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.

Case report: Maternal tyrosinemia type 1a under NTBC treatment with tyrosine- and phenylalanine restricted diet in Chile.

We report the case of a 17-year-old girl with Tyrosinemia type 1a who carried a planned pregnancy to term while being under 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone) treatment and a tyrosine- and phenylalanine-restricted diet. She was on treatment since 2 months of age with poor metabolic control prior to her pregnancy (tyrosine 838 ± 106 umol/L). NTBC and a low tyrosine and phenylalanine diet were continued during her pregnancy. She unfortunately suffered from urinary tract infection and anemia during her pregnancy, with median plasma tyrosine and phenylalanine levels of 613 ± 106 umol/L (200-400 umol/L) and 40.2 ± 8 umol/L (35-90 umol/L), respectively. After 40 weeks of gestation, the patient gave birth to a healthy boy, with no adverse effects related to the use of NTBC. The newborn presented with a transitory elevation of plasma tyrosine levels and normal phenylalanine, methionine, and succinylacetone levels. By 12 months of age, the child was determined to have normal psychomotor development. At 20 months old, he was diagnosed with a mild developmental delay; however, global cognitive evaluation with the Wechsler Intelligence Scale for Children (WISC) test at 5 years old showed normal performance. Here, we discuss one of the few reported cases of nitisinone treatment during pregnancy and demonstrate a lack of teratogenicity and long-term cognitive disabilities.

Búsqueda de afecciones genéticas como etiología de déficit intelectual en individuos que asisten a escuelas de educación especial / Genetic screening to determine an etiologic diagnosis in children with mental retardation

Background: Mental retardation or intellectual disability affects 2 percent ofthe general population, but in 60 percent to 70 percent of cases the real cause ofthis retardation is not known. An early etiologic diagnosis of intellectual disability can lead to opportunities for improved educational interventions, reinforcing weak aáreas and providing a genetic counseling to the family Aim: To search genetic diseases underíying intellectual disabilities of children attending a special education school. Material and methods: A clinical geneticist performed the history and physical examination in one hundred and three students aged between 5 and 24 years (51 males). A blood sample was obtained in 92 of them for a genetic screening that included a standard karyotype, fragile X molecular genetic testing and search for inborn errors of metabolism by tándem mass spectrometry. Results: This approach yielded an etiological diagnosis in as much as 29 patients. Three percent of them had a fragile X syndrome. Inborn errors of metabolism were not detected. Conclusions: This type of screening should be done always in children with intellectual disability to establish an etiological diagnosis.

[Genetic screening to determine an etiologic diagnosis in children with mental retardation]. / Búsqueda de afecciones genéticas como etiología de déficit intelectual en individuos que asisten a escuelas de educación especial.

BACKGROUND: Mental retardation or intellectual disability affects 2% of the general population, but in 60% to 70% of cases the real cause of this retardation is not known. An early etiologic diagnosis of intellectual disability can lead to opportunities for improved educational interventions, reinforcing weak areas and providing a genetic counseling to the family. AIM: To search genetic diseases underlying intellectual disabilities of children attending a special education school. MATERIAL AND METHODS: A clinical geneticist performed the history and physical examination in one hundred and three students aged between 5 and 24 years (51 males). A blood sample was obtained in 92 of them for a genetic screening that included a standard karyotype, fragile X molecular genetic testing and search for inborn errors of metabolism by tandem mass spectrometry. RESULTS: This approach yielded an etiological diagnosis in as much as 29 patients. Three percent of them had a fragile X syndrome. Inborn errors of metabolism were not detected. CONCLUSIONS: This type of screening should be done always in children with intellectual disability to establish an etiological diagnosis.

Evaluation of reliability for urine mucopolysaccharidosis screening by dimethylmethylene blue and Berry spot tests.

BACKGROUND: The mucopolysaccharidosis (MPS) are a group of inherited metabolic disorders resulting from the deficiency of the enzyme responsible for intralysosomal catabolism of glycosaminoglycans (GAGs). GAGs are progressively accumulated in multiple tissues and released into the corporal fluids. The first laboratory approximation to MPS diagnosis is the identification of an increased urinary GAG excretion. For this, several semiquantitative and quantitative methods have been developed. The aim of this retrospective statistical study was to evaluate the reliability of MPS urine screening for the semiquantitative Berry spot test (BST) and the quantitative dimethylmethylene blue test (DMB). METHODS: The 24-h-urine samples (n = 246) were tested through BST, DMB, and for GAG excretion pattern by one-dimensional electrophoresis or thin layer chromatography. RESULTS: the 204 samples that demonstrated a normal GAG excretion pattern were considered as non-MPS samples. Forty-two samples presented an abnormal GAG excretion pattern. Enzyme analysis was available for 31 out of 42 patients (31/42), confirming that all were affected by MPS. Urinary GAG concentrations of MPS patients by DMB were increased 1.04- to 7.1-folds, compared to age-related normal levels. The sensitivity was 100% for DMB and 93.6% for BST. DMB demonstrated a specificity of 74.5%, while BST a specificity of 53.9%. The specificity of MPS screening increased to 84.3%, considering conjunctly DMB and BST. CONCLUSION: The DMB is a sensitive method, however, inclusion of BST could increase the specificity of MPS urine screening.

[Phenylketonuria diagnosed during the neonatal period and breast feeding]. / Fenilquetonuria de diagnóstico neonatal y lactancia materna.

BACKGROUND: Phenylketonuria (PKU) is due to of a defect in the phenylalanine hydroxylase gene (12q22-24.1) leading to hyperphenylalaninemia. Treatment consists in a low phenylalanine (Phe) diet. AIM: To evaluate the evolution of early diagnosed PKU children, receiving direct breast feeding, and a special formula without Phe, during their first six months of life. PATIENTS AND METHODS: Nineteen PKU children diagnosed in the neonatal period (19.29 +/- 13.8 days of age), treated with breast feeding and formula without Phe since diagnosis, were studied. Intake of calories, proteins and dietary Phe were quantified. Blood Phe, nutritional status and psychomotor development were also measured. RESULTS: The diet that these children received during the 6 months period of study, had a mean of 127 +/- 19.9 Kcal/kg/day, 1.95 +/- 0.3 g protein/kg/day and 35.3 +/- 9.5 mg Phe/kg/day. Fifteen children maintained the blood level of Phe under 8 mg/dl, considered an excellent metabolic control. Only 4 cases had intermittently high levels, between 10-12 mg/dl. At 6 months of age, 74% of the children maintained breast feeding as the only source of Phe. Sixty three percent had a normal nutritional status, 5.2% were at nutritional risk and 31.6% were overweight. Eighty one percent had a normal mental development. CONCLUSIONS: The use of direct breast feeding allows a good metabolic control and improves growth and development of early diagnosed PKU children.

[Diagnosis and follow up of 23 children with organic acidurias]. / Diagnóstico y seguimiento de 23 niños con acidurias orgánicas.

BACKGROUND: Propionic aciduria (PA) and Methymalonic aciduria (MMA) result from an inherited abnormality of the enzymes propionyl CoA carboxylase and methylmalonyl CoA mutase respectively. This produces marked increases in the amino acids methionine, threonine, valine and isoleucine (MTVI). Their clinical presentation can be neonatal or late onset forms. AIM: To report 23 children with organic acidurias. MATERIAL AND METHODS: Twenty three cases of organic acidurias diagnosed since 1980 (17 PA and 6 MMA) and followed at the Institute of Nutrition and Food Technology, are reported. RESULTS: The average age of diagnosis was 3.9 days for the neonatal form and 8.3 months for the late onset form. The most frequent symptoms were hypotonia, lethargy and vomiting. Neonatal PA had mean ammonemias of 1089 +/- 678.3 micrograms/dl. The figure for MMA was 933 +/- 801.9 micrograms/dl. Seven children were dialyzed and 30% died. 16 children are followed and 81.2% have normal weight for age. Seven children required gastrostomy because of anorexia and failure to thrive. The nutritional treatment is based on natural and artificial proteins without MTVI, with periodical controls, amino acid and ammonia quantification. Some patients were submitted to enzyme assays and molecular studies. CONCLUSIONS: An early diagnosis and a very strict follow up allows a normal development of children with organic acidurias. There is a relationship between prognosis and the presentation form, the nutritional status and the emergency treatment during acute episodes. The importance of the enzymatic and molecular studies is emphasized because they facilitate treatment, accurate diagnosis and allow an adequate genetic counseling.