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Free radical formation resulting in oxidative stress is a hallmark of mitochondrial dysfunction. Indeed, oxidative stress has been demonstrated to be an underlying pathophysiologic process in various inborn errors of metabolism. Metabolic profiling of oxidative stress may provide a non-specific measure of disease activity that may further enable physicians to monitor disease. In the present study, we investigated two markers of oxidative damage in urinary samples from IEM subjects and controls: F-2 isoprostanes, a measure of lipid peroxidation and di-tyrosine, a measure of protein oxidation. We also determined urinary antioxidant activity in these samples. Subsets of IEM patients showed significantly higher levels of the damage markers isoprostanes and di-tyrosine. Of note, patients with cobalamin disorders (i.e., CblB and CblC) consistently had the highest levels of oxidative damage markers. Lower urine antioxidant capacity was seen in all subject categories, particularly cobalamin disorders and propionic acidemia. Longitudinal studies in subjects with MSUD showed good concordance between markers of oxidative damage and acute decompensation. Overall, quantifying oxidative stress offers a unique perspective to IEM. These measures may provide a means of addressing mitochondrial function in IEM and aid in the development of therapeutic targets and clinical monitoring in this diverse set of disorders.

Heterozygous truncating mutations in CXCR4 have been identified as a cause of WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis). The receptor truncations have been proposed to lead to altered lymphocyte trafficking. The purpose of the described studies was to characterize the B-cell repertoire in WHIM subjects. We confirmed profound B-cell lymphopenia and demonstrated oligoclonality of the circulating B-cell pool by HCDR3 spectratyping. The response to immunization was studied in one subject utilizing a bacteriophage PhiX174 immunization protocol. Spectratyping showed oligoclonality at baseline with normalization of the HCDR3 length distribution by 5 months after immunization with PhiX174 with eventual return to the baseline state. Isotype switching from phage specific neutralizing antibody of the IgM class to IgG was markedly reduced. Overall, these data suggest that impaired CXCR4 signaling in WHIM syndrome results in defective B-cell function and abnormal isotype switching, possibly through effects on germinal center trafficking of lymphocytes.

Over 27 cases of liver transplant, kidney transplant and combined liver–kidney transplant have been reported for the treatment of methylmalonic aciduria. We describe a case of a 5-year-old boy who underwent combined liver–kidney transplant (CLKT) for phenotypic mut0 disease. His history was notable for more than 30 hospitalizations for severe acidosis, metabolic strokes, liver disease, pancreatic disease, chronic renal insufficiency with interstitial nephritis, and decreased quality of life. Post-CLKT, there was a marked reduction in serum (80%) and urine MMA levels (90%) as well as a cessation of metabolic decompensations. Neurologic deterioration continued post-CKLT manifested as a cerebellar stroke. The clinical details and therapeutic implications of solid organ transplant for methylmalonic aciduria are discussed.