The remarkable journey of one female individual with ornithine transcarbamylase deficiency diagnosed post-mortem.

Urea cycle disorders (UCDs) comprise a group of inborn errors of metabolism with impaired ammonia clearance and an incidence of ~1:35 000 individuals. First described in the 1970s, the diagnosis and management of these disorders has evolved dramatically. We report on a 59-year-old woman with a UCD who contributed to advances in the understanding and treatment of this group of disorders. This individual was diagnosed with carbamoyl phosphate synthetase 1 deficiency based on a biochemical assay under a research context predating genetic sequencing, treated longitudinally as having this metabolic disorder, and was among the first participants to trial UCD pharmaceutical therapies. She ultimately succumbed to a SARS-CoV-2 infection while maintaining unexpectedly normal ammonium levels. Postmortem genetic testing revealed ornithine transcarbamylase deficiency. This individual's contributions to the field of UCDs is discussed herein.

Five years of experience in the Epigenetics and Chromatin Clinic: what have we learned and where do we go from here?

The multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins provides comprehensive medical care for individuals with rare disorders that involve disrupted epigenetics. Initially centered on classical imprinting disorders, the focus shifted to the rapidly emerging group of genetic disorders resulting from pathogenic germline variants in epigenetic machinery genes. These are collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), or more broadly, Chromatinopathies. In five years, 741 clinic visits have been completed for 432 individual patients, with 153 having confirmed epigenetic diagnoses. Of these, 115 individuals have one of 26 MDEMs with every single one exhibiting global developmental delay and/or intellectual disability. This supports prior observations that intellectual disability is the most common phenotypic feature of MDEMs. Additional common phenotypes in our clinic include growth abnormalities and neurodevelopmental issues, particularly hypotonia, attention-deficit/hyperactivity disorder (ADHD), and anxiety, with seizures and autism being less common. Overall, our patient population is representative of the broader group of MDEMs and includes mostly autosomal dominant disorders impacting writers more so than erasers, readers, and remodelers of chromatin marks. There is an increased representation of dual function components with a reader and an enzymatic domain. As expected, diagnoses were made mostly by sequencing but were aided in some cases by DNA methylation profiling. Our clinic has helped to facilitate the discovery of two new disorders, and our providers are actively developing and implementing novel therapeutic strategies for MDEMs. These data and our high follow-up rate of over 60% suggest that we are achieving our mission to diagnose, learn from, and provide optimal care for our patients with disrupted epigenetics.

Genome-wide DNA methylation profiling confirms a case of low-level mosaic Kabuki syndrome 1.

Kabuki syndrome is a Mendelian disorder of the epigenetic machinery characterized by typical dysmorphic features, intellectual disability, and postnatal growth deficiency. Pathogenic variants in the genes encoding the chromatin modifiers KMT2D and KDM6A are responsible for Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), respectively. In addition, 11 cases of KS1 caused by mosaic variants in KMT2D have been reported in the literature. Some of these individuals display milder craniofacial and growth phenotypes, and most do not have congenital heart defects. We report the case of an infant with severe hypoplastic left heart syndrome with mitral atresia and aortic atresia (HLHS MA-AA), pulmonary vein stenosis, and atypical facies with a somatic mosaic de novo nonsense variant in KMT2D (c.8200C>T, p.R2734*) identified on trio exome sequencing of peripheral blood and present in 11.2% of sequencing reads. KS was confirmed with EpiSign, a diagnostic genome-wide DNA methylation platform used to identify epigenetic signatures. This case suggests that use of this newly available clinical test can guide the interpretation of low-level mosaic variants identified through sequencing and suggests a new lower limit of mosaicism in whole blood required for a diagnosis of KS.

Apparent Acetaminophen Toxicity in a Patient with Transaldolase Deficiency.

Transaldolase deficiency (MIM#: 606003) is a rare autosomal recessive defect in the pentose phosphate pathway. Affected individuals are at risk for progressive liver failure and hepatocarcinoma. In the transaldolase-deficient mouse model (Taldo1 -/-), these hepatic complications are accentuated by oxidative stress related to acetaminophen administration. We report a 13-month-old transaldolase-deficient male who developed mild liver failure after receiving standard doses of acetaminophen during a febrile respiratory syncytial virus infection. He was admitted for respiratory distress with neutropenia and thrombocytopenia, but developed an enlarged nodular liver with accompanying splenomegaly and rising alpha-fetoprotein which peaked 2 weeks after acetaminophen exposure. Whole exome sequencing revealed compound heterozygous variants c.512_514delCCT (p.Ser171del) and c.931G > T (p.Gly311Trp) in TALDO1 (HGNC:11559), which encodes transaldolase (EC 2.2.1.2), a key enzyme in ribose metabolism. Urine polyols and plasma metabolomics confirmed the diagnosis of transaldolase deficiency. Studies on the Taldo1 -/- mouse model demonstrate acetaminophen-induced liver failure can be prevented by administration of the antioxidant N-acetylcysteine. Moreover, a published report showed treatment of a transaldolase-deficient patient with N-acetylcysteine was associated with a decrease in alpha-fetoprotein levels. After discontinuation of acetaminophen and prior to initiation of N-acetylcysteine treatment, our patient demonstrated resolving alpha-fetoprotein levels suggesting acetaminophen incited the liver failure. Conclusion: Our observations support the conclusion from mouse model studies that transaldolase-deficient patients are uniquely sensitive to acetaminophen and should avoid this antipyretic. Recognition of this individualized toxicity and avoidance of acetaminophen are essential for management of these patients.

Severe Neonatal Manifestations of Infantile Liver Failure Syndrome Type 1 Caused by Cytosolic Leucine-tRNA Synthetase Deficiency.

BACKGROUND: Deleterious mutations in cytosolic leucine-tRNA synthetase (LARS) cause infantile liver failure syndrome, type 1 (ILFS1), a recently recognized, rare autosomal recessive disorder (OMIM151350). Only six families with ILFS1 have been reported in the literature. Patients with ILFS1 are typically diagnosed between 5 and 24 months of age with failure to thrive, developmental delays, encephalopathy, microcytic anemia, and chronic liver dysfunction with recurrent exacerbations following childhood illnesses. Neonatal manifestations of this disorder have not been well documented. CASE REPORT: We report a premature female newborn with intrauterine growth restriction, failure to thrive, congenital anemia, anasarca, and fulminant liver failure leading to lethal multiple organ failure. Liver failure in this infant was characterized by a disproportionate impairment of liver synthetic function, including severe coagulopathy and hypoalbuminemia without significant defects in liver detoxification or evidence of hepatocellular injury during early phase of the disease. Whole-exome sequencing of child-parent trio identified two inherited missense mutations in LARS in this patient. One, c.1292T>A; p.Val431Asp, has been reported in patients with ILFS1, while the other, c.725C>T; p.Pro242Leu, is novel. Both mutations involve amino acid residues in the highly conserved editing domain of LARS, are predicted to be functionally deleterious, and presumably contribute to the clinical manifestations in this patient. CONCLUSION: This is the first case documenting neonatal manifestation of ILFS1, highlighting early, severe, and disproportionate defects in liver synthetic function. Timely diagnosis of ILFS1 is crucial to guide critical clinical management and improve outcomes of this rare and potentially life-threatening disorder.

Juvenile Idiopathic Arthritis Associated with Combined JP-HHT Syndrome: A Novel Phenotype Associated with a Novel Variant in SMAD4.

Juvenile polyposis (JP) syndrome is characterized by multiple hamartomatous polyps of the gastrointestinal tract. Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectasia in the skin, mucous membranes, and arteriovenous malformations in other organs. Individuals with JP-HHT syndrome have variable features of both rare disorders, attributed to heterozygous mutations in the SMAD4 gene. Systemic juvenile idiopathic arthritis (JIA) is a severe, chronic disease marked by arthritis and systemic inflammation for which the cause remains unknown. JIA has never been described in association with SMAD4 -related disease. We describe a case of JP-HHT syndrome with a novel SMAD4 variant, c.1052A > T (p.D351V), in which the child also had JIA manifestation.