Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening

Nie

Journal of Bone and Mineral Research

et al. 2019

At least 15 candidate genes have been implicated in hypoparathyroidism (HP). However, comprehensive screening of causative genes for HP is lacking. Here, we investigated the genotype spectrum in a large group of Chinese patients with childhood onset HP. A total of 173 patients with childhood onset HP were analyzed using targeted next‐generation sequencing (NGS), including 15 candidate genes combined with multiplex ligation‐dependent probe amplification (MLPA) of the TBX1 gene. Twenty‐seven pathogenic or likely pathogenic mutations in five genes (TBX1, AIRE, GATA3, FAM111A, and CASR) including 13 novel variants in 23 patients, and 12 variants of uncertain clinical significance in five genes (GATA3, CASR, FAM111A, GCM2, and PTH) in 11 patients, were identified by NGS. Additionally, an entire gene deletion of TBX1 in 25 patients was found by TBX1‐MLPA. Combined with clinical data, 26 (15.0%) cases of DiGeorge syndrome (OMIM #188400), nine (5.2%) autoimmune polyglandular syndrome type 1 (OMIM #240300), eight (4.6%) autosomal dominant hypocalcemia type 1 (OMIM #601198), four (2.3%) hypoparathyroidism‐deafness‐renal dysplasia syndrome (OMIM #146255), and one (0.6%) Kenny‐Caffey syndrome type 2 (OMIM #127000) were verified. Among them, 16 of 26 (61.5%) DiGeorge syndrome cases were undiagnosed due to the lack of obvious clinical clues before genetic testing. The onset age of patients with mutations (median [interquartile range], 2.8 [0.1, 9.6] years) was significantly earlier than those without mutations (13.0 [8.8, 15.0] years) (p < 0.001). Family history, early onset age, especially prior to 5 years old, and extraparathyroid manifestations were clues for hereditary HP. The combined targeted NGS and TBX‐1 MLPA were conveniently and effectively used for comprehensive genetic screening in this large Chinese cohort of childhood onset HP patients. Genetic defects were identified in 27.7% of early‐onset HP patients, including four kinds of syndromic HP and one isolated HP. A total of 13 novel mutations were detected, which expands the mutation spectrum of hypoparathyroidism. © 2019 American Society for Bone and Mineral Research.

Section: Discussionmentioning

confidence: 79%

Genetic Screening in a Large Chinese Cohort of Childhood Onset Hypoparathyroidism by Next-Generation Sequencing Combined with TBX1-MLPA

Nie

Journal of Bone and Mineral Research

et al. 2019

Molecular Genetics and Metabolism

“…Neonatal triggers were defined as neonatal complications and interventions suggestive of underlying health complications determined by clinician authors as most likely to result in potential MCADD symptoms. Neonatal symptoms were defined by clinician authors as symptoms consistent with MCADD, many based on reports of symptoms manifested in individuals affected with MCADD (9) (14) (15) (16) (17) (18) (19) (20). Neonatal abnormal labs were defined by clinician authors as laboratory test abnormalities of potential concern in the context of MCADD (excluding newborn screening and MCADD diagnostic biochemical and molecular test results).…”

Section: Methodsmentioning

confidence: 99%

221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative

Berry

Thomas²,

Dodge³

et al. 2016

INTRODUCTION There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. METHODS Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism – Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed. RESULTS The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45 days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2 umol/L (median 8.6, range 0.36–43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A>G ACADM gene mutation or compound heterozygous for the c.985A>G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A>G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities. CONCLUSIONS This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system.

Pediatrics International

“…There is still controversy about the use of L‐carnitine, especially in those with normal C0. Furthermore, mixed or formula feeding might be recommended, given that recent research has shown that exclusively breast‐fed MCADD neonates are at a higher risk for early metabolic decompensation . Also, it has been suggested that patients carry an updated emergency letter containing contact information for the patient's metabolic specialists and a brief discussion of emergency treatment methods …”

Section: Discussionmentioning

confidence: 99%

Medium‐chain acyl‐coenzyme A dehydrogenase deficiency: Six cases in the Chinese population

Zhu

Liu

et al. 2019

Background Medium‐chain acyl‐coenzyme A dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder that affects the degradation of medium‐chain fatty acids. Few cases of MCADD have been documented to date in mainland China. Methods Medium‐chain acyl‐coenzyme A dehydrogenase deficiency was diagnosed in six patients (three girls and three boys) from six unrelated Chinese families at ages ranging from 10 days to 3 years old. The diagnosis was confirmed by the identification of a primary biomarker of serum octanoyl‐carnitine (C8) and genetic pathogenic mutations. Results Only two patients were admitted because of vomiting, diarrhea, myasthenia, and coma; the other four patients were diagnosed via the newborn screening process. Six mutations were found in acyl‐CoA dehydrogenase medium chain (ACADM). One mutation (c.727C>T) was novel and the others (c.158G>A, c.387+1delG, c.449_452del, c.1045C>T, and c.1085G>A) have been previously reported. Conclusions Six Chinese cases of MCADD were identified. One novel mutation was found. c.449_452del and c.1085G>A were common mutations in this study.