Acessibilidade / Reportar erro

Clinical and Nutritional Evolution of 24 Patients with Glutaric Aciduria Type 1 in Follow-up at a Center Specialized in Inborn Errors of Metabolism in Chile

Abstract

Introduction:

Glutaric Aciduria Type 1 (GA-1) is produced by the enzymatic deficiency of glutaryl-CoA-dehydrogenase (GCDH), leading to the accumulation of glutaric acid (GA). 90% of patients without early treatment present acute encephalopathic crisis (AEC), followed by disabling neurological symptoms. The treatment consists of a low lysine (Lys) diet, protein substitute lys-free, tryptophan-reduced (PS) and L-carnitine.

Objectives:

Describe the clinical and nutritional evolution of a cohort of GA-1 patients at a national referral center in Chile.

Methodology:

Retrospective study of 24 patients diagnosed with GA-1 between 1998-2020 and referred to the Institute of Nutrition and Food Technology (INTA) of University of Chile.

Results:

Age at diagnosis was 19±27 months; 10/24 presented AEC and neurological sequelae. The cases without AEC (14/24) 8 presented neurological compromise: psychomotor development delay, abnormal movements and pyramidal syndrome. Nutritional evaluation: 12/24 were malnourished by deficiency, <6 years old group (12/24): 11 cases were found to have Lys and PS, ≥6 years old (12/24): 9/12 did not receive PS. All had normal free carnitine levels.

Conclusion:

GA-1 has variable symptoms with neurological involvement AEC or insidious start. Is essential to maintain a long-term follow-up and consider its inclusion in neonatal screening programs.

Keywords:
Glutaric aciduria type I; encephalopathic crisis; macrocephaly; lysine

Introduction

GA-I is a neurometabolic disease caused by the deficiency of the enzyme glutaryl-CoA-dehydrogenase (GCDH), which breaks down the amino acids lysine, hydroxylysine and tryptophan. This deficiency produces accumulation of: GA, 3-hydroxyglutaric acid (3-OH-GA), glutaconic acid and glutarylcarnitine acid (C5DC). It is of autosomal recessive inheritance, the enzyme is encoded in the GCDH gene located on chromosome 19p13.2 and more than 200 mutations have been identified [11. Wang Q, Li X, Ding Y, Liu Y, Song J, Yang Y. Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. Brain Dev. 2014;36(9):813-822. doi:10.1016/j.braindev.2013.11.006
https://doi.org/10.1016/j.braindev.2013....
]. The prevalence is 1: 110,000 live births [22. Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI. Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet. 1991;41(1):89-95. doi:10.1002/ajmg.1320410122
https://doi.org/10.1002/ajmg.1320410122...
].

The diagnosis is made by tandem mass spectrometry to determine levels of C5DC by acylcarnitine analysis and confirmed by urine organic acids analysis [33. Christensen E, Ribes A, Merinero B, Zschocke J. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2004;27(6):861-868. doi:10.1023/B:BOLI.0000045770.93429.3c
https://doi.org/10.1023/B:BOLI.000004577...
-44. Gürbüz BB, Yılmaz DY, Coşkun T, Tokatlı A, Dursun A, Sivri HS. Glutaric aciduria type 1: genetic and phenotypic spectrum in 53 patients. Eur J Med Genet. 2020;63(11):104032. doi:10.1016/j.ejmg.2020.104032
https://doi.org/10.1016/j.ejmg.2020.1040...
]. The most prevalent are macrocephaly, frontal bossing, delayed psychomotor development and muscle hypotonia [55. Couce ML, López-Suárez O, Bóveda MD, et al. Glutaric aciduria type I: outcome of patients with early- versus late-diagnosis. Eur J Paediatr Neurol. 2013;17(4):383-389. doi:10.1016/j.ejpn.2013.01.003
https://doi.org/10.1016/j.ejpn.2013.01.0...
-77. Kölker S, Garbade SF, Greenberg CR, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res. 2006;59(6):840-847. doi:10.1203/01.pdr.0000219387.79887.86
https://doi.org/10.1203/01.pdr.000021938...
]. While findings in neuroimaging tend to be usual for frontotemporal atrophy and subdural hematoma. [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
-1010. Vester MEM, Bilo RAC, Karst WA, Daams JG, Duijst WLJM, van Rijn RR. Subdural hematomas: glutaric aciduria type 1 or abusive head trauma? a systematic review. Forensic Sci Med Pathol. 2015;11(3):405-415. doi:10.1007/s12024-015-9698-0
https://doi.org/10.1007/s12024-015-9698-...
]

Without treatment, 80-90% of patients show acute encephalopathic crisis in early infancy [66. Zayed H, El Khayat HE, Tomoum H, et al. Clinical, biochemical, neuroradiological and molecular characterization of Egyptian patients with glutaric acidemia type 1. Metab Brain Dis. 2019;34(4):1231-1241. doi:10.1007/s11011-019-00422-3
https://doi.org/10.1007/s11011-019-00422...
-77. Kölker S, Garbade SF, Greenberg CR, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res. 2006;59(6):840-847. doi:10.1203/01.pdr.0000219387.79887.86
https://doi.org/10.1203/01.pdr.000021938...
] triggered by catabolic stress, such as infections, vaccination, surgery or prolonged fasting. This can occur between 3 and 36 months of age, although there are cases reported up to 72 months, a critical period in which there is greater brain development. After acute encephalopathic crisis (AEC), patients evolve mainly with sequelae such as abnormal movements, dystonic mostly due to selective injury to the striatum, which can lead to acute striatal necrosis [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
]. In 10-20% of cases, they have an insidious start, that is, despite not having had AEC, they present progressive neurological symptoms, with striatal damage demonstrated by neuroimaging, abnormal movements, and hypotonia [1111. Boy N, Garbade SF, Heringer J, Seitz A, Kölker S, Harting I. Patterns, evolution, and severity of striatal injury in insidious- versus acute-onset glutaric aciduria type 1. J Inherit Metab Dis. 2018. doi:10.1007/s10545-018-0187-y
https://doi.org/10.1007/s10545-018-0187-...
]. Late start presentation is described when the diagnosis is made after 6 years of age, these can present with nonspecific symptoms, predominantly changes in the white matter, headache or diagnosis of maternal glutaric aciduria due to findings in neonatal screening [1212. Boy N, Heringer J, Brackmann R, et al. Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity. Orphanet J Rare Dis. 2017;12(1):77. -1313. Boy N, Mengler K, Thimm E, et al. Newborn screening: a disease-changing intervention for glutaric aciduria type 1. Ann Neurol. 2018;83(5):970-979. doi:10.1002/ana.25233
https://doi.org/10.1002/ana.25233...
]. early initiation of nutritional treatment has been shown to be effective in reducing neurological disability and encephalopathic crisis [1414. Gokmen-Ozel H, MacDonald A, Daly A, Ashmore C, Preece MA, Hendriksz C, Vijay S, Chakrapani A. Dietary practices in glutaric aciduria type 1 over 16 years. J Hum Nutr Diet. 2012;25(6):514-519. doi:10.1111/j.1365-277X.2012.01269.x
https://doi.org/10.1111/j.1365-277X.2012...
-1515. Strauss KA, Williams KB, Carson VJ, et al. Glutaric acidemia type 1: treatment and outcome of 168 patients over three decades. Mol Genet Metab. 2020;131(3):325-340. doi:10.1016/j.ymgme.2020.09.007
https://doi.org/10.1016/j.ymgme.2020.09....
]. This consists of a low-lys diet, consumption of PS and L-carnitine supplementation [1616. Heringer J, Boy SPN, Ensenauer R, et al. Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol. 2010;68(5):743-752. doi:10.1002/ana.22095
https://doi.org/10.1002/ana.22095...
-1717. Boy N, Haege G, Heringer J, et al. Low lysine diet in glutaric aciduria type I--effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis. 2013;36(3):525-533. doi:10.1007/s10545-012-9517-7
https://doi.org/10.1007/s10545-012-9517-...
]. Scientific evidence has not reported cases of AEC after the age of 6, so in recent consensuses it is recommended to suspend the intake of PS, to give an intake of protein of high biological value according to the safe levels of intake recommended by the FAO / WHO, maintain a low-lys diet and supplementation with L-carnitine [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
]. Emergency treatment should be considered at all times when faced with episodes of catabolic stress, the recommendation is to decrease or suspend intact proteins, double the dose of L-carnitine and increase the caloric intake [1818. Tsai F-C, Lee H-J, Wang A-G, et al. Experiences during newborn screening for glutaric aciduria type 1: diagnosis, treatment, genotype, phenotype, and outcomes. J Chin Med Assoc. 2017;80(4):253-261. doi:10.1016/j.jcma.2016.07.006
https://doi.org/10.1016/j.jcma.2016.07.0...
-1919. Boy N, Mengler K, Heringer-Seifert J, Hoffmann GF, Garbade SF, Kölker S. Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis. Genet Med. 2021;23(1):13-21. doi:10.1038/s41436-020-00971-4
https://doi.org/10.1038/s41436-020-00971...
].

The objective of this study is to characterize the clinical and nutritional evolution of 24 Chilean patients with GA-1 under active follow-up at the Genetics and Metabolic Diseases Laboratory of the Institute of Nutrition and Food Technology (INTA), Dr. Fernando Monckeberg, Universidad de Chile.

Methodology

Study Design: It is a retrospective study, in which 46 electronic and/or physical records of patients diagnosed between 1998 and 2020 were reviewed. In the 9 deceased patients, we have not all the records available, but 1 died of acute renal failure and 4 for sepsis. All of them presented with AEC and developed severe neurological compromise and undernutrition. Twenty-four cases were selected that met the inclusion criteria: confirmed diagnosis and active follow-up at INTA (≥ 2 medical-nutritional control in the last 3 years).

Background of the Subjects: Admission data such as age at diagnosis, clinical picture at diagnosis, age of AEC, catabolic stress prior to the crisis, age of treatment initiation and neurological sequelae were obtained.

Neurological Evolution: The study group was divided into two groups according to diagnosis and clinical evolution. Group 1: cases with AEC and neurological sequelae; Group 2: cases without AEC and with or without neurological sequelae.

Anthropometric Evaluation: Height and weight measured during control were collected to determine the indicators: weight for age (W/A), weight for height (W/H) and height for age (H/A) for patients <5 years, body mass index (BMI) for age (BMI/A) and height for age (H/A) for patients aged 5 to 19. The z-score for each indicator was calculated to classify nutritional status according to WHO references in 2006 and 2007 by age and sex [2020. WHO. Who child growth standards length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization; 2006.-2121. WHO. Growth reference data for 5-19 years. Geneva: World Health Organization; 2007. https://www.who.int/toolkits/growth-reference-data-for-5to19-years..
https://www.who.int/toolkits/growth-refe...
].

Nutritional Intake: Of the 24-hour dietary recall recorded, the intake of energy, protein from PS and intact, Lys, L-carnitine, iron, calcium and zinc were analyzed. A differentiation was made between children aged < 6, in which energy intake, PS, Lys (intact protein and/or diet) and L-carnitine were compared with international recommendations [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
] and those children aged ≥ 6 according to protein and energy requirements determined by FAO/WHO/UN according to age [2222. Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition. World Health Organ Tech Rep Ser. 2007;(935)1-265.-2323. Human energy requirements: report of a joint FAO/WHO/UNU Expert Consultation. Food Nutr Bull. 2005;26(1):166.]. and L-carnitine according to international protocol [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
]. Calcium, zinc and iron intakes were all compared according to the recommended daily intake (RDI) and it was considered adequate requirement between 90-110% [2424. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary reference intakes for calcium and vitamin D. [Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium] Washington (DC): National Academies Press; 2011.-2525. Trumbo P, Schlicker S, Yates AA, Poos M. Food and Nutrition Board of the Institute of Medicine, The National Academies. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet Assoc. 2002;102(11):1621-1630. doi:10.1016/s0002-8223(02)90346-9
https://doi.org/10.1016/s0002-8223(02)90...
].

Level in plasma: The last free carnitine plasma levels (FC), esterified carnitine (EC) and total carnitine (TC) were recorded, considering them as reference values for: FC 19-35 μmol/L, EC 4-14 μmol/L and TC 36-56 μmol/L. These values were determined according to our laboratory for the Chilean healthy population, but not for glutaric patients. Then, it is requested that free carnitine be kept within the normal standardized range, according to international protocols [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
].

Informed Consent (IC): Parents or legal guardians signed the IC for the review of physical and/or electronic records of the selected subjects, which was approved by INTA's Ethics Committee in compliance with the Declaration of Helsinki.

Statistics: For the descriptive statistical analysis, the STATA 15.1 software was used, the data are shown as average ± standard deviation.

Results

Sample GA-1 study: Of 24 cases: 15 were boys and 9 were girls, with current ages of 86 ±60 months (range: 8 - 211 months). The diagnostic age was 18±27 months (range: 0.5 - 131 months), 1 case was diagnosed through the expanded neonatal screening pilot program. Regarding diagnostic confirmation: 6/24 had a normal measurement of the C5DC metabolite in the first initial sample, 4 of them showed elevation of C5DC after L-carnitine loading. Regarding the clinical characteristics: 1/24 cases had a history of consanguinity, 10/24 cases presented with AEC (8±3 months old), of these, 8 were associated with infectious conditions, and the diagnosis was made at an average of 24±38 months of age (Table 1A). 14/24 who did not have AEC were diagnosed at an average of 14±17 months of age. Of these, 8 cases had an insidious start with neurological sequelae and 6 had normal development (2 cases diagnosed in the neonatal period by family history of GA-1) (Table 1B).

Table 1A.
Clinical Characteristics GA-1 with AEC (Group 1) prior to diagnosis.
Table 1B.
Clinical characteristics GA-1 prior to diagnosis insidious onset group (Group 2).

Clinical manifestations prior to diagnosis: In the clinical picture prior to diagnosis, 21 patients presented macrocephaly (88%), 10 delayed psychomotor development (42%), 10 abnormal movements (42%) and 8 frontal bossing (33%).

Neurological Evolution During Monitoring: Of the group with AEC, all subjects manifested post-diagnosis neurological sequelae: dystonia, pyramidal syndrome, swallowing disorders and severe psychomotor development delay and/or regression. In the insidious-start group, 8/14 presented neurological sequelae, 8 delay and/or regression of psychomotor development, 7 abnormal movements, 2 pyramidal syndrome and 2 swallowing disorders (Table 2).

Table 2.
Post-Diagnostic Clinical Characteristics GA-1 (Group 1 and 2).

Evaluation of the nutritional state: Of a total of 24 patients, it can be observed that 12 presented malnutrition by deficiency, 6 were eutrophic and 6 had malnutrition by excess (Figure 1). It is important to note that 13 cases required gastrostomy and the placement age was 40±47 months (range: 1 - 128 months).

Figure 1.
Evaluation of the nutritional status of the 24 subjects with AG-1.

Nutritional treatment: The average age for the beginning of treatment was 19±27 months, with an age range between 0.5 and 132 months. Of the total, 12 were under 6 years old, who received an average energy intake of: 83±43 kcal/kg/day, intact proteins: 0.5±0.2 gr/kg/day, PS proteins: 0.9±0.1 g/kg/day, Lys 68±18 mg/kg/day and L-carnitine 85±30 mg/kg/day. When comparing the intake with the international recommendations, it was observed that 3 cases complied with energy intake, 12 with protein intake from PS, 11 with total lysine intake and 8 cases for L-carnitine intake. The remaining 12 cases are older than 6 years, who ingested an energy average of: 69±46 kcal/kg/day, intact protein: 0.9±0.2 gr/kg/day, PS protein: 0.9±0.7 gr/kg/day, Lys 71±26 mg/kg/day and L-carnitine 67±50 mg/kg/day. Of the total, 7 cases met energy recommendations, 9 cases met intact intake, only 3 cases received protein from PS and 8 cases for L-carnitine (Table 3). It should be noted that the group with AEC received an average energy intake of 95±54 kcal/day and the group without AEC of 62±31 kcal/day. This difference is due to the fact that 7/10 patients AEC are malnourished, therefore the caloric intake has increased to improve their nutritional status who could be affected by severe dystonia, as has been suggested in the literature [1717. Boy N, Haege G, Heringer J, et al. Low lysine diet in glutaric aciduria type I--effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis. 2013;36(3):525-533. doi:10.1007/s10545-012-9517-7
https://doi.org/10.1007/s10545-012-9517-...
].

Table 3.
Nutritional treatment in patients with GA-1 under the age of 6 years and over the age of 6 years.

R: Reference (<6-year comparison with international protocol and >6-year comparison with recommendation for age)

The 24 GA-1 patients included in this study met the recommendations of iron, zinc and calcium, according to age, with the need to use pharmacological supplements in 50% of the cases.

Carnitine levels in plasma: 22 reported GA-1 patients (2 no data) had on average a total carnitine of 66±28 μmol/, a free carnitine of 50±20 μmol/L and an esterified carnitine of 17±14 μmol/L (Figure 2).

Figure 2.
Plasma levels of total, free and esterified carnitine.

Discussion

The age in which AEC clinically presented in this cohort was between 5 and 15 months, similar to that described in the literature, this could be correlated to an exponential increase in GA at the brain level in the critical period of development [99. Strauss KA, Puffenberger EG, Robinson DL, Morton DH. Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet. 2003;121C(1):38-52. doi:10.1002/ajmg.c.20007
https://doi.org/10.1002/ajmg.c.20007...
] In relation to macrocephaly, the study detected that 88% of the subjects were born with it, which is over the 50% described in other studies [1010. Vester MEM, Bilo RAC, Karst WA, Daams JG, Duijst WLJM, van Rijn RR. Subdural hematomas: glutaric aciduria type 1 or abusive head trauma? a systematic review. Forensic Sci Med Pathol. 2015;11(3):405-415. doi:10.1007/s12024-015-9698-0
https://doi.org/10.1007/s12024-015-9698-...
] This could be explained by the fact that in these cases the clinical referral as a reason for neuropediatric consultation is made by a specialist in Chile, with macrocephaly being a frequent reason for consultation when inborn errors of metabolism are suspected [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
].

In the study the patients who presented early AEC (10/24) evolved with neurological sequelae: abnormal movements type dystonic (located in hands and feet or generalized) accompanied by delay and/or regression of psychomotor development, hypotonic syndrome, pyramidal syndrome, which is consistent with what is described in the literature [66. Zayed H, El Khayat HE, Tomoum H, et al. Clinical, biochemical, neuroradiological and molecular characterization of Egyptian patients with glutaric acidemia type 1. Metab Brain Dis. 2019;34(4):1231-1241. doi:10.1007/s11011-019-00422-3
https://doi.org/10.1007/s11011-019-00422...
]. 58% of the cases (14/24) presented with an insidious start and neurological alterations without presenting AEC, this form of presentation is more prevalent in this population than in other cohorts studied according to what has been reported. However, it should be considered that the clinical manifestations of the neurological spectrum are what motivated the referral to specialists on inborn errors of metabolism, particularly in countries such as Chile, where GA-1 is not included in neonatal screening programs [44. Gürbüz BB, Yılmaz DY, Coşkun T, Tokatlı A, Dursun A, Sivri HS. Glutaric aciduria type 1: genetic and phenotypic spectrum in 53 patients. Eur J Med Genet. 2020;63(11):104032. doi:10.1016/j.ejmg.2020.104032
https://doi.org/10.1016/j.ejmg.2020.1040...
]

In the insidious forms they presented macrocephaly, accompanied by other neurological symptoms in a variable way such as psychomotor development delay and/or dystonia and hypotonia. This association of symptoms already previously described in the literature [1414. Gokmen-Ozel H, MacDonald A, Daly A, Ashmore C, Preece MA, Hendriksz C, Vijay S, Chakrapani A. Dietary practices in glutaric aciduria type 1 over 16 years. J Hum Nutr Diet. 2012;25(6):514-519. doi:10.1111/j.1365-277X.2012.01269.x
https://doi.org/10.1111/j.1365-277X.2012...
] should increase the index of diagnostic suspicion of GA-1, especially in countries that have not incorporated this condition into screening programs. Some studies relate the presence of alterations in the dorsolateral region of the putamen in patients with insidious start, and it has also been suggested that low adherence to nutritional treatment would be a high-risk factor for developing dystonia [1111. Boy N, Garbade SF, Heringer J, Seitz A, Kölker S, Harting I. Patterns, evolution, and severity of striatal injury in insidious- versus acute-onset glutaric aciduria type 1. J Inherit Metab Dis. 2018. doi:10.1007/s10545-018-0187-y
https://doi.org/10.1007/s10545-018-0187-...
]. This point is difficult to objectively assess in the patients since the diagnosis was mostly made after the encephalopathic crisis or there are few imaging studies available.

The neurological compromise of patients, oral dyskinesia and swallowing disorders increase energy demand and limit food intake, which compromises the patient's nutritional status. Therefore, it is important to raise the need for the application of a gastrostomy as early as possible in order to avoid catabolism [1717. Boy N, Haege G, Heringer J, et al. Low lysine diet in glutaric aciduria type I--effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis. 2013;36(3):525-533. doi:10.1007/s10545-012-9517-7
https://doi.org/10.1007/s10545-012-9517-...
]. Even in the insidious start forms, the need for gastrostomy placement was observed in 2 patients with malnutrition by deficiency.

According to the international follow-up protocol for GA-1 [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
], in this group under 6 years old, 11/12 subjects met 2 important criteria such as the contribution of protein from PS and adequate intake of the amino acid Lys, which favors adequate growth and development. With respect to those over 6 years old, patients who still receive PS are in the process of abandonment and with an adequate intake of intact proteins according to the recommendation established for sex and age. It should be noted that energy intake is adjusted according to the nutritional status of the patient. Particularly in the group of patients older than 6 years, controversy has arisen regarding the need to maintain strict dietary therapy (Lys restriction) since the risk of AEC decreases considerably at this age. However, the current consensus [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
], is to continue treatment beyond the age of 6 years, so maintaining monitoring with clinical and/or laboratory follow-up (free carnitine levels) could be considered in this group. This is given the clinical manifestations in GA-1 that are described even in adulthood, for example: white matter involvement and/or alteration of executive function [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
].

The importance of maintaining a constant follow-up and education of the family to achieve good adherence to treatment and comply with medical indications, to prevent the risk of AEC and/or neurological impairment, must be stressed. This is consistent with the literature, since it is suggested that chronic follow-up be carried out in centers specializing in inborn errors of metabolism in order to achieve a better long-term prognosis [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
]. Within the analysis of this study, it was verified that 3 cases of insidious start that had very low adherence to nutritional treatment and poor management of acute periods, currently present disabling generalized dystonia and one of them presented AEC after an infectious picture at age 12 months.

However, it must be emphasized that 5/6 patients with favorable evolution complied with the nutritional protocol for both PS or intact proteins and Lys intake, according to recommendations [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
]. The favorable evolution in these cases is related to good adherence to treatment together with the early diagnosis and reinforces the concept that expanded neonatal screening programs does not necessarily guarantee normal neurological development.

It has been demonstrated that L-carnitine supplementation is important in the treatment of GA-1 since it contributes to preventing carnitine deficiency and in combination with actual nutritional management recommendations appears to improve neurological outcome [88. Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
https://doi.org/10.1007/s10545-016-9999-...
,1515. Strauss KA, Williams KB, Carson VJ, et al. Glutaric acidemia type 1: treatment and outcome of 168 patients over three decades. Mol Genet Metab. 2020;131(3):325-340. doi:10.1016/j.ymgme.2020.09.007
https://doi.org/10.1016/j.ymgme.2020.09....
]. It is suggested to start the supplementation with a dose of 100 mg/kg/day, but it is necessary to periodically measure the plasma value of free carnitine and to adjust the dose according to the reference range established by the laboratory. The study detected that 3 patients older than 6 years old who ingested less L-carnitine than the international recommendations (30 mg/kg/day of L-carnitine) maintained an average value of free carnitine over 40 μmol/L, considered adequate for the pathology. Together and according to what has been reported in other studies [55. Couce ML, López-Suárez O, Bóveda MD, et al. Glutaric aciduria type I: outcome of patients with early- versus late-diagnosis. Eur J Paediatr Neurol. 2013;17(4):383-389. doi:10.1016/j.ejpn.2013.01.003
https://doi.org/10.1016/j.ejpn.2013.01.0...
], all patients with GA-1 in the study had a free carnitine level within the normal range.

Conclusions

It is necessary to incorporate the GA-1 in the Chilean Neonatal Screening Program, as the symptoms and signs previous to the encephalopathic crisis are usually nonspecific and the neurological consequences of a late diagnosis are invalidating as shown in this study. The clinical presentation of GA-1 is varied and the absence of AEC does not guarantee neurological indemnity. The presentation form of insidious start was prevalent in the analyzed population and the association of symptoms: Macrocephaly, developmental delay and/or regression, abnormal movements should increase diagnostic suspicion of AG-1.

To achieve a favorable nutritional and neurological evolution in the patient, active follow-up with continuous education of the family is of great importance in order to achieve adherence to nutritional treatment. Therefore, this should be done in specialized centers for inborn errors of metabolism to improve the prognosis of this condition.

References

  • 1. Wang Q, Li X, Ding Y, Liu Y, Song J, Yang Y. Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1. Brain Dev 2014;36(9):813-822. doi:10.1016/j.braindev.2013.11.006
    » https://doi.org/10.1016/j.braindev.2013.11.006
  • 2. Morton DH, Bennett MJ, Seargeant LE, Nichter CA, Kelley RI. Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am J Med Genet 1991;41(1):89-95. doi:10.1002/ajmg.1320410122
    » https://doi.org/10.1002/ajmg.1320410122
  • 3. Christensen E, Ribes A, Merinero B, Zschocke J. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2004;27(6):861-868. doi:10.1023/B:BOLI.0000045770.93429.3c
    » https://doi.org/10.1023/B:BOLI.0000045770.93429.3c
  • 4. Gürbüz BB, Yılmaz DY, Coşkun T, Tokatlı A, Dursun A, Sivri HS. Glutaric aciduria type 1: genetic and phenotypic spectrum in 53 patients. Eur J Med Genet 2020;63(11):104032. doi:10.1016/j.ejmg.2020.104032
    » https://doi.org/10.1016/j.ejmg.2020.104032
  • 5. Couce ML, López-Suárez O, Bóveda MD, et al Glutaric aciduria type I: outcome of patients with early- versus late-diagnosis. Eur J Paediatr Neurol 2013;17(4):383-389. doi:10.1016/j.ejpn.2013.01.003
    » https://doi.org/10.1016/j.ejpn.2013.01.003
  • 6. Zayed H, El Khayat HE, Tomoum H, et al Clinical, biochemical, neuroradiological and molecular characterization of Egyptian patients with glutaric acidemia type 1. Metab Brain Dis 2019;34(4):1231-1241. doi:10.1007/s11011-019-00422-3
    » https://doi.org/10.1007/s11011-019-00422-3
  • 7. Kölker S, Garbade SF, Greenberg CR, et al Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr Res 2006;59(6):840-847. doi:10.1203/01.pdr.0000219387.79887.86
    » https://doi.org/10.1203/01.pdr.0000219387.79887.86
  • 8. Boy N, Mühlhausen C, Maier EM, et al Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9
    » https://doi.org/10.1007/s10545-016-9999-9
  • 9. Strauss KA, Puffenberger EG, Robinson DL, Morton DH. Type I glutaric aciduria, part 1: natural history of 77 patients. Am J Med Genet C Semin Med Genet 2003;121C(1):38-52. doi:10.1002/ajmg.c.20007
    » https://doi.org/10.1002/ajmg.c.20007
  • 10. Vester MEM, Bilo RAC, Karst WA, Daams JG, Duijst WLJM, van Rijn RR. Subdural hematomas: glutaric aciduria type 1 or abusive head trauma? a systematic review. Forensic Sci Med Pathol 2015;11(3):405-415. doi:10.1007/s12024-015-9698-0
    » https://doi.org/10.1007/s12024-015-9698-0
  • 11. Boy N, Garbade SF, Heringer J, Seitz A, Kölker S, Harting I. Patterns, evolution, and severity of striatal injury in insidious- versus acute-onset glutaric aciduria type 1. J Inherit Metab Dis 2018. doi:10.1007/s10545-018-0187-y
    » https://doi.org/10.1007/s10545-018-0187-y
  • 12. Boy N, Heringer J, Brackmann R, et al. Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity. Orphanet J Rare Dis 2017;12(1):77.
  • 13. Boy N, Mengler K, Thimm E, et al Newborn screening: a disease-changing intervention for glutaric aciduria type 1. Ann Neurol 2018;83(5):970-979. doi:10.1002/ana.25233
    » https://doi.org/10.1002/ana.25233
  • 14. Gokmen-Ozel H, MacDonald A, Daly A, Ashmore C, Preece MA, Hendriksz C, Vijay S, Chakrapani A. Dietary practices in glutaric aciduria type 1 over 16 years. J Hum Nutr Diet 2012;25(6):514-519. doi:10.1111/j.1365-277X.2012.01269.x
    » https://doi.org/10.1111/j.1365-277X.2012.01269.x
  • 15. Strauss KA, Williams KB, Carson VJ, et al Glutaric acidemia type 1: treatment and outcome of 168 patients over three decades. Mol Genet Metab 2020;131(3):325-340. doi:10.1016/j.ymgme.2020.09.007
    » https://doi.org/10.1016/j.ymgme.2020.09.007
  • 16. Heringer J, Boy SPN, Ensenauer R, et al Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann Neurol 2010;68(5):743-752. doi:10.1002/ana.22095
    » https://doi.org/10.1002/ana.22095
  • 17. Boy N, Haege G, Heringer J, et al Low lysine diet in glutaric aciduria type I--effect on anthropometric and biochemical follow-up parameters. J Inherit Metab Dis 2013;36(3):525-533. doi:10.1007/s10545-012-9517-7
    » https://doi.org/10.1007/s10545-012-9517-7
  • 18. Tsai F-C, Lee H-J, Wang A-G, et al Experiences during newborn screening for glutaric aciduria type 1: diagnosis, treatment, genotype, phenotype, and outcomes. J Chin Med Assoc 2017;80(4):253-261. doi:10.1016/j.jcma.2016.07.006
    » https://doi.org/10.1016/j.jcma.2016.07.006
  • 19. Boy N, Mengler K, Heringer-Seifert J, Hoffmann GF, Garbade SF, Kölker S. Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis. Genet Med 2021;23(1):13-21. doi:10.1038/s41436-020-00971-4
    » https://doi.org/10.1038/s41436-020-00971-4
  • 20. WHO. Who child growth standards length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development Geneva: World Health Organization; 2006.
  • 21. WHO. Growth reference data for 5-19 years. Geneva: World Health Organization; 2007. https://www.who.int/toolkits/growth-reference-data-for-5to19-years.
    » https://www.who.int/toolkits/growth-reference-data-for-5to19-years.
  • 22. Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition. World Health Organ Tech Rep Ser 2007;(935)1-265.
  • 23. Human energy requirements: report of a joint FAO/WHO/UNU Expert Consultation. Food Nutr Bull 2005;26(1):166.
  • 24. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Dietary reference intakes for calcium and vitamin D [Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium] Washington (DC): National Academies Press; 2011.
  • 25. Trumbo P, Schlicker S, Yates AA, Poos M. Food and Nutrition Board of the Institute of Medicine, The National Academies. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. J Am Diet Assoc 2002;102(11):1621-1630. doi:10.1016/s0002-8223(02)90346-9
    » https://doi.org/10.1016/s0002-8223(02)90346-9

Publication Dates

  • Publication in this collection
    09 July 2021
  • Date of issue
    2021

History

  • Received
    28 Jan 2021
  • Reviewed
    18 May 2021
  • Accepted
    24 May 2021
Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br