Clinical, biochemical and molecular characterization of a new case with FDX2-related mitochondrial disorder: Potential biomarkers and treatment options.

Ferredoxin-2 (FDX2) is an electron transport protein required for iron-sulfur clusters biosynthesis. Pathogenic variants in FDX2 have been associated with autosomal recessive FDX2-related disorder characterized by mitochondrial myopathy with or without optic atrophy and leukoencephalopathy. We described a new case harboring compound heterozygous variants in FDX2 who presented with recurrent rhabdomyolysis with severe episodes affecting respiratory muscle. Biochemical analysis of the patients revealed hyperexcretion of 2-hydroxyadipic acid, along with previously reported biochemical abnormalities. The proband demonstrated increased lactate and creatine kinase (CK) with increased amount of glucose infusion. Lactate and CK drastically decreased when parenteral nutrition containing high protein and lipid contents with low glucose was initiated. Overall, we described a new case of FDX2-related disorder and compare clinical, biochemical and molecular findings with previously reported cases. We demonstrated that 2-hydroxyadipic acid biomarker could be used as an adjunct biomarker for FDX2-related disorder and the use of parenteral nutrition as a treatment option for the patient with FDX2-related disorder during rhabdomyolysis episode. Highlights: 2-Hydroxyadipic acid can serve as a potential adjunct biomarker for iron-sulfur assembly defects and lipoic acid biosynthesis disorders. Parenteral nutrition containing high lipid and protein content could be used to reverse acute rhabdomyolysis episodes in the patients with FDX2-related disorder.

Clinical, radiological, biochemical and molecular characterization of a new case with multiple mitochondrial dysfunction syndrome due to IBA57: Lysine and tryptophan metabolites as potential biomarkers.

Iron­sulfur clusters (FeS) are one of the most primitive and ubiquitous cofactors used by various enzymes in multiple pathways. Biosynthesis of FeS is a complex multi-step process that is tightly regulated and requires multiple machineries. IBA57, along with ISCA1 and ISCA2, play a role in maturation of [4Fe-4S] clusters which are required for multiple mitochondrial enzymes including mitochondrial Complex I, Complex II, lipoic acid synthase, and aconitase. Pathogenic variants in IBA57 have been associated with multiple mitochondrial dysfunctions syndrome 3 (MMDS3) characterized by infantile to early childhood-onset psychomotor regression, optic atrophy and nonspecific dysmorphism. Here we report a female proband who had prenatal involvement including IUGR and microcephaly and developed subacute psychomotor regression at the age of 5 weeks in the setting of preceding viral infection. Brain imaging revealed cortical malformation with polymicrogyria and abnormal signal alteration in brainstem and spinal cord. Biochemical analysis revealed increased plasma glycine and hyperexcretion of multiple organic acids in urine, raising the concern for lipoic acid biosynthesis defects and mitochondrial FeS assembly defects. Molecular analysis subsequently detected compound heterozygous variants in IBA57, confirming the diagnosis of MMDS3. Although the number of MMDS3 patients are limited, certain degree of genotype-phenotype correlation has been observed. Unusual brain imaging in the proband highlights the need to include mitochondrial disorders as differential diagnoses of structural brain abnormalities. Lastly, in addition to previously known biomarkers including high blood lactate and plasma glycine levels, the increase of 2-hydroxyadipic and 2-ketoadipic acids in urine organic acid analysis, in the appropriate clinical context, should prompt an evaluation for the lipoic acid biosynthesis defects and mitochondrial FeS assembly defects.

Craniosynostosis in a patient with Fanconi-Bickel syndrome: a case report.

OBJECTIVES: Craniosynostosis may be a rare but severe complication of Fanconi-Bickel syndrome (FBS). Both conditions can be associated with feeding intolerance in young children. Prompt recognition and correction of increased intracranial pressure may lead to improved dietary tolerance in FBS patients and decrease morbidity. CASE PRESENTATION: We present the case of a child with genetically confirmed FBS, severe feeding intolerance and evidence of metabolic bone disease. At two years of age, a diagnosis of multi-sutural craniosynostosis with increased intracranial pressure was made. The patient underwent cranial vault expansion using distraction osteogenesis, after which his feeding intolerance completely resolved. CONCLUSIONS: This case highlights the importance of monitoring for secondary craniosynostosis in patients with FBS and frequent emesis. Objective markers of bone health may help identify children at highest risk, though the actual mechanism of development is likely multifactorial. Increased awareness of this potential association should prompt more routine screening and improve outcomes.

Newborn Pulse Oximetry for Infants Born Out-of-Hospital.

BACKGROUND AND OBJECTIVES: Conventional timing of newborn pulse oximetry screening is not ideal for infants born out-of-hospital. We implemented a newborn pulse oximetry screen to align with typical midwifery care and measure its efficacy at detecting critical congenital heart disease. METHODS: Cohort study of expectant mothers and infants mainly from the Amish and Mennonite (Plain) communities with limited prenatal ultrasound use. Newborns were screened at 1 to 4 hours of life ("early screen") and 24 to 48 hours of life ("late screen"). Newborns were followed up to 6 weeks after delivery to report outcomes. Early screen, late screen, and combined results were analyzed on the basis of strict algorithm interpretation ("algorithm") and the midwife's interpretation in the field ("field") because these did not correspond in all cases. RESULTS: Pulse oximetry screening in 3019 newborns (85% Plain; 50% male; 43% with a prenatal ultrasound) detected critical congenital heart disease in 3 infants. Sensitivity of combined early and late screen was 66.7% (95% confidence interval [CI] 9.4% to 99.2%) for algorithm interpretation and 100% (95% CI 29.2% to 100%) for field interpretation. Positive predictive value was similar for the field interpretation (8.8%; 95% CI 1.9% to 23.7%) and algorithm interpretation (5.4%; 95% CI 0.7% to 18.2%). False-positive rates were ≤1.2% for both algorithm and field interpretations. Other pathologies (noncritical congenital heart disease, pulmonary issues, or infection) were reported in 12 of the false-positive cases. CONCLUSIONS: Newborn pulse oximetry can be adapted to the out-of-hospital setting without compromising sensitivity or prohibitively increasing false-positive rates.

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease.

Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.

Flexion-extension cervical spine MRI in children with skeletal dysplasia: is it safe and effective?

BACKGROUND: Skeletal dysplasias may be associated with cervical spinal instability or stenosis. Cervical spine flexion-extension plain radiographs in children with skeletal dysplasia are difficult to interpret. The purpose of this study was to review the indications, efficacy, and safety of performing flexion-extension magnetic resonance imaging (MRI) under sedation/anesthesia in these children. METHODS: Retrospective, Institutional Review Board-approved review of 31 children with skeletal dysplasia who underwent 38 cervical spine flexion-extension MRI studies under sedation/anesthesia. Indications included abnormal neurological examination, suspected instability, stenosis, or inconclusive findings on flexion-extension radiographs. Studies were performed by the radiology technologist as directed by the radiologist with an anesthesiologist present. MRI was evaluated for odontoid hypoplasia, os odontoideum, cerebrospinal fluid effacement, cord compression, spinal cord changes, cervical canal narrowing in the neutral, flexion, and extension positions. Neurological examinations were recorded before and after MRI to assess safety. RESULTS: The average age at MRI was 3 years, 2 months. In 6 patients whose plain radiographs showed C1-C2 or subaxial instability, flexion-extension MRI showed no cord compression. Nine patients with inconclusive plain radiographs had abnormal MRI findings. An os odontoideum not seen on plain radiographs was diagnosed in 3 patients on flexion-extension MRI. On the basis of the MRI findings, 14 patients underwent surgery, 9/14 had increased cord compression in flexion or extension compared with neutral, and observation was continued in 17 others. Patients who underwent surgery had significant cord compression on MRI. There were no significant changes in the neurological examinations after MRI. CONCLUSIONS: Cervical spine flexion-extension MRI under sedation/anesthesia in children with skeletal dysplasia is safe under adequate supervision and is necessary to guide accurate medical and surgical decision making. Flexion-extension MRI is useful for identifying dynamic changes in canal diameter resulting in cord compression not seen on plain radiographs, and it is also useful for identifying patients with suspected plain film instability who may not have stenosis or cord compression on MRI. STUDY DESIGN: Level IV-retrospective case series.