Gene therapy for organic acidemias: Lessons learned from methylmalonic and propionic acidemia.

Organic acidemias (OA) are a group of rare autosomal recessive disorders of intermediary metabolism that result in a systemic elevation of organic acid. Despite optimal dietary and cofactor therapy, OA patients still suffer from potentially lethal metabolic instability and experience long-term multisystemic complications. Severely affected patients can benefit from elective liver transplantation, which restores hepatic enzymatic activity, improves metabolic stability, and provides the theoretical basis for the pursuit of gene therapy as a new treatment for patients. Because of the poor outcomes reported in those with OA, especially methylmalonic and propionic acidemia, multiple gene therapy approaches have been explored in relevant animal models. Here, we review the results of gene therapy experiments performed using MMA and PA mouse models to illustrate experimental paradigms that could be applicable for all forms of OA.

Retrospective study of propionic acidemia using natural language processing in Mayo Clinic electronic health record data.

BACKGROUND: Propionic acidemia (PA) is a rare autosomal recessive organic acidemia that classically presents within the first days of life with a metabolic crisis or via newborn screening and is confirmed with laboratory tests. Limited data exist on the natural history of patients with PA describing presentation, treatments, and clinical outcomes. OBJECTIVE: To retrospectively describe the natural history of patients with PA in a clinical setting from a real-world database using both structured and unstructured electronic health record (EHR) data using novel data extraction techniques in a unique care setting. DESIGN/METHODS: This retrospective study used EHR data to identify patients with PA seen at the Mayo Clinic. Unstructured clinical text (medical notes, pathology reports) were analyzed using augmented curation natural language processing models to enhance analysis of data extracted by structured data fields (International Classification of Diseases 9th or 10th revision [ICD-9/-10] codes, Current Procedural Terminology [CPT] codes, and medication orders). De-identified health records were also manually reviewed by clinical scientists to ensure data accuracy and completeness. The index date was defined as the patient's date of PA diagnosis at the Mayo Clinic. Results were reported as aggregate descriptive statistics relative to patients' index dates. Complications, therapeutic interventions, laboratory tests, procedures, and hospitalization encounters related to PA were described at and within 6 months of the patient's index date, and from medical history available before the index date. RESULTS: In total, 13 patients with PA were identified, with visits occurring from 1998 to 2022. Age at diagnosis ranged from birth to 3 years; age at initial evaluation at the Mayo Clinic ranged from 3 days to 28 years. The mean number of Mayo Clinic outpatient visits was 31 (median duration of care, 2 years). PA-related complications were documented in 85% of patients and included nutritional difficulties (46%), metabolic decompensation events (MDEs; 38%), neurologic abnormalities (38%), and cardiomyopathy (7%). One pair of affected siblings had mild symptoms and no complications or MDEs. All 5 patients with a history of MDEs presented with developmental delays. Among patients with MDEs, the mean frequency of outpatient clinical care visits was 10 per year, and 3 patients required inpatient hospitalization (mean duration, 16 days). The incidence of severe complications was higher among patients with MDEs than those without MDEs. Of the patients with MDEs, 2 experienced crises while receiving treatment at the Mayo Clinic, with 9 total MDEs occurring between the 2 patients. Symptoms at presentation included hyperammonemia (78%), fever and/or decreased nutritional intake (67%), hyperglycemia/hypoglycemia (56%), intercurrent upper respiratory infection and/or lethargy (44%), constipation (33%), altered mental status (33%), and cough (33%). CONCLUSIONS: This study highlights the range and frequency of clinical outcomes experienced by patients with PA and demonstrates the clinical burden of MDEs.

Evaluating renin and aldosterone levels in children with organic acidemia-therapeutic experience with fludrocortisone.

Hyporeninemic hypoaldosteronism has been reported in only a few cases with methylmalonic acidemia (MMA) and has been attributed to the renal involvement. This study aims to investigate renin-aldosterone levels along with the renal functions of the patients with organic acidemia. This is a cross-sectional study conducted in patients with MMA, propionic acidemia (PA), and isovaleric acidemia (IVA). Serum renin, aldosterone, sodium, and potassium levels were measured, and glomerular filtration rates (GFR) were calculated. Comparisons were made between the MMA and non-MMA (PA+IVA) groups. Thirty-two patients (MMA:PA:IVA = 14:13:5) were included. The median GFR was significantly lower in the MMA group than in the non-MMA group (p < 0.001). MMA patients had the highest incidence of kidney damage (71.4%), followed by PA patients (23%), while none of the IVA patients had reduced GFR. GFR positively correlated with renin levels (p = 0.015, r = 0.433). Although renin levels were significantly lower in the MMA group than the non-MMA group (p = 0.026), no significant difference in aldosterone levels was found between the two groups. Hyporeninemic hypoaldosteronism was found in 3 patients with MMA who had different stages of kidney damage, and fludrocortisone was initiated, which normalized serum sodium and potassium levels.  Conclusions: This study, which has the largest number of patients among the studies investigating the renin-angiotensin system in organic acidemias to date, has demonstrated that hyporeninemic hypoaldosteronism is not a rare entity in the etiology of hyperkalemia in patients with MMA, and the use of fludrocortisone is an effective treatment of choice in selected cases. What is Known: • Hyperkalemia may be observed in cases of methylmalonic acidemia due to renal involvement and can be particularly prominent during metabolic decompensation. • Hyporeninemic hypoaldosteronism has been reported to be associated with hyperkalemia in only a few cases of methylmalonic acidemia. What is New: • Hyporeninemic hypoaldosteronism was found in one-fifth of cases with methylmalonic acidemia. • Fludrocortisone therapy leads to the normalization of serum sodium and potassium levels.

Pathophysiological mechanisms of complications associated with propionic acidemia.

Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle. When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes. While the clinical symptoms and diagnosis of PA are well established, the underlying pathophysiological mechanisms of PA-induced diseases are not fully understood. As a result, there are currently few effective therapies for PA beyond dietary restriction. This review focuses on the pathophysiological mechanisms of the various complications associated with PA, drawing on extensive research and clinical reports. Most research suggests that propionyl-CoA and its metabolites can impair mitochondrial energy metabolism and cause cellular damage by inducing oxidative stress. However, direct evidence from in vivo studies is still lacking. Additionally, elevated levels of ammonia can be toxic, although not all PA patients develop hyperammonemia. The discovery of pathophysiological mechanisms underlying various complications associated with PA can aid in the development of more effective therapeutic treatments. The consequences of elevated odd-chain fatty acids in lipid metabolism and potential gene expression changes mediated by histone propionylation also warrant further investigation.

Combined heart and liver transplantation in a patient supported by left ventricular assist device (LVAD) with propionic acidemia.

Propionic acidemia (PA) is a rare inherited metabolic disease due to inborn errors of metabolism. PA results in the accumulation of abnormal organic acid metabolites in multiple systems, mainly the central nervous system and the heart. Cardiac complications include dilated cardiomyopathy (DCM) and carry a 40-50% increased mortality risk. Liver transplantation (LT) is required in PA patients when medical treatment fails and may prevent or slow down the cardiomyopathy progression. However, severe heart disease may be a serious contraindication to LT. We present a complicated case of a PA patient, supported with a Left Ventricular Assist Device, who underwent a heart and Liver transplant. PA patients are at increased risk for metabolic acidosis during surgery, with increased anion gap and hyperammonemia. A strict multi-disciplinary approach is needed to prevent and treat metabolic decompensation. The patient had a successful heart and liver transplant after a strict treatment protocol in the pre, intra, and post-operative periods. His case highlights the complexity of PA patients and the increased risk for metabolic decompensation during surgery and provides an insight into how to manage such complicated patients.

Detection of early cardiac disease manifestation in propionic acidemia - Results of a monocentric cross-sectional study.

BACKGROUND: In propionic acidemia (PA) myocardial involvement is common and includes development of cardiomyopathy, life-threatening acute heart failure, and acquired long-QT syndrome. We sought to investigate which echocardiographic parameters of left ventricular systolic and diastolic function indicate early cardiac disease manifestation in PA. METHODS: This is a prospective observational study (cross-sectional design) in a Tertiary Medical Care Center. Individuals with confirmed PA were enrolled and the following cardiac investigations were performed in all study individuals: echocardiographic measurements of systolic and diastolic left ventricular (LV) function (LV fractional shortening (LV-FS), LV ejection fraction by biplane modified Simpson's (LV-EF), mitral annular plane systolic excursion (MAPSE), LV global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE), pulsed Doppler analyses of mitral valve (MV) inflow velocities (MV E/A) and MV deceleration time (DT-E), tissue doppler imaging (TDI) of the mitral annulus (MV E/e'), and LV myocardial performance index (LV-MPI)). LV and left atrial (LA) diameters were assessed. 12­lead electrocardiograms (ECG) were recorded and corrected QT intervals (QTc) calculated. Clinical phenotype and laboratory parameters at the time of cardiac investigation were assessed. Besides descriptive analyses we analyzed frequency, onset, and combinations of echocardiographic and ECG data as well as their correlations with clinical and biochemical findings. The effects of 'age at visit' and LV functional parameters on QTc were analyzed with multiple regression. RESULTS: A total of 18 patients with confirmed PA were enrolled. Median age at PA onset was 6 days (range 1-357 days). Median age at visit for cardiac evaluation was 13.1 years (range 0.6-28.1 years). LV-GLS was abnormal in 72.2%, LV-EF in 61.1%, MAPSE in 50%, MV E/e' in 44.4%, LV-MPI in 33.3%, LV-FS in 33.3%, and MV E/A in 27.8%. In cases with normal or near normal LV-FS, LV-GLS was pathological in 5/10, LV-EF in 4/10, and MAPSE in 3/10. The probability of developing LV dysfunction - systolic and diastolic - increases with age. LV-MPI is a reliable parameter to indicate systolic LV-dysfunction in combination with a dilated LV, i. e. dilated cardiomyopathy (DCM) in PA. Multiple regression reveals a significant positive association between LV diameters and QTc. Abnormal LV-GLS significantly correlates with reduced muscle strength, muscle tone and/or abnormal gross motor function. CONCLUSIONS: Our data suggests a high prevalence of cardiac disease manifestation in PA, considerably higher than in previous studies, where only LV-FS was used to assess LV function. Usage of advanced echocardiographic techniques, such as LV-GLS assessment, may allow for early detection of subtle LV dysfunction in PA, and may lead to timely cardiac treatment but also consideration of liver transplantation to prevent development of manifest cardiac complications.

Organic acidemias in the neonatal period: 30 years of experience in a referral center for inborn errors of metabolism.

OBJECTIVES: Neonatal-onset organic acidemias (OAs) account for 80% of neonatal intensive care unit (NICU) admissions due to inborn errors of metabolism. The aim of this study is to analyze clinical features and follow-up of neonates diagnosed with OAs in a metabolic referral center, focusing on perinatal characteristics and the impact of first the metabolic crisis on long-term outcome. METHODS: Perinatal features, clinical and laboratory characteristics on admission and follow-up of 108 neonates diagnosed with OAs were retrospectively analyzed. Global developmental delay, abnormal electroencephalogram (EEG) or brain magnetic resonance imaging (MRI), chronic complications, and overall mortality. Associations between clinical findings on admission and outcome measures were evaluated. RESULTS: Most prevalent OA was maple syrup urine disease (MSUD) (34.3%). Neonates with methylmalonic acidemia (MMA) had significantly lower birth weight (p<0.001). Metabolic acidosis with increased anion gap was more frequent in MMA and propionic acidemia (PA) (p=0.003). 89.1% of OAs were admitted for recurrent metabolic crisis. 46% had chronic non-neurologic complications; 19.3% of MMA had chronic kidney disease. Abnormal findings were present in 26/34 of EEG, 19/29 of MRI studies, and 32/33 of developmental screening tests. Metabolic acidosis on admission was associated with increased incidence of abnormal EEG (p=0.005) and overall mortality (p<0.001). Severe hyperammonemia in MMA was associated with overall mortality (33.3%) (p=0.047). Patients diagnosed between 2007-2017 had lower overall mortality compared to earlier years (p<0.001). CONCLUSIONS: Metabolic acidosis and hyperammonemia are emerging predictors of poor outcome and mortality. Based on a large number of infants from a single center, survival in neonatal-onset OA has increased over the course of 30 years, but long-term complications and neurodevelopmental results remain similar. While prompt onset of more effective treatment may improve survival, newer treatment modalities are urgently needed for prevention and treatment of chronic complications.

Novel compound heterozygous variants in the PCCB gene causing adult-onset propionic acidemia presenting with neuropsychiatric symptoms: a case report and literature review.

BACKGROUND: Propionic acidemia (PA) is a rare autosomal recessive disorder of metabolism caused by mutations in the PCCA or PCCB gene, leading to propionyl CoA carboxylase (PCC) enzyme deficiencies. Most PA patients present variable clinical phenotypes and severity in the neonatal or infant period, with only a few developing symptoms after infancy. This report describes a PA patient with an adult-onset phenotype and a novel compound heterozygous mutation in the PCCB gene. To further explore the genotype-phenotype correlations in late-onset PA, we performed a literature review focusing on and summarizing 11 patients with PCC gene mutations who had the first onset and/or the definite diagnosis after infancy. CASE PRESENTATION: A 21-year-old PA patient presented with weakness of four limbs, gait abnormalities, two episodes of seizures, mental and behavior disorders after severe vomiting. Magnetic Resonance Imaging (MRI) demonstrated sustained bilateral caudate head and putamen symmetrical hyperintensity. Biochemical investigations revealed plasma amino and urine values correlating with a PA profile. Genetic analysis confirmed novel compound heterozygous variants in PCCB, with a newly-found pathogenic mutation (c.467T>C) and the c.1316A>G mutation associated with pathogenicity. CONCLUSION: We identified a novel compound heterozygous mutation in the PCCB gene causing late-onset PA. Patients carrying mutations in the PCCB gene tend to develop late-onset PA and present neuropsychiatric symptoms and/or signs. Further molecular biological research is needed to explore the genotype-phenotype correlations of PA.

Biomarkers for drug development in propionic and methylmalonic acidemias.

There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of 13 C-propionate (exhaled 13 CO2 ), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.

Inborn errors of metabolism and coronavirus disease 2019: Evaluation of the metabolic outcome.

BACKGROUND: Infectious diseases can result in a catabolic state and possibly trigger an acute metabolic decompensation in inborn errors of metabolism (IEM), which could be life threatening. Studies regarding the course of severe acute respiratory syndrome coronavirus 2 infections in patients with IEM are generally limited to case reports. Here, we aimed to evaluate the clinical findings of coronavirus disease 2019 (COVID-19) and describe the impact of severe acute respiratory syndrome coronavirus 2 infections on metabolic outcomes in IEM patients. METHODS: Patients who were diagnosed with different types of IEM and developed microbiologically confirmed COVID-19 infection were included. Clinical findings and laboratory results were recorded retrospectively in terms of both IEM and COVID-19. RESULTS: Eleven patients with diagnosis of intoxication type metabolic disorders, five patients with energy metabolism disorders, and six patients with complex molecular disorders were enrolled. The most frequent clinical finding was fever (52.1%) followed by fatigue/myalgia (47.8%). None of the patients was younger than 1 year. None of the patients presented severe or critical disease. In terms of metabolic decompensation, two patients diagnosed with propionic acidemia, one patient with methylmalonic acidemia and one patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency presented clinical and biochemical findings of an acute metabolic attack. CONCLUSIONS: Based on our results, IEM are not found to be an additional risk factor for severe COVID-19 infection. However, patients with intoxication type and energy metabolism disorders should be considered as a vulnerable population for COVID-19 and have a major risk of developing acute metabolic decompensation that can lead to life-threatening complications.

Functional neurologic disorders in an adult with propionic acidemia: a case report.

BACKGROUND: Inborn errors of metabolism are often characterized by various psychiatric syndromes. Previous studies tend to classify psychiatric manifestations into clinical entities. Among inborn errors of metabolism, propionic acidemia (PA) is a rare inherited organic aciduria that leads to neurologic disabilities. Several studies in children with PA demonstrated that psychiatric disorders are associated to neurological symptoms. To our knowledge, no psychopathological description in adult with propionic acidemia is available. CASE PRESENTATION: We aimed to compare the case of a 53-year-old woman with PA, to the previous psychiatric descriptions in children with PA and in adults with other inborn errors of metabolism. Our patient presented a large variety of signs: functional neurologic disorders, borderline personality traits (emotional dyregulation, dissociative and alexithymic trends, obsessive-compulsive disorders), occurring in a context of neurodevelopmental disorder. CONCLUSION: Clinical and paraclinical examinations are in favor of a mild mental retardation since childhood and disorders of behavior and personality without any definite psychiatric syndrome, as already described in other metabolic diseases (group 3). Nonetheless, further studies are needed to clarify the psychiatric alterations within adult patients with PA.

Orthopaedic Problems in 35 Patients With Organic Acid Disorders.

INTRODUCTION: Organic acid disorders (OADs) are a subset of inborn errors of metabolism that result in a toxic accumulation of organic acids in the body, which can lead to metabolic derangements and encephalopathy. Patients with these disorders are managed by a team of biochemical geneticists and metabolic nutritionists. However, subspecialists such as neurologists and orthopaedic surgeons are often needed to help manage the sequelae of the metabolic derangements. The breadth of orthopaedic sequelae of these disease states is poorly understood. Herein, we describe orthopaedic problems associated with 5 types of OAD most commonly seen at our institution: maple syrup urine disease, methylmalonic aciduria, propionic aciduria, pyruvate dehydrogenase deficiency, and glutaric aciduria type 1. METHODS: We retrospectively reviewed medical records of 35 patients with an OAD who were seen at our academic tertiary care center from May 1999 to May 2020. Patients were grouped into cohorts according to OAD type and analyzed for orthopaedic presentations of hip, knee, or foot disorders, presence and severity of scoliosis, history of fracture, movement disorders, and osteopenia/osteoporosis. RESULTS: Of the 35 patients, 13 had maple syrup urine disease, 12 had methylmalonic aciduria, 4 had propionic aciduria, 4 had pyruvate dehydrogenase deficiency, and 2 had glutaric aciduria type 1. Associated orthopaedic problems included spasticity causing neuromuscular scoliosis and/or hip subluxation or dislocation (10 patients), fractures (7 patients), and osteopenia/osteoporosis (7 patients). Overall, 22 of 35 patients had some orthopaedic condition. CONCLUSIONS: Most in this cohort of patients with OAD also had an orthopaedic abnormality. It is important for physicians treating these patients to understand their propensity for musculoskeletal problems. When treating patients with OAD, it is important to initiate and maintain communication with specialists in several disciplines and to develop collaborative treatments for this unique population. LEVEL OF EVIDENCE: Level IV-prognostic study.

Severe anemia in patients with Propionic acidemia is associated with branched-chain amino acid imbalance.

BACKGROUND: Propionic acidemia (PA), an inborn error of metabolism, is caused by a deficiency in propionyl-CoA carboxylase. Patients have to follow a diet restricted in the propiogenic amino acids isoleucine (Ile), valine (Val), methionine (Met) and threonine (Thr); proper adherence can prevent and treat acute decompensation and increase life expectancy. However, chronic complications occur in several organs even though metabolic control may be largely maintained. Bone marrow aplasia and anemia are among the more common. MATERIALS AND METHODS: In this retrospective study, data for patients with PA being monitored at the Hospital Ramón y Cajal (Madrid, Spain) (n = 10) in the past 10 years were examined to statistically detect relationships between persistent severe anemia outside of metabolic decompensation episodes and dietary practices such as natural protein intake and medical food consumption (special mixture of precursor-free amino acids) along with plasma levels of branched-chain amino acids (BCAA). High ferritin levels were deemed to indicate that a patient had received repeated transfusions for persistent anemia since data on hemoglobin levels at the moment of transfusion were not always passed on by the attending centers. RESULTS: Three patients had severe, persistent anemia that required repeated blood transfusions. Higher medical food consumption and plasma Leu levels were associated with iron overload. Notably, natural protein intake and plasma Val were negatively correlated with ferritin levels. We also observed an inverse relationship between plasma Val/Leu and Ile/Leu ratios and ferritin. CONCLUSION: The present results suggest that severe anemia in patients with PA might be associated with low natural protein intake and BCAA imbalance.

Anesthetic Management for Pediatric Liver Transplantation in a Patient With Propionic Acidemia: A Case Report.

Propionic acidemia is an inborn error of metabolism characterized by accumulation of propionic acid due to deficiency of propionyl-CoA carboxylase. Main stay of treatment focuses on reducing dietary protein. However, orthotropic liver transplantation decreases the frequency of metabolic decompensations and improves life expectancy. We report a case of a 4-year-old boy undergoing orthotropic liver transplantation to treat propionic acidemia. This case highlights the use of intraoperative monitoring of metabolic markers like urine ketones, arterial ammonia, and lactate levels as these patients are at risk for hyperammonemia and metabolic acidosis. Also, the relevance in outcomes when performing early extubation in fast-tracking recovery.

Management of COVID-19 infection in organic acidemias.

The COVID-19 pandemic has affected the health and healthcare of individuals of all ages worldwide. There have been multiple reports and reviews documenting a milder effect and decreased morbidity and mortality in the pediatric population, but there have only been a small number of reports discussing the SARS-CoV-2 infection in the setting of an inborn error of metabolism (IEM). Here, we report two patients with underlying metabolic disorders, propionic acidemia and glutaric aciduria type 1, and discuss their clinical presentation, as well as their infectious and metabolic management. Our report demonstrates that individuals with an underlying IEM are at risk of metabolic decompensation in the setting of a COVID-19 infection. The SARS-CoV-2 virus does not appear to cause a more severe metabolic deterioration than is typical.