Determinación y jerarquización de signos clínicos para diagnóstico temprano de xantomatosis cerebrotendinosa / Determination and hierarchy of clinical signs for early detection of cerebrotendinous xanthomatosis

Background: Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene resulting in a decreased synthesis of bile acids. An early diagnosis and treatment would reduce the longterm complications observed in this disease. Aim: To identify and hierarchize initial clinical signs of CTX to establish an early diagnostic suspicion index. Material and Methods: Clinical information was collected from 387 patients diagnosed with CTX, published in MEDLINE between 1968 and 2016. Clinical manifestations were identified, determining their prevalence and age of onset. Sensitivity, specificity and the positive Likelihood ratio (LR+) was calculated for each clinical sign evaluated. Results: The average ages for early symptoms' onset and CTX diagnosis were 13.3 ± 10.6 years and 34.6 ± 12.6 years respectively. The early clinical signs and their respective LR+ were: juvenile cataracts (143), epilepsy (81), chronic diarrhea (15.6) and psychomotor development delay (3.4). The presence of consanguinity among parents resulted in a LR+ of 31. The combination of two early signs increased the post-test probability to 30%. If the early diagnostic criteria would have been applied in three Chilean patients with diagnosis of CTX, their disease would have been diagnosed from 12 to 25 years earlier. Conclusions: The use of a hierarchical system of predictive clinical signs allows an early screening of CTX, which may avoid the natural progression of the disease using an appropriate treatment.

Diabetes mellitus por mutación en el gen de glucokinasa: caso clínico / Diabetes mellitus caused by a mutation of glucokinase gene: report of an affected family

Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease.

Cortisol y amilasa salival en niñas: variación según la curva diurna, la ingesta de alimentos y la actividad física / Diurnal variation of salivary cortisol and alpha amylase levels in normal girls: effects of meals and physical exercise

Salivary cortisol levels and saliva alpha-amylase enzymatic activity are non-invasive markers of hypothalamic-pituitary-adrenal axis and autonomic nervous system related to stress, which could be associated with excessive energy intake in response to stressors. Aim: To describe the diurnal variation of salivary cortisol levels and á-amylase activity in prepubertal girls and to assess their change after meals and physical activity episodes. Subjects and Methods: Nine normal-weight girls aged 8 to 10 years were monitored for 14 hours, from 6:00 AM to 20:00 h. Three standardized meals were administered across the day with a controlled sport competition performed at the end of the day. Saliva samples were drawn upon awakening, 30 min after awakening, before and after lunch, before and after dinner, and before-after the controlled episode of physical activity. Results: A decreasing salivary cortisol diurnal pattern was confirmed, with an initial increase occurring 30 minutes after waking up. An ascending diurnal pattern was observed for salivary amylase activity. Meals significantly increased cortisol levels, with a non-significant trend to increase amylase activity. The magnitude of physical activity during acute exercise was associated with increased salivary amylase activity (rho = 0.84; P <0.01). Cortisol levels were positively correlated with body mass index z scores (rho = 0.87; P <0.01). Conclusions: We confirmed the existence of a diurnal pattern of salivary cortisol levels and á-amylase activity in saliva that is modulated by diet and exercise. Our preliminary results also show that salivary cortisol might be related with body weight...

Haplotipos HLA en familias chilenas con diabetes tipo 1 / HLA haplotypes in families with type 1 diabetes

Background: Inherited susceptibility to type 1 diabetes is partially determined by HLA genes. HLA-DQA1 and DQB1 alleles have been chosen as the most sensitive susceptibility markers. Family studies are a good method to establish specific relationship between type 1 diabetes and specific haplotypes as risk markers for the disease. Aim: To analyse the role of class II HLA molecules and the distribution of haplotypes in the genetic predisposition to type 1 diabetes in Chilean families. Material and methods: Twelve family groups constituted by 58 individuals were studied. Fourteen children (10 male) less than 15 years old with diabetes and their family members were included. The allele and haplotype frequency of the population was determined in 74 unrelated healthy children. Results: Risk haplotypes such as HLA-DR3/DQB1*0201/DQA1*0501 and HLA-DQB10302/DQA1*0501 were more common among diabetic patients and comparable to the haplotypes described in other Caucasian populations. Meanwhile, protective haplotypes found in relatives without diabetes, such as HLA-DR2/DQB1*0301/DQA1*0301 and HLA-DR8/DQB1*0402/DQA1*0301, were absent in children with diabetes. Conclusions: The general pattern of neutral or protective haplotypes, found with higher frequency in non diabetic individuals, indicates that their presence could confer protection against the disease, with a higher effect over those haplotypes associated to the disease

Polimorfismos del gen de lipoproteína lipasa en diabéticos no insulino-dependientes: estudio preliminar / Lipoprotein gene polymorphism in non dependent diabetics: preliminary study

Background: Lipoprotein lipase plays a crucial role in plasma lipoprotein metabolism. Several lipoprotein lipase gene polymorphisms have been found associated with lipid levels, premature atherosclerosis and cardiovascular disease. Aim: To investigate, in the Chilean population, the genotype distribution of lipoprotein lipase polymorphism and its possible association with lipid levels and obesity. Patients and methods: Hind III and Pvu II polymorphism was determined in 45 non-insulin-dependent diabetic patients and in 52 non diabetic controls from Santiago, Chile. Results: Hind III (+/+) polymorphism had a higher frequency in diabetics as compared to controls (0.6 and 0.29 respectively, p= 0.009). The frequency of heterozygous distribution was higher in non diabetic subjects. Controls and diabetics had comparable gene frequencies for the Pvu II genotype distribution. Analyzing the impact of these polymorphisms on plasma lipid levels, Hind III (+/+) genotype was associated with high Levels of total cholesterol and triglycerides in both groups. The hterozygote (+/-) or homozygote (-/-) state for Hind III was effectively associated with high levels of HDL cholesterol levels, as compared to the (+/+) genotype. There was no relationship between these genotypes and body mass index and waist to hip ratio. Conclusions: An association between genetic variation at the lipoprotein lipase locus with high levels of triglycerides and total cholesterol was confirmed. However, no association of these genetic markers with anthropometric measurements was found

Diabetes mellitus insulino-dependiente en Santiago de Chile: rol patogénico de factores inmunogenéticos y ambientales / Insulin-dependent diabetes mellitus in Santiago, Chile: pathogenic role of immunogenetic and environmental factors

The role of HLA class II alleles in the genetic susceptibility to develop insulin-dependent diabetes mellitus (IDDM) was examined by means of PCR and oligospecific probes in 63 IDDM children and 74 controls subjects. In diabetic patients we found a significant increase in the alleles frequency DR3, DR4, DQB1*0302 and DQA1*0301 compared to the control group, where the most prevalent alleles were DR2, DR14 (DRB1*1402), DQA1*0101 and DQA1*0201. All the risk genotypes in the diabetic group were similar than in other caucasian groups: DR3/DR4-DQB1*0201/0302-DQA1*0301/0501 and DR4/DR4-DQB1*0302/0302-DQA1*0301/0301. The homozygote character no asp57 conferred an absolute risk (AR) of 3.87 and the marker Arg52 an AR of 5.78/100.000 hab year. The homozygosis for both markers (no Asp57+Arg52) had an AR of 7.56/100.000 hab year. Regarding environmental factors associated with IDDM, our population under study showed a low prevalence of infectious agents (mainly mumps and rubella, specifically associated with IDDM) and a high prevalence of effective breast-feeding (over 3 months). These factors could be exercising a protector role in the development of IDDM. The factors that appear to be important in the low incidence of IDDM, the high percentage of breast-feeding children in the population, the reduced frequency of susceptible molecules as DR3, DQB1*0201 (compared to other caucasian groups) and the presence of protective genotypes related to DR13 and DR14 observed in the non diabetic children