Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD

Abstract

Purpose3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD.MethodsWe performed exome sequencing on DNA from 33 cases and 108 healthy controls. We examined these data for associations between either MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases.ResultsWe determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases that are asymptomatic and healthy controls. For 5 of these 10 individuals, we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCCD.ConclusionOur study shows that nonspecific phenotypes attributed to MCCD are associated with consanguinity and are likely not due to mutations in the MCC enzyme but result from rare homozygous mutations in other disease genes.

Early infantile presentation of 3-methylcrotonyl CoA carboxylase deficiency: a case report

“…8 Shepard et al studied children with Specific symptoms of leucine toxicity such as hypoglycemia, acidosis and others and children with non-specific symptoms such as intellectual disability or seizures. 9 The study found that cases with non-specific symptoms were more likely to have increased regions of homozygosity and that likely explained the patient's symptoms. The possibility remains that 3-MCC deficiency might constitute a predisposition to developmental disabilities in the presence of other stressors.…”

Extended Phenotyping and Functional Validation Facilitate Diagnosis of a Complex Patient Harboring Genetic Variants in MCCC1 and GNB5 Causing Overlapping Phenotypes

“…However, the contribution of the GNB5 variant to proband’s ID was complicated by the presence of 3-MCC deficiency, also previously thought to cause mild ID [ 58 , 59 ]. Recent literature on 3-MCC deficiency suggests very low disease penetrance and propose that the neurological symptoms may be unrelated to the disorder [ 36 , 60 ]. Hence, the severe ID in the proband is most consistent with GNB5 -related disorder; however, further investigation is required to examine for any interactions between the two molecular diagnoses.…”

Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency - Report from the Inborn Errors of Metabolism Information System

“…Reported outcome concerns have included fasting abnormalities, failure to thrive and other problems [2,15]. Shepard et al [22] proposed a difference between symptoms suggestive of leucine toxicity such as hypoglycemia, acidosis and others, and “non-specific” symptoms such as intellectual disability or seizures. That study found that cases with “non-specific” symptoms were more likely to have increased regions of homozygosity, and 5/10 “non-specific” symptom cases studied by exome sequencing had another gene identified that likely explained the patient's symptoms.…”