Juan Francisco Cabello

Guidelines for diagnosis and treatment of Hunter Syndrome for clinicians in Latin America

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase®, Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients’ responses.

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.

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.

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.

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.

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.