General introduction

Urea cycle disorders (UCDs) and organic acidurias (OADs) are intoxication type metabolic diseases. These conditions are rare and are caused by inherited deficiency of specific enzymes involved in the degradation of amino acids and the removal of ammonia. The biochemical hallmark of these diseases is accumulation of characteristic metabolites which if accumulating may become toxic (e.g. ammonia) for affected individuals.

The brain is particularly affected (psychomotor retardation, movement disorders, epilepsy, lethargy, behavioral problems, and psychiatric disease) but other organs may be involved as well. Clinical symptoms of UCDs and OADs are thus variable involving the gastrointestional tract (failure to thrive, vomiting, hepatomegaly, pancreatitis, acute hepatic failure, liver cirrhosis), heart (cardiomyopathy, long QT syndrome), kidneys (chronic renal failure), eyes (optic nerve atrophy), skeletal muscle (metabolic myopathy), bone marrow (anemia, neutropenia, thrombocytopenia), and others (premature ovarian failure). Symptoms may manifest acutely during metabolic crises or insidiously (in metabolically stable patients). Metabolic crises in patients with UCDs and classic OADs may already occur in the neonatal period and may be mistaken as neonatal sepsis. A metabolic acidosis with unexplained anion gap, pancytopenia, hypoglycemia, hyperammonemia, and/or hypocalcemia in these patients should result in immediate start of metabolic work-up and therapeutic detoxification strategies. In patients with cerebral OADs (e.g. glutaric aciduria type I), however, an acute clinical presentation is characteristically not accompanied by an apparent metabolic derangement.

Early-onset and late-onset clinical presentations may be observed.

Advanced diagnostic explorations which may add to the routine laboratory data comprise determination of urinary organic acids, acylcarnitines on dried blood spot (which are also used for newborn screening), amino acid chromatography and carnitine profile.
Ultimate diagnosis is given by enzymatic assays and/or molecular biology.

Overall, treatment rests on four major principles: low protein diet (with or without supplementation of precursor-free amino acid mixtures), pharmacotherapy (e.g. supplementation of carnitine and cofactors, nitrogen scavengers), extracorporeal detoxication (in emergency situations) and liver and/or kidney transplantation. Importantly, treatment requires to be adapted to individual needs of each patient and adequate therapy monitoring. Long-term follow-up should be provided by a team of experts including metabolic physicians, child neurologists, dieticians, psychologist, physicotherapists, occupational therapists and speech therapists.

More detailed information may be found below on this web page in the “individual conditions” section.

E-IMD - www.e-imd.net