Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea‐cycle disorders: On the basis of information from a European multicenter registry

Abstract

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma

Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut

“…There are several possible reasons for this: 40% of mut patients have significant feeding difficulties leading to PEG or NG‐tube feeding contrasting to only 15% in the cblA group. A recent study by Molema et al 28 showed that in the E‐IMD MMA patient cohort, plasma l ‐valine and l ‐isoleucine levels were very low, mainly in patients receiving amino acid mix (AAM), despite median daily natural protein intake being at the recommended daily allowance. Patient subgroups were not further subdivided in that study.…”

Protection of Cystinotic Mice by Kidney-Specific Megalin Ablation Supports an Endocytosis-Based Mechanism for Nephropathic Cystinosis Progression

“…Acute suppression of the megalin pathway can be achieved by inhibition with dibasic amino acids, as shown with cultured cells 16,52 and by bolus injection into human volunteers, 15 perfusion in patients with cancer to prevent nephrotoxicity of radiochemicals, 53 or oral gavage in rats. 16 Long-term supplementation with arginine in man is considered safe, 54 is part of the treatment of genetic diseases of the urea cycle, 55 and is commonly used by body builders. Long-term supplementation with lysine is used for prevention of gyrate atrophy in hereditary ornithinemia.…”

Amino Acid Plasma Profiles from a Prolonged-Release Protein Substitute for Phenylketonuria: A Randomized, Single-Dose, Four-Way Crossover Trial in Healthy Volunteers

“…This study addresses dietary management with an AA mixture appropriate for PKU; however, the findings may be generalizable to other conditions that are managed with specific AA mixtures. These might include AA mixtures lacking methionine in homocystinuria [ 4 ], leucine, isoleucine and valine in maple syrup urine disease [ 5 ], phenylalanine and tyrosine in tyrosinemia [ 6 ], lysine and tryptophan in glutaric aciduria type 1 [ 7 ], and isoleucine and valine in some organic acidurias [ 8 ].…”

“…Of these, phenylketonuria (PKU) represents the most common and significant disease entity, with an estimated global incidence of 7/100,000 [ 1 ], although birth incidence varies by ethnicity and consanguinity, and estimates are influenced by the level of ascertainment [ 2 ]. Many inherited disorders of AA metabolism require prompt initiation of treatment at birth and lifelong adherence to a protein-restricted diet supplemented with defined AA mixtures that lack specific AAs [ 3 , 4 , 5 , 6 , 7 , 8 ]. Important products downstream of a metabolic block may need to be supplemented, such as tyrosine in PKU, phenylalanine in tyrosinemia and cysteine in some forms of homocystinuria.…”