Surplus calories are used to prevent protein catabolism in patients with maple syrup urine disease (MSUD) but can also lead to obesity and its related complications. At present, there are no evidence-based guidelines to inform weight loss strategies for patients with inborn errors of metabolism. Obese MSUD patients often resist weight loss due to the fear of metabolic decompensation, and their dietary options are limited by dependence on medical foods with fixed nutritional composition. We examined the anthropometric and biochemical effects of metformin in nine adults with severe (classic) MSUD who were instructed to reduce their calorie intake from medical food by 10%. Eight participants (67% female) completed the 52-week study; one withdrew following elective liver transplantation. Baseline median age, body mass index (BMI), and glycosylated hemoglobin (HgbA1C) were 33.8 years (IQR 25.3-41.6), 38.3 kg/m2 (IQR 31.6-42.2), and 5.3% (IQR 5.0-5.6), respectively. We titrated the daily metformin dose to a median of 2000 mg (IQR 1000-2000) by week 25, at which time seven (88%) participants successfully reduced total calories from medical food by 10%. Metformin was generally well tolerated. Diarrhea was the most common treatment-related complication, affecting 56% of participants, and limited dose escalation in two (22%) of them. No participant achieved the primary outcome of a > 10% BMI change. However, metformin therapy allowed for modest and significant reductions in weight (-2.8%, p = 0.023), BMI (-2.8 kg/m2, p = 0.016), and calories from medical food without altering plasma leucine concentrations or the proportion of dietary protein from intact sources. Serum triglycerides, high-density lipoprotein, and HgbA1C did not change over the study period. Based on these clinical observations, we conclude that classic MSUD patients can safely use metformin to aid weight loss without triggering metabolic instability, and may therefore tolerate more aggressive weight loss strategies.

Classic maple syrup urine disease (MSUD) results from biallelic mutations in genes that encode the branched-chain α-ketoacid dehydrogenase E1α (BCKDHA), E1β (BCKDHB), or dihydrolipoamide branched-chain transacylase (DBT) subunits, which interact to form the mitochondrial BCKDH complex that decarboxylates ketoacid derivatives of leucine, isoleucine, and valine. MSUD is an inborn error of metabolism characterized by recurrent life-threatening neurologic crises and progressive brain injury that can only be managed with an exacting prescription diet or allogeneic liver transplant. To develop a gene replacement therapy for MSUD, we designed a dual-function recombinant adeno-associated virus serotype 9 (rAAV9) vector to deliver codon-optimized BCKDHA and BCKDHB (rAAV9.hA-BiP-hB) to the liver, muscle, heart, and brain. rAAV9.hA-BiP-hB restored coexpression of BCKDHA and BCKDHB as well as BCKDH holoenzyme activity in BCKDHA-/- HEK293T cells and did not perturb physiologic branched-chain amino acid homeostasis in wild-type mice at a systemic dose of 2.7 × 1014 vector genomes per kilogram. In two models of severe MSUD (Bckdha-/- and Bckdhb-/- mice) and a newborn calf homozygous for BCKDHA c.248C>T, one postnatal injection prevented perinatal death, normalized growth, restored coordinated expression of BCKDHA and BCKDHB in the skeletal muscle, liver, heart, and brain, and stabilized MSUD biomarkers in the face of high protein ingestion. In summary, we developed a one-time BCKDHA-BCKDHB systemic dual-gene replacement strategy that holds promise as a therapeutic alternative to prescription diet and liver transplant for treatment of MSUD types 1A and 1B, the two most common forms of MSUD in humans.

To explore the genetic etiology of a patient with classic maple syrup urine disease (MSUD). Next-generation sequencing (NGS) was used to screen the exons of BCKDHA, BCKDHB, DBT and DLD genes. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the protein structure and function. NGS and Sanger sequencing have detected a c.550delT mutation in exon 5 of the BCKDHB gene in the mother and a c.1046G>A mutation in exon 10 of the BCKDHB gene in the father, while no mutation was found with BCKDHA, DBT and DLD genes. Among these, the c.550delT is a novel mutation. Bioinformatic analysis suggested that the two mutations both located in a highly conserved region and may decrease the activity of branched-chain α-ketoacid dehydrogenase complex through alternation of its structure. The compound heterozygous mutations c.550delT and c.1046G>A of the BCKDHB gene probably underlie the clinical manifestations of the patient with classic MSUD.

Liver transplantation were reported in patients with classic maple syrup urine disease in the literature. Branched chain alpha keto acid dehydrogenase activity can be improved in patients after transplant, and a protein-restricted diet is usually not needed. The first patient was a boy aged 2,5 years who presented with frequent ketosis attacks and epileptic seizures, and the second patient was an 11-month-old boy who also presented with frequent ketosis episodes, both despite adherence to diet therapy. Both patients received liver transplantations from live donors. A low protein diet was no longer required and no decline in cognitive functions was observed in either patient in the follow-up. We wanted to present these cases to show that despite a normal diet, plasma levels of branched- chain amino acids remained normal without any decline in cognitive function after liver transplantation in patients with classic maple syrup urine disease patients.

Maple syrup urine disease is caused by a deficiency in the branched chain ketoacid dehydrogenase (BCKAD) complex. This results in the accumulation of branched chain amino acids (BCAA) and branched chain ketoacids in the body. Even when aggressively treated with dietary restriction of BCAA, patients experience long term cognitive, neurological and psychosocial problems. Liver transplantation from deceased donors has been shown to be an effective modality in introducing adequate BCKAD activity, attaining a metabolic cure for patients. Here, we report the clinical course of the first known patient with classic MSUD who received two consecutive partial liver grafts from two different living non-carrier donors and his five year outcome posttransplant. We also show that despite the failure of the first liver graft, and initial acute cellular rejection of the second liver graft in our patient, his metabolic control remained good without metabolic decompensation.