RESUMEN

A frequent polymorphism in the gene coding for 5,10-methylenetetrahydrofolate reductase is the substitution 677C > T which produces a thermolabile and inefficient enzyme. Homozygosity for the 677C > T allele is the most important determinant of hyperhomocys-teinemia, when folic acid intake is reduced. Most studies on the relationship between the 677C > T variant in the mother and defects in the offspring have focused on neural-tube defects. This study is a retrospective case-control investigation of hypoxic-ischemic encephalopathy of the newborn (HIEN) with reference to the 677C > T polymorphism as a genetic risk for this condition. The prevalence of the 677C > T allele was studied in 11 children with HIEN, their respective mothers, and 85 healthy individuals. Plasma homocysteine levels after fasting and methionine loading were determined in both mothers and controls. Ten of 11 patients were evaluated using magnetic resonance (MR) imaging, and all showed multicystic encephalomalacia and severe brain vasculopathy. Seven mothers were homozygous and four heterozygous for the 677C > T allele. Five of the children were homozygous and six heterozygous for this polymorphism. The variant allele frequency was higher in the group of mothers with affected children than in the controls and was associated with an increase in plasma homocysteine after methionine loading, in the group of mothers than in controls. The 677C > T mutation in mothers, either in a homozygous or heterozygous state, together with poor nutritional status (probable folate deficiency) may represent a risk factor for irreversible HIEN in the offspring.

Asunto(s)

RESUMEN

While screening for new mutations in the HEXB gene, which encodes the beta-subunit of beta-hexosaminidase, a TG deletion (deltaTG) was found in the 3' untranslated region (3'UTR) of the gene, 7 bp upstream from the polyadenylation signal. Examination of DNA samples of 145 unrelated Argentinean individuals from different racial backgrounds showed that the deltaTG allele was present with a frequency of approximately 0.1, compared with the wild-type (WT) allele. The deletion was not associated with infantile or variant forms of Sandhoff disease when present in combination with a deleterious allele. Total Hex and Hex B enzymatic activities measured in individuals heterozygous for deltaTG and a null allele, IVS-2 + 1G-->A (G-->A), were approximately 30% lower than the activities of G-->A/WT individuals. Analysis of the HEXB mRNA from leukocytes of deltaTG/WT individuals by RT-PCR of the 3'UTR showed that the deltaTG allele is present at lower level than the WT allele. By polyacrylamide gel electrophoresis, it was determined that a PCR fragment containing the +TG version of the 3'UTR of the HEXB gene had an irregular structure. On inspection of genes containing a TG dinucleotide upstream from the polyadenylation signal we found that this dinucleotide was part of a conserved sequence (TGTTTT) immersed in a A/T-rich region. This sequence arrangement was present in more than 40% analyzed eukaryotic mRNAs, including in the human, mouse and cat HEXB genes. The significance of the TG deletion in reference to Sandhoff disease as well as the possible functional role of the consensus sequence and the DNA structure of the 3'UTR are considered.

Asunto(s)

RESUMEN

The striking and apparent specific elevation of the activity of chitotriosidase found in plasma from patients with Gaucher disease (GD) Type 1 (Mc Kusick 230800) is considered a new diagnostic hallmark of GD and should prove useful in assessing clinical manifestations and monitoring enzyme supplementation therapy. Further data have suggested that the increased levels of chitotriosidade activity in plasma from patients with unexplained diseases may be indicative of a lysosomal storage disorder. We present here an experience of the plasmatic chitotriosidase in an Argentinean population consisting of three groups: a) 25 healthy controls; b) subjects related with GD: 3 patients Type 1, 3 obligated heterocygotes and 1 patient with an atypical variant of GD; c) 42 patients with a precise nosologycal definition of inherited error of metabolism (IEM) and 5 patients presumably affected by a lysosomal pathology but without enzymatic confirmation. Methylumbellypheryl-tri-N-acetyl chitotrioside hydrolase activity was markedly increased: the mean activity being > 600 times and > 100 times the mean value in plasma of our healthy control (mean 17 nmol/min/ml, range 6-60.4 nmol/min/ml) in the plasma of the patients of Gaucher Type 1 disease and an atypical variant of GD, respectively. In the two more affected patients the elevated levels of chitotriosidase activity ran parallel to the severity of the disease and also as a response to the supplementation enzymatic therapy with a decrease of 50% of its activity at 10 months of therapy at a dose of 30 u/kg/month. Moreover, no increase of chitotriosidase activity was found in the 3 obligated heterozygotes of Gaucher Type 1 and Type 2 disease or in any other of the IEM. Chitotriosidase activity was absent in plasma of 2 control subjects and in 4 patients with exact diagnosis of an IEM. The physiological role of the human chitinase still has to be established and warrants further investigation and the natural consequence of the high frequency of a genetic deficiency in man. Meanwhile, reports on the purification and characterization of human chitotriosidase with chitinolytic activity toward chitin-containing pathogens and on the cloning of cDNA encoding chitinase will be crucial to obtain a better insight into this new chapter of medical genetics.

Asunto(s)

Asunto(s)

RESUMEN

In this paper we discuss the first five Argentinean patients presenting isovaleric acidemia (IVA), an alteration of leucine catabolism due to a genetic defect of isovaleryl-CoA dehydrogenase. Belonging to unrelated families, one from native (H. Fam.) and the other from Italian ancestry (M. Fam.); the patients presented the clinical pattern highly suggestive of the disease: they were siblings, had disease-free intervals, vomiting, ketoacidosis crises, "sweaty feet" odor and progression of the neurologic involvement from somnolence and stupor to profound coma. In the four children of H. Fam. the disease had a late but severe beginning; one of the girls died (N.H.). The boy from M. Fam. presented a neonatal form of clearly benign course. The disease was confirmed by gas-chromatography (GC) of volatile acids in serum and also by the typical urinary acid GC-profiles (Fig. 1, A and B); the isovalerylglycine quantitative evaluation in urinary samples collected during crises is shown in Table 1. The morphological findings in liver and brain of N.H. showed at the ultrastructural study, an extensive fatty degeneration and greatly marked mitochondrial alterations in the liver and edema, neuronal karyorrhexis and karyolysis in the brain (Fig. 2). The therapeutic protocol based on a low leucine or low protein diet and use of glycine is described. The evolutionary follow up, more than 10 years for the first case, showed a normal mental development in three of them and retardation in the first child of H. Fam., who had a late diagnosis. IVA is still valuable as a paradigm in the acquisition of a highly clinical suspicion and for its introduction in the study of genetic organic acidemias.

Asunto(s)

RESUMEN

This paper describes the first Argentine case of 3-hydroxy-3-methylglutaric aciduria, a genetic defect of ketogenesis and leucine catabolism step. At the age of 4 months, the patient presented a life-threatening episode of hypoglucemia, metabolic acidosis and hyperammonemia resembling Reye syndrome. The lack of urinary ketone bodies, normal levels of plasma aminoacids and normal urinary excretion of p-hydroxyphenolic acids, led us to look for a ketogenic defect. An abnormal profile of urinary organic acids detected by thin layer chromatography and later characterized and quantified by gas chromatography-mass spectrometry (Figs. 1, 2; Table 1), showed a marked increase in the acidic metabolites typical of the 3-hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids. The activity of 3-hydroxy-3-methylglutaryl coenzyme A lyase was absent in white cell pellets and between 2-5% of the control values in skin fibroblasts (Table 2). Treatment of the disorder, mainly restricted leucine or low-protein diet and addition of L-carnitine had no significant effect on the severe neurological injuries present since the first illness. MRI of the brain, at the age of 1 year and 8 months, showed images in T1 suggestive of marked cerebral atrophy and in T2 hyperintensive images predominating in the right frontal and posterior parietal areas and of the punctiform lesions in the basal ganglia, particularly in the heads of both caudate nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

RESUMEN

La acidemia isovalérica (AIV) es una enfermedad genética causada por una deficiencia de la isovaleril-CoA dehidrogenasa, enzima involucrada en un paso catabólico de la leucina. El cuadro clínico se caracteriza por crisis cetoacidóticas, progresivo compromiso neurológico y olor a "sudor de pies". En este trabajo se presentan los primeros cinco pacientes argentinos pertenecientes a dos familias no emparentadas. En una de ellas, los cuatro hijos afectados manifestaron una severa forma crónica intermitente con muerte de uno de los enfermos (N.H.). En el niño de la segunda familia, la AIV se expresó como una forma neonatal de curso inusualmente benigno. El diagnóstico definitivo se realizó con el análisis de los ácidos orgánicos por cromatografía gaseosa la cual confirmó el masivo incremento sérico del ácido isovalérico durante las crisis y la presencia permanente de la isovaleriglicina en las orinas de crisis y en las de remisión. La ultraestructura del hígado y cerebro de H.H. señlaron para el primero metamorfosis grasa y marcados cambios en las mitocondrias; en el cerebro, las células neuronales y gliales evidencian acentuada tumefacción, alteraciones en sus organoides, cariorrexis. El largo seguimiento clínico, alrededor de diez años para el primer paciente, permitió observar por un lado, una disminución, alteraciones en sus organoides, cariolisis y cariorrexis. El largo seguimiento clínico, alrededor de diez años para el primer paciente, permitió observar por un lado, una disminución gradual de la frecuencia y severidad de las crisis con el desarrollo y tendencia a desaparecer entre los 6 y 7 años de edad; por otra parte fue posible calificar como efecto diferenciado sobre la vida e intelecto de los enfermos, la precocidad del tratamiento de la emergencia metabólica y del dietético pero también dependiente del fenotipo que la heterogeneidad marcó para cada uno de ellos. La experiencia genéticas y para adquirir una alta sospecha clínica frente a estas inéditas patologías en nuestro medio (AU)

Asunto(s)

RESUMEN

This paper describes the first Argentine case of 3-hydroxy-3-methylglutaric aciduria, a genetic defect of ketogenesis and leucine catabolism step. At the age of 4 months, the patient presented a life-threatening episode of hypoglucemia, metabolic acidosis and hyperammonemia resembling Reye syndrome. The lack of urinary ketone bodies, normal levels of plasma aminoacids and normal urinary excretion of p-hydroxyphenolic acids, led us to look for a ketogenic defect. An abnormal profile of urinary organic acids detected by thin layer chromatography and later characterized and quantified by gas chromatography-mass spectrometry (Figs. 1, 2; Table 1), showed a marked increase in the acidic metabolites typical of the 3-hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids. The activity of 3-hydroxy-3-methylglutaryl coenzyme A lyase was absent in white cell pellets and between 2-5

of the control values in skin fibroblasts (Table 2). Treatment of the disorder, mainly restricted leucine or low-protein diet and addition of L-carnitine had no significant effect on the severe neurological injuries present since the first illness. MRI of the brain, at the age of 1 year and 8 months, showed images in T1 suggestive of marked cerebral atrophy and in T2 hyperintensive images predominating in the right frontal and posterior parietal areas and of the punctiform lesions in the basal ganglia, particularly in the heads of both caudate nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

RESUMEN

In this paper we discuss the first five Argentinean patients presenting isovaleric acidemia (IVA), an alteration of leucine catabolism due to a genetic defect of isovaleryl-CoA dehydrogenase. Belonging to unrelated families, one from native (H. Fam.) and the other from Italian ancestry (M. Fam.); the patients presented the clinical pattern highly suggestive of the disease: they were siblings, had disease-free intervals, vomiting, ketoacidosis crises, [quot ]sweaty feet[quot ] odor and progression of the neurologic involvement from somnolence and stupor to profound coma. In the four children of H. Fam. the disease had a late but severe beginning; one of the girls died (N.H.). The boy from M. Fam. presented a neonatal form of clearly benign course. The disease was confirmed by gas-chromatography (GC) of volatile acids in serum and also by the typical urinary acid GC-profiles (Fig. 1, A and B); the isovalerylglycine quantitative evaluation in urinary samples collected during crises is shown in Table 1. The morphological findings in liver and brain of N.H. showed at the ultrastructural study, an extensive fatty degeneration and greatly marked mitochondrial alterations in the liver and edema, neuronal karyorrhexis and karyolysis in the brain (Fig. 2). The therapeutic protocol based on a low leucine or low protein diet and use of glycine is described. The evolutionary follow up, more than 10 years for the first case, showed a normal mental development in three of them and retardation in the first child of H. Fam., who had a late diagnosis. IVA is still valuable as a paradigm in the acquisition of a highly clinical suspicion and for its introduction in the study of genetic organic acidemias.

RESUMEN

This paper describes the first Argentine case of 3-hydroxy-3-methylglutaric aciduria, a genetic defect of ketogenesis and leucine catabolism step. At the age of 4 months, the patient presented a life-threatening episode of hypoglucemia, metabolic acidosis and hyperammonemia resembling Reye syndrome. The lack of urinary ketone bodies, normal levels of plasma aminoacids and normal urinary excretion of p-hydroxyphenolic acids, led us to look for a ketogenic defect. An abnormal profile of urinary organic acids detected by thin layer chromatography and later characterized and quantified by gas chromatography-mass spectrometry (Figs. 1, 2; Table 1), showed a marked increase in the acidic metabolites typical of the 3-hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids. The activity of 3-hydroxy-3-methylglutaryl coenzyme A lyase was absent in white cell pellets and between 2-5

of the control values in skin fibroblasts (Table 2). Treatment of the disorder, mainly restricted leucine or low-protein diet and addition of L-carnitine had no significant effect on the severe neurological injuries present since the first illness. MRI of the brain, at the age of 1 year and 8 months, showed images in T1 suggestive of marked cerebral atrophy and in T2 hyperintensive images predominating in the right frontal and posterior parietal areas and of the punctiform lesions in the basal ganglia, particularly in the heads of both caudate nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

RESUMEN

In this paper we discuss the first five Argentinean patients presenting isovaleric acidemia (IVA), an alteration of leucine catabolism due to a genetic defect of isovaleryl-CoA dehydrogenase. Belonging to unrelated families, one from native (H. Fam.) and the other from Italian ancestry (M. Fam.); the patients presented the clinical pattern highly suggestive of the disease: they were siblings, had disease-free intervals, vomiting, ketoacidosis crises, [quot ]sweaty feet[quot ] odor and progression of the neurologic involvement from somnolence and stupor to profound coma. In the four children of H. Fam. the disease had a late but severe beginning; one of the girls died (N.H.). The boy from M. Fam. presented a neonatal form of clearly benign course. The disease was confirmed by gas-chromatography (GC) of volatile acids in serum and also by the typical urinary acid GC-profiles (Fig. 1, A and B); the isovalerylglycine quantitative evaluation in urinary samples collected during crises is shown in Table 1. The morphological findings in liver and brain of N.H. showed at the ultrastructural study, an extensive fatty degeneration and greatly marked mitochondrial alterations in the liver and edema, neuronal karyorrhexis and karyolysis in the brain (Fig. 2). The therapeutic protocol based on a low leucine or low protein diet and use of glycine is described. The evolutionary follow up, more than 10 years for the first case, showed a normal mental development in three of them and retardation in the first child of H. Fam., who had a late diagnosis. IVA is still valuable as a paradigm in the acquisition of a highly clinical suspicion and for its introduction in the study of genetic organic acidemias.

RESUMEN

La acidemia isovalérica (AIV) es una enfermedad genética causada por una deficiencia de la isovaleril-CoA dehidrogenasa, enzima involucrada en un paso catabólico de la leucina. El cuadro clínico se caracteriza por crisis cetoacidóticas, progresivo compromiso neurológico y olor a "sudor de pies". En este trabajo se presentan los primeros cinco pacientes argentinos pertenecientes a dos familias no emparentadas. En una de ellas, los cuatro hijos afectados manifestaron una severa forma crónica intermitente con muerte de uno de los enfermos (N.H.). En el niño de la segunda familia, la AIV se expresó como una forma neonatal de curso inusualmente benigno. El diagnóstico definitivo se realizó con el análisis de los ácidos orgánicos por cromatografía gaseosa la cual confirmó el masivo incremento sérico del ácido isovalérico durante las crisis y la presencia permanente de la isovaleriglicina en las orinas de crisis y en las de remisión. La ultraestructura del hígado y cerebro de H.H. señlaron para el primero metamorfosis grasa y marcados cambios en las mitocondrias; en el cerebro, las células neuronales y gliales evidencian acentuada tumefacción, alteraciones en sus organoides, cariorrexis. El largo seguimiento clínico, alrededor de diez años para el primer paciente, permitió observar por un lado, una disminución, alteraciones en sus organoides, cariolisis y cariorrexis. El largo seguimiento clínico, alrededor de diez años para el primer paciente, permitió observar por un lado, una disminución gradual de la frecuencia y severidad de las crisis con el desarrollo y tendencia a desaparecer entre los 6 y 7 años de edad; por otra parte fue posible calificar como efecto diferenciado sobre la vida e intelecto de los enfermos, la precocidad del tratamiento de la emergencia metabólica y del dietético pero también dependiente del fenotipo que la heterogeneidad marcó para cada uno de ellos. La experiencia genéticas y para adquirir una alta sospecha clínica frente a estas inéditas patologías en nuestro medio

Asunto(s)

RESUMEN

En los 26 años transcurridos desde la descripción original de la deficiencia en glucógeno sintetasa hepática, sólo una observación casuística más fue referida en 1977. Nosotros presentamos los estudios efectuados en un niño argentino de ascendencia italiana quién manifestó a partir de los 21 meses de edad, signos de disfunción hepática con escasa sintomatología clínica que contrastaba con una muy marcada metamorfosis grasa de su hígado. Una respuesta totalmente atípica a la sobrecarga con fructosa fue la clave inicial de orientación diagnóstica. El glucagon no modificó significativamente los niveles de glucosa después de un ayuno de 12 horas pero sí elevó la glucemia, con caída del lactato y alanina a las 3 horas de una comida. Un perfil metabólico de 24 horas demostró hipoglucemia, hipercetonemia, bajas concentraciones de alanina y moderada lactoacidemia en ayunas e hiperglucemia y marcado aumento del lactato en condiciones postprandiales; este perfil reducido a 14 horas, 12 horas de ayuno y a 2 horas posteriores a una ingesta, reveló iguales alteraciones en un hermano menmor asintomático. El curso de la investigación condujo a una segunda biopsia hepática que confirmó la esteatosis hepática y al examen ultraestructural alteracioens subcelulares en hígado y tambien en músculo; además se comprobó el bajo contenido del flucogéno hepático y una actividad de la glucógeno sintetasa entre el 20,25% de los controles siendo por el contrario normal la actividad de la enzima en músculo y en fibroblastos cultivados de una biopsia de piel. La falta de expresión clínica de la hipoglucemia, incluyendo convulsiones y/o retardo mental y un desarrollo pondoestatural normal, señalan a esta casuística argentina como una variante menos severa de la enfermedad respecto a las descripciones previas, observación que podría estar en correlación al defecto parcial en la actividad de la glucógeno sintetasa hepática (AU)

Asunto(s)

RESUMEN

En los 26 años transcurridos desde la descripción original de la deficiencia en glucógeno sintetasa hepática, sólo una observación casuística más fue referida en 1977. Nosotros presentamos los estudios efectuados en un niño argentino de ascendencia italiana quién manifestó a partir de los 21 meses de edad, signos de disfunción hepática con escasa sintomatología clínica que contrastaba con una muy marcada metamorfosis grasa de su hígado. Una respuesta totalmente atípica a la sobrecarga con fructosa fue la clave inicial de orientación diagnóstica. El glucagon no modificó significativamente los niveles de glucosa después de un ayuno de 12 horas pero sí elevó la glucemia, con caída del lactato y alanina a las 3 horas de una comida. Un perfil metabólico de 24 horas demostró hipoglucemia, hipercetonemia, bajas concentraciones de alanina y moderada lactoacidemia en ayunas e hiperglucemia y marcado aumento del lactato en condiciones postprandiales; este perfil reducido a 14 horas, 12 horas de ayuno y a 2 horas posteriores a una ingesta, reveló iguales alteraciones en un hermano menmor asintomático. El curso de la investigación condujo a una segunda biopsia hepática que confirmó la esteatosis hepática y al examen ultraestructural alteracioens subcelulares en hígado y tambien en músculo; además se comprobó el bajo contenido del flucogéno hepático y una actividad de la glucógeno sintetasa entre el 20,25% de los controles siendo por el contrario normal la actividad de la enzima en músculo y en fibroblastos cultivados de una biopsia de piel. La falta de expresión clínica de la hipoglucemia, incluyendo convulsiones y/o retardo mental y un desarrollo pondoestatural normal, señalan a esta casuística argentina como una variante menos severa de la enfermedad respecto a las descripciones previas, observación que podría estar en correlación al defecto parcial en la actividad de la glucógeno sintetasa hepática

Asunto(s)

RESUMEN

Studies in three sibs from an Argentine family, aged 29, 18 and 9 years, suffering from a severe neurological disease, revealed in the two older brothers (the third died), ultrastructural changes in cellular vacuolization in diverse peripheral tissues (conjunctival, gum and skin biopsies) and in blood lymphocytes. These data were suggestive of mucopolysaccharidosis, mucolipidosis or glycoproteinosis. However, the activity of lysosomal enzymes, the excretion of mucopolysaccharides and oligosaccharides reactive to orcinol, as well as the search for aspartylglucosaminuria gave normal values. The main biochemical finding was the detection of a substantial urinary increase of a unique resorcinol-positive compound, which by thin-layer chromatography was identified as N-acetylneuraminic acid (NANA-Free) and when quantified by the thiobarbituric acid method previously passed through a gel filtration column (Sephadex G-15) or through ion exchange resins, showed a NANA-Free concentration about 15 times higher than in controls of similar age (Table 2). The ultrastructural findings (Figs. 3-5), the hypersialuria and the present clinical state of these patients (Table 1, Figs. 1, 2) were compatible with Salla disease, a rare lysosomal storage disease originally observed in Finland. The precocity and severity of the neurological damage in our patients were evident since birth and without maturing accomplishments in their first years, contrary to the progressive neurological regression described for the classical syndrome. Based on these facts we suggest that the Argentine patients would constitute a new clinical form of Salla disease.

Asunto(s)

RESUMEN

En tres hermanos de una familia argentina, de veintinueve, dieciocho y nueve años de edad, afectados de un grave proceso neurológico, los estudios revelaron en los dos primeros (el tercero fallecido) cambios ultraestructurales de vacuolización en células de diversos tejidos periféricos (biopsias de conjuntiva, encía ypiel) y en linfocitos, dato que fue sugestivo de mucopolisacaridosis, mucolipidosis o glicoproteinosis; sin embargo, las actividades de las enzimas lisosomales, la excreción de mucopolisacáridos y de oligosacáridos orcinol reactivos como la investigación de aspartilglucosaminuria resultaron normales. El hallazgo bioquínmico principal fue la detección de un marcado incremento urinario de un único compuesto resorcinol positivo, identificado por cromatografía en capa delgada como ácido N-acetilneuraminico (NANA-Libre) y cuya cuantificación por el método del ácito tiobarbitúrico, previo pasaje por columna del gel filtración (Sephadex G-15) o por resinas de intercambio iónico demostró por ambos métodos, una concentración de NANA-Libre alrededor de 15 veces superior al de los valores controles para edades similares. La conjunci[on de los hallazgos ultraestructurales, hipersialuria y el cuadro clínico actual permitieron establecer correspondencia entre los pacientes presentados y la Sialuria Tipo Finlandés o Enfermedad de Salla (ESA) originalmente descripta en Finlandia, aunque resultó distintivo en los primeros la prococidad y severidad del daño neurológico, expresado a partir... (AU)

Asunto(s)

RESUMEN

Studies in three sibs from an Argentine family, aged 29, 18 and 9 years, suffering from a severe neurological disease, revealed in the two older brothers (the third died), ultrastructural changes in cellular vacuolization in diverse peripheral tissues (conjunctival, gum and skin biopsies) and in blood lymphocytes. These data were suggestive of mucopolysaccharidosis, mucolipidosis or glycoproteinosis. However, the activity of lysosomal enzymes, the excretion of mucopolysaccharides and oligosaccharides reactive to orcinol, as well as the search for aspartylglucosaminuria gave normal values. The main biochemical finding was the detection of a substantial urinary increase of a unique resorcinol-positive compound, which by thin-layer chromatography was identified as N-acetylneuraminic acid (NANA-Free) and when quantified by the thiobarbituric acid method previously passed through a gel filtration column (Sephadex G-15) or through ion exchange resins, showed a NANA-Free concentration about 15 times higher than in controls of similar age (Table 2). The ultrastructural findings (Figs. 3-5), the hypersialuria and the present clinical state of these patients (Table 1, Figs. 1, 2) were compatible with Salla disease, a rare lysosomal storage disease originally observed in Finland. The precocity and severity of the neurological damage in our patients were evident since birth and without maturing accomplishments in their first years, contrary to the progressive neurological regression described for the classical syndrome. Based on these facts we suggest that the Argentine patients would constitute a new clinical form of Salla disease.

RESUMEN

En tres hermanos de una familia argentina, de veintinueve, dieciocho y nueve años de edad, afectados de un grave proceso neurológico, los estudios revelaron en los dos primeros (el tercero fallecido) cambios ultraestructurales de vacuolización en células de diversos tejidos periféricos (biopsias de conjuntiva, encía ypiel) y en linfocitos, dato que fue sugestivo de mucopolisacaridosis, mucolipidosis o glicoproteinosis; sin embargo, las actividades de las enzimas lisosomales, la excreción de mucopolisacáridos y de oligosacáridos orcinol reactivos como la investigación de aspartilglucosaminuria resultaron normales. El hallazgo bioquínmico principal fue la detección de un marcado incremento urinario de un único compuesto resorcinol positivo, identificado por cromatografía en capa delgada como ácido N-acetilneuraminico (NANA-Libre) y cuya cuantificación por el método del ácito tiobarbitúrico, previo pasaje por columna del gel filtración (Sephadex G-15) o por resinas de intercambio iónico demostró por ambos métodos, una concentración de NANA-Libre alrededor de 15 veces superior al de los valores controles para edades similares. La conjunci[on de los hallazgos ultraestructurales, hipersialuria y el cuadro clínico actual permitieron establecer correspondencia entre los pacientes presentados y la Sialuria Tipo Finlandés o Enfermedad de Salla (ESA) originalmente descripta en Finlandia, aunque resultó distintivo en los primeros la prococidad y severidad del daño neurológico, expresado a partir...

Asunto(s)

RESUMEN

En trabajos preliminares hemos evidenciado una alta frecuencia de la Enfermedad de Sandhoff (ES), deficiencia génica de la actividad hidrolítica de la hexosaminidasa (Hex) en sus dos mayores isoenzimas Hex A y Hex B, en niños criollos de un semi-aislado geográfico de la Argentina. La presente comunicación se refiere a la estimación de la proporción de portadores del gen anormal entre 1400 escolares de la zona mediante la determinación con sustratos artificiales de la Hex Total y Hex B Sérica. Los valores de las actividades enzimáticas de 32 heterocigotos testigos, 15 de ellos obligados (padres), sirvieron de patrón de referencia autóctono para la detección de 71 heterocigotos de la muestra problema (4,93%). Los límites de confidencia del 99% determinaron que la proporción de los heterocigotos en la población estaba en el intervalo 0,0346-0,0636 o sea 1 portador por cada 16 a 29 habitantes de la región, resultado similar a la heterocigosis calculada según la ley de Hardy-Weinberg (1:14 a 1:26). El análisis estadístico de las dos variables empleadas (Hex Total y Hex B) de los subgrupos referenciales homocigotos normales y heterocigotos testigos, permitió la elaboración de una función discriminante cuadrática (FDC) capaz de discernir, con alta probabilidad, entre un genotipo mutado y otro normal. Los datos obtenidos indican una heterocigosis de ES exepcionalmente alta en la población de riesgo y coherente con la frecuencia de homocigotos enfermos reconocidos, otorgándose fundamento a un programa preventivo a nivel regional. Entre tanto, la FDC elaborada provee un recurso eficaz y práctivo de asesoramiento individual, sobre todo en el ámbito clínico vinculado al problema (AU)

Asunto(s)