Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut −/− mice as a stable transgene under the control of an albumin (INS-Alb- Mut ) promoter. Mut −/− ;Tg INS-Alb- Mut mice, although completely rescued from neonatal lethality that was displayed by Mut −/− mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut −/− ;Tg INS-Alb- Mut kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort ( ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut −/− ;Tg INS-Alb- Mut mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

related to MMA filed by the NIH on their behalf. Lina Li is an employee of LLN Consultant Inc. and founder of CELiD Biotechnologies Inc. GME is a consultant for Moderna Therapeutics, LogicBio Therapeutics, Horizon Pharma, and Natera; a data-monitoring committee member for BioMarin, Audentes Therapeutics, Amicus, RegenxBio, and NeuroVia; and an investigator on clinical trials for Aeglea, BioElectron, and Stealth Therapeutics. LHV is an inventor of AncAAV and other AAV technologies, which are licensed to various biotechnology and pharmaceutical entities. LHV is a consultant to a number of companies with gene therapy interest, including Selecta Biosciences and Lonza, licensees of AncAAV technology. CPV has received funding to support AAV gene therapy research for MMA from Selecta Biosciences and LogicBio Therapeutics.

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The 22q13.3 deletion syndrome is a recognizable malformation syndrome associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic facies. The prevalence of this disorder is unknown, but it is likely under-diagnosed. Age at diagnosis has varied widely, from cases diagnosed prenatally to 46 years. Males and females are equally affected. The distal 22q deletion can be detected occasionally by routine or high resolution chromosome analysis; however, the majority of cases are detected by FISH analysis, associated with deletion of the ARSA (control) probe when performing a FISH analysis for the velocardiofacial syndrome (del 22q11.2). The 22q13.3 deletion syndrome can accompany a simple chromosome deletion, an unbalanced translocation, or a ring chromosome. Primary care physicians, in addition to numerous specialists, play an important role in caring for patients with this disorder. Although the dysmorphic features observed in this condition are nonspecific, it is an important consideration in the differential diagnosis of children with developmental delay, hypotonia, marked speech and language disability, autistic-like features, multiple minor anomalies, and normal growth and head circumference.