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Charles P. Venditti - One of the best experts on this subject based on the ideXlab platform.
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Isolated Methylmalonic Acidemia
2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Charles P. VendittiAbstract:Clinical characteristics Isolated methylmalonic Acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic Acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic Acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic Acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy. Diagnosis/testing Diagnosis of isolated methylmalonic Acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific subtype of methylmalonic Acidemia requires cellular biochemical studies (including 14C propionate incorporation and B12 responsiveness, complementation analysis, and cobalamin distribution assays) and molecular genetic testing. The finding of biallelic pathogenic variants in one of the five genes (MMUT, MMAA, MMAB, MCEE, and MMADHC) associated with isolated methylmalonic Acidemia – with confirmation of carrier status in the parents – can establish the diagnosis. Management Treatment of manifestations: Critically ill individuals are stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections. Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy. Prevention of primary manifestations: In some cases, newborn screening allows for presymptomatic detection of affected newborns and early treatment. Agents/circumstances to avoid: Fasting and increased dietary protein. Other: Medic Alert® bracelets and up-to-date, easily accessed, detailed emergency treatment protocols facilitate care. Genetic counseling Isolated methylmalonic Acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known. In some circumstances, prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis).
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a critical reappraisal of dietary practices in methylmalonic Acidemia raises concerns about the safety of medical foods part 1 isolated methylmalonic Acidemias
Genetics in Medicine, 2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Jennifer G Myles, Oleg A Shchelochkov, Charles P. VendittiAbstract:Medical foods for methylmalonic Acidemias (MMAs) and propionic Acidemias contain minimal valine, isoleucine, methionine, and threonine but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of patients with MMA ascertained via a natural history study. Cross-sectional anthropometric and body-composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA, and 6 cblB). Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut0: 99.45 ± 32.05% RDA). However, 85% received medical foods, in which the protein equivalent often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight- and height-for-age z-scores correlated negatively with the leucine-to-valine intake ratio (r = −0.453; P = 0.014; R2 = 0.209 and r = −0.341; P = 0.05; R2 = 0.123, respectively). Increased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively to ensure efficacy and safety. Genet Med 18 4, 386–395.
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Renal growth in isolated methylmalonic Acidemia.
Genetics in medicine : official journal of the American College of Medical Genetics, 2013Co-Authors: Paul Kruszka, Jennifer L. Sloan, Irini Manoli, Jeffrey B. Kopp, Charles P. VendittiAbstract:We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic Acidemia, a group of disorders associated with chronic kidney disease. Fifty patients with methylmalonic Acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses. Comparisons with age-matched controls showed that renal length in subjects with methylmalonic Acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic Acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 × age for the controls and 6.80 + 0.09 × age for the methylmalonic Acidemia cohort (P < 0.001; constant and slope). Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic Acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population. Genet Med 15 12, 990–996.
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Neurocognitive phenotype of isolated methylmalonic Acidemia.
Pediatrics, 2012Co-Authors: Colin J. O’shea, Jennifer L. Sloan, Andrea L. Gropman, Irini Manoli, Charles P. Venditti, Eva H. Baker, Edythe Wiggs, Maryland Pao, Joseph SnowAbstract:OBJECTIVE: Methylmalonic Acidemia (MMA) is a metabolic disorder with a poorly defined long-term neurocognitive phenotype. We studied the neuropsychological outcomes of patients and examined clinical covariates that influenced cognition. METHODS: A diverse cohort with mut , cblA , or cblB subtypes of isolated MMA ( N = 43), ages 2 to 32 years, were evaluated at a single center over a 6-year period. The influence of clinical, laboratory, and metabolic parameters on neuropsychological testing results was determined. RESULTS: Early-onset mut patients ( n = 21) manifested the most severe neurocognitive impairments, with a mean ± SD full-scale IQ (FSIQ) of 71.1 ± 14.75. Late-onset mut patients ( n = 6) had a mean FSIQ of 88.5 ± 27.62. cblA ( n = 7), cblB ( n = 6), and mut patients diagnosed prenatally or by newborn screening ( n = 3) obtained mean FSIQs in the average range (100.7 ± 10.95, 96.6 ± 10.92, and 106.7 ± 6.66, respectively). Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ ( P = .001 and P = .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not. FSIQ remained stable over longitudinal testing ( n = 10). Decreased scores on processing speed, compared with all other intellectual domains, emerged as a specific neurocognitive manifestation. CONCLUSIONS: The neurocognitive outcomes seen in isolated MMA are highly variable. An earlier age of disease onset, the presence of hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairment. In all patient subtypes, selective deficits in processing speed were present. * Abbreviations: MMA — : methylmalonic Acidemia FSIQ — : full-scale IQ P/NBS — : prenatal or newborn screening diagnosis
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long term rescue of a lethal murine model of methylmalonic Acidemia using adeno associated viral gene therapy
Molecular Therapy, 2010Co-Authors: Randy J. Chandler, Charles P. VendittiAbstract:Methylmalonic Acidemia (MMA) is an organic Acidemia caused by deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). This disorder is associated with lethal metabolic instability and carries a poor prognosis for long-term survival. A murine model of MMA that replicates a severe clinical phenotype was used to examine the efficacy of recombinant adeno-associated virus (rAAV) serotype 8 gene therapy as a treatment for MMA. Lifespan extension, body weight, circulating metabolites, transgene expression, and whole animal propionate oxidation were examined as outcome parameters after gene therapy. One-hundred percent of the untreated Mut−/− mice (n = 58) died by day of life (DOL) 72, whereas >95% of the adeno-associated virus–treated Mut−/− mice (n = 27) have survived for ≥1 year. Despite a gradual loss of transgene expression and elevated circulating metabolites in the treated Mut−/− mice, the animals are indistinguishable from unaffected control littermates in size and activity levels. These experiments provide the first definitive evidence that gene therapy will have clinical utility in the treatment of MMA and support the development of gene therapy for other organic Acidemias.
George A. Macones - One of the best experts on this subject based on the ideXlab platform.
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a prospective cohort study of fetal heart rate monitoring deceleration area is predictive of fetal Acidemia
American Journal of Obstetrics and Gynecology, 2018Co-Authors: Alison G. Cahill, Methodius G Tuuli, Molly J Stout, Julia D Lopez, George A. MaconesAbstract:Background Intrapartum electronic fetal monitoring is the most commonly used tool in obstetrics in the United States; however, which electronic fetal monitoring patterns predict Acidemia remains unclear. Objective This study was designed to describe the frequency of patterns seen in labor using modern nomenclature, and to test the hypothesis that visually interpreted patterns are associated with Acidemia and morbidities in term infants. We further identified patterns prior to delivery, alone or in combination, predictive of Acidemia and neonatal morbidity. Study Design This was a prospective cohort study of 8580 women from 2010 through 2015. Patients were all consecutive women laboring at ≥37 weeks’ gestation with a singleton cephalic fetus. Electronic fetal monitoring patterns during the 120 minutes prior to delivery were interpreted in 10-minute epochs. Interpretation included the category system and individual electronic fetal monitoring patterns per the Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria as well as novel patterns. The primary outcome was fetal Acidemia (umbilical artery pH ≤7.10); neonatal morbidities were also assessed. Final regression models for Acidemia adjusted for nulliparity, pregestational diabetes, and advanced maternal age. Area under the receiver operating characteristic curves were used to assess the test characteristics of individual models for Acidemia and neonatal morbidity. Results Of 8580 women, 149 (1.7%) delivered acidemic infants. Composite neonatal morbidity was diagnosed in 757 (8.8%) neonates within the total cohort. Persistent category I, and 10-minute period of category III, were significantly associated with normal pH and Acidemia, respectively. Total deceleration area was most discriminative of Acidemia (area under the receiver operating characteristic curves, 0.76; 95% confidence interval, 0.72–0.80), and deceleration area with any 10 minutes of tachycardia had the greatest discriminative ability for neonatal morbidity (area under the receiver operating characteristic curves, 0.77; 95% confidence interval, 0.75–0.79). Once the threshold of deceleration area is reached the number of cesareans needed-to-be performed to potentially prevent 1 case of Acidemia and morbidity is 5 and 6, respectively. Conclusion Deceleration area is the most predictive electronic fetal monitoring pattern for Acidemia, and combined with tachycardia for significant risk of morbidity, from the electronic fetal monitoring patterns studied. It is important to acknowledge that this study was performed in patients delivering ≥37 weeks, which may limit the generalizability to preterm populations. We also did not use computerized analysis of the electronic fetal monitoring patterns because human visual interpretation was the basis for the Eunice Kennedy Shriver National Institute of Child Health and Human Development categories, and importantly, it is how electronic fetal monitoring is used clinically.
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a prospective cohort study of fetal heart rate monitoring deceleration area is predictive of fetal Acidemia
American Journal of Obstetrics and Gynecology, 2018Co-Authors: Alison G. Cahill, Methodius G Tuuli, Molly J Stout, Julia D Lopez, George A. MaconesAbstract:Background Intrapartum electronic fetal monitoring is the most commonly used tool in obstetrics in the United States; however, which electronic fetal monitoring patterns predict Acidemia remains unclear. Objective This study was designed to describe the frequency of patterns seen in labor using modern nomenclature, and to test the hypothesis that visually interpreted patterns are associated with Acidemia and morbidities in term infants. We further identified patterns prior to delivery, alone or in combination, predictive of Acidemia and neonatal morbidity. Study Design This was a prospective cohort study of 8580 women from 2010 through 2015. Patients were all consecutive women laboring at ≥37 weeks’ gestation with a singleton cephalic fetus. Electronic fetal monitoring patterns during the 120 minutes prior to delivery were interpreted in 10-minute epochs. Interpretation included the category system and individual electronic fetal monitoring patterns per the Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria as well as novel patterns. The primary outcome was fetal Acidemia (umbilical artery pH ≤7.10); neonatal morbidities were also assessed. Final regression models for Acidemia adjusted for nulliparity, pregestational diabetes, and advanced maternal age. Area under the receiver operating characteristic curves were used to assess the test characteristics of individual models for Acidemia and neonatal morbidity. Results Of 8580 women, 149 (1.7%) delivered acidemic infants. Composite neonatal morbidity was diagnosed in 757 (8.8%) neonates within the total cohort. Persistent category I, and 10-minute period of category III, were significantly associated with normal pH and Acidemia, respectively. Total deceleration area was most discriminative of Acidemia (area under the receiver operating characteristic curves, 0.76; 95% confidence interval, 0.72–0.80), and deceleration area with any 10 minutes of tachycardia had the greatest discriminative ability for neonatal morbidity (area under the receiver operating characteristic curves, 0.77; 95% confidence interval, 0.75–0.79). Once the threshold of deceleration area is reached the number of cesareans needed-to-be performed to potentially prevent 1 case of Acidemia and morbidity is 5 and 6, respectively. Conclusion Deceleration area is the most predictive electronic fetal monitoring pattern for Acidemia, and combined with tachycardia for significant risk of morbidity, from the electronic fetal monitoring patterns studied. It is important to acknowledge that this study was performed in patients delivering ≥37 weeks, which may limit the generalizability to preterm populations. We also did not use computerized analysis of the electronic fetal monitoring patterns because human visual interpretation was the basis for the Eunice Kennedy Shriver National Institute of Child Health and Human Development categories, and importantly, it is how electronic fetal monitoring is used clinically.
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Association of atypical decelerations with Acidemia.
Obstetrics & Gynecology, 2012Co-Authors: Alison G. Cahill, Anthony Odibo, Kimberly A. Roehl, George A. MaconesAbstract:OBJECTIVE: To estimate the incidence of atypical fetal heart rate deceleration characteristics in term labor and their association with Acidemia. METHODS: A 5-year retrospective cohort study was performed of all singleton, nonanomalous gestations delivered at 37 weeks or after. Thirty minutes of electronic fetal monitoring before delivery were interpreted by two formally trained research nurses, blind to clinical and outcome data, using American College of Obstetricians and Gynecologists (the College) guidelines as well as deceleration features historically referred to as atypica such as shoulders, slow return, and variability within the deceleration. Acidemia was defined as umbilical cord arterial pH 7.10 or less. Incidence of atypical features was estimated; univariable and multivariable analyses were performed. RESULTS: Within 5,388 women, the atypical feature seen with the most frequency was shoulders (n=2,914 [54.1%]) followed by slow return (n=2,618 [48.6%]), minimal deceleration variability (n=430 [8.0%]), and absent deceleration variability (n=4 [0.07%]). There was no difference in the incidence of atypical features between neonates with Acidemia (n=57) and without (n=5,331). There was no association between shoulders (adjusted odds ratio [OR] 1.06, 95% confidence interval [CI] 0.63-1.81) or slow returns (adjusted OR 0.91, 95% CI 0.54-1.53) and Acidemia. Similarly, compared with patients with moderate variability within deceleration nadirs, neither minimal (adjusted OR 0.82, 95% CI 0.43-1.55) nor marked (adjusted OR 0.65, 95% CI 0.27-1.55) variability was significantly associated with Acidemia. CONCLUSION: These data support the absence of these specific atypical deceleration characteristics from the recognized definitions of decelerations stipulated by the College and the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2008 given their lack of association with Acidemia or neonatal depression.
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association and prediction of neonatal Acidemia
American Journal of Obstetrics and Gynecology, 2012Co-Authors: Alison G. Cahill, Anthony Odibo, Kimberly A. Roehl, George A. MaconesAbstract:Objective The objective of this study was to estimate the predictive ability of electronic fetal monitoring (EFM) patterns immediately prior to delivery for Acidemia at term birth. Study Design This was a 4-year retrospective cohort study of 5388 consecutive singleton, nonanomalous gestations of 37 weeks or longer. The primary exposure was the EFM pattern in the 30 minutes preceding delivery. EFM patterns were prospectively interpreted using Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) nomenclature as well as non-NICHD measurements of decelerations. The primary outcome was umbilical cord arterial pH of 7.10 or less. Results Four NICHD-defined EFM features within the 30 minutes prior to birth demonstrated the greatest association with Acidemia: repetitive prolonged decelerations (area under the curve [AUC] 0.81), baseline tachycardia (AUC 0.80), repetitive variable decelerations (AUC 0.79), and repetitive late decelerations (0.78) after adjusting for nulliparity, fever, prolonged first stage, and obesity. A non-NICHD measure, total deceleration area, demonstrated superior predictive ability for Acidemia (AUC 0.83, P = .04). Conclusion A non-NICHD measure of deceleration frequency and severity in the second stage performed superior to 4 NICHD EFM features for predicting fetal Acidemia.
Jennifer L. Sloan - One of the best experts on this subject based on the ideXlab platform.
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chronic kidney disease in propionic Acidemia
Genetics in Medicine, 2019Co-Authors: Oleg A Shchelochkov, Jennifer L. Sloan, Irini Manoli, Jennifer G Myles, Peter J Mcguire, Susan Ferry, Alexandra Pass, Carol Van Ryzin, Megan Schoenfeld, Douglas R RosingAbstract: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.
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Isolated Methylmalonic Acidemia
2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Charles P. VendittiAbstract:Clinical characteristics Isolated methylmalonic Acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic Acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic Acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic Acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy. Diagnosis/testing Diagnosis of isolated methylmalonic Acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific subtype of methylmalonic Acidemia requires cellular biochemical studies (including 14C propionate incorporation and B12 responsiveness, complementation analysis, and cobalamin distribution assays) and molecular genetic testing. The finding of biallelic pathogenic variants in one of the five genes (MMUT, MMAA, MMAB, MCEE, and MMADHC) associated with isolated methylmalonic Acidemia – with confirmation of carrier status in the parents – can establish the diagnosis. Management Treatment of manifestations: Critically ill individuals are stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections. Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy. Prevention of primary manifestations: In some cases, newborn screening allows for presymptomatic detection of affected newborns and early treatment. Agents/circumstances to avoid: Fasting and increased dietary protein. Other: Medic Alert® bracelets and up-to-date, easily accessed, detailed emergency treatment protocols facilitate care. Genetic counseling Isolated methylmalonic Acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known. In some circumstances, prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis).
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a critical reappraisal of dietary practices in methylmalonic Acidemia raises concerns about the safety of medical foods part 1 isolated methylmalonic Acidemias
Genetics in Medicine, 2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Jennifer G Myles, Oleg A Shchelochkov, Charles P. VendittiAbstract:Medical foods for methylmalonic Acidemias (MMAs) and propionic Acidemias contain minimal valine, isoleucine, methionine, and threonine but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of patients with MMA ascertained via a natural history study. Cross-sectional anthropometric and body-composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA, and 6 cblB). Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut0: 99.45 ± 32.05% RDA). However, 85% received medical foods, in which the protein equivalent often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight- and height-for-age z-scores correlated negatively with the leucine-to-valine intake ratio (r = −0.453; P = 0.014; R2 = 0.209 and r = −0.341; P = 0.05; R2 = 0.123, respectively). Increased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively to ensure efficacy and safety. Genet Med 18 4, 386–395.
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Renal growth in isolated methylmalonic Acidemia.
Genetics in medicine : official journal of the American College of Medical Genetics, 2013Co-Authors: Paul Kruszka, Jennifer L. Sloan, Irini Manoli, Jeffrey B. Kopp, Charles P. VendittiAbstract:We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic Acidemia, a group of disorders associated with chronic kidney disease. Fifty patients with methylmalonic Acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses. Comparisons with age-matched controls showed that renal length in subjects with methylmalonic Acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic Acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 × age for the controls and 6.80 + 0.09 × age for the methylmalonic Acidemia cohort (P < 0.001; constant and slope). Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic Acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population. Genet Med 15 12, 990–996.
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Neurocognitive phenotype of isolated methylmalonic Acidemia.
Pediatrics, 2012Co-Authors: Colin J. O’shea, Jennifer L. Sloan, Andrea L. Gropman, Irini Manoli, Charles P. Venditti, Eva H. Baker, Edythe Wiggs, Maryland Pao, Joseph SnowAbstract:OBJECTIVE: Methylmalonic Acidemia (MMA) is a metabolic disorder with a poorly defined long-term neurocognitive phenotype. We studied the neuropsychological outcomes of patients and examined clinical covariates that influenced cognition. METHODS: A diverse cohort with mut , cblA , or cblB subtypes of isolated MMA ( N = 43), ages 2 to 32 years, were evaluated at a single center over a 6-year period. The influence of clinical, laboratory, and metabolic parameters on neuropsychological testing results was determined. RESULTS: Early-onset mut patients ( n = 21) manifested the most severe neurocognitive impairments, with a mean ± SD full-scale IQ (FSIQ) of 71.1 ± 14.75. Late-onset mut patients ( n = 6) had a mean FSIQ of 88.5 ± 27.62. cblA ( n = 7), cblB ( n = 6), and mut patients diagnosed prenatally or by newborn screening ( n = 3) obtained mean FSIQs in the average range (100.7 ± 10.95, 96.6 ± 10.92, and 106.7 ± 6.66, respectively). Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ ( P = .001 and P = .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not. FSIQ remained stable over longitudinal testing ( n = 10). Decreased scores on processing speed, compared with all other intellectual domains, emerged as a specific neurocognitive manifestation. CONCLUSIONS: The neurocognitive outcomes seen in isolated MMA are highly variable. An earlier age of disease onset, the presence of hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairment. In all patient subtypes, selective deficits in processing speed were present. * Abbreviations: MMA — : methylmalonic Acidemia FSIQ — : full-scale IQ P/NBS — : prenatal or newborn screening diagnosis
Thomas R Hornick - One of the best experts on this subject based on the ideXlab platform.
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lactic Acidemia associated with metformin
Annals of Pharmacotherapy, 2003Co-Authors: Jamshed K Khan, Muralidhar Pallaki, Sandra R Tolbert, Thomas R HornickAbstract:OBJECTIVETo report 2 cases of lactic Acidemia associated with the use of metformin in patients with normal renal function.CASE SUMMARYAn 82-year-old African American man and a 76-year-old white man developed an elevated serum lactic acid concentration a few weeks after initiation of metformin therapy for type 2 diabetes. After the patients discontinued metformin, the serum lactic acid concentration normalized in both cases. An objective causality assessment revealed that the adverse drug event was probably related to the use of metformin.DISCUSSIONMetformin interferes with the production and elimination of lactic acid by a variety of mechanisms that are not well understood. Few systematic data are available on changes in plasma lactic acid concentrations in patients with type 2 diabetes and normal renal function. Clinical significance of a high serum lactic acid concentration needs clarification.CONCLUSIONSMetformin therapy can be associated with subclinical elevation of lactic acid concentration in the a...
Irini Manoli - One of the best experts on this subject based on the ideXlab platform.
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chronic kidney disease in propionic Acidemia
Genetics in Medicine, 2019Co-Authors: Oleg A Shchelochkov, Jennifer L. Sloan, Irini Manoli, Jennifer G Myles, Peter J Mcguire, Susan Ferry, Alexandra Pass, Carol Van Ryzin, Megan Schoenfeld, Douglas R RosingAbstract: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.
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Isolated Methylmalonic Acidemia
2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Charles P. VendittiAbstract:Clinical characteristics Isolated methylmalonic Acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic Acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic Acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic Acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy. Diagnosis/testing Diagnosis of isolated methylmalonic Acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific subtype of methylmalonic Acidemia requires cellular biochemical studies (including 14C propionate incorporation and B12 responsiveness, complementation analysis, and cobalamin distribution assays) and molecular genetic testing. The finding of biallelic pathogenic variants in one of the five genes (MMUT, MMAA, MMAB, MCEE, and MMADHC) associated with isolated methylmalonic Acidemia – with confirmation of carrier status in the parents – can establish the diagnosis. Management Treatment of manifestations: Critically ill individuals are stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections. Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy. Prevention of primary manifestations: In some cases, newborn screening allows for presymptomatic detection of affected newborns and early treatment. Agents/circumstances to avoid: Fasting and increased dietary protein. Other: Medic Alert® bracelets and up-to-date, easily accessed, detailed emergency treatment protocols facilitate care. Genetic counseling Isolated methylmalonic Acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known. In some circumstances, prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis).
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a critical reappraisal of dietary practices in methylmalonic Acidemia raises concerns about the safety of medical foods part 1 isolated methylmalonic Acidemias
Genetics in Medicine, 2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Jennifer G Myles, Oleg A Shchelochkov, Charles P. VendittiAbstract:Medical foods for methylmalonic Acidemias (MMAs) and propionic Acidemias contain minimal valine, isoleucine, methionine, and threonine but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of patients with MMA ascertained via a natural history study. Cross-sectional anthropometric and body-composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA, and 6 cblB). Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut0: 99.45 ± 32.05% RDA). However, 85% received medical foods, in which the protein equivalent often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight- and height-for-age z-scores correlated negatively with the leucine-to-valine intake ratio (r = −0.453; P = 0.014; R2 = 0.209 and r = −0.341; P = 0.05; R2 = 0.123, respectively). Increased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively to ensure efficacy and safety. Genet Med 18 4, 386–395.
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Renal growth in isolated methylmalonic Acidemia.
Genetics in medicine : official journal of the American College of Medical Genetics, 2013Co-Authors: Paul Kruszka, Jennifer L. Sloan, Irini Manoli, Jeffrey B. Kopp, Charles P. VendittiAbstract:We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic Acidemia, a group of disorders associated with chronic kidney disease. Fifty patients with methylmalonic Acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses. Comparisons with age-matched controls showed that renal length in subjects with methylmalonic Acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic Acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 × age for the controls and 6.80 + 0.09 × age for the methylmalonic Acidemia cohort (P < 0.001; constant and slope). Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic Acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population. Genet Med 15 12, 990–996.
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Neurocognitive phenotype of isolated methylmalonic Acidemia.
Pediatrics, 2012Co-Authors: Colin J. O’shea, Jennifer L. Sloan, Andrea L. Gropman, Irini Manoli, Charles P. Venditti, Eva H. Baker, Edythe Wiggs, Maryland Pao, Joseph SnowAbstract:OBJECTIVE: Methylmalonic Acidemia (MMA) is a metabolic disorder with a poorly defined long-term neurocognitive phenotype. We studied the neuropsychological outcomes of patients and examined clinical covariates that influenced cognition. METHODS: A diverse cohort with mut , cblA , or cblB subtypes of isolated MMA ( N = 43), ages 2 to 32 years, were evaluated at a single center over a 6-year period. The influence of clinical, laboratory, and metabolic parameters on neuropsychological testing results was determined. RESULTS: Early-onset mut patients ( n = 21) manifested the most severe neurocognitive impairments, with a mean ± SD full-scale IQ (FSIQ) of 71.1 ± 14.75. Late-onset mut patients ( n = 6) had a mean FSIQ of 88.5 ± 27.62. cblA ( n = 7), cblB ( n = 6), and mut patients diagnosed prenatally or by newborn screening ( n = 3) obtained mean FSIQs in the average range (100.7 ± 10.95, 96.6 ± 10.92, and 106.7 ± 6.66, respectively). Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ ( P = .001 and P = .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not. FSIQ remained stable over longitudinal testing ( n = 10). Decreased scores on processing speed, compared with all other intellectual domains, emerged as a specific neurocognitive manifestation. CONCLUSIONS: The neurocognitive outcomes seen in isolated MMA are highly variable. An earlier age of disease onset, the presence of hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairment. In all patient subtypes, selective deficits in processing speed were present. * Abbreviations: MMA — : methylmalonic Acidemia FSIQ — : full-scale IQ P/NBS — : prenatal or newborn screening diagnosis
