Diverse and unselected adults with clinically relevant ACADS variants lack evidence of metabolic disease.

INTRODUCTION: The clinical significance of Short-chain acyl CoA dehydrogenase deficiency (SCADD), caused by biallelic variation in the ACADS gene, is contested. Clinically ascertained individuals have a range of reported metabolic and physical symptoms. Conversely, individuals identified through newborn screening remain overwhelmingly asymptomatic. Two common ACADS variants, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser) are known to reduce enzymatic activity with undetermined clinical correlate. We applied a genome-first approach to evaluate the prevalence and clinical consequences of ACADS variants in an ancestrally diverse and unselected patient population. MATERIAL AND METHODS: We used exome sequence data linked to electronic health records (EHRs) to identify clinically relevant ACADS variants, and estimate their prevalence and clinical implications in 27,447 ancestrally diverse and unrelated adults from the BioMe Biobank in New York, NY. We extracted International Classification of Diseases, ninth (ICD-9) and tenth (ICD-10) revision codes corresponding to eight SCADD-associated phenotypes relevant to adults from participants' EHRs. Phenotypes included intellectual disability, behavioral disorders with onset in childhood, epilepsy or seizure disorders, hypoglycemia, muscle weakness, metabolic acidosis, fatty liver, and a diagnosis of SCADD or disorder of fatty acid oxidation. We performed manual chart reviews for individuals homozygous for rare pathogenic variants. Multivariate logistic regression was used to determine the association between clinically relevant ACADS variants and phenotypes of interest. RESULTS: 1 in 10,000 BioMe participants were homozygous for rare pathogenic variants (PVs) in ACADS, 1 in 20 were homozygous or presumed compound heterozygous for common variants (CVs), and 1 in 300 harbored both a PV and a CV. Of the 2035 variant positive individuals, none had a documented diagnosis of SCADD. We identified five PV/PV positive individuals, none of whom had evidence of symptomatic SCADD on manual chart review. CV/CV positive and CV/PV positive individuals did not have increased odds of any of the eight ACADS phenotypes evaluated compared to variant negative individuals (OR for CV/CV 0.99, 95% CI 0.86-1.1, p = .88; OR for CV/PV OR 1.49, 95% CI 0.87-2.6, p = .15). CONCLUSIONS: The prevalence of clinically relevant ACADS variants in an unselected population was higher than previously reported SCADD prevalence of 1 in 35,000 in the United States. Clinically relevant variants in ACADS were not associated with evidence of metabolic disease in a large and ancestrally diverse adult population. These findings support the assertion that SCADD is more likely a biochemical entity without clinical correlate, in particular when caused by one or more common variants.

Severe central sleep apnea in a child with biallelic variants in NALCN.

The sodium leak channel, nonselective (NALCN), is necessary for the proper function of the neurons that play an important role in the sleep-wake cycle and regulation of breathing patterns during wakefulness and sleep. We report a 38-month-old male with developmental delay, hypotonia, and severe central sleep apnea with periodic breathing requiring noninvasive ventilation during sleep, who was found to have novel biallelic pathogenic variants in NALCN. A review of the literature illustrates 17 additional children with biallelic variants in the NALCN gene. The clinical and sleep manifestations of these children are discussed. CITATION: Maselli K, Park H, Breilyn MS, Arens R. Severe central sleep apnea in a child with biallelic variants in NALCN. J Clin Sleep Med. 2022;18(10):2507-2513.

Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy.

The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

Plasma lyso-sphingomyelin levels are positively associated with clinical severity in acid sphingomyelinase deficiency.

INTRODUCTION: A reliable biomarker is urgently needed in the diagnosis and management of acid sphingomyelinase deficiency (ASMD, also known as Niemann Pick A, A/B, and B). Lyso-sphingomyelin (LSM) has previously been proposed as a biomarker for this disease. However, existing studies have not investigated the relationship between LSM levels and clinical subtype or severity. The purpose of this study is to address this gap in knowledge. MATERIAL AND METHODS: We present a cross-sectional study of 28 patients with ASMD, enrolled in an ongoing natural history study at the Icahn School of Medicine at Mount Sinai and The Children's Hospital at Montefiore. Plasma LSM levels from 28 patients were analyzed, including 7 patients with the infantile neurovisceral phenotype (ASMD type A), 3 patients with chronic neurovisceral disease (ASMD type A/B) and 18 patients with chronic visceral ASMD (ASMD type B). The association between LSM levels and clinical subtype, dichotomized as infantile (type A) or chronic (type A/B and B), was analyzed using the Wilcoxon rank sum test. In secondary analysis, the association between LSM levels and clinical severity among the chronic ASMD patients was analyzed using the Kruskal-Wallis test. RESULTS: LSM levels were elevated in all patients with ASMD when compared to a reference range of (0.04-3.8 (ng/mL)). Median LSM levels were higher in patients with infantile ASMD (386 ng/mL [314, 605]) compared to chronic ASMD (133 ng/mL [90, 209]), p < .001. Additionally, among individuals with chronic ASMD there was a positive association between LSM level and clinical severity (p = .01, p for trend <0.001). CONCLUSION: We identified greater LSM elevations in patients with infantile ASMD compared to those with chronic ASMD. Among patients with chronic ASMD, LSM levels were positively associated with clinical severity. These data support investigation of LSM as a biomarker for ASMD. Future studies are required to determine if LSM levels are predictive of phenotype in pre-symptomatic patients and how such levels correlate in response to treatment.

The future of newborn screening for lysosomal disorders.

The goal of newborn screening is to enhance the outcome of individuals with serious, treatable disorders through early, pre-symptomatic detection. The lysosomal storage disorders (LSDs) comprise a group of more than 50 diseases with a combined frequency of approximately 1:7000. With the availability of existing and new enzyme replacement therapies, small molecule treatments and gene therapies, there is increasing interest in screening newborns for LSDs with the goal of reducing disease-related morbidity and mortality through early detection. Novel screening methods are being developed, including efforts to enhance accuracy of screening using an array of multi-tiered, genomic, statistical, and bioinformatic approaches. While NBS data for Gaucher disease, Fabry disease, Krabbe disease, MPS I, and Pompe disease has demonstrated the feasibility of widespread screening, it has also highlighted some of the complexities of screening for LSDs. These include the identification of infants with later-onset, untreatable, and uncertain phenotypes, raising interesting ethical concerns that should be addressed as part of the NBS implementation process. Taken together, these efforts will provide critical, detailed data to help guide objective, ethically sensitive decision-making about NBS for LSDs.

Established and Emerging Treatments for Patients with Inborn Errors of Metabolism.

Inborn errors of metabolism (IEMs) are inherited defects in a metabolic pathway resulting in clinical disease. The overall goal of therapy is to restore metabolic homeostasis while minimizing the deleterious effects of the interruption. Conventional treatments focus on decreasing substrate, providing product, and replacing deficient enzyme or cofactor. We discuss examples of established, novel, and emerging therapies to provide a framework for understanding the principles of management for patients with IEMs.

Clinical Manifestations of Noonan Syndrome and Related Disorders.

Noonan syndrome represents a heterogeneous group of genetic disorders caused by mutations in genes of the RAS/MAPK pathway. Related syndromes include cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines and Costello syndrome. The common phenotypic features of Noonan syndrome include facial dysmorphisms, short stature, congenital heart defects and genitourinary abnormalities. These and other findings as well as features of related disorders are discussed. In addition we briefly review clinical diagnosis and prenatal findings of these syndromes and genetic counseling implications.