Molecular genetic analysis identified the variants as a rare form of mitochondrial complex I deficiency. One variant had previously been annotated in ClinVar as a variant of uncertain significance, while the other was described as novel. The abstract reports these findings without providing details about the analyses performed or the patient’s subsequent course.

The authors characterize the presentation as unusual because prominent axonal neuropathy occurred without evident systemic metabolic dysfunction. They conclude that the case expands the phenotypic and genetic spectrum linked to NDUFS1-related disorders, highlighting a rare and atypical manifestation of mitochondrial complex I deficiency.

Because this is a single-patient case report, the findings are limited to the clinical and genetic observations reported in that case and do not establish the frequency, range, or broader clinical course of this presentation. The supplied abstract also does not report treatment, long-term outcomes, or recommendations for clinical management; assessing the complete methods and other case details would require the full article.

Subject of Research: A case report of compound heterozygous NDUFS1 variants associated with atypical axonal sensorimotor polyneuropathy in one adolescent boy.

Article Title: Axonal polyneuropathy: compound heterozygous mutations in NDUFS1—a case report

Article References: Sawaya, R. A., Bannout, A. A., Makhoul, N. J., Karam, P., & Boustany, R.-M. (2026). Axonal polyneuropathy: compound heterozygous mutations in NDUFS1—a case report. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07687-5

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07687-5

Keywords: NDUFS1, axonal polyneuropathy, sensorimotor polyneuropathy, mitochondrial complex I deficiency, compound heterozygous variants, case report, genetic diagnosis, ClinVar, Axonal, polyneuropathy, compound, heterozygous

The research team enrolled 30 patients whose pain had been refractory to medication for at least one year, including gabapentinoids, and whose daily morphine-equivalent dose remained below 120 mg. The cohort comprised 11 patients with diabetic peripheral neuropathy (DPN), 8 with chemotherapy-induced peripheral neuropathy (CIPN), 9 with chronic idiopathic axonal polyneuropathy (CIAP), and single patients with amyloidosis and Fabry disease. Mean age was 60 years, two-thirds were male, and mean pain duration was 8.2 years, underscoring how long these patients had endured severe symptoms before reaching advanced therapy.

Baseline characterization revealed striking clinical differences across etiologies that likely reflect distinct underlying disease mechanisms. Patients with CIAP reported the heaviest pain symptom burden, with higher levels of evoked pain such as hyperalgesia and allodynia, greater burning feet, and a more pronounced affective pain component, a pattern the authors interpret as greater central sensitization, possibly amplified by the prolonged diagnostic uncertainty these patients face. In contrast, patients with DPN carried more neurological deficits, with higher Utah Early Neuropathy Scale scores (20.3 versus 13.3 in CIAP), worse pin sensation, and lower intraepidermal nerve fiber density at both distal-leg and proximal-thigh biopsy sites, indicating a more aggressive neurodegenerative process affecting both small and large fibers. CIPN patients had notably shorter pain duration (3.8 years versus 10.2 in CIAP), consistent with the more acute onset that follows chemotherapy exposure.

Across the whole cohort, baseline disease burden was severe by every measure. Mean pain intensity on the visual analog scale was 8.6 out of 10, the Neuropathic Pain Symptom Inventory score was 61.1 out of 100, and the Short-Form McGill Pain Questionnaire-2 reached 115.5 out of 220, all within the severe range. Autonomic involvement was moderate, with abnormal sweating, orthostatic intolerance, gastrointestinal and urogenital disturbances evident on the Survey of Autonomic Symptoms and the Small Fiber Neuropathy Symptoms Inventory Questionnaire. Health-related quality of life was profoundly impaired, with a mean EQ-VAS of 38.8 out of 100, substantial pain-related sleep interference, and reduced global functioning.

All patients underwent implantation of two percutaneous epidural leads at the T10–T11 vertebral levels to target lower-limb pain, with a third cervical lead at C4–C7 added for the 40 percent of patients who also had upper-limb symptoms, reflecting the length-dependent pattern typical of polyneuropathy. Following a 7–14 day trial with an external stimulator, patients achieving at least 50 percent pain relief received a permanent implantable pulse generator. The trial-to-permanent ratio was 86 percent. Programming was individualized: 83 percent of patients selected a low-frequency (90 Hz) fast-acting sub-perception modality delivering stimulation below the perception threshold, while 17 percent chose combination therapy integrating supra-perception paresthesia-based stimulation with an anatomically guided sub-perception configuration designed to maximize modulation of dorsal horn elements.

The results were remarkable. Mean VAS pain intensity plummeted from 8.6 at baseline to 2.0 at 12 months, an approximate 75 percent reduction that was sustained across all follow-up visits (p < 0.001). Multidimensional pain severity on the SF-MPQ-2 fell from 115.5 to 23.0, and the NPSI neuropathic symptom score dropped from 61.1 to 11.1, far exceeding established minimal clinically important difference thresholds. Linear mixed-effects models confirmed significant improvements over time across every patient-reported outcome, with the largest effects in pain-related measures. Notably, the magnitude of response differed by etiology: estimated pain reductions were approximately 85 percent in DPN, 75 percent in CIPN, and 70 percent in CIAP, with the group effect significantly favoring DPN over CIAP (p < 0.001). Even the single patients with Fabry disease and amyloidosis experienced roughly 55 percent reductions in pain intensity, with the amyloidosis patient showing 70–80 percent reductions in overall pain and neuropathic symptom scores.

Beyond pain, the therapy produced unexpected benefits in autonomic and wellbeing domains. Autonomic symptom burden fell by roughly 40 percent across etiologies, with the SAS decreasing from 16.5 to 9.9 (p = 0.02) and the SFN-SIQ dropping 46 percent from 13.5 to 7.3 (p = 0.001). Item-level analyses revealed significant improvements in sensitive skin, hot flashes, dizziness on standing, diarrhea, cold feet, nausea and bloating, and lightheadedness, findings the authors suggest may reflect improved vasomotor regulation, peripheral perfusion and thermoregulatory activity, mechanisms previously described in peripheral vascular disease and spinal cord injury. Erectile dysfunction, particularly prevalent in DPN, showed limited response, indicating that further optimization of stimulation parameters may be needed to target this impairment specifically.

Quality of life transformed in parallel. The EQ-VAS rose from 38.8 to 77.9 and the EQ-index from 0.70 to 0.93, improvements that vastly exceeded the reported minimal clinically important difference of 0.05 and reached normative thresholds for age-matched Spanish populations. Pain-related sleep interference collapsed from severe to mild impairment, with CPSI-3 scores falling from 18.4 to 3.5 (p < 0.001). Global functioning improved from 63.9 to 86.1 on the GAF scale. Medication burden fell dramatically: 59 percent of patients completely discontinued analgesic medications and the remaining 41 percent reduced their use. At final follow-up, 96 percent of participants rated themselves as much or very much improved on the patient global impression of change.

Perhaps the most intriguing finding concerns small nerve fiber integrity. Intraepidermal nerve fiber density, the gold standard for quantifying small-fiber involvement, was assessed through skin punch biopsies at baseline and 12 months. Given that IENFD is expected to decline by approximately 11 percent annually in these conditions, the overall stability observed over 12 months, with proximal values changing from 5.0 to 4.8 fibers/mm and distal values remaining unchanged at 3.1 fibers/mm, suggests attenuation or stabilization of small-fiber degeneration following SCS. Increases outnumbered decreases in the non-parametric analysis, although changes were modest and not statistically significant. The authors caution that larger controlled studies are needed to establish causality, particularly in CIPN, where the natural history of fiber loss remains uncertain.

Neurological signs themselves, including sensory and motor tests on the UENS, remained largely unchanged (17.3 to 16.4; p = 0.96), with only the allodynia subscore showing significant group-level improvement. The authors attribute this discrepancy between symptom relief and sign stability to the distinction between rapid modulation of neural activity and central pain processing versus the slower processes of axonal regeneration and remyelination required for structural recovery. The complication rate was low, with one explantation due to infection, one lead revision, and one exclusion for atypical clinical evolution. The study’s main limitations include its small sample size, single-center design, and etiological heterogeneity, which constrain subgroup comparisons. Nevertheless, the authors argue that their findings begin to fill a critical evidence gap for CIAP, a subtype potentially accounting for up to one-third of polyneuropathy cases, and extend support for SCS in CIPN, whose incidence is expected to rise with improving cancer survival rates. For patients trapped in the cycle of failed medications and escalating pain, the message is clear: neuromodulation deserves consideration far earlier and across far more diagnostic categories than convention has allowed.

Subject of Research: Clinical phenotypes and outcomes of spinal cord stimulation in painful peripheral polyneuropathy: a cohort including diabetic, chemotherapy-induced, and idiopathic etiologies

Article Title: Clinical phenotypes and outcomes of spinal cord stimulation in painful peripheral polyneuropathy: a cohort including diabetic, chemotherapy-induced, and idiopathic etiologies

Article References: Canós, Á., Castel, B., Bermejo, A., Izquierdo Aguirre, R. M., Robledo, R., Gallach, E., Sevilla, T., Argente, P., & Huertas, I. (2026). Clinical phenotypes and outcomes of spinal cord stimulation in painful peripheral polyneuropathy: a cohort including diabetic, chemotherapy-induced, and idiopathic etiologies. Frontiers in Pain Research, 7, Article 1954493. https://doi.org/10.3389/fpain.2026.1954493

Image Credits: AI Generated

DOI: 10.3389/fpain.2026.1954493

Keywords: Clinical, phenotypes, outcomes, spinal, cord, stimulation, painful, peripheral, polyneuropathy, cohort, including, diabetic

Myotonic dystrophies are autosomal dominant, multisystem disorders caused by toxic repeat expansions in DNA. DM1, the more common and generally more severe form, stems from an expanded CTG repeat in the DMPK gene, while DM2 arises from a CCTG expansion in intron 1 of the CNBP gene, formerly known as ZNF9. In both conditions, the mutant RNA accumulates in cell nuclei and sequesters RNA-binding proteins, producing a splicing defect that disrupts dozens of downstream genes. The result is a bewildering clinical spectrum: myotonia, the delayed relaxation of muscles after contraction; progressive weakness that in DM1 typically begins distally and in DM2 proximally; cataracts; cardiac conduction disturbances; respiratory insufficiency; endocrine dysfunction including diabetes and hypogonadism; and cognitive and gastrointestinal involvement. Because the molecular bottleneck is shared, both diseases overlap in many features, yet they differ markedly in age at onset, severity, and pace of progression, with DM2 often presenting as a milder, later-onset condition.

The Serbian team, led by Ana Azanjac Arsic and Stojan Peric, conducted a cross-sectional analysis of 391 patients with DM1 and 196 with DM2, all enrolled in a national registry whose establishment was approved by the relevant ethics committees. Each participant underwent a comprehensive workup: a detailed neuromuscular examination, electrophysiological testing, cardiac and respiratory evaluation, endocrine and laboratory assessment, skeletal and ophthalmologic examination, and measurement of functional status. Muscle strength was quantified using a modified Medical Research Council score, a standard grading system for assessing power in defined muscle groups. Because the study was explicitly exploratory, the investigators did not apply corrections for multiple statistical comparisons, a point they acknowledge; the results should therefore be viewed as hypothesis-generating signals that will need confirmation in independent cohorts.

In DM1, the sex distribution was nearly even, with a male-to-female ratio of 1.1 to 1, but the clinical burden was not. Men with DM1 carried a distinctly heavier neuromuscular load. They showed weaker grip and hand muscles in the distal upper limbs and weaker proximal lower limb muscles, and their myotonia lasted measurably longer on electrophysiological testing. Speech involvement in the form of dysarthria was more common in men, as was dysphagia, difficulty swallowing that carries a real risk of aspiration. Peripheral polyneuropathy, skeletal deformities, baldness, and infertility were all reported more frequently in male patients, and electrocardiographic abnormalities appeared more often as well. Taken together, the picture in DM1 is one of a more aggressive neuromuscular and cardiac disease in men, consistent with earlier hints from French national databases that male sex predicts greater severity and mortality in this disorder.

DM2 told a strikingly different story. Women outnumbered men in the cohort by a ratio of 1.5 to 1, an imbalance that echoes prior observations in European DM2 registries and remains one of the intriguing epidemiological puzzles of this disease. More importantly, the phenotypic axis of sex difference flipped. Women with DM2 displayed more pronounced weakness in the proximal muscles of the lower limbs, reduced respiratory capacity on pulmonary function testing, and a higher prevalence of cataracts. The cataract finding is particularly interesting because population studies have long suggested that estrogen protects the lens, and the loss of that protection after menopause may interact with the RNA toxicity that drives DM2 pathology. For women with DM2, the practical message is that breathing function and lens status deserve especially close surveillance.

Men with DM2 were not spared, however; their excess burden simply shifted to other systems. Male DM2 patients had longer myotonia duration, more frequent polyneuropathy, and higher rates of baldness and infertility, mirroring some of the male-predominant features seen in DM1. They also showed more hyperglycemia, pointing to a greater metabolic and endocrine load, and they required pacemaker implantation more often, a concrete marker of clinically significant cardiac conduction disease. The authors summarize this asymmetry elegantly: the greater neuromuscular burden falls on DM1 males and DM2 females, while cardiologic and endocrinologic or metabolic complications cluster in males across both disease types.

Why would sex sculpt the phenotype of an RNA-mediated disease so differently depending on which gene harbors the repeat? Several biological mechanisms offer plausible explanations. Sex hormones modulate muscle mass, insulin sensitivity, and cardiac electrophysiology, and estrogen in particular has documented protective effects on lens transparency and vascular function. Alternative splicing, the very process corrupted in myotonic dystrophy, is itself influenced by sex hormone-regulated splicing factors, meaning the toxic RNA may hijack different cellular programs in male and female tissues. Differences in repeat instability dynamics, X-chromosome-linked modifiers, and body composition could also contribute. None of these mechanisms has been definitively proven in humans, and the Serbian authors are careful to frame their study as descriptive; but the consistency of the male cardiac and metabolic signal across both DM1 and DM2 suggests a shared biological substrate rather than statistical noise.

The clinical implications are immediate and practical. A man with DM1, according to these data, warrants particularly vigilant monitoring of swallow function, speech, peripheral nerve status, and cardiac rhythm, with a low threshold for electrophysiological follow-up and pacemaker evaluation. A woman with DM2 should receive focused attention on proximal leg strength, respiratory function, and early cataract screening, while her male counterpart needs closer metabolic surveillance and cardiac follow-up. Risk stratification tools and clinical trial design have historically treated myotonic dystrophy cohorts as homogeneous; this study adds weight to the argument that sex must be incorporated as a stratifying variable, both to balance trial arms fairly and to detect treatment effects that might be masked or amplified in one sex. As antisense oligonucleotide and small-molecule therapies for myotonic dystrophy move toward the clinic, understanding which patients are most vulnerable to which complications could determine who benefits most and when.

The study also highlights the quiet power of national rare disease registries. No single center could have assembled 587 genetically confirmed myotonic dystrophy patients with this depth of phenotyping; a coordinated national effort spanning Belgrade, Kragujevac, Novi Sad, and Nis could. The cross-sectional design cannot establish whether sex differences emerge at disease onset or accumulate over time, and the absence of multiple-comparison correction means individual findings should be interpreted with appropriate caution. Yet the overall pattern, converging with prior reports from France, Germany, and international collaborations, paints a coherent picture: myotonic dystrophy is not one disease experienced identically by all patients, but a family of sex-modified trajectories. For the hundreds of thousands of people worldwide living with DM1 and DM2, that insight moves precision medicine one practical step closer, turning a demographic variable into a roadmap for personalized monitoring and care.

Subject of Research: Sex-related phenotypic differences in genetically confirmed myotonic dystrophy types 1 and 2 in a nationwide Serbian registry cohort

Article Title: Sex-related phenotypic differences in myotonic dystrophy types 1 and 2: a nationwide registry study from Serbia

Article References: Azanjac Arsic, A., Andrejic, N., Viric, V., Gunjic, I., Sreckovic, S., Rajic, S., Jovin, Z., Bozovic, I., Djordjevic, G., Basta, I., & Peric, S. (2026). Sex-related phenotypic differences in myotonic dystrophy types 1 and 2: a nationwide registry study from Serbia. Journal of Neurology, 273(10), Article 645. https://doi.org/10.1007/s00415-026-14190-5

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14190-5

Keywords: myotonic dystrophy type 1, myotonic dystrophy type 2, sex differences, muscle strength, myotonia, cardiac conduction, polyneuropathy, cataracts, respiratory function, infertility, patient registry, Serbia