A case of treatable encephalopathy, developmental regression, and proximal tremor.

Tyrosine hydroxylase (TH) deficiency is an autosomal recessive condition first described as a progressive, early-onset hypokinetic-rigid and dystonic syndrome that was responsive to levodopa. Here we present a child with developmental regression, proximal tremor, and encephalopathy found to have tyrosine hydroxylase deficiency in whom treatment resulted in acquisition of developmental milestones.

Genetic Testing and Counseling and Child Neurology.

Advances in genetic technology have decreased the cost and increased the accessibility of genetic testing, and introduced new therapeutic options for many genetic conditions. With new treatments available for previously untreatable neurogenetic conditions, identifying a genetic diagnosis has become of great importance. This article provides a review of basic genetic concepts, ethical and counseling considerations with genetic testing, and genetic testing strategies, and highlights a series of clinical care pearls.

Increased parental anxiety and a benign clinical course: Infants identified with short-chain acyl-CoA dehydrogenase deficiency and isobutyryl-CoA dehydrogenase deficiency through newborn screening in Georgia.

The long-term consequences and need for therapy in children with short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBDD) identified via newborn screening (NBS) remains controversial. Initial clinical descriptions were severe; however, while most cases identified through NBS have remained asymptomatic, clinical concerns have been raised in these populations. It is not clear whether these children are asymptomatic because of the success of NBS, or because the normal clinical course of these disorders is relatively benign. To evaluate these possibilities in our program, we evaluated the clinical outcomes of children with SCADD or IBDD identified by the Georgia NBS compared to the health status of a healthy age-matched control group. We also assessed parental anxiety during a phone interview both subjectively and objectively using the Pediatric Inventory for Parents (PIP), a validated measure of illness-related parental stress. The general health of 52 SCADD and nine IBDD cases from 2007 to 2016 were compared to the general health of unaffected control children obtained through the Centers for Disease Control and Prevention (CDC) parent listserv. We also collected statements from parents who participated in a phone survey regarding events they experienced during and after their diagnostic process. Overall, the children with SCADD and IBDD had no major health problems. There was no significant difference in cognitive development (p = .207). We identified a slightly higher incidence of reported neonatal hypoglycemia in the SCADD group; two of these occurred in the context of maternal diabetes. All interviewed parents reported extreme anxiety during the diagnostic period and current feelings of uncertainty about their child's future. PIP scores for all six caregivers who responded to that portion of the survey were consistent with some degree of parental stress. The greatest reported stressor was the unknown long-term impact of the illness. All children with SCADD and IBDD had no significant long-term sequelae. The phone interviews revealed substantial parental anxiety about the identification and follow-up of SCADD and IBDD. Based on our findings, the anxiety parents experience may be unwarranted given that we see no disease-associated morbidity or mortality in these children. Consideration should be given to the removal of these conditions from NBS panels, or if that is not possible, clinicians could educate parents on the benign nature of these diagnoses and release them from follow-up without treatment.

Edematous severe acute malnutrition is characterized by hypomethylation of DNA.

Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.

Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency.

Defects in the tricarboxylic acid cycle (TCA) are associated with a spectrum of neurological phenotypes that are often difficult to diagnose and manage. Whole-exome sequencing (WES) led to a rapid expansion of diagnostic capabilities in such disorders and facilitated a better understanding of disease pathogenesis, although functional characterization remains a bottleneck to the interpretation of potential pathological variants. We report a 2-year-old boy of Afro-Caribbean ancestry, who presented with neuromuscular symptoms without significant abnormalities on routine diagnostic evaluation. WES revealed compound heterozygous missense variants of uncertain significance in mitochondrial aconitase (ACO2), which encodes the TCA enzyme ACO2. Pathogenic variants in ACO2 have been described in a handful of families as the cause of infantile cerebellar-retinal degeneration syndrome. Using biochemical and cellular assays in patient fibroblasts, we found that ACO2 expression was quantitatively normal, but ACO2 enzyme activity was <20% of that observed in control cells. We also observed a deficiency in cellular respiration and, for the first time, demonstrate evidence of mitochondrial DNA depletion and altered expression of some TCA components and electron transport chain subunits. The observed cellular defects were completely restored with ACO2 gene rescue. Our findings demonstrate the pathogenicity of two VUS in ACO2, provide novel mechanistic insights to TCA disturbances in ACO2 deficiency, and implicate mitochondrial DNA depletion in the pathogenesis of this recently described disorder.