Development and application of an ethical framework for pediatric metabolic and bariatric surgery evaluation.

BACKGROUND: As severe obesity continues to rise among youth, metabolic and bariatric surgery (MBS) will increasingly be used as a treatment of choice for durable weight loss and improvement of obesity-related complications. MBS for youth with intellectual and developmental disabilities (IDD) and for preadolescents has raised ethical questions. OBJECTIVES: The purpose of this article is to present the creation and application of an ethical framework that supports why MBS should be considered in pediatrics based on the principle of justice without automatic exclusions. This framework also provides a guide for how to conduct a robust, ethically grounded evaluation of pediatric patients presenting for MBS in general, and among subpopulations including youth with IDD and preadolescents. SETTING: Academic medical center, United States. METHODS: An ethical framework was developed and applied through a collaboration between an MBS center at a children's hospital and the institution's ethics consult service. RESULTS: Application of the ethical framework to address 4 core ethical questions is illustrated using 2 hypothetical cases: 1 that highlights an adolescent with IDD and 1 that highlights a preadolescent. CONCLUSIONS: We have demonstrated the application of a novel, overarching framework to conduct the ethical evaluation of youth presenting for MBS. This framework resulted from a collaboration between MBS and ethics consult teams and has the potential to be used as a prototype for other youth-focused MBS programs. Next steps include prospective data collection to test the framework and determine its validity in the target population.

Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease.

Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.

Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background.

PURPOSE: In response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org ) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians. METHODS: We present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N = 18), nongenetics specialists (N = 27), and genetics clinicians (N = 32) on both rubrics. RESULTS: Formative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a "typical" patient. CONCLUSION: We propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling.

Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly.

An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I.

Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder.

BACKGROUND: Mitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial DNA or POLG are often present, other nuclear defects in mitochondrial DNA replication and protein translation have been associated with a severe epileptic encephalopathy. METHODS AND RESULTS: We identified a proband with an epileptic encephalopathy, complex movement disorder and a combined mitochondrial respiratory chain enzyme deficiency. The child presented with neurological regression, complex movement disorder and intractable seizures. A combined deficiency of mitochondrial complexes I, III and IV was noted in liver tissue, along with increased mitochondrial DNA content in skeletal muscle. Incomplete assembly of complex V, using blue native polyacrylamide gel electrophoretic analysis and complex I, using western blotting, suggested a disorder of mitochondrial transcription or translation. Exome sequencing identified compound heterozygous mutations in CARS2, a mitochondrial aminoacyl-tRNA synthetase. Both mutations affect highly conserved amino acids located within the functional ligase domain of the cysteinyl-tRNA synthase. A specific decrease in the amount of charged mt-tRNA(Cys) was detected in patient fibroblasts compared with controls. Retroviral transfection of the wild-type CARS2 into patient skin fibroblasts led to the correction of the incomplete assembly of complex V, providing functional evidence for the role of CARS2 mutations in disease aetiology. CONCLUSIONS: Our findings indicate that mutations in CARS2 result in a mitochondrial translational defect as seen in individuals with mitochondrial epileptic encephalopathy.

Genotype-phenotype correlations: sudden death in an infant with very-long-chain acyl-CoA dehydrogenase deficiency.

Very-long-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. The phenotype of VLCADD is heterogeneous, and patients are typically classified into three categories based upon onset of symptoms and clinical findings. As a result of early diagnosis and treatment, many patients with VLCADD have remained asymptomatic. A general genotype-phenotype correlation has been elicited. A genotype that is associated with residual enzyme activity is more likely to present with an attenuated phenotype. One prevailing mutation, the c.848T>C (p.V283A), has been associated with residual enzyme activity and has been identified in many asymptomatic individuals diagnosed through either newborn or family screening. We present a patient who died as a result of fatal hypoglycemia at 38 h of life before diagnosis of VLCADD could be established by newborn screening. Despite the early onset of the disease, the patient was found to have a missense mutation within the ACADVL gene with a c.848T>C, c.342+1G>C genotype. Genotype alone remains limited in its predictive ability to determine which affected individuals are at risk for fatal complications.

Penicillamine therapy for pediatric cystinuria: experience from a cohort of American children.

PURPOSE: Cystinuria, an inherited defect of dibasic amino acid transport, causes accumulation of urinary cystine and cystine urolithiasis. In adults penicillamine reduces stone formation but has a high incidence of dose limiting toxicity. We evaluated the effects of penicillamine in preventing stone formation and with respect to toxicity in our cystinuria cohort at a pediatric biochemical genetics clinic. MATERIALS AND METHODS: We reviewed the charts of all 11 children with cystinuria treated at our clinic using a gradual dose escalation of penicillamine. Mean +/- SD patient age at diagnosis was 5.8 +/- 4.3 years (range 1.2 to 12). We tracked urinary cystine concentration before and after initiation of treatment, penicillamine side effects and incidence of new stones during maintenance therapy. RESULTS: During the gradual escalation of penicillamine to the target dose none of the 11 patients experienced toxicity and all had improved urinary cystine concentration (mean +/- SD percent reduction 54% +/- 25%, range 5% to 81%). We followed the patients for a total of 1,203 months (mean +/- SD 109 +/- 73 months, range 41 to 221), periodically assessing urinary cystine concentration, urine protein content, complete blood count, blood urea nitrogen, creatinine and liver function. During this time only 2 patients experienced significant side effects and no patient had stones or stone crises while compliant with treatment. CONCLUSIONS: In our cohort penicillamine was well tolerated after gradual initiation and it reduced urinary cystine concentration. Long-term compliance with the medication appeared to protect patients from acute stone crises.