A common mutation in IVD associated with asymptomatic isovaleric acidemia: implications for newborn screening

BACKGROUND Electrospray ionization–tandem mass spectrometry (ESI-MS/MS) has been used in the Bavarian newborn screening (NBS) program since 1999. The use of ESI-MS/MS has led to the inclusion of isovaleric acidemia (IVA) into NBS. We retrospectively evaluated data on more than 1.6 million newborns screened during 9.5 years. METHODS Acylcarnitines from whole blood spotted on filter paper were converted to their corresponding butyl esters, and the samples were analyzed by use of ESI-MS/MS with stable isotope labeled internal standards. RESULTS A total of 24 individuals with IVA were detected by use of a multiparametric threshold criteria panel including isovalerylcarnitine (C5) and the ratios of C5 to octanoyl-, butyryl-, and propionylcarnitine. A cutoff set at the 99.99th percentile for isolated C5 or at the 99th percentile for C5 plus at least 2 ratios resulted in a positive predictive value for IVA screening of 7.0% and an overall recall rate of 0.024%. Adjusted reference ranges for age and birth weight were applied, and the incidence of IVA in the study population was calculated to be 1 in 67 000. Missed cases were not brought to our attention. IVA was also detectable in cord blood and early postnatal blood samples. CONCLUSIONS IVA can be reliably detected in NBS through acylcarnitine analysis in dried blood spots by using multiparametric threshold criteria. Further improvement (positive predictive value 13.0%, recall rate 0.01%) can be achieved by using more stringent recall criteria. In view of the potentially life-threatening natural course of IVA in early life, presymptomatic diagnosis may thus prevent mortality and morbidity.

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Useful second-tier tests in expanded newborn screening of isovaleric acidemia and methylmalonic aciduria

Journal of Inherited Metabolic Disease ◽

10.1007/s10545-010-9111-9 ◽

2010 ◽

Vol 33 (S2) ◽

pp. 283-288 ◽

Cited By ~ 24

Author(s):

Yosuke Shigematsu ◽

Ikue Hata ◽

Go Tajima

Keyword(s):

Newborn Screening ◽

Methylmalonic Aciduria ◽

Isovaleric Acidemia ◽

Expanded Newborn Screening ◽

Second Tier

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3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary?

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0536 ◽

2019 ◽

Vol 32 (12) ◽

pp. 1321-1326

Author(s):

Huaiyan Wang ◽

Shuang Liu ◽

Benjing Wang ◽

Yuqi Yang ◽

Bin Yu ◽

...

Keyword(s):

Newborn Screening ◽

Metabolic Diseases ◽

Clinical Symptoms ◽

Massively Parallel Sequencing ◽

Dried Blood Spots ◽

Jiangsu Province ◽

Common Mutation ◽

Illumina Hiseq ◽

Feeding Difficulties

Abstract Objective To evaluate whether 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) should be routinely screened in newborns. Methods Dried blood spots (DBS) were collected and analyzed by tandem mass spectrometry (TMS). Blood samples were collected from infants with positive 3-MCCD results. Targeted sequencing was performed using the extended panel for inherited metabolic diseases to detect 306 genes. The sequencing libraries were quantified and used for massively parallel sequencing on the Illumina HiSeq 2500 platform. Results A total of 536,008 infants underwent newborn screening (NBS) and 14 cases of 3-MCCD were diagnosed. The incidence of 3-MCCD in Jiangsu province was 1:38,286. During the last 3 years of follow-up, none of the subjects with 3-MCCD exhibited obvious clinical symptoms. Only two children had mild feeding difficulties and vomiting. Eleven patients had complex variants of the MCCC1 gene, and three patients had mutations in MCCC2. In total, 17 types of MCCC1 or MCCC2 variants were found, and c.639 + 2t > a was the most common mutation. Conclusions As far as the current results are concerned, 3-MCCD may be benign in Jiangsu province. However, additional investigations and a longer follow-up period are necessary to decide whether NBS of 3-MCCD is necessary or not.

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Spinal muscular atrophy (5qSMA): best practice of diagnostics, newborn screening and therapy

Medizinische Genetik ◽

10.1515/medgen-2020-2033 ◽

2020 ◽

Vol 32 (3) ◽

pp. 263-272

Author(s):

Katja Eggermann ◽

Dieter Gläser ◽

Angela Abicht ◽

Brunhilde Wirth

Keyword(s):

Spinal Muscular Atrophy ◽

Newborn Screening ◽

Best Practice ◽

Muscular Atrophy ◽

Neuromuscular Disorders ◽

Genetic Defect ◽

Homozygous Deletion ◽

Survival Motor Neuron ◽

Compound Heterozygous ◽

Common Mutation

Abstract Proximal spinal muscular atrophy (SMA) is an autosomal-recessive inherited neuromuscular disorder caused by the degeneration of alpha motor neurons in the anterior horn of the spinal cord. Patients show hypotonia, muscular atrophy and weakness of voluntary proximal muscles. SMA is one of the most common genetic diseases, with a frequency of about 1 in 7,000 newborns in Germany. The vast majority of patients carry a homozygous deletion of exons 7 and 8 of the survival motor neuron (SMN) 1 gene on chromosome 5q13.2; only about 3–4 % of patients are compound heterozygous for this common mutation and an additional subtle mutation in SMN1. The severity of the disease is mainly influenced by the copy number of the highly homologous SMN2. Since the discovery of the underlying genetic defect 25 years ago, both the diagnostics of SMA and its treatment have undergone constant and in recent times rapid improvements. SMA has become one of the first neuromuscular disorders with effective therapies based on gene targeted strategies such as splice correction of SMN2 via antisense oligonucleotides or small molecules or gene replacement therapy with a self-complementary adeno-associated virus 9 expressing the SMN1-cDNA. With the availability of treatment options, which are most effective when therapy starts at a pre-symptomatic stage, a newborn screening is indispensable and about to be introduced in Germany. New challenges for diagnostic labs as well as for genetic counsellors are inevitable. This article aims at summarising the current state of SMA diagnostics, treatment and perspectives for this disorder and offering best practice testing guidelines to diagnostic labs.

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