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Indian Journal of Pediatrics Jul 2024
Topics: Humans; Infant, Newborn; Amino Acid Metabolism, Inborn Errors
PubMed: 38580803
DOI: 10.1007/s12098-024-05121-1 -
Journal of Inherited Metabolic Disease Apr 2024The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies...
The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine β-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-β-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.
PubMed: 38563533
DOI: 10.1002/jimd.12731 -
International Journal of Neonatal... Mar 2024Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left...
Newborn screening (NBS) is an important public health program that aims to identify pre-symptomatic healthy babies that will develop significant disease if left undiagnosed and untreated. The number of conditions being screened globally is expanding rapidly in parallel with advances in technology, diagnosis, and treatment availability for these conditions. In Hong Kong, NBS for inborn errors of metabolism (NBSIEM) began as a pilot program in October 2015 and was implemented to all birthing hospitals within the public healthcare system in phases, with completion in October 2020. The number of conditions screened for increased from 21 to 24 in April 2016 and then to 26 in October 2019. The overall recruitment rate of the NBS program was 99.5%. In the period between October 2015 and December 2022, 125,688 newborns were screened and 295 were referred back for abnormal results. The recall rate was reduced from 0.26% to 0.12% after the implementation of second-tier testing. An inherited metabolic disorder (IMD) was eventually confirmed in 47 infants, making the prevalence of IMD in Hong Kong 1 in 2674. At the time of the NBS result, 78.7% of the newborns with IMD were asymptomatic. There were two deaths reported: one newborn with methylmalonic acidemia cobalamin B type (MMACblB) died after the initial crisis and another case of carnitine palmitoyltransferase II deficiency (CPTII) died at 18 months of age after metabolic decompensation. The most common IMD noted were disorders of fatty acid oxidation metabolism (40%, 19 cases), closely followed by disorders of amino acid metabolism (38%, 18 cases), with carnitine uptake defect (19.1%, 9 cases) and citrullinemia type II (17%, 8 cases) being the two most common IMD picked up by the NBSIEM in Hong Kong. Out of the all the IMDs identified, 19.1% belonged to diverse ethnic groups. False negative cases were reported for citrullinemia type II and congenital adrenal hyperplasia during this period.
PubMed: 38535127
DOI: 10.3390/ijns10010023 -
Journal of Assisted Reproduction and... May 2024Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases.
Preimplantation genetic testing for monogenic disorders (PGT-M) offers an alternative strategy to prevent children from being born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes: a retrospective study.
BACKGROUND
Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases.
MATERIAL AND METHODS
In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases. After PGT-M, unaffected (i.e., normal) embryos after genetic detection were transferred into the uterus of their corresponding mothers.
RESULTS
A total of 43 carrier couples with the following hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes underwent PGT-M: Duchenne muscular dystrophy (13 families); methylmalonic acidemia (7 families); spinal muscular atrophy (5 families); infantile neuroaxonal dystrophy and intellectual developmental disorder (3 families each); Cockayne syndrome (2 families); Menkes disease, spinocerebellar ataxia, glycine encephalopathy with epilepsy, Charcot-Marie-Tooth disease, mucopolysaccharidosis, Aicardi-Goutieres syndrome, adrenoleukodystrophy, phenylketonuria, amyotrophic lateral sclerosis, and Dravet syndrome (1 family each). After 53 PGT-M cycles, the final transferable embryo rate was 12.45%, the clinical pregnancy rate was 74.19%, and the live birth rate was 89.47%; a total of 18 unaffected (i.e., healthy) children were born to these families.
CONCLUSIONS
This study highlights the importance of PGT-M in preventing children born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes.
Topics: Humans; Preimplantation Diagnosis; Female; Pregnancy; Genetic Testing; Metabolic Diseases; Retrospective Studies; Male; Nervous System Diseases; Phenotype; Adult; Child; Embryo Transfer; Mutation
PubMed: 38470552
DOI: 10.1007/s10815-024-03057-1 -
Heliyon Mar 2024Methylmalonic acidemia (MMA) is a rare inborn genetic disorder that is characterized by increased levels of methylmalonic acid in blood plasma and urine. Isolated...
OBJECTIVES
Methylmalonic acidemia (MMA) is a rare inborn genetic disorder that is characterized by increased levels of methylmalonic acid in blood plasma and urine. Isolated methylmalonic acidemia is one of the most common types of MMA and is caused by mutations in the gene encoding methyl-malonyl coenzyme A mutase (). In this study, we investigated the possible mechanisms underlying the symptoms of isolated MMA in a patient by molecular analysis.
METHODS
PCR amplification and Sanger sequencing analysis was performed to identify variants in the gene in the proband and his family. Furthermore, minigene constructs were generated to validate the splicing defects in the gene variant identified in the proband.
RESULTS
The 3-year-old patient was admitted to the hospital with symptoms of MMA, including fever, convulsions, and vomiting. He showed metabolic acidosis, high levels of methylmalonic acid in blood and urine, and normal blood homocysteine levels. Genetic analysis demonstrated that the patient was a compound heterozygous carrier of two variants in the gene: a missense c.278G > A variant that has already been reported in a patient with the severe mut⁰ phenotype; and a novel splice site variant c.2125-2A > G. RT-PCR analysis showed that, while the novel variant clearly alters splicing, a minor amount of a full-length transcript is generated, suggesting that a wild-type protein may be produced although at a lower quantitative level. The patient's condition improved after treatment with vitamin B12. Serious complications were not reported during follow-up at age 5.
CONCLUSIONS
We identified a novel splice site variant that partially disrupts normal splicing of the pre-mRNA. Production of a reduced amount of full-length transcript is responsible for the mild clinical phenotype observed in this patient. Functional studies have proven useful in exploring the genotype-phenotype association and in providing guidance for the genetic diagnosis of MMA.
PubMed: 38455531
DOI: 10.1016/j.heliyon.2024.e26912 -
JIMD Reports Mar 2024Methylmalonic acidemia cblB type (MMA cblB) is an autosomal recessive inborn error of amino acid metabolism that results in impaired synthesis of adenosylcobalamin, a...
Methylmalonic acidemia cblB type (MMA cblB) is an autosomal recessive inborn error of amino acid metabolism that results in impaired synthesis of adenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. It presents with episodes of coma, vomiting, hypotonia, metabolic acidosis, and hyperammonemia. End-stage kidney disease is a long-term complication. Treatments include vitamin B12 supplementation, L-carnitine, and a low-protein diet. Liver, kidney, or combined liver-kidney transplantations are promising options, but they are not without complications. We report a patient suffering from MMA cblB who developed end-stage kidney disease at 18 years of age. Kidney transplantation allowed him to recover normal kidney function and good metabolic control. Unfortunately, after two decades, he developed non-Hodgkin lymphoma and severe chemotherapy toxicity which led to his death. The risk of lymphoproliferative diseases is known to increase after solid organ transplantation. However, in MMA, factors including mitochondrial dysfunction and oncometabolites, may further increase the risk of malignancy and drug toxicity. Our report highlights the importance of considering the increased risk of cancer in long-term follow-up of MMA cblB patients, especially after solid organ transplantation. Moreover, when chemotherapy is needed, the increased risk of toxicity and metabolic decompensation should be considered and monitored.
PubMed: 38444575
DOI: 10.1002/jmd2.12411 -
Pediatric Transplantation Mar 2024Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in propionyl-CoA (P-CoA) catabolism; of note, liver neoplasms rarely occur as a... (Review)
Review
BACKGROUND
Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by defects in propionyl-CoA (P-CoA) catabolism; of note, liver neoplasms rarely occur as a long-term complication of the disorder. Herein, we report the case of a patient with MMA and hepatocellular carcinoma (HCC) who was successfully treated with a living-donor liver transplant (LDLT) following prior kidney transplantation.
CASE REPORT
A 25-year-old male patient with MMA underwent LDLT with a left lobe graft because of metabolic instability and liver neoplasms. He had presented with chronic symptoms of MMA, which had been diagnosed by genetic testing. Additionally, he had undergone living-donor kidney transplantation with his father as the donor due to end-stage kidney disease 6 years before the LDLT. He had an episode of metabolic decompensation triggered by coronavirus disease in 2019. Imaging studies revealed an intrahepatic neoplasm in the right hepatic lobe. Due to concerns about metabolic decompensation after hepatectomy, LDLT was performed using a left lobe graft obtained from the patient's mother. Pathological findings were consistent with the characteristics of well-to-moderately differentiated HCC. The postoperative course was uneventful, and the patient was discharged 48 days after the LDLT without any complications. At the 9-month follow-up, the patient's condition was satisfactory, with sufficient liver graft function and without metabolic decompensation.
CONCLUSION
This case indicates that although HCC is a rare complication in patients with MMA, clinicians should be aware of hepatic malignancies during long-term follow-up.
Topics: Male; Humans; Adult; Liver Transplantation; Carcinoma, Hepatocellular; Living Donors; Liver Neoplasms; Amino Acid Metabolism, Inborn Errors
PubMed: 38433569
DOI: 10.1111/petr.14719 -
World Journal of Pediatrics : WJP Feb 2024Methylmalonic acidemia (MMA) is a disorder of autosomal recessive inheritance, with an estimated prevalence of 1:50,000. First-tier clinical diagnostic tests often...
INTRODUCTION
Methylmalonic acidemia (MMA) is a disorder of autosomal recessive inheritance, with an estimated prevalence of 1:50,000. First-tier clinical diagnostic tests often return many false positives [five false positive (FP): one true positive (TP)]. In this work, our goal was to refine a classification model that can minimize the number of false positives, currently an unmet need in the upstream diagnostics of MMA.
METHODS
We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction. We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients, followed by additional ratio feature construction. Feature selection strategies (selection by filter, recursive feature elimination, and learned vector quantization) were used to determine the input set for evaluating the performance of 14 classification models to identify a candidate model set for an ensemble model development.
RESULTS
Our work identified computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity. The best results [area under the receiver operating characteristic curve (AUROC) of 97%, sensitivity of 92%, and specificity of 95%] were obtained utilizing an ensemble of the algorithms random forest, C5.0, sparse linear discriminant analysis, and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor. The model achieved a good performance trade-off for a screening application with 6% false-positive rate (FPR) at 95% sensitivity, 35% FPR at 99% sensitivity, and 39% FPR at 100% sensitivity.
CONCLUSIONS
The classification results and approach of this research can be utilized by clinicians globally, to improve the overall discovery of MMA in pediatric patients. The improved method, when adjusted to 100% precision, can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families.
PubMed: 38401044
DOI: 10.1007/s12519-023-00788-6 -
Journal of Medical Case Reports Feb 2024Methylmalonic acidemia is a very rare genetic metabolic disease. Patients with isolated methylmalonic acidemia typically present with acute alterations of consciousness,...
BACKGROUND
Methylmalonic acidemia is a very rare genetic metabolic disease. Patients with isolated methylmalonic acidemia typically present with acute alterations of consciousness, failure to thrive, anorexia, vomiting, respiratory distress, and muscular hypotonia. Despite the evidence-based management, affected individuals experience significant morbidity and mortality. Hyperkalemia is one of the unusual complications of methylmalonic acidemia.
CASE PRESENTATION
In this paper, we describe a 4-year-old Persian boy with methylmalonic acidemia who developed life-threatening arrhythmia following severe hyperkalemia and metabolic acidosis. Emergent management of the condition was successfully carried out, and the rhythm changed to normal sinus rhythm by effectively reducing the serum potassium level. We discuss the possible etiology of this lethal condition and describe its management on the basis of the available evidence.
CONCLUSION
During metabolic decompensation in methylmalonic acidemia, frequent blood gas and electrolyte testing to prescribe and adjust therapy and annual echocardiogram and electrocardiogram screening are essential.
Topics: Male; Humans; Child, Preschool; Hyperkalemia; Amino Acid Metabolism, Inborn Errors; Acidosis; Arrhythmias, Cardiac
PubMed: 38395924
DOI: 10.1186/s13256-024-04406-5 -
Molecular Genetics and Metabolism May 2024Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B metabolism. In cblC, deficient activation of cobalamin results...
Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), "compounds"), and four c.271dupA homozygotes ("homozygotes"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 μM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 μM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.
Topics: Humans; Hydroxocobalamin; Male; Female; Phenotype; Vitamin B 12 Deficiency; Vitamin B 12; Child, Preschool; Carrier Proteins; Retrospective Studies; Oxidoreductases; Child; Methylmalonic Acid; Homocystinuria; Infant; Mutation, Missense; Homozygote; Heterozygote; Homocysteine; Adolescent; Amino Acid Metabolism, Inborn Errors; Adult
PubMed: 38387306
DOI: 10.1016/j.ymgme.2024.108345