Background

Inborn errors of metabolism are on the differential for patients presenting with a cyclic vomiting syndrome phenotype. Classes of disorders to consider include: mitochondrial disorders, fatty acid oxidation disorders, urea cycle defects, organic acidurias, and acute intermittent porphyria.

Aim

This article reviews the metabolic differential diagnosis and approach to screening for inborn errors in children and adults presenting with a cyclic or recurrent vomiting phenotype.

Conclusion

Cyclic vomiting syndrome is thought to be an episodic syndrome that may be associated with migraine. It is a diagnosis of exclusion. Inborn errors of metabolism should be considered in the patient presenting with a recurrent vomiting phenotype. Mitochondrial dysfunction may play a role in cyclic vomiting syndrome, and true mitochondrial disorders can present with a true cyclic vomiting phenotype.

Objective

To determine the frequency of significant liver injury and acute liver failure (ALF) in patients with ornithine transcarbamylase deficiency (OTCD), the most common urea cycle defect.

Study design

In this historical cohort study, charts of 71 patients with OTCD at 2 centers were reviewed to assess the prevalence of ALF (international normalized ratio [INR] ≥2.0), liver dysfunction (INR 1.5-1.99), and hepatocellular injury (aspartate aminotransferase/alanine aminotransferase ≥250 IU/L).

Results

More than one-half (57%) of the 49 patients with symptomatic OTCD had liver involvement; 29% met the criteria for ALF, 20% had liver dysfunction, and 8% had isolated hepatocellular injury. The prevalence of ALF was highest in the patients with more severe OTCD, including those with markedly elevated ammonia levels (>1000 μmol/L). Some patients with severe liver involvement (INR ≥2.0 and aspartate aminotransferase/alanine aminotransferase >1000 IU/L) had only moderate hyperammonemia (ammonia 100-400 μmol/L). ALF was the initial presenting symptom of OTCD in at least 3 of 49 symptomatic patients with OTCD.

Conclusion

Episodes of hepatocellular injury, liver dysfunction, and ALF were identified in a high proportion of children with symptomatic OTCD. The more severely affected patients had a higher likelihood of ALF. The diagnosis of a urea cycle defect should be considered in patients with unexplained ALF, liver dysfunction, or hepatocellular injury.

Newborn screening (NBS) is a population-based program with a goal of reducing the burden of disease for conditions with significant clinical impact on neonates. Screening tests were originally developed and implemented one at a time, but newer methods have allowed the use of multiplex technologies to expand additions more rapidly to standard panels. Recent improvements in next-generation sequencing are also evolving rapidly from first focusing on individual genes, then panels, and finally all genes as encompassed by whole exome and genome sequencing. The intersection of these two technologies brings the revolutionary possibility of identifying all genetic disorders in newborns, allowing implementation of therapies at the optimum time regardless of symptoms. This article reviews the history of newborn screening and early studies examining the use of whole genome and exome sequencing as a screening tool. Lessons learned from these studies are discussed, along with technical, ethical, and societal challenges to broad implementation.

Cobalamin D deficiency (cblD) is one of the least common cobalamin metabolism disorders. It may result in isolated homocystinuria, isolated methylmalonic aciduria, or combined methylmalonic aciduria and homocystinuria (cblD-combined). Only seven cases of the combined cblD form have been reported to date. Due to the rarity of this disorder, the presentation and symptoms are not well described. We present an eighth case of the cblD-combined subtype, who had a positive newborn screen (NBS) on day of life 3. She was symptomatic and developed lethargy and poor oral intake at 8 days of life. She was treated with 10% dextrose, folinic acid, intramuscular hydroxocobalamin, and betaine. Despite the early initiation of treatment, she developed complications of the disease and was found to have abnormal brain imaging findings at 17 days of age and macular atrophy at 3 months of age and has global developmental delay. We provide detailed description of her presentation, her treatment, and her complications to aid in the understanding of this rare disorder, which is very similar to the more common cobalamin C disorder (cblC).

Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the

Background

Lysosomal storage diseases (LSDs) are inherited metabolic disorders that may lead to severe multi-organ disease. Current ERTs are limited by anti-drug antibodies, the blood-brain barrier, and early disease onset and progression before ERT is started. We have opened a phase I clinical trial of enzyme replacement therapy (ERT) for fetuses with LSDs (NCT04532047). We evaluated the attitudes of parents and patients with LSDs towards fetal clinical trials and therapies.

Methods

A multidisciplinary team designed a survey which was distributed by five international patient advocacy groups. We collected patients' demographic, diagnostic, and treatment information. Associations between respondent characteristics and attitudes towards fetal therapies/trials were analyzed using multivariate ordinal logistic regression.

Results

The survey was completed by 181 adults from 19 countries. The majority of respondents were mothers from the United States. The most common diseases were MPS1 (26%), MPS3 (19%), and infantile-onset Pompe (14%). Most patients (88%) were diagnosed after birth, at a median of 21 months. Altogether, 65% of participating patients and children of participants had received ERT, 27% a stem cell transplant, and 4% gene therapy. We found that half (49%) of respondents were unlikely to terminate a future affected pregnancy, 55% would enroll in a phase I clinical trial for fetal ERT, and 46% would enroll in a fetal gene therapy trial. Respondents who received postnatal ERT were significantly more likely enroll in a trial for fetal ERT or gene therapy (ERT OR 4.48, 95% CI 2.13-9.44, p < 0.0001; gene therapy OR 3.03, 95% CI 1.43-6.43, p = 0.0038). Respondents who used clinicaltrials.gov as a main source of information were more likely to choose to participate in a fetal trial (ERT OR 2.43, 95% CI 1.18-5.01, p = 0.016; gene therapy OR 2.86, 95% CI 1.27-6.46, p = 0.011).

Conclusions

Familiarity with postnatal ERT increased respondents' likelihood of pursuing fetal therapies. Families who use clinicaltrials.gov may be more receptive to innovative fetal treatments. The patient community has a favorable attitude towards fetal therapy; over half of respondents would enroll in a phase I clinical trial to assess the safety and efficacy of fetal ERT.

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive disorder of β-oxidation caused by pathogenic variants in the ACADS gene. Analyte testing for SCADD in blood and urine, including newborn screening (NBS) using tandem mass spectrometry (MS/MS) on dried blood spots (DBSs), is complicated by the presence of two relatively common ACADS variants (c.625G>A and c.511C>T). Individuals homozygous for these variants or compound heterozygous do not have clinical disease but do have reduced short-chain acyl-CoA dehydrogenase (SCAD) activity, resulting in elevated blood and urine metabolites. As part of a larger study of the potential role of exome sequencing in NBS in California, we reviewed ACADS sequence and MS/MS data from DBSs from a cohort of 74 patients identified to have SCADD. Of this cohort, approximately 60% had one or more of the common variants and did not have the two rare variants, and thus would need no further testing. Retrospective analysis of ethylmalonic acid, glutaric acid, 2-hydroxyglutaric acid, 3-hydroxyglutaric acid, and methylsuccinic acid demonstrated that second-tier testing applied before the release of the newborn screening result could reduce referrals by over 50% and improve the positive predictive value for SCADD to above 75%.