About

Steven S. Scherer, M.D., Ph.D., is an Emeritus Professor of Neurology at the University of Pennsylvania's Perelman School of Medicine. He is a member of the Mahoney Institute for Neurological Science and serves on the Department of Neurology Executive Committee. His research primarily focuses on the pathogenesis of demyelinating diseases, especially those caused by mutations in genes encoding gap junction proteins Cx32 and Cx47. His scientific projects include studying the role of Cx32 in inherited demyelinating neuropathy, how gap junctions between astrocytes and oligodendrocytes influence CNS myelin structure and function, the organization of the myelin sheath in relation to axonal structure, and developing animal models of inherited neuropathies. Clinically, he specializes in diagnosing and managing peripheral neuropathies, performing comprehensive histories, neurological examinations, and neurophysiological assessments such as EMG to classify neuropathies and guide treatment, including pain management. His contributions include extensive research and clinical work in neurogenetics and neuropathology.

Research topics

• Psychiatry
• Medicine
• Internal medicine
• Bioinformatics
• Family medicine
• Biology
• Pathology
• Genetics
• Demography
• Environmental health
• Gerontology
• Intensive care medicine

Selected publications

• Charcot–Marie–Tooth disease and related neuropathies

  Nature Reviews Disease Primers · 2026-01-22 · 4 citations

  articleSenior author
  PublisherDOI

• Chronic Severe Neutropenia Associated With Intravenous Immunoglobulin for Multifocal Motor Neuropathy

  eJHaem · 2025-01-27 · 1 citations

  articleOpen access

  ABSTRACT Intravenous immunoglobulin (IVIG) is an immunomodulatory therapy derived from pooled donor immunoglobulins and used for treatment of various autoimmune conditions. Here we report the diagnosis and management of IVIG‐induced chronic severe neutropenia with absolute neutrophil count <0.5×10 3 /µL in a patient with multifocal motor neuropathy. Serial blood count showed a cyclical pattern of neutropenia: worsening 24–48 h post‐IVIG, then gradually improving before the next infusion. IVIG‐induced neutropenia is rare, with previous reports of predominantly mild transient neutropenia. Our case describes chronic severe neutropenia that developed years after starting IVIG. We summarize available evidence and management strategies for IVIG‐associated neutropenia.

  PublisherOA PDFDOI

• Disease Progression in Charcot‐Marie‐Tooth Disease Type <scp>4B</scp> (<scp>CMT4B</scp>) Associated With Mutations in Myotubularin‐Related Proteins 2 and 13

  European Journal of Neurology · 2025-02-01 · 1 citations

  articleOpen access

  BACKGROUND AND AIMS: In 2019, we conducted a cross-sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium. MATERIALS AND METHODS: We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot-Marie-Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow-up visits. Thirteen centres from four continents were involved. RESULTS: Thirteen CMT4B1 and 13 CMT4B2 patients were followed up for 7.1 ± 4.9 and 7.9 ± 4.5 years, respectively. During follow-up, walking aid dependency increased: two CMT4B1 patients adopted AFOs (overall 11/12 at follow-up), and one started using wheelchair (6/12 at follow-up) at the age of 19; among CMT4B2 patients, two more required unilateral support in walking (4/11 at follow-up) by the age of 33 and 49 years, respectively. We found that disease progression, as measured by CMTES, was faster in CMT4B1 as compared to CMT4B2 patients (ΔCMTES/year 0.7 vs. 0.3, p = 0.037) but tended to slow down over time as burden of disease increased. At the end of follow-up, CMT4B1 was associated to higher disability. CONCLUSIONS: This international collective effort enabled collection of relevant data for characterizing natural history and estimating disease progression of CMT4B1/CMT4B2 ultrarare diseases, aiming at improving their management and paving the way for designing future clinical trials.

  PublisherOA PDFDOI

• Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD

  Brain · 2025-01-27 · 7 citations

  articleOpen access

  Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicentre phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified, mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy. Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score ≤ 1). One-fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in a quarter of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.

  PublisherOA PDFDOI

• Charcot-Marie-Tooth disease type 1E: Clinical Natural History and Molecular Impact of <i>PMP22</i> Variants

  medRxiv · 2025-05-02 · 3 citations

  preprintOpen access

  Abstract Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 ( PMP22 ) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity. Twenty-four, presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within in transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes. Reduced expression of PMP22 at the cell surface, and the location of missense variants within in the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.

  PublisherOA PDFDOI

• Association of the Recurrent <i>ATP1</i> <i>A1</i> Variant p.Gly549Arg With Intermediate CMT and Loss of Na,K-ATPase Function

  Neurology Genetics · 2025-09-30

  articleOpen accessCorresponding

  Background and Objectives: variant causing dominant intermediate CMT disease and the functional characterization of the variant in the heterologous expression system. Methods: oocytes or HEK293 cells, respectively. Localization of the variants was evaluated by fluorescence microscopy of HEK293 cells expressing fluorescently tagged sodium pumps. Results: . The reduced plasma membrane density was also observed in HEK293 cells simultaneously expressing wildtype and Gly549Arg variants, marked with fluorescent proteins of different colors, suggesting that the mutant may be partially retained in intracellular membranes. No clear dominant-negative effects were identified in these experimental systems. Discussion: Our results demonstrate that the pathogenic nature of this variant causes considerable loss of function due to diminished plasma membrane localization and kinetic impairments on the enzyme, without obvious dominant-negative effects. Our findings are similar to those previously reported for other CMT disease-causing ATP1A1 variants.

  PublisherDOI

• Charcot-Marie-Tooth disease type 1E: clinical natural history and molecular impact of <i>PMP22</i> variants

  Brain · 2025-06-06 · 2 citations

  articleOpen access

  Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant peripheral neuropathy caused by missense variants, deletions, and truncations within the peripheral myelin protein-22 (PMP22) gene. CMT1E phenotypes vary depending on the specific variant, ranging from mild to severe, and there is little natural history and phenotypic progression data on individuals with CMT1E. Patients with CMT1E were evaluated during initial and follow-up visits at sites within the Inherited Neuropathy Consortium. Clinical characteristics were obtained from history, neurological exams, and nerve conduction studies. Clinical outcome measures were used to quantify baseline and longitudinal changes, including the Rasch-modified CMT Examination Score version 2 (CMTESv2-R) and the CMT Pediatric Scale (CMTPedS). The trafficking of PMP22 variants in transfected cells was correlated to disease severity. Twenty-four presumed disease-causing PMP22 variants were identified in 50 individuals from 35 families, including 19 missense variants, three in-frame deletions, and two truncations. Twenty-nine patients presented with delayed walking during childhood. At their baseline evaluation, the mean CMTESv2-R in 46 patients was 16 ± 7.72 (out of 32), and the mean CMTPedS from 17 patients was 28 ± 6.35 (out of 44). Six individuals presented with hearing loss, eleven with scoliosis, three with hip dysplasia, and one with both scoliosis and hip dysplasia. Twenty variants were localized within transmembrane domains; 31 of 35 individuals with these variants had moderate to severe phenotypes. Three variants were found in the extracellular domain and were associated with milder phenotypes. Reduced expression of PMP22 at the cell surface, and the location of missense variants within the transmembrane domain correlated with disease severity. Pathogenic PMP22 variants located within the transmembrane regions usually cause a moderate to severe clinical phenotype, beginning in early childhood, and have impaired trafficking to the plasma membrane.

  PublisherOA PDFDOI

• SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights

  Brain · 2024-03-26 · 10 citations

  articleOpen access

  Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect ∼10 000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioural tests as well as biochemical, physiological and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, CSF and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion-tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding-enlarged 'ballooned' myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.

  PublisherOA PDFDOI

• Disparities in Genetic Testing for Neurologic Disorders

  Neurology · 2024 · 23 citations

  • Medicine
  • Demography
  • Gerontology

  BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

  PublisherOA PDFDOI

• The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics

  Biology · 2024-02-02 · 1 citations

  articleOpen access

  Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.

  PublisherOA PDFDOI

Recent grants

• NIH Grant K08NS001565

  NIH · $443k · 1997

• NIH Grant R01NS055284

  NIH · $2.9M · 2017

• NIH Grant R29NS034528

  NIH · $597k · 2000

• How do dominant PMP2 mutations cause demyelinating neuropathy?

  NIH · $443k · 2017–2019

• NIH Grant R01NS037100

  NIH · $560k · 2002

Frequent coauthors

• Mary M. Reilly

  National Hospital for Neurology and Neurosurgery

  688 shared

• Michael E. Shy

  University of Iowa

  612 shared

• Sabrina W. Yum

  586 shared

• Joshua Burns

  Sydney Children’s Hospitals Network

  582 shared

• Davide Pareyson

  Sydney Children’s Hospitals Network

  580 shared

• Matilde Laurá

  National Hospital for Neurology and Neurosurgery

  574 shared

• David N. Herrmann

  573 shared

• John Day

  Kaiser Permanente

  565 shared

Labs

• Scherer LaboratoryPI