Chronic Management 

of Organic Acidurias 
 
Professor Sufin Yap 
Sheffield Children’s Hospital, UK 
Long-Term Management of Organic Acidurias (OA):   
The treatment strategies include the dietary restriction of precursor amino acids and the usage
of adjunctive compounds to dispose of toxic metabolites. The long-term care requires frequent
monitoring of growth, development and biochemical parameters. Unfortunately, OA is not UCD
(urea cycle disorders), ammonia maybe acutely damaging but remains a secondary problem in
OA. 
 
Literature Review:  

1.In a single center cohort study of MMA(methylmalonic academia) & PA(propionic academia)
on long term CGA, 8 patients show no decompensation episodes post CGA (carglumic
acid).  Ammonia concentration is reduced after CGA. (CGA dose: 50mg/kg/day) and protein
intake is increased 20 to 50%, weight gain is up to 6.5 kg after a month.  The level of ammonia,
lactate and uric acid is also reduced. The branched chain amino acid, such as isoleucine is
normalized.  
 
The conclusion is that the effect of CGA is not apparent in acute treatment
of hyperammonaemia, but becomes apparent after long term treatment. We believe CGA does
not alter hepatic propionyl Co-A, which inhibits glycine cleavage system. The CGA augments
ureagenesis normalizes branched-chain amino acid and shows the stabilization of cardiac
function. The CGA has beneficial effect on mitochondrial cardiomyopathy1.
 
2.One case report of PA on long term CGA.  Since initiation of NCG 100 mg/kg/day at 9 years of
age, a male Caucasian patient’s (now 15 years old) plasma ammonia level is decreased
significantly. (76 vs. 140 mcmol/L before NCG therapy, p < 0.005).  After NCG treatment at 9
years of age, only 2 episodes happen during 6 years vs. 6-10 episodes/year prior to NCG
initiation.  
 
The conclusion is that the chronic NCG use is associated with decrease in plasma ammonia level
and reduction in the frequency of metabolic decompensations.  No clinically significant adverse
reactions to the therapy, and no evidence of progression of multi-organ involvement. The
evidence from literatures shows that several reports have been published on the use of NCG in
secondary defects of urea cycle. Since 2005, more than 20 publications have been available on
clinical application of NCG in OAs (mainly in PA), and they demonstrate response and safety
during decompensation episodes of OAs2.  

 
3.The classic OAs can cause a series of cellular metabolic disruptions in the cells, and carglumic
acid can interfere in some of these mechanisms by exerting a rescue effect on urea
cycle. Carglumic acid efficacy has been demonstrated in OAs (IVA, PA, MMA). The available
evidences on carglumic acid safety highlight the need for further research into its potential in
clinical practice and in long-term usage3.  
 
Ongoing Clinical Trials:   
1.PROTECT study tries to understand the long-term management of OA patients with carglumic
acid (May 2019). From 32 clinical sites, there are 62 patients involved in the trial. Patients need
to be diagnosed with PA or MMA, and also need to receive carglumic acid treatment for at least
6 months.  The final review will be on the third quarter of 2020.
 
2.LOTUS study tries to understand the long-term carglumic acid use in PA and MMA patients.  It
is a milticentric, non-interventioanl, prospective, non-comparative, single-armed, observational
study. Currently, there are 7 sites in Italy confirmed the recruitment, and still welcome other
sites to get involved. The proposed objectives include accessing efficacy of long-term carglumic
acid, exploring other efficacy parameters, determing the most efficient dose of carglumic acid
to maintain an acceptable level of ammonia, and understanding the safety of long-term
carglumic acid use. The initiation dose of 50mg/kg/day for the first 12 months is given, and
potentially reduce to 25mg/kg/day.  
 
3.CAMP study tries to evaluate the effectiveness and safety of the use of carglumic acid in
patients with PA (propionic acidemia)  or MMA (methylmalonic acidemia).  This is a phase 3(b)
randomized, multicenter, comparative trial. There are 33 participants, and the estimated study
completion date is March, 2019.
 

These 3 ongoing studies will elucidate and confirm effectiveness of NCG in the long-term
treatment of organic acidurias.

Ref:
(1) Burlina et al, Mol Genet Metab Rep. 2016; 8: 34-40.
(2) Tummolo et al, Journal of Medical Case Reportsvolume 12, Article number: 103 (2018). 
(3) Blair, H.A. Drugs Ther Perspect (2019) 35: 101.