United States

Background
Vulvovaginal diseases are under-reported and there is limited research on the nature of these conditions, the prevalence, and their impact patient on experience. Current estimates suggest 1 in 6 people with vulvas experience undiagnosed and untreated vulvovaginal discomfort over their lifetime. This may result from patient experiences of shame and stigma, lack of provider familiarity, or misunderstanding about these treatable conditions. Two of these conditions are vulvodynia and lichen sclerosus/lichen planus (LS/LP). Vulvodynia is a neuropathic pain condition and estimated to have a prevalence of 8% in the United States. LS/LP are chronic inflammatory and scarring disorders with a diagnosed prevalence of 0.05% in the United States, which is likely an underestimate.
Quality of life is a comprehensive method of evaluating physical and psychosexual aspects of vulvar disease. The Vulvar Quality of Life Index (VQLI) is a 15 question survey scored out of 45 with lower scores indicating lower quality of life. It has been validated to assess individual health and treatment response. This study aimed to better understand of how the quality of life differs for patients with LS/LP and vulvodynia compared to controls and how it changes over time with treatment. 

Methods
We are conducting a prospective cohort study using a baseline and follow-up surveys with the VQLI. Participants include adults in three groups: individuals with LS/LP, individuals with vulvodynia, and a control group without vulvar conditions (n=90). All participants completed an initial standardized questionnaire assessing vulvar quality of life. A follow-up survey was conducted five months later to evaluate changes over time. Comparative analyses were performed between groups to assess differences in baseline and follow-up outcomes. 

Results
Preliminary results include 51 participants: n=16 (control), n=23 (LS/LP), and n=12 (vulvodynia), with follow-up data from n=11, n=10, and n=4, respectively. Mean total scores differed significantly by group (ANOVA p=2.26×10⁷). Post hoc testing showed the greatest mean difference between vulvodynia and control, with additional significant differences between LS/LP and control and between vulvodynia and LS/LP. 

Conclusion
These findings demonstrate that vulvodynia and LS/LP severely impact quality of life compared to controls. As the study progresses, further data will clarify which variables most affect quality of life in vulvovaginal diseases. This may guide targeted counseling and follow-up. Treatment success may also be evaluated by its impact on quality of life.


AMA Research Challenge 2025 

Assessing the Impact of Vulvodynia and Lichen Sclerosus/Planus Using the Vulvar Quality of Life Index


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Background
The Soong classification grades the prominence of volar locking plates used to treat distal radius fractures in relation to the volar rim. The basis of the classification scheme is that increasing plate prominence over the volar rim and distal radius watershed zone is associated with increased likelihood of flexor tendon irritation and need for plate removal. However, recent studies report mixed results on the predictive value of the Soong classification for these outcomes. We hypothesized that the decreased predictive accuracy of Soong classification is due to misclassification between Soong grades secondary to a suboptimal correlation between the Soong classification on radiographs (XR) and computed tomography (CT). 

Methods
Fifty volarly displaced distal radius fractures treated with a volar locking plate in the international and publicly available ICUC database were reviewed. All cases with a postoperative XR and CT were included. Soong classification of the volar locking plate in relation to the volar ulnar rim was determined on both XR and CT by two independent, fellowship-trained hand surgeons using CT imaging as the gold standard. The distribution of Soong grades on XR and CT was compared using Pearson’s chi-square test, and correlation was calculated using the Matthews’ correlation coefficient (MCC). A multi-class confusion matrix was used to calculate each grade's positive predictive value (PPV). 

Results
We found the interrater correlation coefficient (ICC) between the two observers to be 100% for the grades as determined separately on radiographs and CT imaging. The MCC was 0.65, indicating only moderate correlation between the two modalities. Per individual Soong grade, the PPV was the highest for grade 2 (0.96), with lower PPVs for grade 0 (0.63) and grade 1 (0.60). 

Conclusions
Inter-observer Soong grading demonstrated an excellent correlation for radiographs and CT independently, though not between grades from XR and those using CT. This points to the Soong grading system being affected by imaging modality. Because of this, Soong grades based on radiographs should not be the only consideration for a physician when deciding whether to remove a VLP following the healing of distal radius fractures.


Soong Classification Using X-Rays Only Moderately Correlates with Distal Radius Plate Position on CT

Background: Women develop substance use disorders and seek treatment after fewer years of drug use compared to men, a pattern known as the telescoping effect. This phenomenon has been consistently demonstrated across epidemiological studies of cocaine, alcohol, opioids, and tobacco, and replicated in preclinical models with cocaine and opioids, strongly suggesting it is biologically driven. However, its underlying mechanisms remain unexplored. Using a rat model, we tested the hypothesis that calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens core (NAc), which are critical for cocaine craving in males, also drive the development of enhanced drug motivation, another key addiction-like feature in rodents, and that this process is accelerated in females, providing a potential mechanism underlying the telescoping effect.

Methods: Motivation for cocaine was assessed under a progressive-ratio schedule before (Pre-ExA PR) and after (Post-ExA PR) extended-access cocaine self-administration (24 h/day, 96 infusions/day, 10 days) and a 7-day withdrawal period. During withdrawal, females received intraperitoneal injections of the mGluR1 positive allosteric modulator SYN119 (SYN; 0 or10 mg/kg), which has been shown to prevent the recruitment of CP-AMPAR in the NAc, while males received intraperitoneal injections of the mGluR1 antagonist JNJ16259685 (JNJ; 0 or 5 mg/kg), which has been shown to accelerate the recruitment of CP-AMPAR in the NAc. Once a stable level of motivation was established after the withdrawal period, the effect of intra-NAc infusions of the CP-AMPAR antagonist Naspm (40 µg/side) was examined. In a separate cohort, NAc GluA1 and GluA2 protein levels were quantified to assess receptor composition after 7-days of withdrawal relative non-addiction controls (0-day timepoint).

Results: Females, but not males, developed enhanced motivation for cocaine following the 7-day withdrawal period (defined as a greater than 15% increase from Pre- to Post-ExA PR testing), recapitulating the telescoping effect. As predicted, this motivational shift was blocked in SYN-treated females and induced in JNJ-treated males. Intra-NAc Naspm infusions reduced cocaine motivation only in JNJ-treated males, confirming the functional contribution of CP-AMPARs. Molecular analyses in untreated controls revealed that only females showed GluA1-specific increases after 7 days of withdrawal, consistent with the recruitment of GluA2-lacking CP-AMPARs.

Conclusion: Together, these findings extend the role of CP-AMPARs in the NAc to include the development of enhanced drug motivation and highlight their significance in mediating the accelerated trajectory toward addiction in females. This work underscores CP-AMPAR recruitment as a key mechanism underlying multiple addiction-like behaviors and a promising target for developing novel treatment strategies.

CP-AMPA Receptors Drive the Telescoping Effect in a Rat Model of Cocaine Addiction

Abstract Title: 
Spontaneous Coronary Artery Dissection with Elevated Homocysteine – A Call for Surveillance in Patients with the MTHFR Mutation 

Background:
Elevated homocysteine is a known risk factor for vascular events1. Patients with the methylenetetrahydrofolate reductase (MTHFR) mutation are at increased risk for hyperhomocysteinemia, particularly in the setting of nutritional deficiencies2. We present a case of spontaneous coronary artery dissection (SCAD) associated with hyperhomocysteinemia in a patient with chronic alcohol use, nutritional deficiencies, and known MTHFR mutation.

Case Presentation:
A 52-year-old woman with a history of left subclavian deep vein thrombosis (18 years prior) and known MTHFR mutation presented with several months of exertional chest heaviness, accompanied by nausea, vomiting, and intermittent dizziness. A few days prior, an abnormal EKG (with baseline ST abnormalities) was noted during preoperative clearance for urethral sling surgery. An outpatient exercise stress test demonstrated markedly reduced functional capacity, though results were deemed equivocal due to baseline ST depression.

Initial workup in the ED revealed a normal cardiac exam, non-elevated troponins, and non-ischemic EKG. Transthoracic echocardiogram showed normal left ventricular systolic function without regional wall motion abnormalities. Given ongoing exertional symptoms, equivocal stress test results, and concern for unstable angina or SCAD, CT-derived fractional flow reserve imaging was acquired to minimize risk associated with coronary angiography. Imaging identified a type 3 SCAD in the mid-left anterior descending artery.

Laboratory studies revealed a markedly elevated homocysteine level (61 µmol/L; normal <14 µmol/L) and borderline folate (4.8 ng/mL). Although diagnosed with MTHFR mutation 13 years prior during prenatal testing, her homocysteine level had not been re-evaluated since. The patient endorsed longstanding alcohol use, intermittent bulimia nervosa, and poor nutritional intake. Notably, levels of vitamins B6, B9, and B12 had not been assessed within the past five years. She was managed conservatively with metoprolol, aspirin, and atorvastatin.

Discussion:
This case highlights an underrecognized intersection between genetic predisposition, nutritional status, and vascular risk. While SCAD is increasingly recognized as a non-atherosclerotic cause of myocardial ischemia, more commonly in younger women3, its association with hyperhomocysteinemia remains understudied. The MTHFR mutation alone does not typically result in hyperhomocysteinemia unless compounded by nutritional deficiencies. Current guidelines do not recommend routine homocysteine screening in patients with MTHFR mutations; however, this case illustrates the potential value of targeted surveillance in at-risk individuals. Periodic assessment of homocysteine and related cofactors (B6, B9, B12) may help identify modifiable contributors to vascular pathology before the development of irreversible events. Clinicians should maintain a high index of suspicion for hyperhomocysteinemia in patients with the MTHFR mutation and risk factors for nutritional deficiencies. 


Spontaneous Coronary Artery Dissection with Elevated Homocysteine – A Call for Surveillance in Patients with the MTHFR Mutation


Abstract Title:
A Diagnostic Challenge: Multi-System Serositis and Seropositivity in Adult-Onset Still’s Disease

Background: 
Adult-onset Still&#39;s disease (AOSD) is a rare, systemic autoinflammatory disorder of unknown etiology, which involves dysregulated innate immunity, with a central role for macrophage activation and overproduction of pro-inflammatory cytokines, particularly interleukin IL-1, IL-6, and IL-18. In AOSD, the absence of definitive diagnostic markers, and the requirement to exclude a broad range of mimicking conditions including infections, malignancies, and other rheumatological diseases, often leads to protracted diagnostic workups, and delayed delivery of care. 

Case Presentation: 
A 41-year-old previously healthy woman presented with high-grade fevers, headache, photophobia, sore throat, shortness of breath, and diffuse arthralgia. She was septic. Examination revealed cervical lymphadenopathy, and a maculopapular rash on her thighs. Initial laboratory studies were notable for leukocytosis, hyperferritinemia, transaminitis, and elevated troponins. Chest imaging (X-ray and CT) showed bilateral pleural effusions and pulmonary infiltrates. Blood and sputum cultures, along with a comprehensive infectious workup, were negative. An Echocardiogram showed myocardial edema suspicious of myocarditis. CT of abdomen revealed splenomegaly. Pleural fluid analysis showed an exudative effusion without organisms. A lumbar puncture showed aseptic meningitis. Broad-spectrum antibiotics were initiated but patient continued to be septic despite a 7-day course. Rheumatologic testing was positive for Rheumatoid Factor (RF), Antinuclear (ANA), Anti-Centromere, and Anti-Mitochondrial antibodies. Patient also developed odynophagia. Upper endoscopy revealed esophagitis and antral gastritis; biopsies showed non-infectious inflammation. Despite positive autoimmune antibodies corresponding with certain diseases, the lack of diagnostic clinical features and the rarity of widespread serosal inflammation in these conditions made an autoimmune cause unlikely. Subsequently, the patient met Yamaguchi criteria for AOSD, and a diagnosis was established after 2 weeks. (11) Antibiotics were discontinued, and the patient received intravenous Methylprednisolone for two days, then daily oral Prednisone. IL-6 inhibitor therapy was initiated. Sepsis rapidly resolved and remarkable recovery of symptoms was observed within 24 hours of steroid initiation.

Discussion:
This case illustrates the importance of maintaining a broad differential in patients with sepsis, atypical multisystemic inflammation, and negative cultures, especially when classic autoimmune criteria are not fully met. Additionally, while autoimmune serologies are typically negative in AOSD, their presence does not rule out the diagnosis. The pathogenesis involves innate and adaptive immunity, intersecting with autoimmune diseases. Nonetheless, overlap between AOSD and systemic autoimmune conditions is rare, primarily documented in isolated case reports. Current evidence refutes an increased risk of autoimmune disease in AOSD patients. This makes seropositivity a diagnostic challenge rather than an exclusion criterion.

A Diagnostic Challenge: Multi-System Serositis and Seropositivity 
In Adult-Onset Still’s Disease

Background:
Racial disparities in breast cancer incidence and outcomes remain a critical public health issue in the United States, with Black women experiencing earlier onset, more aggressive subtypes, and higher mortality rates than White women. Structural inequities in healthcare access are thought to drive these gaps, and more information is needed to characterize local cancer biorepositories.
This study leverages patient data from the Prisma Health Cancer Institute Biorepository in Upstate South Carolina for comparison with national data.
Methods:
We conducted a retrospective cohort analysis of 1,688 breast cancer cases treated at the Prisma Health Cancer Institute between January 2014 and December 2022. Demographic, lifestyle, and clinical variables—including age, race, BMI, presence of diabetes, smoking status, receptor (ER/PR/HER2) status, histology, and cancer stage—were extracted from the cancer patient records. Multiple correspondence analysis (MCA) of five categorical tumor markers (ER, PR, HER2, stage, histology) was followed by K-means clustering (optimal k=4) to identify biologically distinct patient subgroups. Odds ratios were calculated to explore associations between combined lifestyle factors and the likelihood of developing Triple Negative Breast Cancer (TNBC) versus Luminal A subtype. To provide the national context, comparative analyses were performed against the age-adjusted incidence and stage-at-diagnosis data from the 2018–2022 Surveillance, Epidemiology, and End Results (SEER) Program.
Results:
Black patients comprised 16.4% of the cohort but exhibited a higher proportion of TNBC (10.9% vs. 7.7% in White patients), higher obesity rates (mean BMI 32.9 vs. 29.4), and were more likely to be diagnosed before age 40 (5.7% vs. 4.8%). Clustering analysis confirmed four tumor biology–driven subgroups that differed significantly by stage and histology (p<0.05), but not by race, age, BMI, or menopausal status (all p>0.2). National SEER data show that non-Hispanic
Black women have roughly double the age-adjusted incidence of TNBC (25.3 vs. 12.6 per 100,000) and lower rates of localized-stage detection (55.3% vs. 63.8%) compared to White women. Our cohort mirrored these patterns with earlier onset and more advanced-stage presentation among Black patients. Lifestyle factor analyses yielded non-significant trends (e.g., diabetic overweight smokers had 0.45-fold odds of TNBC vs. non-smokers).
Conclusion:
Local breast cancer patterns among Black women align with national disparities in tumor subtype and stage at diagnosis. These findings underscore the need for culturally responsive screening strategies and targeted interventions to reduce inequities in breast cancer outcomes.

Breast Cancer in Focus: Analysis of Population-Based Differences at Prisma Health Cancer Institute

Abstract Title: Sociocultural Dynamics in Peer Evaluation: A Mixed-Methods Analysis in Undergraduate Medical Education
Justin Romero, BS; Cindy Carvajal, BS; Heather Laird-Fick, MD, MPH, FACP; Ling Wang, MS, PhD
Michigan State University- College of Human Medicine

Background
Peer evaluations have gained prominence in medical education for fostering feedback literacy, collaboration, and professional identity formation. At Michigan State University’s College of Human Medicine (CHM), peer feedback is central to Longitudinal Scholar Groups (LSGs), where students evaluate peers using structured prompts aligned with professionalism and teamwork. Despite growing use, little is known about how sociocultural factors like gender and race/ethnicity influence peer evaluation tone and content over time. This study aims to examine
patterns in peer feedback across M1 and M2 and explores whether demographic differences shape how students are assessed by their peers.

Methods
We analyzed 15,136 de-identified peer evaluations from M1 and M2, linked to self-reported sociodemographic data. Each included open-text responses to three questions on strengths, growth areas, and general comments. A subset (n=400 per cohort) was manually coded for themes (participation, personal skills, knowledge background, professionalism, leadership, teamwork, confidence, and no added value) and tone (positive/negative). A few-shot Large Language Model (Gemini 2.5 Flash) predicted themes for the remaining comments, which annotators double-verified. Chi-square tests examined differences across demographic and curricular variables.

Results
We analyzed evaluations for 378 students (170 male, 210 females; 219 White, 55 Asian, 22 Black, and 82 other races). Participation and personal skills were the most frequently cited strengths. Statistically significant differences by race and gender emerged across curricularcphases. Positive participation feedback differed by race in M1 (P = 0.003) and fall M2 (P =0.005), but not spring M2. Gender-based differences in participation appeared in M1 (P = 0.020) and fall M2 (P = 0.004). Personal skills showed racial significance only in M1 (P = 0.001), while gender-based differences appeared in fall (P = 0.038) and spring M2 (P = 0.043). Knowledge background feedback showed no early racial differences but was significant in spring M2 (P = 0.008), suggesting evolving peer feedback priorities. Notably, confidence-related feedback differed by gender in MCE Spring (P = 0.017), while no significant patterns were found in leadership evaluations across cohorts. These findings suggest that sociocultural dynamics, including gender and race, subtly but significantly influence peer feedback over time.

Conclusion
Peer evaluations within CHM LSGs consistently emphasize participation and interpersonal dynamics. Preliminary data support the hypothesis that feedback tone and content may shift with educational stage and be influenced by gender and race. These findings provide a foundation for refining equitable peer-assessment practices in medical education.

Sociocultural Dynamics in Peer Evaluation:
A Mixed-Methods Analysis in Undergraduate Medical Education

Abstract Title
Improving Access and Outcomes: A Comprehensive Look at Breast Cancer Care in Ghana
Background
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related mortality among Ghanaian women, accounting for nearly one-third of new cancer cases in 2020. Diagnosis typically occurs around age 49, with nearly half of patients presenting at advanced stages. Although cancer services have expanded, access to early detection and follow-up care continues to vary based on geography and socioeconomic status. This review examines national trends in breast cancer screening, treatment availability, and survivorship, with a focus on actionable strategies to improve access and outcomes.
Methods
We conducted a comprehensive review of peer-reviewed literature, national datasets, and clinical trial registries, including analysis of the 2022 Ghana Demographic and Health Survey. To evaluate how access to screening varied across sociodemographic groups, we used chi-square tests and built a multivariable logistic regression model to calculate adjusted odds ratios (ORs) for breast cancer screening by wealth quintile, education level, and residence.
Results
Survey data suggest that fewer than one in five women aged 15–49 in Ghana have ever received a breast cancer screening. Screening rates were significantly higher among women with greater wealth, education, and those living in urban areas (p < 0.0001 for all comparisons). Women in the highest wealth quintile had over six times the odds of screening compared to those in the lowest (OR 6.11; 95% CI: 5.18–7.20). Education had an even stronger association, with women who had more than secondary schooling nearly nine times more likely to be screened than those with no formal education (OR 8.98; 95% CI: 7.57–10.66). Urban residence was associated with twice the odds of screening compared to rural residence (OR 2.13; 95% CI: 1.95–2.33).
Patterns of inequity are also mirrored in the distribution of treatment services. For instance, chemotherapy and radiation remain primarily available in Accra, Kumasi, and Tamale. Services essential for survivorship, including surveillance imaging and psychosocial support, also remain concentrated at major referral hospitals.
Conclusion
These findings highlight persistent differences in breast cancer screening and treatment access across wealth, education, and geography, and emphasize the need for targeted improvements to reach underserved populations. Addressing these issues through data-driven planning, patient-centered education, and coordinated service delivery can lead to more equitable care and earlier detection. This work offers a meaningful contribution to breast cancer research in Ghana and informs future strategies for improving access, reducing delays, and supporting patients across all stages of care.

Improving Access and Outcomes: A Comprehensive Look at Breast Cancer in Ghana

Background:
Cutaneous malignancies pose a significant burden to public health, with prevention
being critical for improving health outcomes. This study analyzed the demographic and clinical characteristics of 435 uninsured patients presenting to an outpatient, low-income, community dermatology clinic. The goal was to assess the incidence of
cutaneous neoplasms and pre-cancer lesions and identify disparities in preventive care.

Methods:
We retrospectively analyzed 435 electronic medical records collected from an
outpatient, predominantly low-income, community dermatology clinic from 2021 to 2024. Diagnoses and management plans were made by board-certified dermatologists or resident physicians under dermatologist supervision. Data on race, ethnicity, sex, age, diagnoses and treatment plans were extracted for analysis.

Results:
Demographic data were collected, among 435 patients, yielding: Race: White (n=230), Black (n=87), Asian/Pacific Islander (n=24), Hispanic (n=12), Prefer not to answer (n=82). Ethnicity: Hispanic or Latino (n=95), Not Hispanic or Latino (n=294), Unknown (n=34), Prefer not to answer (n=12). Gender: Male (n=160), Female (n=275). The mean age was 50.8 (SD 12.4). Our data reveal a total of 86 (20%) patients diagnosed with cutaneous neoplasms or pre-cancerous lesions. Actinic keratoses were diagnosed in 38 (9%) patients, basal cell carcinomas in 29 (6%), squamous cell carcinomas in 15 (3%), and melanoma in 4 (1%). A total of three patients were using chemoprevention, with 2 (0.5%) using 5-fluorouracil and 1 (0.2%) using acitretin.

Discussion:
Our data underscores the high prevalence of pre-cancerous and cancerous lesions in low-income communities, but the underutilization of therapies that could mitigate
disease progression. Notably, 20% of patients were diagnosed with a pre-cancerous or cancerous lesion, but less than 1% of patients were receiving chemo-preventative care.

Conclusion:
Cutaneous neoplasms and pre-cancerous lesions were noted at a considerably high
incidence in our free clinic population. However, chemo-prevention was relatively low compared to the diagnosed cancers and pre-cancers. Further research should evaluate the perceptions and barriers for chemoprevention among low-income populations at risk of skin cancer.

Cutaneous Malignancies and Chemoprevention in Underserved Communities: A Retrospective Analysis

Background
Ehlers-Danlos Syndrome (EDS) is a group of connective tissue disorders often associated with hyperflexibility, dysautonomia, and gastrointestinal (GI) dysmotility. Although gastroparesis related to EDS is often underrecognized, it can lead to significant morbidity and impacts on quality of life when refractory to many medical therapies. We present a case of medically refractory gastroparesis in a young female patient with hypermobile EDS (hEDS; EDS Type 3), gastroparesis, sick sinus syndrome (SSS), and postural orthostatic hypotension (POTS) who experienced clinical improvement following gastric per-oral endoscopic myotomy (G-POEM).
Case Presentation
A 23-year-old woman with hEDS, gastroparesis with a gastrojejunal feeding tube, POTS, and SSS with a pacemaker presented with intractable nausea and vomiting. She had a prior diagnosis of gastroparesis confirmed by a gastric emptying study. She had undergone extensive outpatient and inpatient trials of both standard and atypical antiemetics and prokinetics without meaningful relief. She was hospitalized for nearly a month for symptomatic and nutritional support, with no clear cause on imaging.
During admission, a PICC line was placed, and she was started on TPN for nutritional support due to inability to tolerate gastrojejunal (GJ) tube feeds. Additionally, she received a gastric pylorus botulinum toxin injection, which provided minimal relief. The patient was ultimately discharged on TPN with outpatient follow up with GI for G-POEM procedure.
The patient underwent an uncomplicated G-POEM procedure. Within one month, the patient reported improvement in her nausea and oral intake and was weaning herself off TPN while gaining weight.
Discussion
Gastroparesis in patients with hEDS is likely multifactorial, involving autonomic dysfunction, visceral smooth muscle impairment, and connective tissue abnormalities. In this case, the patient received extensive pharmacological therapies and pyloric botulinum toxin without substantial benefit, ultimately requiring TPN. 
G-POEM, a minimally invasive procedure that cuts the pyloric sphincter muscle, is gaining popularity as a treatment for refractory gastroparesis. Although its role in hEDS is still under investigation, this case highlights its potential benefit, especially in cases where patients fail medical management and require nutritional support


Refractory gastroparesis in a patient with Ehlers-Danlos Syndrome: Symptomatic improvement following G-POEM

Authors:
Paola P. Colón Terrón, B.S. 1,3, Linda Pérez, , DrPH, MSc 1,3, Elinette M. Albino, , MT(ASCP), PhD, MS 2,3
1 San Juan Bautista School of Medicine 2 School of Health Professions, University of Puerto Rico Medical Science Campus 3 Puerto Rico Genetics Laboratory

Abstract Title:
Subclinical Elevations of C5DC in Puerto Rican Children with Neurodevelopmental Disorders: Exploring a Potential Metabolic Signature of Neurogenetic Risk

Background:
Glutarylcarnitine (C5DC) is a dicarboxylic acylcarnitine involved in the catabolism of lysine and tryptophan. Its accumulation is typically associated with glutaric acidemia type I (GA1), a rare metabolic disorder. However, in Puerto Rico, a population with a high burden of rare and recessive genetic conditions, C5DC levels have been observed to be consistently elevated in children with neurodevelopmental symptoms, though not reaching the threshold required for a GA1 diagnosis. This pattern raises the possibility that subclinical elevations of C5DC may reflect
an underlying metabolic signature associated with broader neurogenetic risk.

Methods:
We conducted a retrospective analysis of acylcarnitine profiles in a cohort of Puerto Rican pediatric patients (n = 98) with clinical features suggestive of neurogenetic disorders. C5DC levels were measured via tandem mass spectrometry and correlated with clinical phenotypes, neuroimaging findings, and genetic testing results.

Results:
LASSO linear regression with 10-fold cross-validation identified seventeen phenotypes associated with C5DC levels: Bell’s palsy, behavioral delays, encephalopathy, gender, aggressive behavior, hearing loss, hypotonia, epilepsy, developmental disorder of speech, sensory issues, intellectual disability, Charcot-Marie-Tooth disease, and autism spectrum disorder, among others. Post-LASSO linear regression analysis showed statistically significant associations between C5DC levels and behavioral delays (p < 0.010), aggressive behavior (p < 0.05), hearing loss (p < 0.05), epilepsy (p < 0.05), and sensory issues (p < 0.05). Notably, the majority of cases were clustered in the northern region of Puerto Rico, with the top five municipalities being San Juan, Vega Baja, Carolina, Bayamon, and Toa Alta.

Conclusion:
These preliminary findings suggest that subclinical elevations of C5DC may be indicative of neurogenetic vulnerability in Puerto Rican children. C5DC may serve as a metabolic biomarker worthy of further investigation for inclusion in neurogenetic screening panels, especially in genetically isolated populations with known founder effects and high consanguinity. Continued research is needed to elucidate the mechanistic basis of this association and its diagnostic potential.

Subclinical Elevations of C5DC in Puerto Rican Children with Neurodevelopmental Disorders: Exploring a Potential Metabolic Signature of Neurogenetic Risk

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