Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria: A comparison between two genetic disorders affecting the same metabolic pathway.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile.

Maple urine syrup disease (MSUD) is an autosomal recessive disorder characterized by deficient activity of the branched-chain alpha ketoacid dehydrogenase (BCKAD) enzymatic complex due to biallelic variants in the alpha (BCKDHA) or beta (BCKDHB) subunits or the acyltransferase component (DBT). Treatment consists in leucine (LEU), isoleucine (ILE), and valine (VAL) (branched-chain amino acids) dietary restriction and strict metabolic control. to determine the characteristics of the Chilean cohort with MSUD currently in follow-up at Instituto de Nutrición y Tecnología de los Alimentos, during the 1990-2017 period Retrospective analytical study in 45 MSUD cases. Measured: biochemical parameters (LEU, ILE, and VAL), anthropometric evaluation, and neurocognitive development. In 18 cases undergoing genetic study were analyzed according to the gene and protein location, number of affected alleles, and type of posttranslational modification affected. Then, 45 patients with MSUD diagnosis were identified during the period: 37 were alive at the time of the study. Average diagnosis age was 71 ± 231 days. Average serum diagnosis LEU concentrations: 1.463 ± 854.1 µmol/L, VAL 550 ± 598 µmol/L and ILE 454 ± 458 µmol/L. BCKDHB variants explain 89% cases, while BCKDHA and DBT variants explain 5.5% of cases each. Variants p.Thr338Ile in BCKDHA, p.Pro240Thr and p.Ser342Asn in BCKDHB have not been previously reported in literature. Average serum follow-up LEU concentrations were 252.7 ± 16.9 µmol/L in the <5 years group and 299 ± 123.2 µmol/L in ≥5 years. Most cases presented some degree of developmental delay. Early diagnosis and treatment is essential to improve the long-term prognosis. Frequent blood LEU measurements are required to optimize metabolic control and to establish relationships between different aspects analyzed.

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.

First-year metabolic control guidelines and their impact on future metabolic control and neurocognitive functioning in children with PKU.

There is a consensus on the importance of early and life-long treatment for PKU patients. Still, differences exist on target blood phenylalanine (Phe) concentrations for children with PKU in different countries and treatment centers. For the first time, long-term metabolic control and child development and cognitive functioning is compared between children with mean phenylalanine concentrations under 240 µmol/L (group A), between 240 and 360 µmol/L (group B) or over 360 µmol/L (group C) during their first year of life. METHODS: 70 patients diagnosed with PKU through neonatal screening with Phe > 900 µmol/L, were divided into 3 groups: A, B and C, according to mean Phe concentrations and standard deviation (SD). Metabolic control during childhood, psychomotor development and IQ were compared. RESULTS: In group A, Phe was maintained within the recommended range until 6 years of age, in Group B, until 3 years of age, and in group C, Phe was always over the recommended range. No significant differences were found between the three groups in mental development index (MDI) and motor development index (PDI) scores at 12, 24, and 30 months of age, but group C had the lowest scores on MDI at all age periods. At preschool and school age, IQ was higher in group A compared to group C. CONCLUSION: Results show that mean blood Phe concentrations between 120 and 240 µmol/L during first year of life have a positive impact in metabolic control and cognitive functioning during childhood.

Treatment adherence during childhood in individuals with phenylketonuria: Early signs of treatment discontinuation.

INTRODUCTION: Phenylketonuria (PKU) is an autosomal recessive disorder characterized by a deficiency in phenylalanine (Phe) hydroxylase activity. Early diagnosis and continuous treatment with a low Phe diet prevents severe neurological and cognitive impairment. AIMS: 1. Analyze how treatment adherence evolves through infancy, childhood, and early adolescence in individuals with PKU. 2. Identify early signs of treatment discontinuation. METHODOLOGY: This longitudinal, retrospective study included 75 children diagnosed through newborn screening, ages 7 to 13 years. Data on blood Phe concentration, number of blood samples sent, proportion of samples with Phe concentrations over the recommended range, and number of visits to the metabolism clinic were recorded. Logistic regression analysis was used to identify the variables that predict treatment discontinuation before 13 years of age. RESULTS: A progressive increase in mean blood Phe concentrations with age was identified. The greatest increase occurred between the first and second years of life. By age ten, mean Phe blood concentration of the group was above the recommended range. The proportion of samples with Phe concentrations over the recommended range also increased with age, from an average of 13% during the first year of life to 67% in early adolescence. Sixty-eight percent of the children attended the outpatient clinic and sent samples from birth to the time of the study. Individuals who discontinued follow-up showed significantly higher mean blood Phe concentrations (360 vs. 220.9 µmol/L; p = 0.004) and the proportion of samples over the recommended range (37% vs. 12% p = 0.002) was significantly higher during the second year of life. Mean age for children who discontinued treatment was 5.5 years of age. Blood Phe concentration values at 12 to 23 months of age and at 6 to 8 years of age significantly predicted treatment discontinuation before 13 years of age. CONCLUSION: Treatment adherence in PKU diminishes with age. Early signs of treatment discontinuation can be identified during the second year of life, allowing preventive interventions in high risk groups.

Long-term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein-restricted diet.

INTRODUCTION: Tyrosinemia Type 1 (HT1) is an autosomal recessive disorder caused by a defect in the enzyme fumarylacetoacetate hydroxylase in the tyrosine pathway. Implementation of nitisinone (NTBC) treatment has dramatically improved survival rate of individuals with HT1, yet recent reports on cognitive impairment in treated patients exist. AIMS: Describe long-term neurocognitive outcome individuals with HT1 treated with nitisinone and protein restricted diet. METHODOLOGY: Twelve individuals with HT1 were analyzed with respect to psychomotor development and cognitive functioning using standardized psychometric tests. Plasma tyrosine and phenylalanine concentrations were also collected and analyzed, as part of the regular HT1 follow up program in our clinic. RESULTS: Delayed performance in Bayley scale mental developmental index (MDI) was identified in 29% to 38% of the patients assessed at different ages. At preschool age, mean full scale IQ (FSIQ) was 88 ± 16; six out of nine assessed children preformed within normal range, and one child presented with intellectual disability. At school age mean FSIQ was 79 ± 18, three out of nine children preformed within normal range and two showed intellectual disability. Repeated measures showed IQ decline over time in four out of eight patients, all of whom presented with symptoms in their first months of life. Patients that showed no progressive IQ decline were 8 months or older at diagnosis, with a mean age of 17 months. Significant correlation between Phe/Tyr ratio and FSIQ at school age was identified (r = - 0.689; p < 0.044). CONCLUSION: Some patients with HT1 treated with nitisinone and protein restricted diet are at risk of presenting developmental delay and impaired cognitive functioning. Patients with early onset of symptoms could be at risk for progressive cognitive functioning decline over time.

Cognitive functioning in mild hyperphenylalaninemia.

BACKGROUND: Hyperphenylalaninemia is a hereditary metabolic disorder that causes elevated blood phenylalanine (Phe). Hyperphenylalaninemias are classified as Phenylketonuria PKU (Phe > 6 mg/dL) or mild hyperphenylalaninemia (mHPA) (Phe 2­6 mg/dL). This study examines the cognitive functioning of early diagnosed children with mHPA compared with early diagnosed and treated children with PKU. SAMPLE AND METHODS: Psychomotor development (BSID-II) at 12 and 36 months of age, and cognitive performance at 4 and 7 years of age (WPPSI and WISC-R), were assessed in 118 PKU and 97 mHPA patients. Cognitive profile analysis of WISC-R subscales in school age children was performed and results were compared between the two groups. RESULTS: Both groups preformed within the average range. Scores were significantly higher in the mHPA group. The mean Mental Development Index (MDI) at 12 months of age was 98.1 in the mHPA group and 92.3 in the PKU group (p < 0.0002). At 36 months the MDI was 94.6 in the mHPA group and 84.7 in the PKU group (p = 0.0001. At age four years the mean Full Scale IQ was 106.5 (mHPA group) and 95.9 (PKU group) (p < 0.0001). At age seven years the mean Full Scale IQ was 100.9 (mHPA group) and 89.9 (PKU group) (p < 0.005). The pattern of deficits was similar in both groups, with relative weaknesses in working memory and attention. CONCLUSIONS: Children with mHPA achieved cognitive performance well within the average range and attained significantly higher scores than children with PKU. However, they appeared to have relative weaknesses in working memory and attention, similar to children with PKU.

Propionic acidemia and optic neuropathy: a report of two cases.

INTRODUCTION: Propionic acidemia is a metabolic disease produced by a deficiency of the enzyme propionyl-CoA carboxylase. It can lead to coma, with severe neurologic encephalopathy or present later in life with vomiting, hypotonia, and seizures. An early diagnosis with adequate treatment helps to prevent the sequelae. Among the described complications is optic neuropathy, although not commonly reported, it is very disabling. OBJECTIVES: To describe two patients with propionic acidemia and optic neuropathy. PATIENTS AND METHODS: Patient 1: 16 years old, male, parents without consanguinity. He was diagnosed at 5 months of age because of hypotonia and seizures. Until the age of 9 years, he evolved satisfactorily; therefore, he stopped treatment. At 13 years, he presented bilateral optic neuropathy. Patient 2: 20 years, female, parents without consanguinity. She was diagnosed with PA at 11 months of age because of hypotonia and seizures. She evolved satisfactorily until the age of 9 years when she presented a metabolic decompensation followed by a bad metabolic control. At 18 years, she presented bilateral progressive optic neuropathy. RESULTS: Both patients have psychometric scores with borderline IQ 84-75 (WISC-R) beside optic neuropathy. They were evaluated by an ophthalmologist and also by neuroimaging (MRI of optic pathway). CONCLUSIONS: Pathophysiology of optic neuropathy is not completely understood. There is evidence that the damage is due to an accumulation of neurotoxic compounds secondary to the metabolic block increasing the oxidative stress. We suggest an annual ophthalmologic evaluation in the long-term follow-up of organic acidurias with visual loss, in order to detect this disabling sequela at an earlier stage.

[Clinical follow up of Chilean patients with tyrosinemia type 1 treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-ciclohexanedione (NTBC)]. / Evolución clínica de pacientes chilenos con tirosinemia tipo I tratados con 2-(2-nitro-4-trifluorometilbenzoil)-1,3-ciclohexanediona (NTBC).

BACKGROUND: Tyrosinemia type I is an inborn error of metabolism due to deficiency of fumarilacetoacetase. Acute presentation is with liver failure, hypophosphatemic rickets and peripheral neuropathy. Chronic presentation is with visceromegaly and subclinical rickets. The most severe complications are hepatic cancer and acute neurological crises. Without treatment, tyrosinemia type 1 is fatal. In 1992 treatment for tyrosinemia type 1 with 2-(2-nitro-4-trifluoromethybenzoyl)-1,3-ciclohexanedione (NTBC) was proposed. A clinical response was reported in 90% of patients. In cases that did not respond, a successful liver transplantation was performed, reducing mortality to 5%. AIM: To report the follow up of 12 patients treated with NTBC. PATIENTS AND METHODS: Review of clinical records of 12 Chilean cases treated with NTBC at the Instituto de Nutrición y Tecnología de los Alimentos (INTA) from January 2004 until June 2010. RESULTS: In all patients, a rapid metabolic control was achieved. Two patients developed hepatocarcinoma. One of these patients died and one was successfully treated with liver transplantation. One patient died after receiving a liver transplantation. Nine patients have at present good liver function, but 2 had peripheral neuropathy due to late diagnosis and discontinuing NTBC treatment. CONCLUSIONS: Treatment with NTBC allows metabolic normalization in tyrosinemia type 1, prevents liver cirrhosis and hepatic cancer, improving survival rates and quality of life in the patients. Neonatal screening is essential for the early diagnosis of this treatable disease, that otherwise may be lethal.

Evolución clínica de pacientes chilenos con tirosinemia tipo I tratados con 2-(2-nitro-4-trifluorometilbenzoil)-1,3-ciclohexanediona (NTBC) / Clinical follow up of Chilean patients with tyrosinemia type 1 treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-ciclohexanedione (NTBC)

Background: Tyrosinemia type I is an inborn error of metabolism due to deficiency of fumarilacetoacetase. Acute presentation is with liver failure, hypophosphatemic rickets and peripheral neuropathy. Chronic presentation is with visceromegaly and subclinical rickets. The most severe complications are hepatic cancer and acute neurological crises. Without treatment, tyrosinemia type 1 is fatal. In 1992 treatment for tyrosinemia type 1 with 2-(2-nitro-4-trifluoromethybenzoyl)-1,3-ciclohexanedione (NTBC) was proposed. A clinical response was reported in 90% of patients. In cases that did not respond, a successful liver transplantation was performed, reducing mortality to 5%. Aim: To report the follow up of 12 patients treated with NTBC. Patients and Methods: Review of clinical records of 12 Chilean cases treated with NTBC at the Instituto de Nutrición y Tecnología de los Alimentos (INTA) from January 2004 until June 2010. Results: In all patients, a rapid metabolic control was achieved. Two patients developed hepatocarcinoma. One of these patients died and one was successfully treated with liver transplantation. One patient died after receiving a liver transplantation. Nine patients have at present good liver function, but 2 had peripheral neuropathy due to late diagnosis and discontinuing NTBC treatment. Conclusions: Treatment with NTBC allows metabolic normalization in tyrosinemia type 1, prevents liver cirrhosis and hepatic cancer, improving survival rates and quality of life in the patients. Neonatal screening is essential for the early diagnosis of this treatable disease, that otherwise may be lethal.

[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.