Severe Hypertriglyceridemia in Patients with Type 2 Diabetes Mellitus Participating in the AMD Annals Initiative.

Background: Familial chylomicronemia syndrome (FCS) is a rare inherited condition due to lipoprotein lipase deficiency, characterized by hyperchylomicronemia and severe hypertriglyceridemia. Diagnosis is often delayed, thus increasing the risk of acute pancreatitis and hospitalization. Hypertriglyceridemia is a common finding in patients with type 2 diabetes (T2D), who may harbor FCS among the most severe forms. Aim of the Study: We investigated the prevalence and clinical characteristics associated with severe hypertriglyceridemia in a range indicative of FCS, in a large population of subjects with T2D. Methods: Within the large population of the AMD Annals Initiative, patients with T2D with a lipid profile suggestive of FCS [triglycerides >880 mg/dL and/or high-density lipoprotein (HDL)-cholesterol <22 mg/dL or non-HDL-cholesterol ≤70 mg/dL] and their clinical features have been identified. Results: Overall, 8592 patients had triglyceride values >880 mg/dL in a single examination, 613 in two examinations, and 34 in three or more measurements. Patients with high triglyceride levels were mostly male (80%), with a relatively young age (54 years), short duration of diabetes (6.3 years), and elevated hemoglobin A1c (HbA1c) levels (9.4%). By stratifying this group of patients according to the severity of hypertriglyceridemia, more severe hypertriglyceridemia (triglyceride levels ≥2000 mg/dL) was associated with an even younger age (52 vs. 54 years), even higher mean HbA1c values (10.0% vs. 9.4%), and significantly higher HDL-cholesterol levels (37.9 vs. 32.4 mg/dL; P < 0.0001). Patients with persistently elevated triglyceride levels (n = 34), on three measurements, had a younger age; lower body mass index, HbA1c, and HDL-cholesterol levels; more frequent use of fibrates and insulin; and a higher prevalence of major cardiovascular events. Conclusions: Severe hypertriglyceridemia is a frequent condition in outpatients with T2D participating in the AMD Annals Initiative, and it is associated with male sex, young age, short disease duration, and a worse glycemic profile. Among patients with persistent severe hypertriglyceridemia, hidden FCS may be present.

Distinct structural brain network properties in children with familial versus non-familial attention-deficit/hyperactivity disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is among the most prevalent, inheritable, and heterogeneous childhood-onset neurodevelopmental disorders. Children with a hereditary background of ADHD have heightened risk of having ADHD and persistent impairment symptoms into adulthood. These facts suggest distinct familial-specific neuropathological substrates in ADHD that may exist in anatomical components subserving attention and cognitive control processing pathways during development. The objective of this study is to investigate the topological properties of the gray matter (GM) structural brain networks in children with familial ADHD (ADHD-F), non-familial ADHD (ADHD-NF), as well as matched controls. A total of 452 participants were involved, including 132, 165 and 155 in groups of ADHD-F, ADHD-NF and typically developed children, respectively. The GM structural brain network was constructed for each group using graph theoretical techniques with cortical and subcortical structures as nodes and correlations between volume of each pair of the nodes within each group as edges, while controlled for confounding factors using regression analysis. Relative to controls, children in both ADHD-F and ADHD-NF groups showed significantly higher nodal global and nodal local efficiencies in the left caudal middle frontal gyrus. Compared to controls and ADHD-NF, children with ADHD-F showed distinct structural network topological patterns associated with right precuneus (significantly higher nodal global efficiency and significantly higher nodal strength), left paracentral gyrus (significantly higher nodal strength and trend toward significantly higher nodal local efficiency) and left putamen (significantly higher nodal global efficiency and trend toward significantly higher nodal local efficiency). Our results for the first time in the field provide evidence of familial-specific structural brain network alterations in ADHD, that may contribute to distinct clinical/behavioral symptomology and developmental trajectories in children with ADHD-F.

The increased chromosomal DNA damage in patients with Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disease. In this study, we aimed to assess chromosomal DNA damage and cell proliferation by using cytokinesis-block micronucleus cytome (CBMN-cyt) assay in the peripheral blood lymphocytes of untreated FMF patients carrying M694V and R202Q mutations, which are the most common MEFV gene mutations in Turkish society. The study included 20 untreated FMF patients with M694V and R202Q mutations and 20 healthy individuals of similar age and sex as the control group. Micronucleus (MN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) were scored in the obtained bi-nucleated (BN) cells. Additionally, the nuclear division index (NDI) was calculated using the scores of mononuclear, binuclear, and multinuclear cells. We found that MN and NPBs frequencies in FMF patients were significantly higher than in controls, and number of metaphases was significantly lower (respectively, p < 0.05, p < 0.01, and p < 0.01). However, there was no significant difference in NBUDs frequencies and NDI values between FMF patients and controls (p > 0.05). Our study is the first to evaluate FMF patients' lymphocytes using the CBMN-cyt assay, as no previous research has been found in this respect. Increased MN and NPB frequencies may be useful as biomarkers for chromosomal DNA damage, and may indicate a potential for elevated cancer risk in untreated FMF patients.

Solving a diagnostic dilemma in a patient with periodic fever-When the pieces of the puzzle finally fit.

The lack of pediatric subspecialists locally prior to 5 years ago, meant that some of our patients with rare, relapsing conditions were left behind. Familial Mediterranean fever can be diagnosed clinically and supported via genetic panel studies. Although neurological symptoms can be non-specific, this system symptomatology may lead patients and carers to seek medical attention. When neurological symptoms progress, seemingly refractory to first-line treatment, or suggestive of colchicine resistance, CNS demyelination should be considered by the neurologist. Abstract: Familial Mediterranean fever (FMF) is an inherited disorder with episodic fevers accompanied by pain in the abdomen, joints, or chest. It is a clinical entity that can be confirmed with a specific genetic mutation. Neurological symptoms have not been a focal point in clinical case descriptions. We aim to present the long road to diagnosing our patient, where the diagnostic clues centered around her neurological symptoms.

Familial 46, XY Disorder of Sexual Development identified in a Ph+BCR::ABL1P210+ Acute Lymphoblastic Leukemia septuagenarian female with RCBTB2::LPAR6 fusion gene: a case report.

Background: Familial 46, XY Disorder of Sexual Development (DSD) was discovered in a Ph+, BCR::ABL1P210+ Acute Lymphoblastic Leukemia (ALL) female with RCBTB2::LPAR6 fusion gene. Siblings developing 46, XY DSD are extremely rare. Patients with 46, XY DSD have much higher rates of gonadal cancers. Nevertheless, the incidence of hematologic malignancies in patients with DSDs has received little attention. RCBTB2::LPAR6 is a rarely reported fusion gene in ALL. Case presentation: Herein, we report a rare case of a newly diagnosed Ph+, BCR::ABL1P210+ ALL patient who was 77 years old and female by social sex. Whole Exome Sequencing (WES) and RNA sequencing revealed TET2 and NF1 mutations in addition to a rarely reported RCBTB2::LPAR6 fusion gene and 17 other genes with uncertain clinical significance. The patient was surprisingly found to have a male karyotype. On ultrasound, neither the uterus nor the ovaries were discernible. A detailed family and marital history revealed that the patient had undergone surgery at an early age for an unexplained inguinal mass. She had slow pubertal development, scanty menstruation, and few overtly feminine characteristics. She had three marriages, but none succeeded in getting pregnant. The patient had never sought therapy for infertility due to the inaccessibility of medical treatment and a lack of medical knowledge. Her sister, 73 years old and female by social sex, who had amenorrhea in adolescence and was unable to conceive, had the same experience. To our surprise, she also had a male karyotype. Conclusions: Due to the absence of long-term social attention and follow-up, studies on the incidence of hematologic malignancies in patients with 46, XY DSD are incredibly uncommon. Siblings developing 46, XY DSD is extremely rare. We report the oldest patient diagnosed with 46, XY DSD. There have not yet been any reports of familial 46, XY DSD with a concurrent diagnosis of Ph+BCR::ABL1P210+ ALL with a rarely reported RCBTB2::LPAR6 fusion gene.

In vivo Mapping of the Mouse Galnt3-specific O-Glycoproteome.

The UDP-N-acetylgalactosamine polypeptide:N-acetylgalactosaminyltransferase (GalNAc-T) family of enzymes initiates O-linked glycosylation by catalyzing the addition of the first GalNAc sugar to serine or threonine on proteins destined to be membrane-bound or secreted. Defects in individual isoforms of the GalNAc-T family can lead to certain congenital disorders of glycosylation (CDG). The GALNT3-CDG, is caused by mutations in GALNT3, resulting in hyperphosphatemic familial tumoral calcinosis (HFTC) due to impaired glycosylation of the phosphate-regulating hormone FGF23 within osteocytes of the bone. Patients with hyperphosphatemia present altered bone density, abnormal tooth structure and calcified masses throughout the body. It is therefore important to identify all potential substrates of GalNAc-T3 throughout the body to understand the complex disease phenotypes. Here, we compared the Galnt3-/- mouse model, which partially phenocopies GALNT3-CDG, with wild-type mice and employed a multi-component approach utilizing chemoenzymatic conditions, a product-dependent method constructed using EThcD triggered scans in a mass spectrometry workflow, quantitative O-glycoproteomics, and global proteomics to identify 663 Galnt3-specific O-glycosites from 269 glycoproteins across multiple tissues. Consistent with the mouse and human phenotypes, functional networks of glycoproteins that contain GalNAc-T3-specific O-glycosites involved in skeletal morphology, mineral level maintenance and hemostasis were identified. This library of in vivo GalNAc-T3-specific substrate proteins and O-glycosites will serve as a valuable resource to understand the functional implications of O-glycosylation and to unravel the underlying causes of complex human GALNT3-CDG phenotypes.

Impact of Consanguinity and Familial Aggregation on Vitiligo Epidemiology in Saudi Arabia: A Case-Control Study.

Background Vitiligo, characterized by depigmented patches due to melanocyte loss, involves genetic, autoimmune, and environmental factors. Recent studies suggest a link between family history, consanguinity, and vitiligo prevalence, particularly in regions with prevalent consanguineous marriages. This study explored the relationship between consanguinity and familial vitiligo prevalence in Saudi Arabia. Methods A case-control study enrolled 792 participants from Saudi dermatology clinics (382 vitiligo cases, 408 controls). Family histories and consanguinity levels were assessed. Logistic regression analysis, adjusting for relevant variables, evaluated associations. Results Significant associations were found between vitiligo and both parental consanguinity and family history. Cases had higher consanguinity rates, with 246 out of 382 (64.4%), compared to controls, with 161 out of 408 (39.5%). A positive family history of vitiligo was more common in cases, with 184 out of 382 (48.2%) than in controls, with 90 out of 408 (22.1%). Logistic regression identified parental consanguinity and positive family history as significant risk factors for vitiligo, with adjusted odds ratios (aOR) of 2.39 and 2.92, respectively. Their synergistic effect notably amplified the risk (aOR = 7.58), indicating a complex genetic and familial influence on vitiligo in Saudi Arabia. Conclusions Consanguinity showed a significant association with vitiligo prevalence, highlighting genetic factors' role. Further genetic research is needed to identify specific mutations in vitiligo among consanguineous populations. Genetic counseling and awareness programs are crucial in regions with high consanguinity rates to mitigate vitiligo and other genetic disorders' risks.

[Challenges in diagnosing familial Mediterranean fever: exploring atypical clinical features. Clinical case].

This clinical case series presents descriptions of 3 patients with familial Mediterranean fever (FMF) who have atypical manifestations and abnormal inheritance mechanisms in terms of Gregor Mendel's laws. Although molecular genetic testing can help with disease diagnosis, it is not always conclusive. The primary need for genetic testing in atypical cases is to explain the mechanism of inflammation and to select the optimal therapy. These clinical observations demonstrate the changes in the spectrum of phenotypic manifestations of FMF in the context of the widespread introduction of molecular genetic methods.

Multiple Cavernous Malformation Syndrome in an Infant: A Case Report.

Cerebral cavernomas belong to a group of vascular lesions characterized by varying structural properties and presentations. Clinical manifestations vary among patients and are particularly influenced by age, posing challenges in diagnosis and treatment. Here, we present a pediatric case of a cerebral cavernoma, which is very rare. We further aim to emphasize the importance of a good physical examination.

Hypolipidemia due to Familial Hypobetalipoproteinemia in Adolescents.

Background/Objective: Individuals with heterozygous familial hypobetalipoproteinemia (h-FHBL) due to loss-of-function mutation in the apolipoprotein B gene are typically asymptomatic with mild liver dysfunction, which is often detected incidentally. About 5% to 10% of those with h-FHBL develop steatohepatitis which occasionally progress to cirrhosis especially in the presence of alcohol use, excess calorie consumption, or liver injury. We report 3 patients with hypobetalipoproteinemia, 2 with confirmed h-FHBL, and 1 with suspected h-FHBL. Case Report: Three asymptomatic adolescents presented with low lipid levels detected on screening laboratory studies. Patient 1, a 13 6/12-year-old male and patient 2, a 15 9/12-year-old female, were siblings. Patient 3 was a 12 6/12-year-old female. All had total cholesterol ranging from 61 to 87 mg/dL, low-density lipoprotein cholesterol 10 to 28 mg/dL, and triglycerides 19 to 36 mg/dL. Aspartate transaminase and alanine transaminase levels were normal in patients 1 and 3 and were elevated in patient 2. Liver ultrasounds of patients 2 and 3 showed hepatic steatosis. Molecular testing identified pathogenic variant of apolipoprotein B gene in patients 1 and 2, c.133C>T(p.Arg.45Ter) confirming the diagnosis of h-FHBL. Discussion: More studies are needed in children with h-FHBL and other forms of hypobetalipoproteinemia to improve awareness of these disorders and to develop guidelines for monitoring and risk reduction in affected patients. Conclusion: Health care providers should be aware that persistent hypolipidemia may indicate h-FHBL, which can be a risk factor for liver dysfunction. Youth with h-FHBL should be counseled about lifestyle modifications and screened for the development of metabolic dysfunction-associated steatotic liver disease.

Familial aggregation of urolithiasis: findings from a Nationwide Middle Eastern study.

This study aimed to determine the potential effect of genetic factors and positive family history on the familial aggregation of urolithiasis in Iran. Of the total 44,186 participants in the Iran National Stone Survey (INSS) database, 34,953 individuals who were members of 8629 nuclear families were included in this study. The mean prevalence of urolithiasis was 5.7% [95%CI: 5.5 - 6.0%] in this subpopulation. Familial aggregation of urolithiasis was analyzed in 34,745 participants (99.6% of those originally included) utilizing a multivariable logistic regression with second order generalized estimating equations approach (GEE2) to adjust for sex, age, urbanization status and ethnicity. Recurrence risk ratios (λ) were used to evaluate the degree of familial aggregation. Our multivariable analysis demonstrated a strong familial aggregation of urolithiasis within sibling pairs (λs = 78.35), parent-offspring pairs (λo = 40.12) and spouse pairs (λsp = 21.62). The respective ORs were 5.65 [95%CI: 3.49, 9.14] for siblings, 2.85 [95%CI: 2.20, 3.68] for parents and 1.27 [95%CI: 1.06, 1.54] for spouses. Urinary stone disease tends to aggregate in families with a positive history of urolithiasis in either the parents or siblings. Siblings have a more prominent effect in inducing familial aggregation compared to parents. Despite the prominent role of familial genetic components in urolithiasis aggregation, shared environmental factors appear to partake in this phenomenon to some extent, as suggested by urolithiasis aggregation among spouse pairs.

A cohort analysis of familial partial lipodystrophy from two Mediterranean countries.

AIM: To assess the disease burden of familial partial lipodystrophy (FPLD) caused by LMNA (FPLD2) and PPARG (FPLD3) variants to augment the knowledge of these rare disorders characterized by selective fat loss and metabolic complications. MATERIALS AND METHODS: An observational longitudinal study, including 157 patients (FPLD2: 139 patients, mean age 46 ± 17 years, 70% women; FPLD3: 18 patients, mean age: 44 ± 17 years, 78% women) from 66 independent families in two countries (83 from Turkey and 74 from Spain), was conducted. RESULTS: Patients were diagnosed at a mean age of 39 ± 19 years, 20 ± 16 years after the first clinical signs appeared. Men reported symptoms later than women. Symptom onset was earlier in FPLD2. Fat loss was less prominent in FPLD3. In total, 92 subjects (59%) had diabetes (age at diagnosis: 34 ± 1 years). Retinopathy was more commonly detected in FPLD3 (P < .05). Severe hypertriglyceridaemia was more frequent among patients with FPLD3 (44% vs. 17%, P = .01). Hepatic steatosis was detected in 100 subjects (66%) (age at diagnosis: 36 ± 2 years). Coronary artery disease developed in 26 patients (17%) and 17 (11%) suffered from a myocardial infarction. Turkish patients had a lower body mass index, a higher prevalence of hepatic steatosis, greater triglyceride levels and a tendency towards a higher prevalence of coronary artery disease. A total of 17 patients died, with a mean time to death of 75 ± 3 years, which was shorter in the Turkish cohort (68 ± 2 vs. 83 ± 4 years, P = .01). Cardiovascular events were a major cause of death. CONCLUSIONS: Our analysis highlights severe organ complications in patients with FPLD, showing differences between genotypes and Mediterranean countries. FPLD3 presents a milder phenotype than FPLD2, but with comparable or even greater severity of metabolic disturbances.

Potential association between M694V homozygous mutation in familial Mediterranean fever and eosinophilic intestinal inflammation: a pediatric case series.

Familial Mediterranean fever (FMF) is the most common hereditary systemic auto-inflammatory disease. Digestive complaint is a common feature during FMF attacks. Nevertheless, digestive complaint in attack-free period has scarcely been studied. This retrospective monocentric study aimed to describe the clinical, histological, and genetic features of pediatric patients with FMF who underwent endo-colonoscopy in this setting. Out of 115 patients with a diagnosis of FMF, 10 (8, 7%) underwent endoscopy or colonoscopy. All displayed homozygote MEFV M694V mutation and presented chronic abdominal pain, iron deficiency, and/or growth retardation. On the histological level, all patients displayed low-grade mucosal inflammation, characterized by a moderate eosinophilic infiltrate in the lamina propria sometimes associated with increased crypt apoptosis. The proportion of patients explored with endoscopy or colonoscopy was 0.4 patients per year in our center, compared with 5.7 patients per year nationwide. This study identified a specific intestinal phenotype that does not respond to the criteria of classical inflammatory bowel disease: pediatric FMF pediatric patients with homozygous MEFV M694V, abdominal pain, iron deficiency, and growth retardation should benefit from specialized gastroenterological advice.

Exploring Familial Adenomatous Polyposis Through Radiology: A Case Series and Literature Review.

Familial adenomatous polyposis (FAP) is a dominantly inherited, autosomal form of hereditary condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. The early development of adenomatous polyps in the colon and rectum predisposes to rampant proliferation, which usually leads to colorectal cancer. Hence, this condition demands intensive surveillance and aggressive intervention. This case report epitomizes the convergence of advanced imaging with genetic diagnosis and, in essence, points toward a complete multidisciplinary approach as critical for proper management of FAP. The detailed evaluation of two siblings presenting with similar gut symptoms from this article focused on the individualization that this condition needs when managed, although underpinning the critical role coordinated care plays in changing disease outcomes.

Discovery of a Novel Shared Variant Among RTEL1 Gene and RTEL1-TNFRSF6B lncRNA at Chromosome 20q13.33 in Familial Progressive Myoclonus Epilepsy.

Background: Progressive myoclonus epilepsy (PME) is a neurodegenerative disorder marked by recurrent seizures and progressive myoclonus. To date, based on the phenotypes and causal genes, more than 40 subtypes of PMEs have been identified, and more remain to be characterized. Our study is aimed at identifying the aberrant gene(s) possibly associated with PMEs in two siblings born to asymptomatic parents, in the absence of known genetic mutations. Methods: Clinical assessments and molecular analyses, such as the repeat expansion test for CSTB; SCA1, 2, 3, 6, and 7; whole exome sequencing (WES); and mitochondrial genome sequencing coupled with computational analysis, were performed. Results: A family-based segregation analysis of WES data was performed to identify novel genes associated with PMEs. The potassium channel, KCNH8 [c.298T>C; (p.Tyr100His)], a DNA repair gene, regulator of telomere elongation helicase 1 (RTEL1) [c.691G>T; (p.Asp231Tyr)] and long noncoding RNA, RTEL1-TNFRSF6B [chr20:62298898_G>T; NR_037882.1, hg19] were among the candidate genes that were found to be associated with PMEs. These homozygous variations in siblings belong to genes with a loss-of-function intolerant (pLI) score of ≤ 0.86, expected to be detrimental by multiple computational analyses, and were heterozygous in parents. Additionally, computational analysis and the expression of RTEL1 and RTEL1-TNFRSF6B revealed that RTEL1-TNFRSF6B may modulate RTEL1 via hsa-miR-3529-3p. In the patient with the severe phenotype, a further deleterious mutation in SLC22A17 was identified. No de novo variants specific to these probands were identified in the mitochondrial genome. Conclusions: Our study is the first to report variants in KCNH8, RTEL1, and RTEL1-TNFRSF6B among PME cases. These genes when characterized fully may shed light on pathogenicity and have the potential to be used in the diagnosis of PME.

Acute Coronary Syndrome in a 9-Year-Old Girl With Homozygous Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a prevalent and underrecognized disorder. A young girl with previously undiagnosed homozygous FH presented with acute coronary syndrome. Severe coronary ostial stenosis and severe supravalvular aortic stenosis from atheromatous plaque was discovered. This case highlights the importance of screening and timely diagnosis of FH.

Use of Evolocumab in Familial Hyperlipidemia With Isolated Heart Transplant.

We describe a novel use of evolocumab for successful postoperative lipid control in a patient with familial hyperlipidemia who underwent isolated heart transplantation. We believe that this case carries valuable lessons regarding post-transplant proprotein convertase subtilisin kexin 9 inhibitor use with implications for the future of combined organ allocation and transplantation waitlist times.

How do gene mutation diversity and disease severity scoring affect physical capacity and quality of life in children/adolescents with Familial Mediterranean Fever?

OBJECTIVES: The aim of this study is to examine how gene mutation diversity and disease severity affect physical capacity and quality of life in children/adolescents with Familial Mediterranean Fever (FMF). METHODS: Eighty children/adolescents (42 female, 38 male) diagnosed with FMF according to Tell-Hashomer diagnostic criteria were included in this study. Disease severity score (PRAS), running speed and agility and strength subtests of Bruininks-Oseretsky Test of Motor Proficiency Second Edition Short Form (BOT-2 SF), Physical Activity Questionnaire, Pediatric Quality of Life Inventory 3.0 Arthritis Module (PedsQL) was used for evaluation. Participants were divided into 2 groups as M694V and other mutations according to MEFV gene mutation and were divided into 3 groups as mild, moderate and severe according to PRAS. RESULTS: When the data were compared between groups; in terms of gene mutation, a significant difference was observed in treatment subtest of PedsQL-parent form in favor of the M694V gene mutation group (p<0.05). In terms of PRAS, significant difference was seen in the pain, treatment subtests and total score of the PedsQL-child form, and in the pain, treatment, worry subtests and total score of the PedsQL-parent form in favor of the mild group (p<0.05). CONCLUSIONS: MEFV gene mutations in children and adolescents with FMF did not differ on physical capacity and quality of life. PRAS was not effective on physical parameters, but quality of life decreased as the severity score increased. Encouraging children/adolescents with FMF to participate in physical activity and to support them psychosocially can be important to improve their quality of life.

Novel Drp1 GTPase Inhibitor, Drpitor1a: Efficacy in Pulmonary Hypertension.

BACKGROUND: Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH). We developed a potent Drp1 GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy in PAH are unknown. METHODS: Drpitor1a's ability to inhibit recombinant and endogenous Drp1-GTPase was assessed. Drpitor1a's effects on fission were studied in control and PAH human pulmonary artery smooth muscle cells (hPASMC) and blood outgrowth endothelial cells (BOEC). Cell proliferation and apoptosis were studied in hPASMC. Pharmacokinetics and tissue concentrations were measured following intravenous and oral drug administration. Drpitor1a's efficacy in regressing monocrotaline-PAH was assessed in rats. In a pilot study, Drpitor1a reduced PA remodeling only in females. Subsequently, we compared Drpitor1a to vehicles in normal and monocrotaline-PAH females. RESULTS: Drp1 GTPase activity was increased in PAH hPASMC. Drpitor1a inhibited the GTPase activity of recombinant and endogenous Drp1 and reversed the increased fission, seen in PAH hPASMC and PAH BOEC. Drpitor1a inhibited proliferation and induced apoptosis in PAH hPASMC without affecting electron transport chain activity, respiration, fission/fusion mediator expression, or mitochondrial Drp1 translocation. Drpitor1a did not inhibit proliferation or alter mitochondrial dynamics in normal hPASMC. Drpitor1a regressed monocrotaline-PAH without systemic vascular effects or toxicity. CONCLUSIONS: Drpitor1a is a specific Drp1-GTPase inhibitor that reduces mitochondrial fission in PAH hPASMC and PAH BOEC. Drpitor1a reduces proliferation and induces apoptosis in PAH-hPASMC and regresses monocrotaline-PAH. Drp1 is a therapeutic target in PAH, and Drpitor1a is a potential therapy with an interesting therapeutic sexual dimorphism.