scholarly journals Retrospective evaluation of the Dutch pre‐newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia: What to aim, expect, and evaluate from newborn screening?

2019 ◽  
Vol 43 (3) ◽  
pp. 424-437 ◽  
Author(s):  
Hanneke A. Haijes ◽  
Femke Molema ◽  
Mirjam Langeveld ◽  
Mirian C. Janssen ◽  
Annet M. Bosch ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Propionic Acidemia ◽  
Methylmalonic Acidemia ◽  
Retrospective Evaluation

Inborn errors of metabolism detectable by tandem mass spectrometry in Beijing

2020 ◽  
Vol 33 (5) ◽  
pp. 639-645
Author(s):  
Nan Yang ◽  
Li-fei Gong ◽  
Jin-qi Zhao ◽  
Hai-he Yang ◽  
Zhi-jun Ma ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Genetic Analysis ◽  
Tandem Mass Spectrometry ◽  
Newborn Screening ◽  
Inborn Errors Of Metabolism ◽  
Propionic Acidemia ◽  
Methylmalonic Acidemia ◽  
Tandem Mass ◽  
Inborn Errors ◽  
Screening Programs

AbstractBackgroundIndividual inborn errors of metabolism (IEMs) are rare disorders. Expanded newborn screening for IEMs by tandem mass spectrometry (TMS) is an efficient approach for early diagnosis. Here we provide the newborn screening program for the application of this approach (between July 2014 and March 2019) to the identification of newborns in Beijing at risk of developing a potentially fatal disease.MethodsThe amino acids and acylcarnitines in dried blood spots were analyzed by TMS. Diagnoses of newborns with elevated metabolites were confirmed by gas chromatography-mass spectrometry, biochemical studies, and genetic analysis.ResultsAmong the healthy newborns, 16 metabolic disorder cases were confirmed, giving a total birth prevalence of 1:3666 live births. Organic acidemia (OA) was the most common (9/16 patients; 56%), and methylmalonic acidemia was the most frequently observed OA (7/9 patients; 89%). Five infants were diagnosed with methylmalonic acidemia with homocystinuria type CblC, two with isolated methylmalonic acidemia, one with propionic acidemia, and one with isovaleric acidemia. Four patients (4/16, 25%) were diagnosed with hyperphenylalaninemia. One suffered with medium-chain acyl CoA dehydrogenase deficiency, one with carnitine uptake deficiency, and one with citrin deficiency. Eleven cases underwent genetic analysis. Seventeen mutations in eight IEM-associated genes were identified in 11 confirmed cases. Symptoms were already present within 2 days after birth in 44% (7/16) cases. The infant with propionic acidemia died at 7 days after birth. The other cases received timely diagnosis and treatment, and most of them grew well.ConclusionsThe results illustrate challenges encountered in disease management highlighting the importance of newborn screening for inherited metabolic disorders, which is not yet nationally available in our country. Regional newborn screening programs will provide a better estimation of the incidence of IEM.

scholarly journals Newborn Screening for Methylmalonic Acidemia/propionic Acidemia: Systematic Evaluation of a Two-pronged Approach Based on MS/MS and UPLC-MS/MS

2021 ◽  
Author(s):  
Wei Zhou ◽  
Jinxiu Song ◽  
Huizhong Li ◽  
Zhe Ji ◽  
Xin Yin ◽  
...  
Keyword(s):  
Birth Weight ◽  
Newborn Screening ◽  
False Positive ◽  
False Positive Rate ◽  
Propionic Acidemia ◽  
Methylmalonic Acidemia ◽  
Systematic Evaluation ◽  
Care Hospital ◽  
Positive Rate ◽  
Second Tier

Abstract Background: An improved second-tier test is needed to reduce the false-positive rate of newborn screening (NBS) for inborn metabolic disorders in Xuzhou, China.Methods: We designed an expanded second-tier assay using newborn dried blood spots (DBSs). Analytical and clinical performance were evaluated in 53 newborns with methylmalonic acidemia (MMA) or propionic acidemia (PA) reported by the Xuzhou Maternity and Child Health Care Hospital NBS program. Additionally, we analyzed NBS data regarding seasonal variation of metabolites, birth weight and gestational age to improve the identification of true positive MMA/PA individuals.Results: Among the 53 MMA/PA individuals assessed, two pathogenic or likely pathogenic (P/LP) variants in an MMA/PA-associated gene were identified in 46 patients, and a pathogenic variant and a variant of unknown significance (VUS) were identified in 7 patients. No such variants were detected in MMA/PA false-positive individuals or healthy controls. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based analysis of the initial NBS metabolic profile correctly identified MMA/PA individuals and reduced the initial NBS false-positive rate by 98.86%. MMA/PA false-positive infants in Xuzhou, China, were most likely to be summer-born.Conclusion: We established a two-pronged approach to reduce false positives by nearly 99% and provided a novel NBS strategy. Challenges in neonate metabolic testing and DNA variant interpretation regarding season, birth weight and pregnancy status remain for this Chinese population.

scholarly journals Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ruixue Zhang ◽  
Rong Qiang ◽  
Chengrong Song ◽  
Xiaoping Ma ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Inborn Errors Of Metabolism ◽  
Northwest China ◽  
Methylmalonic Acidemia ◽  
Shaanxi Province ◽  
Inborn Errors ◽  
Organic Acidurias ◽  
Genetic Characteristics ◽  
Disease Spectrum ◽  
Expanded Newborn Screening

AbstractExpanded newborn screening facilitates early identification and intervention of patients with inborn errors of metabolism (IEMs), There is a lack of disease spectrum data for many areas in China. To determine the disease spectrum and genetic characteristics of IEMs in Xi'an city of Shaanxi province in northwest China, 146152 newborns were screening by MSMS from January 2014 to December 2019 and 61 patients were referred to genetic analysis by next generation sequencing (NGS) and validated by Sanger sequencing. Seventy-five newborns and two mothers were diagnosed with IEMs, with an overall incidence of 1:1898 (1:1949 without mothers). There were 35 newborns with amino acidemias (45.45%, 1:4176), 28 newborns with organic acidurias (36.36%, 1:5220), and 12 newborns and two mothers with FAO disorders (18.18%; 1:10439 or 1:12179 without mothers). Phenylketonuria and methylmalonic acidemia were the two most common disorders, accounting for 65.33% (49/75) of all confirmed newborn. Some hotspot mutations were observed for several IEMs, including PAH gene c.728G>A for phenylketonuria; MMACHC gene c.609G>A and c.567dupT, MMUT gene c.323G>A for methylmalonic acidemia and SLC25A13 gene c.852_855del for citrin deficiency. Our study provides effective clinical guidance for the popularization and application of expanded newborn screening, genetic screening, and genetic counseling of IEMs in this region.

scholarly journals Identification of 2,2-Dimethylbutanoic Acid (HST5040), a Clinical Development Candidate for the Treatment of Propionic Acidemia and Methylmalonic Acidemia

2021 ◽  
Vol 64 (8) ◽  
pp. 5037-5048
Author(s):  
Allison J. Armstrong ◽  
Brad R. Henke ◽  
Maria Sol Collado ◽  
Justin M. Taylor ◽  
Taylor D. Pourtaheri ◽  
...  
Keyword(s):  
Propionic Acidemia ◽  
Clinical Development ◽  
Methylmalonic Acidemia

scholarly journals SARS-CoV-2 infection in a patient with propionic acidemia

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Anna Caciotti ◽  
Elena Procopio ◽  
Francesca Pochiero ◽  
Silvia Falliano ◽  
Giuseppe Indolfi ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Propionic Acidemia ◽  
Psychomotor Development ◽  
Inborn Errors ◽  
Clinical Complications ◽  
Metabolic Crisis ◽  
Previous Diagnosis ◽  
Expanded Newborn Screening ◽  
Clinical Consequences

Abstract We describe a 14-month-old boy, with a previous diagnosis of propionic acidemia (PA) by expanded newborn screening, who, admitted for a suspected metabolic crisis, tested positive for SARS-CoV-2. Since propionic acidemia was diagnosed, the patient has followed the recommended diet for this inborn error of metabolism. Although propionic acidemia patients are at a high risk of suffering metabolic crises, frequently associated with permanent clinical complications, psychomotor development of this patient was normal. The SARS-CoV-2 infection (at about 1 year of age) caused the patient’s first metabolic crisis. However, his clinical course was in keeping with a mild clinical form of COVID-19, and he recovered without experiencing severe clinical consequences. We describe this patient in order to improve the knowledge about follow up of PA patients identified by newborn screening and to increase the limited number of reports of SARS-CoV-2 infection in children with comorbidities, especially inborn errors of metabolism.

scholarly journals A rare mutation c.1663G>A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients

2020 ◽  
Author(s):  
Lili Liang ◽  
Ruixue Shuai ◽  
Yue Yu ◽  
Wenjuan Qiu ◽  
Linghua Shen ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Vitamin B12 ◽  
Disease Onset ◽  
Methylmalonic Acidemia ◽  
Chinese Patients ◽  
Causative Gene ◽  
Rare Type ◽  
Rare Mutation ◽  
Wide Range ◽  
Before And After

Abstract Background Methylmalonic acidemia is an inherited organic acid metabolic disease. it involves multiple physiological systems and has variable manifestations. The primary causative gene MMUT carries wide range of mutations, and one of them, c.1663G > A (p.A555T), is considered to be of an extremely rare type. So far, little is known about the clinical features of patients carrying this mutation. In the present study, we aimed to define the clinical and biochemical features of the patients with this genotype.Methods Among 328 mut type methylmalonic acidemia patients from multiple hospitals in China, we collected 30 patients sharing the mutation c.1663G > A (p.A555T) in the MMUT gene. Their clinical characteristics and biochemical index were described in detail and compared with methylmalonic acidemia patients without this variant.Results Most of these patients were diagnosed via newborn screening (26/30), treated in a timely manner, and kept healthy (24/30). Disease onset occurred in 7 patients. Mental retardation occurred in 4 patients. Vitamin B12 is responsive in 100% of these patients (29/29). The blood propionylcarnitine, blood propionylcarnitine/acetylcarnitine ratio, urinary methylmalonic acid, urinary methylcitric acid before and after treatment in c.1663G > A (p.A555T) carrying patients were much lower than those in non-c.1663G > A (p.A555T) carrying patients.Conclusion Compared to patients with other mutations in the MMUT gene, patients with the c.1663G > A (p.A555T) mutation showed later onset, milder clinical phenotype, lighter biochemical abnormalities, better vitamin B12 responsiveness, lower morbidity, easier metabolic control, and thereby better prognosis. Newborn screening project plays an important role in early diagnosis, treatment, and prognosis of these patients.

scholarly journals A False-Positive Case of Methylmalonic Aciduria by Tandem Mass Spectrometry Newborn Screening Dependent on Maternal Malnutrition in Pregnancy

2020 ◽  
Vol 17 (10) ◽  
pp. 3601 ◽  
Author(s):  
Claudia Rossi ◽  
Ilaria Cicalini ◽  
Cristiano Rizzo ◽  
Mirco Zucchelli ◽  
Ada Consalvo ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
Vitamin B12 Deficiency ◽  
Propionic Acidemia ◽  
Dried Blood Spots ◽  
Specific Marker ◽  
Inborn Errors ◽  
Maternal Malnutrition ◽  
Ms Analysis ◽  
Second Tier

Methylmalonic Acidurias (MMAs) are a group of inborn errors of metabolism (IEMs), specifically of propionate catabolism characterized by gastrointestinal and neurometabolic manifestations resulting from a deficiency in the function of methylmalonyl-CoA mutase, methylmalonyl-CoA epimerase, and cobalamin metabolism. In Expanded Newborn Screening (NBS), increased levels of propionylcarnitine (C3) and/or of its ratios by MS/MS analysis of dried blood spots (DBS) samples are suggestive for either Propionic Acidemia or MMAs. C3 elevation is not considered a specific marker for these disorders, resulting in high false-positive rates. The use of analyte ratios improves specificity, but it still cannot resolve the diagnostic issue. Second-tier testing are strongly recommended as confirmation of primary NBS results and for a differential diagnosis. LC-MS/MS analysis allows the quantification of more specific markers of the disorder. Here, we report the case of a newborn with a suspected MMA at Expanded NBS and at second-tier test. Given the urgent situation, in-depth diagnostic investigations were performed. Further investigations surprisingly revealed a Vitamin B12 deficiency due to a maternal malnutrition during pregnancy. This case emphasized that metabolic alterations at NBS may not only be influenced by genome and related to IEMs, but also to external factors and to maternal conditions.

scholarly journals A rare mutation c.1663G>A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients

2020 ◽  
Author(s):  
Lili Liang ◽  
Ruixue Shuai ◽  
Yue Yu ◽  
Wenjuan Qiu ◽  
Linghua Shen ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Vitamin B12 ◽  
Disease Onset ◽  
Methylmalonic Acidemia ◽  
Chinese Patients ◽  
Compound Heterozygous ◽  
Causative Gene ◽  
Rare Type ◽  
Wide Range ◽  
Before And After

Abstract Background: Methylmalonic acidemia is an inherited organic acid metabolic disease. it involves multiple physiological systems and has variable manifestations. The primary causative gene MMUT carries wide range of mutations, and one of them, c.1663G>A (p.A555T), is considered to be of an extremely rare type. So far, little is known about the clinical features of patients carrying this mutation. In the present study, we aimed to define the clinical and biochemical features of the patients with this genotype.Methods: Among 328 mut type methylmalonic acidemia patients from multiple hospitals in China, we collected 30 compound heterozygous patients sharing the mutation c.1663G>A (p.A555T) in the MMUT gene. Their clinical characteristics and biochemical index were described in detail and compared with methylmalonic acidemia patients without this variant. Results: Most of these patients were diagnosed via newborn screening (26/30), treated in a timely manner, and kept healthy (24/30). Disease onset occurred in 7 patients. Developmental delay or intellectual impairment occurred in 4 patients. Vitamin B12 is responsive in 100% of these patients (29/29). The blood propionylcarnitine, blood propionylcarnitine/acetylcarnitine ratio, urinary methylmalonic acid, urinary methylcitric acid before and after treatment in c.1663G>A (p.A555T) carrying patients were much lower than those in non-c.1663G>A (p.A555T) carrying patients.Conclusion: Compared to patients with other mutations in the MMUT gene, patients with the c.1663G>A (p.A555T) mutation showed later onset, milder clinical phenotype, lighter biochemical abnormalities, better vitamin B12 responsiveness, lower morbidity, easier metabolic control, and thereby better prognosis. Newborn screening project plays an important role in early diagnosis, treatment, and prognosis of these patients.

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