PROPIONIC ACIDEMIA MELISSA ALEX DISEASE OVERVIEW Propionic acidemia

PROPIONIC ACIDEMIA MELISSA ALEX

DISEASE OVERVIEW Propionic acidemia (PPA) is an organic academia caused by mutations in the propionyl-Co. A carboxylase (PCC) gene – mitochondrial biotin dependent enzyme – catabolism of valine, isoleucine, methionine, threonine, CHL, odd chain FA • Propionyl Co. A → methylmalonyl Co. A • Block in propionyl PW – accumulation organic acids • Blood, cerebrospinal fluid, urine • Results – toxic manifestations • acidosis, neurological disease • Enzyme deficiency – generation of significant derangements • Intracellular MTB • Mitochondrial MTB Organic acidemia (OA) – subset AA disorders • Deficiency – PCC activity • Not a dysfunction of AA MTB • Intermediary product of MTB • Affected AA – val, ile, met, thr

ETIOLOGY Classification • Inherited • Autosomal recessive • Organic acid disorder • Reported in families of Amish ancestry • 1: 80, 000 1961 • characterized by ↑ serum glycine level (now indicates multiple enzyme deficiency disorders) suspected disorder of AA MTB w/ ↑ serum and urine propionate 1969 • peripheral blood leukocytes demonstrated deficiency of PCC activity PCC dodecamer (12 subunits- tetrahedral) • Chromosome 13 q 22 -q 34 • 6 β subunits • 6 biotin - containing α subunits • Defects within both subunits

SYMPTOMOLOGY • Presents 1 st few days to weeks of life – rare late adult onset • Hx family disease /unexplained neonatal death/acidopathic sibling • Degree of disease symptoms – enzyme impairment d/t genetic lesion • Neonates • Neurological deterioration, feeding refusal, vomiting, wt. loss, hypotonia, abnormal posturing/movements, lethargy, seizures, coma, severe brain damage, or death within days • Late manifest • Immune and bone morrow suppression, recurrent infections, neurological sequlae, mental retardation • Pt previous dx – acute onset abnormal movement → signs infraction basil ganglia • Metabolic acidosis, ↑ plasma ammonia/propionic acid, ↑ urine methylcitric acid • Cardiomyopathy – ¼ pt starting at 10 months to adulthood • ↓ cardiac carnitine – serum carnitine WNL

BIOCHEMICAL PATHWAY • Interruption of formation – energy producing intermediates of CAC • Major precursor glu ruminants • Gluconeogenesis – CAC • Esterification with Co. A • Catalyzed – Propionyl Co. A Carboxylase (PCC) • Non-ruminants • Propionate – B ox OCFA in ruminant lipids, oxidation isoleucine side chain of CHL, minor gluconeogenesis substrate • PCC – mitochondria/biotin containing enzyme • Defective BCAA & OCFA MTB → propinoyl accumulation • Defects PA → toxic metabolites ↑ propionic acid (brain/NS) • Dysfunction PW – toxic endothelial cells & basil ganglia

https: //www. researchgate. net/figure/Metabolic-pathway-for-propionyl-Co. A-carboxylase-PCC-The-pathways-in-a-normal-patient_fig 1_23489438

https: //basicmedicalkey. com/gluconeogenesis-the-control-of-blood-glucose/

NUTRITIONAL IMPLICATIONS • Metabolic crisis • Feeding changes 2º infections • Recurrent episodes • Metabolic decomposition d/t inadequate PO feeding • Illness w/fever endogenous catabolism • Dehydration • Gastrointestinal bacteria – produce propionic acid • Tx – metronidazole • Constipation • Essential FA deficiency • Feeding problems • Recurrent episodes

MEDICAL NUTRITION THERAPY • ↓ Pro foods – formula w/o ile, met, thr, val • Restrict AA (dietary precursors) –reduce toxic OA • Synthetic AA based formulas – 50% pro/d • Milder genotypes • Intact Pro – LBVP • Fruits, veggies, limited grains • Infant pro intake: 1 -1. 5 g Pro/kg • Dilute standard formula – add pro free formula • Formula – limits thr, ile & omits met, val • Moderate pro/high energy – CHO/FAT • Similar requirements PKU diet • Fluid – 64 oz. min • ↑ fluid needs – removal of abnormal metabolites

MEDICAL NUTRITION THERAPY • Avoid fasting – prevent muscle pro catabolism → OA build up • Frequent meals – q 2 -3 h • “Sick Day Diet” • Natural Pro intake ↓ 50% - ↑ non pro kcal • Small, frequent meals/snacks as tol • Formula supplement • Electrolyte drink, Drip Drop • Preventative Measurements • PEG – effective ↓ hospitalization & chronic management adequate nutrition • Nasogastric – acute relapse/feeding aversion • Goals • Maintenance energy/fluid intake • Biochemical balance – promote anabolism, normal growth/development • Prevent catabolism/dehydration • Prevent metabolic acidosis relapse – infection, high pro intake, constipation • ↑ fluid requirements – monitor electrolyte balance • Encourage PO intake • Collaboration – SLP

MONITORING/EVALUATION • Education • Early signs: dehydration, poor PO intake, formula/food preparation, diet recommendations, label reading & food choices • Labs • Alb, prealb, total pro, ammonia, plasma AA, Na, K, Cl, BUN, Cr, bicarbonate (CO 2), BGL, urine ketones, serum lactate, serum pyruvate, uric acids, carnitine • PO Intake • Pro/kcal • Chewing/swallowing/feeding problems, decrease appetite, feeding refusal • Hydration • Fluid intake - I/O • Ht. /Wt. • Essential FA deficiency, vitamins, minerals - NFPE • Illness relapse

ADJUNCT TREATMENT • Carnitine • Binds OA, Na benzoate/Na phenylbutyrate removes excess Nitrogen - ↓ ammonia production • Supplementation: 200 – 300 mg/kg bid/tid • Recurrent metabolic decomposition/hyperammonia (↑ range) • Laxative • ↓ serum ammonia, ↓ propionylglycine urine excretion • ↑ratio free total carnitine (protein motility) • Biotin • evidence conflicts - ↑ isoleucine MTB & ↓ propionate production • Bicarbonate • Acute episodes • IV fluids • Liver transplant – limit intellectual disability & cardiac damage • MVT

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