background Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation‐driven neurodegeneration. Methods Medline, Embase, Scopus and Web of Science were searched for articles published from inception until October 2023. Studies focused on mtDNA haplogroups or hereditary pathogenic variants were excluded. Critical appraisal was performed using the Quality Assessment for Diagnostic Accuracy Studies criteria. Results Fifty‐nine original studies met our a priori‐defined inclusion criteria. The majority of CSF‐focused studies showed (i) decreased mtDNA levels in PD and AD; (ii) increased levels in MS compared to controls. No studies evaluated CSF mtDNA in ALS. Results focused on blood cell‐free and intracellular mtDNA were contradictory, even within studies evaluating the same disease. This poor reproducibility is likely due to the lack of consideration of the many factors known to affect mtDNA levels. mtDNA damage and methylation levels were increased and reduced in patients compared to controls, respectively. A few studies investigated the correlation between mtDNA and disease severity, with conflicting results. Conclusions Additional well‐designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of “mitochondrial subtypes” of disease may enable novel precision medicine strategies to counteract neurodegeneration.

Background and Purpose This study was undertaken to compare the sensitivity and specificity of the 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria for multifocal motor neuropathy (MMN) with those of the American Association of Electrodiagnostic Medicine (AAEM). Methods Sensitivity and specificity of the two sets of criteria were retrospectively evaluated in 53 patients with MMN and 280 controls with axonal peripheral neuropathy, inflammatory demyelinating polyneuropathy, or amyotrophic lateral sclerosis. Comparison of the utility of nerve conduction studies with different numbers of nerves examined was also assessed. Results The 2010 EFNS/PNS criteria had a sensitivity of 47% for definite MMN and 57% for probable/definite MMN, whereas the AAEM criteria had a sensitivity of 28% for definite MMN and 53% for probable/definite MMN. The sensitivity of the AAEM criteria was higher when utilizing area compared to amplitude reduction to define conduction block. Using supportive criteria, the sensitivity of the 2010 EFNS/PNS criteria for probable/definite MMN increased to 64%, and an additional 36% patients fulfilled the criteria (possible MMN). Specificity values for definite and probable/definite MMN were slightly higher with the AAEM criteria (100%) compared to the EFNS/PNS criteria (98.5% and 97%). Extended nerve conduction studies yielded slightly increased diagnostic sensitivity for both sets of criteria without significantly affecting specificity. Conclusions In our patient populations, the 2010 EFNS/PNS criteria demonstrated higher sensitivity but slightly lower specificity compared to the AAEM criteria. Extended nerve conduction studies are advised to achieve slightly higher sensitivity while maintaining very high specificity.