ABSTRACT
BACKGROUND: Organic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data. STUDY DESIGN/METHODS: We performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected. RESULTS: The median age of transplantation for subjects with MMA was 7.2â¯years with a median follow up of 4.3â¯years. The median age of transplantation for subjects with PA was 1.9â¯years with a median follow up of 5.4â¯years. The survival rate at 1â¯year and 5â¯years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT. CONCLUSION: In a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.
Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , Liver Transplantation , Propionic Acidemia/therapy , Adolescent , Alleles , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/mortality , Biomarkers , Child , Child, Preschool , Follow-Up Studies , Genotype , Hospitalization , Humans , Infant , Infant, Newborn , Liver Function Tests , Liver Transplantation/adverse effects , Liver Transplantation/methods , Magnetic Resonance Imaging , Mutation , Phenotype , Prognosis , Propionic Acidemia/diagnosis , Propionic Acidemia/genetics , Propionic Acidemia/mortality , Retrospective StudiesABSTRACT
Due to immunosenescence, older adults are particularly susceptible to lung-based viral infections, with increased severity of symptoms in those with underlying chronic lung disease. Repeated respiratory viral infections produce lung maladaptations, accelerating pulmonary dysfunction. Toll like 3 receptor (TLR3) is a membrane protein that senses exogenous double-stranded RNA to activate the innate immune response to a viral infection. Polyinosinic-polycytidylic acid [poly(I:C)] mimics double stranded RNA and has been shown to activate TLR3. Utilizing an established mouse viral exacerbation model produced by repetitive intranasal poly(I:C) administration, we sought to determine whether repetitive poly(I:C) treatment induced negative muscle adaptations (i.e. atrophy, weakness, and loss of function). We determined skeletal muscle morphological properties (e.g. fiber-type, fiber cross-sectional area, muscle wet mass, etc.) from a treated group ((poly(I:C), nâ¯=â¯9) and a sham-treated control group (PBS, nâ¯=â¯9); age approximately 5â¯months. In a subset (nâ¯=â¯4 for both groups), we determined in vivo physical function (using grip test for strength, rotarod for overall motor function, and treadmill for endurance) and muscle contractile properties with in vitro physiology (in the EDL, soleus and diaphragm). Our findings demonstrate that poly(I:C)-treated mice exhibit both muscle morphological and functional deficits. Changes of note when comparing poly(I:C)-treated mice to PBS-treated controls include reductions in fiber cross-sectional area (-27% gastrocnemius, -25% soleus, -16% diaphragm), contractile dysfunction (soleus peak tetanic force, -26%), muscle mass (gastrocnemius -19%, soleus -23%), physical function (grip test -34%), body mass (-20%), and altered oxidative capacity (140% increase in succinate dehydrogenase activity in the diaphragm, but 66% lower in the gastrocnemius). Our data is supportive of a new model of cachexia/sarcopenia that has potential for future research into the mechanisms underlying muscle wasting.
