Erna Raimann

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.

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.

Molecular Characterization Of Phenylalanine Hydroxylase Deficiency In Chile

Non-lethal OI III (OMIM 259420) is caused by structural aberrations of collagen I. We report four novel glycine substitutions, one in the a1 (I) chain of collagen I (G688S) and three in the a2 (I) chain (G241D, G247C, G883V). In each of two families (G241D and G883V), we found parental mosaicism for the substitution explaining recurrence and intrafamilial variability of OI. The G247C and the G883V are the most N-terminally and C-terminally, respectively, placed cysteine and valine substitutions reported. The new substitutions add important information to the genotype-phenotype map and in particular the importance of a-chain stoichiometry is underlined. Data regarding the G688S substitution may suggest a different effect of the two a-chains in the development of dentinogenesis imperfecta (DI).Both the haplotype distribution and the mutational spectrum of the phenylalanine hydroxylase (PAH) gene has been defined for the Chilean phenylketonuria (PKU) population. Mutation analysis was performed using a combined approach of screening for common European and Oriental mutations and application of the DGGE scanning method in the remaining uncharacterized alleles. A total of 16 different mutations have been identified, including two novel ones, Q232X and IVS11nt5. The most frequent mutations were IVS10nt‐11 and V388M present both in the 13% of the mutant chromosomes. The rest of the mutations are rare. The haplotype association including VNTR and STR alleles, was examined to investigated the origin and distribution of PAH alleles in Chile. Our results are consistent with Southern Europeans as the major source of PAH mutations in Latin America. However, we have also detected mutations from East and Central Europe, such IVS12nt1, R408W and R252W. It is clear that the PKU mutation present in each Latin American country varies with the demographic profile and specific mutation scanning is necessary in each population both for diagnostic and prognostic purposes. The correlation between the genotypes and the phenotypes is consistent with the emerging pattern of mutation severity deduced from previous studies in related populations. Hum Mutat 13:503, 1999.

Energy Expenditure in Chilean Children with Maple Syrup Urine Disease (MSUD)

INTRODUCTION Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by a blockage of branched-chain keto acid of BCAA (branched-chain keto acid dehydrogenase, BCKDH) leading to neurological damage induced by accumulation of leucine and metabolites. MSUD expenditure and energy requirement information is limited. OBJECTIVE To determine if basal/total energy expenditure (BEE/TEE) is comparable between different determination methods and if values agree with recommendations of energy in MSUD children, and whether they relate to nutritional status. METHODS Case-control study between MSUD (n = 16) and healthy children (n = 11) aged 6-18 years. Current nutritional status, physical activity level, body composition by DEXA and BEE/TEE by indirect calorimetry (BEEr) and predictive equations (FAO/WHO/ONU - WHO - and Schofield) were assessed; STATA 2013 (p < 0.05). RESULTS When comparing the energy expenditure variables, there was no significant difference between groups. Moreover, compared to BEEr, equations underestimate according to BEE WHO and Schofield, respectively (P = 0.00; 0.02). The WHO equation had lower average calorie difference, greater concordance correlation and association with indirect calorimetry compared to the Schofield equation for both groups, being the best predictor of the BEE for MSUD group. CONCLUSION Energy recommendations for MSUD children are according to energy expenditure; thus the use of WHO equation is a clinically and statistically feasible tool for its determination.

Qué debe saber el pediatra de las hiperfenilalaninemias

Hyperphenylalaninaemias are defined by a blood phenylalanine over 2mg/dl. The main cause is due to a mutation in the gene that codes the phenylalanine hydroxylase that catalyses the reaction that converts phenylalanine into tyrosine. The hyperphenylalaninaemias are classified into benign or mild hyperphenylalaninaemias, or mild, moderate or classic phenylketonurias. Due to its delayed detection outside the neonatal period it causes severe mental retardation. Its detection along with congenital hypothyroidism has been part of the National Neonatal Screening Program since 1992 in Chile. This article aims to answer the most common questions asked by the paediatrician when faced with a patient with hyperphenylalaninaemias.

Eight Year of Follow up in Early Diagnosed Phenylketonuria

Phenylketonuria (PKU) is the most frecuent inborn error of metabolism. It is produced by a defect in the phenylalanine hidroxilase (PAH) gen, inducing hyperphenylalaninemia, with irreversible damage in the central nervous system. Early diagnosis and a phenylalanine (Phe) restricted diet prevent mental retardation. In 1988 a newborn screening program for PKU was started; until now we have diagnosed 40 PKU cases. We present 23 PKU children detected through the national screening program and 17 who were born in private clinics. Diagnosis was made in average at 20 ± 12.6 days of age (range 2-60 days) and the Phe levels in serum at begining was 27.14 ± 8.65 mg%. All children were examined to rule out a DHPR cofactor deficiency, at the same time molecular genetics was studied. The follow up included medical, nutritional, biochemical, neurological and psychometric periodic evaluations. Treatment was based on a restricted Phe intake (15-45 mg/wt/day), 1.5 ± 3.0 g/prot/wt/day, 90-130 kcal/wt/day. Phe plasma levels was maintained in the range of 2-10 mg%. Patients had normal growth (between percentils 10 to 90, NCHS tables. Patients are evaluated by Bayley scale until 30 month of age. In later agesthe Stanford-Binet Scale was used. 90% of PKU children remained having normal psychometric evaluation. The remaining 10% were bordeline and all of them have other associate pathologies. We emphasize that early diagnosis and strict follow up permit normal mental and psychomotor development.

Propionic acidaemia : two cases in Chile

Case 1 F.D.S., male, birth weight 2980g. At the second day of life he presented hypoglycaemia and 24 h later developed metabolic acidosis. At the 6th day of life he had vomiting, hypotonia and hyperreflexia that progressed to seizures and coma. Blood analyses showed metabolic acidosis and hyperammonaemia. The diagnosis of propionic acidaemia was confirmed by the study of organic acids in urine by gas chromatography, which showed large increases in the excretion of lactic, 3-hydroxypropionic, and methylcitric acids and in propiony!glycine, with a slight increase in 3-hydroxyisovaleric acid. A low protein, hypercaloric diet (1 g protein/kg per day, 200cal/kg per day) was started at the 10th day of life. Although severely undernourished, with treatment he recovered weight and height. At 5 months he had a psychomotor development of 3 months. One month later he had a bronchopneumonia and a severe metabolic imbalance and died. Case 2 J.G.F., 9-year-old boy. This boy developed normally until the age of 3 months, when he started vomiting, became severely hypotonic and started to present psychomotor delay. The diagnosis of propionic acidaemia was made at 16 months of age using gas chromatography (large increases in 3-hydroxypropionic, 3-hydroxyisovaleric and methylcitric acids and in propionylglycine). The treatment (a low protein, hypercaloric diet) was started at the age of diagnosis with 1 g protein/kg/day and 150 cal/kg per day. His physical development is normal and he has a borderline intelligence quotient.