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.

Prevalence of propionic acidemia in China.

Propionic acidemia (PA) is a rare autosomal recessive congenital disease caused by mutations in the PCCA or PCCB genes. Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA. Early-onset PA can lead to acute deterioration, metabolic acidosis, and hyperammonemia shortly after birth, which can result in high mortality and disability. Late-onset cases of PA have a more heterogeneous clinical spectra, including growth retardation, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease. Timely and accurate diagnosis and appropriate treatment are crucial to saving patients' lives and improving their prognosis. Recently, the number of reported PA cases in China has increased due to advanced diagnostic techniques and increased research attention. However, an overview of PA prevalence in China is lacking. Therefore, this review provides an overview of recent advances in the pathogenesis, diagnostic strategies, and treatment of PA, including epidemiological data on PA in China. The most frequent variants among Chinese PA patients are c.2002G > A in PCCA and c.1301C > T in PCCB, which are often associated with severe clinical symptoms. At present, liver transplantation from a living (heterozygous parental) donor is a better option for treating PA in China, especially for those exhibiting a severe metabolic phenotype and/or end-organ dysfunction. However, a comprehensive risk-benefit analysis should be conducted as an integral part of the decision-making process. This review will provide valuable information for the medical care of Chinese patients with PA.

PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only.

Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole-exome sequencing or targeted next-generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%-20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH-only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH-only phenotype of PHKA2.

High protein prescription in methylmalonic and propionic acidemia patients and its negative association with long-term outcome.

BACKGROUND AND OBJECTIVE: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inborn errors of metabolism. While survival of MMA and PA patients has improved in recent decades, long-term outcome is still unsatisfactory. A protein restricted diet is the mainstay for treatment. Additional amino acid mixtures (AAM) can be prescribed if natural protein is insufficient. It is unknown if dietary treatment can have an impact on outcome. DESIGN: We performed a nationwide retrospective cohort study and evaluated both longitudinal dietary treatment and clinical course of Dutch MMA and PA patients. Protein prescription was compared to the recommended daily allowances (RDA); the safe level of protein intake as provided by the World Health Organization. The association of longitudinal dietary treatment with long-term outcome was evaluated. RESULTS: The cohort included 76 patients with a median retrospective follow-up period of 15 years (min-max: 0-48 years) and a total of 1063 patient years on a protein restricted diet. Natural protein prescription exceeded the RDA in 37% (470/1287) of all prescriptions and due to AAM prescription, the total protein prescription exceeded RDA in 84% (1070/1277). Higher protein prescriptions were associated with adverse outcomes in severely affected patients. In PA early onset patients a higher natural protein prescription was associated with more frequent AMD. In MMA vitamin B12 unresponsive patients, both a higher total protein prescription and AAM protein prescription were associated with more mitochondrial complications. A higher AAM protein prescription was associated with an increased frequency of cognitive impairment in the entire. CONCLUSION: Protein intake in excess of recommendations is frequent and is associated with poor outcome.

Incidence of newborn screening disorders among 56632 infants in Central Saudi Arabia. A 6-year study.

OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.

Methylmalonic and propionic acidemia among hospitalized pediatric patients: a nationwide report.

BACKGROUND: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are two kinds of diseases caused by inborn errors of metabolism. So far, the epidemiological data on them are limited in China. The aim of our study is to investigate the proportion and characteristics of hospitalized pediatric patients with MMA and PA in China. METHODS: The data in this study were obtained from the Hospital Quality Monitoring System, a national inpatient database in China, with information on the patients hospitalized during the period from 2013 to 2017. We identified the data related to the patients who were under 18 years old and were diagnosed with MMA/PA, and extracted the information on demographic characteristics, hospital location, total cost and other related clinical presentations from the data. RESULTS: Among all hospitalized pediatric patients with liver diseases, there were increasing trends in the proportion of individuals diagnosed with MMA or PA during the period from 2013 (0.76% for MMA; 0.13% for PA) to 2017 (1.61% for MMA; 0.32% for PA). For both MMA and PA, children under 2-year-old accounted for the highest proportion. The median of total cost per hospitalization was relatively high (RMB 7388.53 for MMA; RMB 4999.66 for PA). Moreover, most patients hospitalized in tertiary class A hospitals (MMA: 80.96%, PA: 76.21%); and a majority of pediatric patients admitted in the hospitals in Shanghai and Beijing are from outside districts. Manifestations of nervous system-related symptoms, and metabolic acidosis or anemia in laboratory findings were more common during hospitalization. CONCLUSIONS: The study is the first nationwide one in providing epidemiological and clinical information on hospitalized pediatric patients with MMA/PA. An increasing hospitalization with various presentations and a heavy financial burden were observed. In addition, geographically, the medical resources in China have been unevenly distributed.

Chronic kidney disease in propionic acidemia.

PURPOSE: Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. METHODS: Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342). RESULTS: Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P < 0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P < 0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P < 0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex. CONCLUSION: CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.

Systematic literature review and meta-analysis on the epidemiology of propionic acidemia.

Propionic acidemia (PA, OMIM #606054) is a serious, life-threatening, inherited, metabolic disorder caused by the deficiency of the mitochondrial enzyme propionyl-coenzyme A (CoA) carboxylase (EC 6.4.1.3). The primary objective of this study was to conduct a systematic literature review and meta-analysis on the epidemiology of PA. The literature search was performed covering Medline, Embase, Cochrane Database of Systematic Reviews, CRD Database, Academic Search Complete, CINAHL and PROSPERO databases. Websites of rare disease organizations were also searched for eligible studies. Of the 2338 identified records, 188 articles were assessed for eligibility in full text, 43 articles reported on disease epidemiology, and 31 studies were included into the quantitative synthesis. Due to the rarity of PA, broadly targeted population-based prevalence studies are not available. Nonetheless, implementation of newborn screening programs has allowed the estimation of the birth prevalence data of PA across multiple geographic regions. The pooled point estimates indicated detection rates of 0.29; 0.33; 0.33 and 4.24 in the Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively. Our systematic literature review and meta-analysis confirm that PA is an ultra-rare disorder, with similar detection rates across all regions with the exception of the MENA region where the disease, similar to other inherited metabolic disorders, is more frequent.

Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea-cycle disorders: On the basis of information from a European multicenter registry.

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.

Antenatal and Intrapartum Risk Factors for Hypoxic-Ischemic Encephalopathy in a US Birth Cohort.

OBJECTIVE: To identify risk factors for hypoxic-ischemic encephalopathy (HIE) within a recent US birth cohort. STUDY DESIGN: In a retrospective cohort study of 44 572 singleton infants ≥36 weeks of gestation born at Kaiser Permanente Northern California in 2008-2015, we identified all infants with HIE based on the presence of 3 inclusion criteria: clinical signs of neonatal encephalopathy, NICU admission, and either a 10-minute Apgar of ≤5 or a base excess of ≤-15 mmol/L. Neonatal acidemia was defined as a base excess of ≤-12 mmol/L. We ascertained antenatal and intrapartum complications from electronic records. Multivariable analysis was performed using logistic regression. RESULTS: There were 45 infants (1.0 per 1000) with HIE and 197 (4.4 per 1000) with neonatal acidemia. Of the infants with HIE, 64% had an intrapartum complication consisting of a sentinel event (36%), clinical chorioamnionitis (40%), or both (11%). Risk factors for HIE on multivariable analysis were sentinel event (relative risk [RR], 16.1; 95% CI, 8.4-33) and clinical chorioamnionitis (RR, 5.2; 95% CI, 2.7-9.9). After removing the 16 infants with HIE who were exposed to a sentinel event from multivariate analysis, maternal age of ≥35 years (RR, 2.5; 95% CI, 1.1-5.6) and a urinary tract infection during pregnancy (RR, 2.6; 95% CI, 1.0-6.5) emerged as potential antenatal risk factors for HIE. CONCLUSIONS: A significant proportion of HIE is preceded by a sentinel event, emphasizing the importance of developing improved methodologies to predict and prevent this perinatal complication. Strategies focused on reducing other complications such as clinical chorioamnionitis and/or maternal pyrexia may also improve our ability to prevent HIE.

Propionic acidemia in the Arab World.

The autosomal recessive disease propionic acidemia (PA) is an inborn error of metabolism with highly variable clinical manifestations, caused by a deficiency of propionyl-CoA carboxylase (PCC) enzyme, due to mutations in either PCCA or PCCB genes, which encode the alpha and beta subunits of the PCC enzyme, respectively. The classical clinical presentation consists of poor feeding, vomiting, metabolic acidosis, hyperammonemia, lethargy, neurological problems, and developmental delay. PA seems to be a prevalent disease in the Arab World. Arab patients with PA seem to have the same classical clinical picture for PA with distinctive associated complications and other diseases. Most of the mutations found in Arab patients seem to be specific to the Arab population, and not observed in other ethnic groups. In this review, I will discuss in details the clinical and molecular profile of Arab patients with PA.

Propionic acidaemia: demographic characteristics and complications.

BACKGROUND: Propionic acidaemia is a global, metabolic disease, highly prevalent in Kingdom of Saudi Arabia. It may produce an array of complications which significantly deteriorate the patient's quality of life. OBJECTIVES: To find out the demographic characteristics and complications of patients with propionic acidemia. METHODS: The records of diagnosed cases of propionic acidaemia were reviewed, retrospectively. RESULTS: Of 24 patients, 16 (67%) were male. Consanguineous parents were 16 (67%). Ten (42%) patients had diseased siblings. Mean age at diagnosis was 0.13±0.27 year. Twenty-two (92%) patients had early onset and 2 (8%) had late onset disease. Eighteen (75%) patients had developmental delay, 11 (46%) had hypotonia, 3 (12%) had hypertonia, 13 (54%) had hyperreflexia and 12 (50%) had seizures. Two (8%) children each, had intracranial haemorrhage, spastic quadriplegia, hemiplegia and 1 (4%) had paraplegia. Cerebral atrophy and nasogastric/gastrotomy, tube feeding, each was found in 6 (25%) patients. Under nutrition was revealed in 20 (83%), short stature in 18 (75%), rickets in 1 (4%) and pancreatitis in 2 (8%) patients. During metabolic crisis, cerebral oedema and pancytopenia each were found in 4 (17%), hypoglycaemia in 6 (25%), hyperglycaemia in 2 (8%), hyperammonaemia in all 24 (100%) and metabolic acidosis in 20 (83%) cases. CONCLUSION: Propionic acidaemia is a rare hereditary disorder that has wide spectrum of neurological and other complications, which perhaps with early diagnosis and intervention may be preventable, more effectively.

Survey of health status and complications among propionic acidemia patients.

Propionic acidemia (PA) is a rare organic acidemia that is due to deficiency in the enzyme propionyl-coA carboxylase. Complications are currently described mostly in the form of case reports. We sampled a population of affected individuals in order to estimate the frequency of complications amongst the sample. The study is a cross-sectional retrospective review with a survey instrument and recruitment through the Propionic Acidemia Foundation. Responses for 58 individuals were tabulated for each question as how frequently the complication was reported among responders. Commonly reported findings included seizures, arrhythmia, leucopenia, and anemia. Developmental and cognitive disabilities were reported in the majority of individuals. Heart failure or cardiomyopathy was reported in over half of deceased individuals at time of death. Pancreatitis was reported in a minority of the sample, yet more than half of these reported a recurrence. These results update and extend our current knowledge of recognized complications among individuals with PA. The results also provide new information regarding developmental outcomes and previously unreported morbidity from cardiac and gastrointestinal complications. Longitudinal studies exploring associated biochemical and clinical parameters are necessary to further our understanding of the pathophysiology of PA and its complications.