To the Editor:
We thank Dr McClelland and coworkers for their helpful comments to our recently published study on glutaryl-CoA dehydrogenase deficiency (1). This article already includes statistical evidence for the beneficial effect of lysine restriction in patients who were diagnosed presymptomatically (Fig. 5A). As clearly outlined we have used recursive partitioning (2) to determine predictors for categorical outcome variables, e.g., acute encephalopathic crises. This statistical procedure has been chosen because it can handle numerical data that are highly skewed or multi-modal, as well as categorical predictors with either ordinal or nonordinal structure. It is important to note that the division of the subgroups “Lysine restriction” (n = 38) and “Protein restriction or no diet” (n = 23) has not been made arbitrarily but is the result of this statistical analysis. This subgrouping is explained by the higher frequency of encephalopathic crises in patients receiving protein restriction (42.1%; n = 19) or no diet (100%; n = 4) compared with those receiving lysine restriction (10.5%; n = 38). Furthermore, we have demonstrated (Fig. 4A, C) the variable frequency of acute encephalopathic crises and the variable degree of disability of presymptomatically diagnosed patients in countries commonly using lysine restriction or protein restriction.
However, since the results of this study may have consequences for the current practice of metabolic centers, we have performed additional statistical analyses (Kruskal-Wallis rank sum test, Pearson's χ2 test, Kaplan-Maier analysis) on the same dataset to stress our findings. In fact, these additional results confirm that lysine restriction is particularly beneficial for presymptomatically diagnosed patients in that it reduces the frequency of acute encephalopathic crises and the degree of disability and morbidity (Table 1). In comparison to the “lysine restriction” group patients receiving protein restriction and especially those receiving no dietary treatment had a significantly poorer outcome (Table 1). In analogy, Kaplan-Maier analysis showed significant differences in the survival rates between these dietary groups (χ (2) (2) = 27.2; p < 0.001). The highest survival rate was observed in the “lysine restriction” group (100% of patients). In symptomatic patients, who usually have suffered encephalopathic crises before the diagnosis has been made, lysine restriction was less effective (Table 2). Although the survival rate seemed highest in the “lysine restriction” group, Kaplan-Maier analysis showed no statistical significance between dietary groups in symptomatic patients (χ (2) (2) = 3.7; p = 0.156).
Lysine is the major precursor of glutxaryl-CoA, glutaric acid and 3-hydroxyglutaric acid. These dicarboxylic acids are suggested to be directly involved in the pathophysiology of glutaryl-CoA dehydrogenase deficiency (3, 4). The blood-brain barrier has a low permeability for dicarboxylic acids and thus these metabolites may accumulate in the CNS. We have hypothesized that intracerebral accumulation of dicarboxylic acids is a common pathomechanism in some organic acidurias, including glutaryl-CoA dehydrogenase deficiency. In fact, it has been demonstrated in post mortem studies (5, 6) and in Gcdh-deficient mice (7), an animal model for glutaryl-CoA dehydrogenase deficiency, that glutaric and 3-hydroxyglutaric acid strongly accumulate in the CNS. Furthermore, acute cerebral injury resembling encephalopathic crises accompanied by massive increase in glutaric acid concentrations has been induced in young Gcdh-deficient mice using lysine loading (8). In contrast, lysine restriction resulted in near normalization of cerebral concentrations of these metabolites in two patients (9, 10).
In conclusion, it is likely to assume that the neuroprotective effect of dietary lysine restriction is mediated via reduced lysine transport to the CNS and secondarily reduced intracerebral production of glutaric and 3-hydroxyglutaric acid. Since the occurrence of acute encephalopathic crises is the prognostically relevant event in this disease, the best therapeutic effect of lysine restriction is achieved when it is started before such crises. A prospective follow-up study has been initiated to specify the efficacy of dietary treatment in this disease (URL: http://www.metabnet.de ).
References
Kölker S, Garbade SF, Greenberg CR, Leonard JV, Saudubray JM, Ribes A, Kalkanoglu HS, Lund AM, Merinero B, Wajner M, Troncoso M, Williams M, Walter JH, Campistol J, Martí-Herrero M, Caswill M, Burlina AB, Lagler F, Maier EM, Schwahn B, Tokatli A, Dursun A, Coskun T, Chalmers RA, Koeller DM, Zschocke J, Christensen E, Burgard P, Hoffmann GF 2006 Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 59: 840–847
Breiman L, Friedman JH, Olshen RA, Stone CJ 1984 Classification and regression trees. Chapman & Hall, New York, pp 1–342
Kölker S, Koeller DM, Okun JG, Hoffmann GF 2004 Pathomechanisms of neurodegeneration in glutaryl-CoA dehydrogenase deficiency. Ann Neurol 55: 7–12
Sauer SW, Okun JG, Schwab MA, Crnic LR, Hoffmann GF, Goodman SI, Koeller DM, Kölker S 2005 Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency, a role for glutaryl-coenzyme A. J Biol Chem 280: 21830–21836
Goodman SI, Norenberg MD, Shikes RH, Breslich DJ, Moe PG 1977 Glutaric aciduria: biochemical and morphologic considerations. J Pediatr 90: 746–750
Funk CB, Prasad AN, Frosk P, Sauer S, Kölker S, Greenberg CR, del Bigio M 2005 Neuropathological, biochemical, and molecular findings in a glutaric acidemia type 1 cohort. Brain 128: 711–722
Sauer SW, Okun JG, Fricker G, Mahringer A, Müller I, Crnic LR, Mühlhausen C, Hoffmann GF, Hörster F, Goodman SI, Harding CO, Koeller DM, Kölker S 2006 Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood-brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 97: 899–910
Zinnanti WJ, Lazovic J, Wolpert EB, Antonetti DA, Smith MB, Connor JR, Woontner M, Goodman SI, Cheng KC 2006 A diet-induced mouse model for glutaric aciduria type I. Brain 129: 899–910
Bennett MJ, Marlow N, Pollitt RJ, Wales JK 1986 Glutaric aciduria type 1: biochemical investigations and post-mortem findings. Eur J Pediatr 145: 403–405
Kölker S, Hoffmann GF, Schor DS, Feyh P, Wagner L, Jeffrey I, Pourfarzam M, Okun JG, Zschocke J, Baric I, Bain MD, Jakobs C, Chalmers RA 2003 Glutaryl-CoA dehydrogenase deficiency: region-specific analysis of organic acids and acylcarnitines in post mortem brain predicts vulnerability of the putamen. Neuropediatrics 34: 253–260
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kölker, S., Garbade, S., Burgard, P. et al. Response. Pediatr Res 61, 134–135 (2007). https://doi.org/10.1203/01.pdr.0b013e31802d9ab4
Issue Date:
DOI: https://doi.org/10.1203/01.pdr.0b013e31802d9ab4