Charcot-Marie-Tooth disease type 1A, or CMT1A, is the most common hereditary neuropathy in the world, caused by a 1.5-million-base-pair duplication on chromosome 17 that includes the PMP22 gene, which encodes a critical protein of peripheral myelin. The result is a dysmyelinating disorder in which nerve conduction slows uniformly across the peripheral nerves, and the large myelinated fibers that power movement and fine touch bear the brunt of the damage. RFC1 disease, by contrast, stems from biallelic AAGGG pentanucleotide repeat expansions in intron 2 of the RFC1 gene and typically announces itself as a late-onset sensory neuronopathy, often packaged together with cerebellar ataxia and vestibular areflexia in the syndrome known as CANVAS. Its true prevalence is likely underestimated because many carriers remain undiagnosed.

Small fibers — the thinly myelinated Aδ fibers and the unmyelinated C fibers — have long been the poor cousins of neurology. They do not show up on conventional nerve conduction studies, yet they mediate pinprick sensation, heat perception, and the automatic control of blood pressure, sweating, and gut function. When they fail, patients can suffer burning pain, insensitivity to injury, dizziness on standing, and devastating gastrointestinal problems. Capturing their dysfunction has always required a patchwork of imperfect tools, which is precisely why the Italian research team behind the new study assembled such an unusually broad battery of tests.

The study enrolled 21 patients with genetically confirmed CMT1A, 16 patients with confirmed biallelic RFC1 expansions, and 21 healthy controls at a single referral center in Genoa. Participants with diabetes, paraproteinemia, vitamin deficiencies, or other neuropathy risk factors were excluded to keep the picture clean. Each patient underwent neurological examination with standardized severity scales, autonomic questionnaires including the COMPASS-31 and the Compound Autonomic Dysfunction Test, electrochemical skin conductance measurement with a Sudoscan device, somatosensory evoked potentials, skin biopsies at the distal leg and thigh, and — most innovatively — two kinds of evoked potential recordings elicited through a micropatterned interdigitated electrode with an inter-rail gap of just 150 micrometers.

That electrode, developed in Italy and applied to the hairy skin of the hand, delivers electrical pulses fine enough to activate intraepidermal nerve endings directly, bypassing the thicker structures that normally dominate a surface stimulus. When driven in sustained rhythmic bursts, it produces what the researchers call nociceptive evoked potentials, whose early N40 component is thought to reflect the arrival of fast Aδ-mediated pain signals at the primary somatosensory cortex. When driven in sparse, randomized bursts, the same electrode elicits pain-related evoked potentials, whose later N1 and N2-P2 components reflect higher-order cortical processing of the painful input. In effect, the team could probe both the express lane and the processing center of the brain’s pain circuitry using a single stimulus site.

The clinical contrasts between the two patient groups were dramatic. Neuropathic pain, defined by a DN4 questionnaire score of four or higher, affected 33 percent of the CMT1A patients but a staggering 81 percent of those with RFC1 disease. Autonomic dysfunction told a similar story: 94 percent of RFC1 patients had abnormal autonomic test scores, with COMPASS-31 symptom scores ranging from 7 to 46, and 63 percent showed reduced electrochemical skin conductance, compared with only 24 percent of CMT1A patients. RFC1 patients commonly reported orthostatic intolerance, bowel and bladder dysfunction, and in severe cases even intestinal volvulus requiring surgery or urinary retention requiring catheterization. Two RFC1 patients had suffered accidental burns because they could no longer feel heat properly — a sobering reminder that losing small fibers can be as dangerous as gaining pain.

The neurophysiology sharpened the distinction further. In CMT1A, the N40 nociceptive responses were either absent in a third of patients or markedly delayed, with latencies exceeding three standard deviations above the control mean, and the later N2 pain-related responses were prolonged and frequently absent as well. This pattern of slowed but surviving pathways fits neatly with the underlying dysmyelinating process, which is known to thin and distort the myelin sheaths of even the small myelinated afferents. In RFC1 disease, the opposite emerged: responses were simply non-recordable in roughly half of patients, while the latencies of the responses that could be recorded were relatively preserved. The researchers interpret this as evidence that in RFC1 disease the nociceptive afferents are not slowed but lost outright, consistent with the neuron death that defines a sensory neuronopathy.

Skin biopsies delivered the most visually compelling confirmation. In CMT1A, the density of intraepidermal nerve fibers — the tiny C-fiber endings that snake up between skin cells — was reduced below the fifth percentile in 12 of 13 biopsied patients, but the loss was concentrated in the distal leg and spared the thigh, a classic length-dependent gradient in which the longest nerves die first. In RFC1 disease, the denervation was catastrophic and indiscriminate: median fiber density collapsed to just 1.0 fiber per millimeter in the distal leg and 0.4 fibers per millimeter in the distal thigh, with nearly complete loss at both proximal and distal sites. That non-length-dependent pattern mirrors the destruction of sensory neuron cell bodies in the dorsal root ganglia rather than a dying-back process along the nerve length, and it aligns with the diffuse allodynia some RFC1 patients reported across the trunk, head, and limbs.

The authors are careful about the limits of their work: the sample was small, the design was cross-sectional, quantitative sensory testing was not performed, and normative values for the new electrode-based evoked potentials do not yet exist, so the technique cannot yet stand alone as a diagnostic biomarker. One intriguing case, however, hints at what longitudinal studies might find — a patient whose burning pain and skin-biopsy denervation appeared years before any abnormality on conventional nerve conduction studies, only to be genetically diagnosed with RFC1 disease later. If small-fiber damage truly precedes large-fiber failure in RFC1 disease, the multimodal toolkit assembled in this study could one day catch the illness at its earliest, most treatable stage. For now, the message is clear: two diseases once defined by their large-fiber damage are also small-fiber diseases, and each writes its signature in a different hand.

Subject of Research: Small nerve fiber dysfunction in CMT1A and RFC1-related hereditary neuropathy

Article Title: Distinct small-fiber dysfunction profiles in CMT1A and RFC1 disease: a multimodal study

Article References: Massucco, S., Leandri, M., Bruzzone, V., Nobbio, L., Hamedani, M., Stara, S., Bellone, E., Geroldi, A., Venturi, C., Gemelli, C., Schenone, A., Marinelli, L., & Grandis, M. (2026). Distinct small-fiber dysfunction profiles in CMT1A and RFC1 disease: a multimodal study. Journal of Neurology, 273(10), Article 602. https://doi.org/10.1007/s00415-026-14145-w

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14145-w

Keywords: CMT1A, RFC1 disease, CANVAS, small fiber neuropathy, peripheral neuropathy, neuropathic pain, autonomic dysfunction, skin biopsy, nociceptive evoked potentials, electrochemical skin conductance, PMP22, sensory neuronopathy

Sjögren’s disease is best known as a chronic autoimmune disorder that dries out the mouth and eyes by destroying exocrine glands, but in a substantial minority of patients it turns its inflammatory sights on the nerves themselves. Neurological involvement is reported in roughly 8 to 49 percent of cases, averaging around 20 percent, and it can strike both the peripheral nervous system, causing neuropathies, and the central nervous system, producing encephalitis, myelitis, or vasculitis. When it does, the consequences can be severe: disability, poor prognosis, and markedly reduced quality of life. Neurologists and rheumatologists call this presentation Neuro-Sjögren, and it is notoriously hard to pin down.

The difficulty lies in the disease’s habit of hiding. Some patients arrive with neurological symptoms as their first and only complaint, lacking the characteristic sicca symptoms of dryness and testing negative for anti-SSA, the antibody that anchors most Sjögren’s diagnoses. Studies cited by the authors indicate that the average diagnostic delay for Neuro-Sjögren stretches from three to six years, and that the wait is even longer in patients who are anti-SSA positive or who first present with neurological symptoms. Every year of delay is a year in which an autoimmune process may be quietly damaging nerves that cannot easily repair themselves.

Enter the labial gland biopsy. The procedure involves removing a small cluster of minor salivary glands from the inner lip and having a pathologist count lymphocytic foci, dense aggregates of at least 50 mononuclear immune cells, per 4 square millimeters of tissue. A focus score of 1 or higher is not diagnostic on its own, but it is a key component of the 2016 ACR/EULAR classification criteria for Sjögren’s disease and can support a clinical diagnosis when combined with other findings. The test is not trivial: it carries risks of local scarring, infection, and permanent numbness, and it demands both an experienced clinician and expert pathological interpretation. That is precisely why knowing who truly benefits from it matters.

The Beijing team, led by Zhen Tian and colleagues, enrolled 456 hospitalized patients with suspected Sjögren’s disease, of whom 412 met the inclusion criteria. Within this cohort, 135 patients had suspected Neuro-Sjögren, meaning their neurological symptoms had been confirmed by a neurologist and, wherever possible, corroborated by objective evidence such as MRI, PET, nerve conduction studies, electromyography, or cerebrospinal fluid analysis. The remaining 277 patients, suspected of Sjögren’s without neurological involvement, served as a comparison group. The researchers deliberately excluded patients whose neurological complaints could be explained by alternative diagnoses, and they excluded anyone with other connective tissue diseases, recent malignancy, active infection, or conditions making biopsy unsafe.

The diagnostic pathway followed real-world practice. Patients who were anti-SSA positive and had objective evidence of glandular impairment could be classified under the 2016 ACR/EULAR criteria without a biopsy. Everyone else, whose serological and glandular findings were insufficient, underwent labial gland biopsy as part of the work-up. Among the 135 suspected Neuro-Sjögren patients, 91 fell into this biopsy-required category, compared with 44 who could be classified without histology. The numbers tell a striking story: biopsy was required in 67.4 percent of suspected Neuro-Sjögren patients versus 56.3 percent of the non-neurological group, a statistically significant difference. Even more compelling, when a biopsy was performed, it came back positive, with a focus score of at least 1, in 81.3 percent of the Neuro-Sjögren group versus just 51.3 percent of the others.

The most eye-catching figure concerns the patients clinicians worry about most. Among anti-SSA-negative patients with suspected Neuro-Sjögren, the biopsy positivity rate reached 77.3 percent. In other words, for roughly three out of four patients who lacked the classic antibody and whose glandular tests were uninformative, the lip biopsy still revealed the focal lymphocytic inflammation that defines Sjögren’s disease. Only 12 patients in the cohort were both anti-SSA negative and biopsy negative, and these individuals could not be classified as having Sjögren’s disease under the 2016 criteria. For a population where diagnosis often stalls for years, that is a meaningful yield from a procedure taking minutes.

Who, then, ends up needing the biopsy? Multivariable logistic regression identified two independent predictors of biopsy requirement: younger age at onset, with an odds ratio of 0.960 per year of age, and early-onset neurological symptoms, meaning neurological manifestations that appeared before the typical sicca symptoms, which more than tripled the odds at an odds ratio of 3.634. In the biopsy-required group, 65.9 percent of patients had presented with neurological symptoms first, compared with 36.4 percent of those classified without biopsy. Conversely, anti-SSB positivity and antinuclear antibody titers of 1:320 or higher were independently associated with a lower likelihood of needing a biopsy, presumably because such patients already carried stronger serological evidence. Elevated IgG showed only a borderline association. The authors are careful to note that these factors reflect their center’s diagnostic pathway, not intrinsic properties of the disease, and should not be read as universal indications for or against biopsy.

Among the patients who actually underwent biopsy, a second pattern emerged. Those with positive results more frequently showed higher erythrocyte sedimentation rates, elevated IgG, and ANA titers of at least 1:320 than biopsy-negative patients. The researchers interpret these as non-specific markers of broader immune activation rather than disease-specific signatures, cautioning that they should never be used in isolation to justify the procedure. Interestingly, while the difference was not statistically significant, biopsy positivity was numerically higher in patients with peripheral nervous system involvement, 87.2 percent, than in those with central nervous system involvement, 77.1 percent, hinting that peripheral phenotypes may be more tightly linked to histopathological glandular inflammation. The study also noted, contrary to much prior literature, a slightly higher proportion of central than peripheral involvement in their cohort, which the authors attribute to center-specific referral patterns and neurological expertise.

The findings align with a growing body of work. Previous studies have shown that positive labial gland biopsies associate with autonomic dysfunction, that more than 90 percent of patients with sensory ganglionopathy test positive on both Schirmer’s test and biopsy despite few sicca symptoms, and that among patients with small fiber neuropathy, up to 30 percent are ultimately diagnosed with Sjögren’s disease. The Beijing study adds a quantitative framework: in serologically ambiguous patients with neurological presentations, the biopsy is not a last resort but frequently the decisive test. The authors acknowledge the limitations of their retrospective, single-center design, including possible selection bias toward more complex inpatient cases and the modest number of outcome events in their regression model. They call for prospective, multicenter studies with richer histological profiling. Still, the practical message for clinicians is clear: when a patient, especially a younger one, presents with neurological symptoms that precede any dryness, and the antibody panel comes back empty, the small glands of the lower lip may hold the answer that blood tests cannot.

Subject of Research: Clinical utility of labial gland biopsy in diagnosing suspected Neuro-Sjögren

Article Title: The Clinical Utility of Labial Gland Biopsy in Patients With Suspected Neuro‐Sjögren

Article References: Tian, Z., Li, X., Li, X., Wang, Y., Wang, C., & Zhao, Y. (2026). The Clinical Utility of Labial Gland Biopsy in Patients With Suspected Neuro‐Sjögren. Immunity, Inflammation and Disease, 14(9), Article e70507. https://doi.org/10.1002/iid3.70507

Image Credits: AI Generated

DOI: 10.1002/iid3.70507

Keywords: Neuro-Sjögren, Sjögren's disease, labial gland biopsy, focus score, anti-SSA, autoimmune disease, peripheral neuropathy, central nervous system, ACR/EULAR criteria, diagnostic delay, small fiber neuropathy, rheumatology

Fabry disease is an X-linked lysosomal storage disorder characterized by a deficiency of the enzyme alpha-galactosidase A. This deficiency leads to the accumulation of a specific type of fat, globotriaosylceramide, affecting various bodily organs, including the skin, kidneys, heart, and nervous system. While traditionally considered a male-dominated disease, the heterozygous female carriers exhibit a wide spectrum of clinical presentations, often complicating diagnosis and management. This highlights the need for further exploration into the phenotypic variations among female carriers.

The case report by Castellar-Leones and colleagues presents two twin sisters, both of whom were diagnosed with Fabry disease. Notably, the study reveals that these sisters exhibit a rare manifestation of the disease – small fiber neuropathy. Small fiber neuropathy is a condition that affects the small nerve fibers responsible for transmitting pain and temperature sensations. Those afflicted often experience a range of debilitating symptoms, from pain and tingling in the extremities to severe dysautonomia. Understanding the prevalence of small fiber neuropathy in female heterozygotes is crucial to offering targeted treatment modalities.

Diagnosis of small fiber neuropathy can often be elusive. Traditional electrodiagnostic studies might not detect changes in small fibers due to their diminutive size. Therefore, skin biopsy has emerged as a vital tool for diagnosing this condition. The authors emphasize the importance of utilizing immunohistochemical techniques to analyze the density of nerve fibers within skin samples, which can serve as a reliable marker for assessing nerve fiber integrity. This approach underscores a paradigm shift in how neurological disorders related to genetic conditions are diagnosed.

What makes this twin case particularly intriguing is the potential contribution of genetic and environmental factors to the development of symptoms in both sisters. Despite having the same genetic background, the expression of Fabry disease can differ vastly between individuals. This discrepancy can be attributed to a multitude of factors including epigenetic influences, gene dosage, and other intrafamilial environmental dynamics. Therefore, an in-depth exploration of these differences can yield essential insights into the pathology of the disease.

The report also addresses the therapeutic approaches currently available for managing symptoms associated with Fabry disease. Enzyme replacement therapy (ERT) represents a cornerstone in the treatment for Agalsidase beta. ERT helps to mitigate the progression of symptoms and improve the quality of life for these patients. However, it is essential to approach ERT as part of a comprehensive management strategy that encompasses symptomatic treatment of neuropathic pain, particularly crucial for individuals affected by small fiber neuropathy.

The emotional and psychological implications of living with Fabry disease cannot be underestimated. Many families face challenges, not only from a clinical perspective but also with regard to societal perception and psychological well-being. Supportive interventions, including counseling and patient support groups, play a crucial role in helping families adapt to the challenges posed by this condition. Acknowledging the need for holistic care is paramount in the clinical management of rare diseases like Fabry.

As the medical community continues to deepen its understanding of conditions such as Fabry disease, innovative research methodologies are likely to emerge. Large-scale population studies can enhance our comprehension of the variety of manifestations in heterozygous females, while also illuminating the importance of genetic counseling in affected families. This could pave the way for preemptive strategies in managing and potentially mitigating the onset of symptoms in asymptomatic carriers.

In addition, future research initiatives will benefit greatly from interdisciplinary collaboration. Neurologists, geneticists, and genetic counselors can work cohesively to navigate the intricate nature of Fabry disease in female patients. By sharing their unique perspectives and expertise, these professionals can better address the multi-faceted challenges this disorder presents, ultimately improving clinical outcomes for patients and families alike.

In summary, the case study presented by Castellar-Leones and collaborators marks a significant contribution to the existing body of knowledge surrounding Fabry disease. It emphasizes the critical importance of recognizing and investigating small fiber neuropathy in pediatric female heterozygotes. The multifactorial nature of disease manifestation calls for tailored approaches in diagnosis and management, ensuring that all aspects of a patient’s experience are addressed comprehensively.

Moreover, studies such as this one serve as a reminder of the uniqueness of each patient’s journey with a genetic disorder. They encourage ongoing dialogue within the scientific community about the best clinical practices, and the need for further research. Engaging with patients and their families when devising treatment plans is essential for optimizing their outcomes. As the landscape of genetic disorders continues to evolve, we must remain dedicated to exploring uncharted territories in research, ensuring that every patient receives the attention and care they deserve.

In conclusion, efforts to amplify awareness and understanding of rare diseases like Fabry are crucial. By disseminating findings from impactful studies, such as the one authored by Castellar-Leones and colleagues, the medical community can promote education and improve the lives of those affected by such conditions. Only through increased vigilance and recognition of these complexities can we ensure that no patient is left behind.

Subject of Research: Small Fiber Neuropathy in Pediatric Female Heterozygotes of Fabry Disease

Article Title: Small fiber neuropathy in pediatric female heterozygotes of Fabry disease: a twin case report

Article References:

Castellar-Leones, S.M., Ortiz-Corredor, F., González-Camargo, J. et al. Small fiber neuropathy in pediatric female heterozygotes of Fabry disease: a twin case report.
BMC Pediatr (2025). https://doi.org/10.1186/s12887-025-06437-3

Image Credits: AI Generated

DOI: 10.1186/s12887-025-06437-3

Keywords: Fabry disease, small fiber neuropathy, pediatric, heterozygotes, twins, neurological disorders, genetic condition, enzyme replacement therapy.