Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria
Elena SchnabelStefan KölkerFlorian GleichPatrik FeyhFriederike HörsterDorothea HaasJunmin Fang‐HoffmannMarina A. MorathGwendolyn GramerWulf RöschingerSven F. GarbadeGeorg F. HoffmannJürgen G. OkunUlrike Mütze
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Abstract:
Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B12 deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study "NGS2025" from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B12 deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B12 deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B12, vitamin B6 respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels.Keywords:
Homocystinuria
Methylmalonic acidemia
Methylmalonic aciduria
Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B12 deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study "NGS2025" from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B12 deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B12 deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B12, vitamin B6 respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels.
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Abstract Background Isolated methylmalonic aciduria can be caused by pathogenic mutations in the gene for methylmalonyl-CoA mutase or in the genes encoding enzymes involved in the intracellular metabolism of cobalamin. Some of these mutations may be cobalamin responsive. The type of methylmalonic aciduria cannot always be assumed from clinical manifestation and the responsiveness to cobalamin has to be assessed for appropriate cobalamin administration, or to avoid unnecessary treatment. The cases presented herein highlight the importance of genetic testing in methylmalonic aciduria cases and the need for standardisation of the in vivo cobalamin-responsiveness assessment. Case presentation We describe two patients who presented in the first week of life with rapid neurological deterioration caused by metabolic acidosis with severe hyperammonaemia requiring extracorporeal elimination in addition to protein restriction, energy support, carnitine, and vitamin B12 treatment. The severity of the clinical symptoms and high methylmalonic acid concentrations in the urine (>30,000 μmol/mmol of creatinine) without hyperhomocysteinaemia in both of our patients suggested isolated methylmalonic aciduria. Based on the neonatal manifestation and the high methylmalonic acid urine levels, we assumed the cobalamin non-responsive form. The in vivo test of responsiveness to cobalamin was performed in both patients. Patient 1 was evaluated as non-responsive; thus, intensive treatment with vitamin B12 was not used. Patient 2 was responsive to cobalamin, but the dose was decreased to 1 mg i.m. every two weeks with daily oral treatment due to non-compliance. Genetic tests revealed bi-allelic mutations in the genes MMAB and MMAA in Patient 1 and 2, respectively. Based on these results, we were able to start intensive treatment with hydroxocobalamin in both patients. After the treatment intensification, there was no acute crisis requiring hospitalisation in Patient 1, and the urine methylmalonic acid levels further decreased in Patient 2. Conclusions Despite carrying out the in vivo test of responsiveness to cobalamin in both patients, only the results of molecular genetic tests led us to the correct diagnosis and enabled intensive treatment with hydroxocobalamin. The combination of the standardized in vivo test of cobalamin responsiveness and genetic testing is needed for accurate diagnosis and appropriate treatment of isolated methylmalonic aciduria.
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Combined methylmalonic acidemia and homocystinuria, is a rare autosomal recessive disorder due to defective intracellular cobalamin metabolism. We report an 18-year-old Chinese male who presented with hypermyotonia, seizures, and congenital heart diseases. Mutation analysis revealed c.365A>T and c.482 G>A mutations in the MMACHC gene, diagnosed with methylmalonic aciduria and homocystinuria (CblC type). After treatment with vitamin B12, L-carnitine, betaine, and folate, which resulted in an improvement in his clinical symptoms and laboratory values. This case emphasizes that inborn errors of metabolism should be considered for a teenager presenting with challenging or neurologic symptoms, especially when combined with unexplained heart diseases.
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We have identified a patient with methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism of the cb1C type mutant. At the time of admission at eight months of age the patient was malnourished, hypotonic and had macrocytic anemia. Neonatal screening for hypermethioninemia associated with homocystinuria had been normal. Serum vitamin B12 was markedly increased and folate concentration was above normal, as were urinary homocystine and methylmalonic acid. The patient had abnormal brain stem auditory and visual evoked potentials. Fibroblast activity of N5-methyltetrahydrofolate: homocysteine methyltransferase was reduced to approximately 10% of concurrent controls. A course of therapy with hydroxocobalamin resulted in a 90% reduction in excretion of methylmalonic acid and normalization of the evoked potentials. These studies support the efficacy of hydroxocobalamin therapy in this disease, suggest that methylmalonic acid may be the most appropriate metabolite to monitor for therapeutic response, and indicate the importance of electrophysiologic studies in characterizing and in objectively monitoring the response to treatment of this metabolic disease.
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Combined methylmalonic acidemia with homocystinuria is a common form of methylmalonic acidemia in China. Patients with this disease can progress to death without timely and effective treatment. This study aimed to analyze the treatment outcomes of patients with combined methylmalonic acidemia and homocystinuria.From September 2004 to April 2012, 58 patients with combined methylmalonic acidemia and homocystinuria (34 males and 24 females) were diagnosed and treated in our hospital. Fifty cases were from clinical patients including 42 early-onset cases and 8 late-onset cases. Their age when they were diagnosed ranged from 18 days to 30.8 years. The other 8 cases were from newborn screening. All the patients were treated with vitamin B12, betaine, folic acid, vitamin B6, and L-carnitine. The physical and neuropsychological development, general laboratory tests, the levels of amino acids, acylcarnitines, and homocysteine in blood, and organic acids in urine were followed up.The follow-up period ranged from 1 month to 7.1 years. Three cases died (all were early-onset cases). In the other patients after treatment, the symptoms such as recurrent vomiting, seizures, lethargy, and poor feeding disappeared, muscle strength and muscle tension were improved, and general biochemical abnormalities such as anemia and metabolic acidosis were corrected. Among the surviving 55 cases, 49 had neurological impairments such as developmental delay and mental retardation. The median levels of blood propionylcarnitine and its ratio with acetylcarnitine, serum homocysteine, and urine methylmalonic acid were significantly decreased (P < 0.01), from 7.73 µmol/L (ranged from 1.5 to 18.61 µmol/L), 0.74 (ranged from 0.29 to 2.06), 97.3 µmol/L (ranged from 25.1 to 250 µmol/L) and 168.55 (ranged from 3.66 to 1032.82) before treatment to 2.74 µmol/L (ranged from 0.47 to 12.09 µmol/L), 0.16 (ranged from 0.03 to 0.62), 43.8 µmol/L (ranged from 17 to 97.8 µmol/L) and 6.81 (ranged from 0 to 95.43) after treatment, respectively.Patients with combined methylmalonic acidemia and homocystinuria respond to a combined treatment consisting of supplementation of hydroxycobalamin, betaine, folic acid, vitamin B6 and L-carnitine with clinical and biochemical improvement. But the long-term outcomes are unsatisfactory, with neurological sequelae in most patients.
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Screening neonates for methylmalonic aciduria is part of routine screening for metabolic disorders in Massachusetts. The process of urine collection by the parent and transmitted to the central screening laboratory was described in a previous publication (Pediatrics 49: 825, 1972). The primary objective of screening for methylmalonic aciduria is to detect methylmalonic acidemia, an inherited organic acid disorder. During the most recent 5 1/2-year period when the sensitive fast blue B stain was used in the analysis, four infants with methylmalonic acidemia were detected among 293,535 screened. Additional infants and children who came to attention because of clinical illness or family study also could be readily detected. Prior to this period, 325,634 neonates had been screened with the aniline-xylose method, which proved to be not sensitive enough for the identification of methylmalonic aciduria. Some affected infants have responded well to therapy and are clinically normal while two have shown poor biochemical response and are developmentally delayed. Four children in two families appear to have a benign variant of methylmalonic acidemia. Based on these studies the observed incidence of methylmalonic acidemia in Massachusetts is 1:48,000. Screening for methylmalonic aciduria may be an appropriate addition to newborn screening programs.
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Abstract Background: Combined methylmalonic acidemia and homocystinuria, cobalamin C type (cblC defect) is the most common inborn error of cobalamin metabolism. Even with rapid diagnosis and treatment, the long-term outcome remains poor. A reliable method for the prenatal diagnosis of cblC defect is needed for parental decisions regarding continuation of pregnancies of cblC defect fetuses.Results: The between-day and within-day imprecision of Hcy assay were 1.60%∼5.87% and 1.11%∼4.31%, respectively. For the 248 at-risk fetuses, there were 63 affected fetuses with cblC defect and 185 unaffected fetuses. The levels of Hcy in 63 affected fetuses were significantly higher than those in 185 unaffected fetuses, without overlap between the affected and unaffected groups. Sixteen fetuses displayed inconclusive genetic results of MMACHC variants, in which seven fetuses were determined to be affected with elevated amniotic fluid levels of Hcy, C3, C3/C2 and MMA. The remaining nine fetuses were considered unaffected based on a normal amniotic fluid metabolite profile. The diagnostic sensitivities of Hcy and other characteristic metabolites including propionylcarnitine (C3), ratio of C3 to acetylcarnitine (C2; C3/C2), methylmalonic acid (MMA), and methylcitrate acid (MCA) in amniotic fluid were 100%, 87.50%, 100%, 85.71%, and 28.57%, respectively. The respective specificities were 92.05%, 100%, 100%, 97.73%, and 99.43%. Conclusions: Hcy appears to be another sensitive characteristic metabolite biomarker for the prenatal diagnosis of cblC defect. The combination of Hcy assay with acylcarnitine and organic acid analysis is a fast, sensitive, and reliable prenatal diagnostic biochemical approach. This approach could overcome the challenge of the lack of genetic analysis for families with at-risk cblC defect fetuses.
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