Organic acidurias in adults: late complications and management

Abstract

Organic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids ("organic acids") and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-threatening acute metabolic crises and acute multi-organ failure. Tandem mass spectrometry-based newborn screening programmes, in particular for isovaleric aciduria and glutaric aciduria type 1, have significantly reduced diagnostic delay. Dietary treatment with low protein intake or reduced intake of the precursor amino acid(s), carnitine supplementation, cofactor treatment (in responsive patients) and nonadsorbable antibiotics is commonly used for maintenance treatment. Emergency treatment options with high carbohydrate/glucose intake, pharmacological and extracorporeal detoxification of accumulating toxic metabolites for intensified therapy during threatening episodes exist. Diagnostic and therapeutic measures have improved survival and overall outcome in individuals with OADs. However, it has become increasingly evident that the manifestation of late disease complications cannot be reliably predicted and prevented. Conventional metabolic treatment often fails to prevent irreversible organ dysfunction with increasing age, even if patients are considered to be "metabolically stable". This has challenged our understanding of OADs and has elicited the discussion on optimized therapy, including (early) organ transplantation, and long-term care.

Newborn screening and disease variants predict neurological outcome in isovaleric aciduria

“…None of the individuals with mild IVA (N = 67) experienced a metabolic decompensation during the study period, while 17 of 24 (71%) individuals of the classic IVA group had at least one metabolic decompensation, 13 of these (54%) already during the newborn period (EO group, Figure 1) and 11 (46%) before the NBS result was known. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] days; P = .0018; Table 2), with highest frequencies (mean [SD]) during the first year of life (classic 1.7 [1.6]; mild 0.5 [1.1]). The major cause of hospitalization in classic IVA was prevention of (impending) metabolic decompensation (83.5%).…”

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

“…Most strikingly, early diagnosis and adherence to recommended conservative metabolic management using combinations of dietary treatment, cofactors, carnitine supplementation, nonabsorbable antibiotics, and intensified emergency management during catabolic episodes cannot reliably prevent disease progression, which does not even spare those who have not had a single acute metabolic decompensation for years (if ever). [20][21][22][23][24][25] Furthermore, a growing number of individuals with OADs are found to develop cerebral neoplasms such as in L-2-hydroxyglutaric aciduria (OMIM #236792) and GA1, 26,27 and hepatic neoplasms like in MMA. 28,29 Lastly, although plasma ammonium, acid-base balance, and anion gap are useful to estimate the risk of a metabolic decompensation in a "classic" OAD patient and to guide therapeutic decision-making, 30,31 these basic biomarkers as well as disease-specific carbonic acids and acylcarnitines have a low predictive value for the long-term outcome.…”

“…With improved survival and longer follow‐up, knowledge about OADs is increasing, unraveling major gaps and new challenges. Most strikingly, early diagnosis and adherence to recommended conservative metabolic management using combinations of dietary treatment, cofactors, carnitine supplementation, nonabsorbable antibiotics, and intensified emergency management during catabolic episodes cannot reliably prevent disease progression, which does not even spare those who have not had a single acute metabolic decompensation for years (if ever) 20‐25 . Furthermore, a growing number of individuals with OADs are found to develop cerebral neoplasms such as in l ‐2‐hydroxyglutaric aciduria (OMIM #236792) and GA1, 26,27 and hepatic neoplasms like in MMA 28,29 .…”

Education and training in adult metabolic medicine: Results of an international survey

“…It is critical that these patients can be transitioned to AMS. The timing of transition is not easy to define, especially for patients who may develop severe visceral or neuropsychiatric complications, which requires the identification of the right adult structures and professionals for care continuity . Some countries, such as Portugal, UK, France, and the Netherlands have already made important advances in this direction.…”