Glutaric aciduria type 1 (GA-1) is a cerebral organic aciduria characterized by a striatal injury and a progressive movement disorder [1
]. The neurologic injury is often precipitated by an intercurrent illness within the first three years of life, although approximately 10–20% of affected patients have an insidious presentation [2
]. Historically, 80–90% of undiagnosed and untreated patients developed striatal necrosis, although newborn screening has dramatically changed the natural history of this disease [5
]. With early diagnosis and aggressive medical intervention during acute illness, most patients remain healthy into adulthood, emphasizing the importance of treatment.
GA-1 results from the deficiency of glutaryl-CoA dehydrogenase (GCDH, E.C. 184.108.40.206), which is a key enzyme in lysine oxidation and decarboxylation. GCDH catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA, and the deficiency of GCDH results in the accumulation of glutaryl-CoA, glutaconic acid, glutaric acid and 3-hydroxyglutaric acid [7
]. Although the pathophysiology of this disorder is still incompletely understood, the accumulation of 3-hydroxyglutaric acid is thought to play a role in cell damage and development of striatal injury [8
]. Current therapeutic strategies focus on limiting the accumulation of metabolites through aggressive management of illness to limit catabolism and the use of carnitine to enhance detoxification of glutaryl-CoA and prevent a secondary carnitine deficiency [5
]. Similarly, dietary-based treatments reduce precursor amino acids lysine and tryptophan and subsequently decrease the accumulation of glutaric acid and 3-hydroxyglutaric acid. Patients with GA-1 have been managed with intact protein-restricted diets for over forty years, although it is often unclear how clinicians implement these chronic dietary-based therapies.
Initially, patients who presented to care after an acute neurologic injury were treated with generalized protein restriction, which resulted in mild improvement in biochemical parameters and limited improvement in clinical symptoms [1
]. In small case series, presymptomatic protein restriction was associated with a decreased risk of neurologic injury, although these results were confounded by concomitant treatment with acute illness management and carnitine supplementation [3
]. Furthermore, patients who were treated with only acute management and carnitine also remained asymptomatic [3
], which raised questions about the impact of protein restriction on the development of neurologic disease [16
]. Despite these concerns, dietary-based therapies remain central to the treatment of patients with GA-1 [11
Over time, nutrition management shifted from a general restriction of intact protein to the targeted restriction of lysine and tryptophan [19
]. The goal of both therapeutic strategies is to reduce lysine intake while ensuring adequate intakes of other essential and nonessential amino acids, vitamins and minerals [19
]. Recent guidelines advocate for a low-lysine diet through the use of lysine-free, tryptophan-reduced amino acid supplements (medical foods) [11
], and it is unclear how many patients are currently managed with a generalized intact protein restriction [21
Adults with GA-1 can present with a variety of neurologic symptoms, including chronic headaches, peripheral neuropathy, white matter abnormalities and subependymal nodules [22
]. These late-onset presentations are consistent with a chronic neurologic deterioration as opposed to the acute encephalopathic crisis and subsequent striatal injury that occurs in the first few years of life. As a result, many clinicians have liberalized patient’s intact protein restriction over time, although there are few recommendations on how and when to change a patient’s treatment. Guidelines for dietary management of patients over the age of six are unclear and range from avoiding excessive intake of intact protein [17
] to recommendations for controlling protein intake with a focus on protein sources with low lysine content [11
Observational studies have demonstrated the importance of aggressive management, especially in an asymptomatic infant [6
], although the implementation of dietary recommendations is often not clear. Herein we present results from an international empiric study on the nutritional management of patients with GA-1.
For patients identified with GA-1 by newborn screening, striatal injury can be prevented by appropriate management, including aggressive intervention during illness in early life [5
]. When coupled with medical and nutrition management, newborn screening for GA-1 can result in positive clinical outcomes [30
]. Treatment guidelines during illness are well accepted; however, chronic approaches to nutrition management are not consistent among institutions.
Guidelines for GA-1 management have been published and revised [11
]. Approaches to management are disparate based on established clinical dogma and experience. This is not uncommon in rare metabolic disorders due to the dearth of the full understanding of the natural history of the disease. In the current survey, the authors focused on nutritional management approaches to identify current real-world experiences and how they compare to established guidelines. The survey suggests that inconsistencies in practice exist in several major areas, including what diet liberalization means, when the diet should be liberalized and nutrition counseling for patients both on and off diet.
To most of the clinicians surveyed, diet liberalization and a “protein-controlled diet” means restricting intact protein intake to the standard reference, defined in this survey as the US Dietary Reference Intake [31
], or an equivalent international reference. Yet, to many, it also means reducing the intake of medical food (as is likely to occur as intact protein increases), and to some, liberalization means no restriction of protein.
The DRI for protein intake for an adult is 56 g of protein per day. However, US diet intake data show that for most, meeting but not exceeding the DRI would mean consuming far less protein than the typical adult. National Health and Nutrition Examination Survey (NHANES) data show that protein intake was 82.3 ± 0.8 g/day (mean ± SE), almost half of which is consumed as animal protein [32
]. Moreover, for children, the gap between the minimum amount of protein required and typical intakes is even greater. NHANES results indicate that for children 4–8 years of age, the average daily protein intake was 61.6 + 0.5 g (mean ± SE), yet the DRI recommended dietary allowance for this age group is 19 g of protein [33
]. The average protein intake was 13.6% of energy intake, which is within the acceptable recommended macronutrient distribution for protein of 10–35% of energy intake and, therefore, does not represent excessive protein intake [33
]. Thus, if the recommendation is for a patient with GA-1 to liberalize diet at age six years and limit protein intake to the DRI, the patient’s protein intake would be very low compared to average intakes, not considered to be a free diet. The need for individualization of nutrition management, including assessing sufficient protein adequacy, is in line with Boy et al. [11
The survey results showing that 87% of respondents use amino acid-based medical foods as an integral part of diet plan in children under 6 years of age is complementary to the current and previous guidelines [11
]. Positive growth and neurological outcomes have been described when instituting lysine-free amino acid medical foods in conjunction with low lysine foods, carnitine and emergency treatment [30
]. Researchers have reported muted clinical effects when quantifying intact proteins alone compared to lysine in the absence of medical foods [5
Counting intact protein (grams) is simpler than quantifying lysine (milligrams), but it is less precise and does not consider the quality of protein consumed nor differences in lysine content of common foods. Despite these concerns, conversion to a food protein-counting method is often used in nutrition management as patients age and is in line with current guidelines [11
The overwhelming majority of survey respondents do not recommend supplementing the diets of patients with L-arginine per se, but rather calculate the contribution from the amino acid-based medical foods. The amount of arginine from medical foods varies, as does arginine from protein-containing foods depending on the type and amount of protein consumed. Consequently, L-arginine intake can have significant variance that must be calculated by the clinician. Despite the trend to reduce and even eliminate amino acid-based medical foods, the main contributor of arginine, guidelines do not recommend supplementing arginine [11
The revised guidelines strongly recommend a low lysine diet with amino acid-based medical foods up to age six years [11
]. After age six years, the recommendation is to transition to an individualized age-appropriate “protein-controlled” diet. Despite this recommendation, fewer than half of survey respondents (45%) recommend diet liberalization after age 6 years in patients who were identified via newborn screening and have not had a striatal injury. Twenty percent of respondents “never” liberalize diet. The time of liberalization is variable and individualized. Some respondents approach liberalization slowly at six years or older, and they may continue the use of medical food. One reason for the hesitation in liberalizing the diet may be the concern among families and patients who are reluctant to change nutrition management due to fear of neurodegeneration, even if the patient has had striatal injury.
This survey has the limitations that respondents were self-selected and may not be representative of metabolic clinicians; in particular, there was only one respondent from Europe. Survey responses about nutrition management practices were not linked to outcomes in patients with GA-1.
GA-1 is challenging to manage nutritionally because the typical biomarkers, such as amino acids or organic acids, are not good correlates for assessing the appropriateness of a patient’s diet, nor are they related to patient outcomes. Consequently, nutrition management approaches to patients with GA-1 are divergent among clinicians. Although in this survey, there was agreement among responders to the current GA-1 guidelines, there is still uncertainty of how to best counsel families and patients on diet optimization and time for liberalization. What is needed is a clearer definition of what “liberalized”, and “protein-controlled” diets mean as well as consideration as to whether only meeting minimum protein requirements is optimal nutrition management once the diet is liberalized. Ongoing clinical research, contributing to the natural history of this disease, will help establish stronger recommendations from which clinicians can best counsel families.