[Cerebellar ataxia of Norman-Jaeken. Presentation of seven Spanish patients]. / Ataxia cerebelosa de Norman-Jaeken. Presentación de siete pacientes españoles.

AIM: To show that the cerebellar ataxias described by Norman and by Jaeken (CDG1a) are the same disease. PATIENTS AND METHODS: Seven patients, five females and two males (there were two siblings pairs), who presented a severe cerebellar disease slowly progressive associated with generalized cerebellar atrophy. The sister of one of the patients of the series had been studied because of psychomotor retardation but she died at two years of age due to respiratory problems. An autopsy was carried out that showed severe cerebellar atrophy, and the histological study revealed loss of granular cells and diverse abnormalities of Purkinje's cells, especially focal swellings of 'asteroid bodies' or 'cactus like' type. This suggested to us that Norman's ataxia and CDG1a could be the same pathological entity. RESULTS: All seven patients had severe cerebellar hypoplasia-atrophy and a small brainstem. Most patients showed peripheral neuropathy with decreased motor nerve conduction velocity, but very little decreased sensory nerve conduction velocity. All seven patients had highly raised serum concentrations of asialotransferrin, and heterozygous molecular PMM2 deficit (CDG1a). One of these seven cases was the patient whose sister had histological cerebellar changes corresponding to Norman's ataxia. CONCLUSION: The findings observed in our series suggest that the diseases described by Norman and Jaeken are the same pathological entity and CDG1a can be the biological basis of the histological changes of the cerebellum in Norman's ataxia. We suggest the name of Norman-Jaeken ataxia or disease for this entity.

Ataxia cerebelosa de Norman-Jaeken. Presentación de siete pacientes españoles / Cerebellar ataxia of norman-jaeken. Presentation of seven spanish patients

Objetivo. Mostrar que las ataxias cerebelosas descritas por Norman y por Jaeken (CDG1a) son el mismo trastorno. Pacientes y métodos. Siete pacientes, cinco mujeres y dos varones (había dos pares de hermanos), que presentaban una ataxia aguda lentamente progresiva asociada con atrofia cerebelosa generalizada. La hermana de uno de los pacientes de esta serie había sido objeto de estudio por un retraso psicomotor, pero murió a los dos años de edad debido a problemas respiratorios. La autopsia mostraba atrofia cerebelosa aguda, y el estudio histológico revelaba pérdida de la capa de los granos y diversas anormalidades de las células de Purkinje, especialmente inflamación focal de tipo ‘cuerpos asteroides' o cactus-like. Esto nos hizo pensar que la ataxia de Norman y laCDG1a podrían ser la misma entidad patológica. Resultados. Los siete pacientes tenían hipoplasia-atrofia aguda y disminución del grosor del tronco cerebral. La mayoría de los pacientes mostraba una neuropatía periférica con reducción de la velocidad de conducción motora, pero con muy poca disminución de la conducción sensitiva. Los siete pacientes tenían aumentados los niveles séricos deasia lotransferrina, y presentaban una deficiencia molecular heterocigótica PMM2 (CDG1a). Uno de estos siete casos era el paciente cuya hermana tenía cambios histológicos cerebelosos correspondientes a la ataxia de Norman. Conclusiones. Los hechos clínicos y de imagen de los pacientes de nuestra serie, a los que se les había diagnosticado la enfermedad de Norman, son similares a los descritos en los pacientes con síndrome de Jaeken. Ello nos hace pensar que ambas enfermedades son una misma entidad patológica. Los hallazgos obtenidos en nuestra serie indican que la CDG1a es la base bioquímica de los cambios histológicos en el cerebelo en los casos de ataxia de Norman (AU)

Aim. To show that the cerebellar ataxias described by Norman and by Jaeken (CDG1a) are the same disease. Patients and methods. Seven patients, five females and two males (there were two siblings pairs), who presented a severe cerebellar disease slowly progressive associated with generalized cerebellar atrophy. The sister of one of the patients of the series had been studied because of psychomotor retardation but she died at two years of age due to respiratory problems. An autopsy was carried out that showed severe cerebellar atrophy, and the histological study revealed loss of granular cells and diverse abnormalities of Purkinje’s cells, especially focal swellings of ‘asteroid bodies’ or ‘cactus like’ type. This suggested tous that Norman’s ataxia and CDG1a could be the same pathological entity. Results. All seven patients had severe cerebellar hypoplasia-atrophy and a small brainstem. Most patients showed peripheral neuropathy with decreased motor nerve conduction velocity, but very little decreased sensory nerve conduction velocity. All seven patients had highly raised serum concentrations of asial o transferrin, and heterozygous molecular PMM2 deficit (CDG1a). One of these seven cases was the patient whose sister had histological cerebellar changes corresponding to Norman’s ataxia. Conclusion. The findings observed in our series suggest that the diseases described by Norman and Jaeken are the same pathological entity and CDG1a can be the biological basis of the histological changes of the cerebellum in Norman’s ataxia. We suggest the name of Norman-Jaeken ataxia or disease for this entity (AU)

Atrofia cerebelosa de Norman-Jaeken / Norman-Jaeken cerebellar atrophy

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Congenital disorder of glycosylation (CDG) type Ie. A new patient.

CDG Ie is caused by a deficiency of dolichol-phosphate-mannose synthase 1 (DPM1), an enzyme involved in N-glycan assembly in the endoplasmic reticulum. Three proteins are known to be part of the synthase complex: DPM 1, DPM2 and DPM3. Only mutations in DPM1, the catalytic subunit, have been described in three families. One was homozygous for the c274C>G (R92G) mutation in DPM1 and two others were compound heterozygous for R92G and a c628delC deletion or a c331-343del13, respectively. Clinical features were a severe infantile encephalopathy, early intractable seizures, acquired microcephaly, and some dysmorphic features. We report a patient with milder symptoms: microcephaly, dysmorphic features, developmental delay, optic atrophy, and cerebellar dysfunction without cerebellar atrophy. The patient is homozygous for a new mutation in exon 9 of the DPM1 gene (c742T>C (S248P)). Our findings extend the spectrum of CDG Ie.

Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia.

We present our experience with the diagnosis of 26 patients (19 families) with congenital disorders of glycosylation classified as type Ia due to PMM deficiency. In all but one of these CDG Ia families the patients are compound heterozygous for mutations in PMM2. Eighteen different mutations were detected. In contrast to other series in which R141H represents 43-50% of the alleles, only 9/36 (25%) alleles have this mutation. Two mutations (R123Q and T237M) have been found on three disease chromosomes, four (V44A, Y64C, P113L and F207S) on two disease chromosomes and 12 mutations (D65Y, Y76C, IVS3+2C>T, E93A, R123X, V129M, I153T, F157S, E197A, N216I, T226S, C241S) only on one disease chromosome. V44A and D65Y probably originated in the Iberian peninsula, as they have only been reported in Portuguese and Latin-American patients; Y64C, Y76C, R123X and F207S have not been detected in other patients. R123X is the only stop codon mutation so far described in PMM2. The common European F119L mutation has not been found in our patients, although it is very frequent in other populations (43% allele frequency in Danish patients). Probably because of this genetic heterogeneity, Spanish patients show very diverse phenotypes that are, in general, milder than in other series. This points to the necessity of widening the criteria for CDG in the routine screening for inborn metabolic diseases.

[Changes in the lipid profile in chronic hepatopathies]. / Cambios en el perfil lipídico en hepatopatías crónicas.

BACKGROUND: The pattern of lipoproteins and apolipoproteins has been studied in a group of patients with chronic liver disease. The differences in this pattern were analysed in relation with the stage of liver disease and the presence of cholestasis. METHODS: Twenty one patients with hepatic cirrhosis and 12 with primary biliary cirrhosis were studied. Two subgroups were established according to the disease severity and to the Scheuer classification, respectively. Plasma lipoproteins were separated by ultracentrifugation, and the lipid and apolipoprotein composition were determined. Lipoprotein X was identified by means of agarose gel electrophoresis. RESULTS: In the subgroups with less severe liver disease, only minimal changes were found, such as the decreases in esterified cholesterol and Apo E contents in VLDL in the cirrhotic patients, and the increase of HDL-cholesterol in the patients with primary biliary cirrhosis in the first stages. In patients with severe hepatic cirrhosis, total esterified cholesterol, triglycerides, VLDL and HDL were diminished. Apo E in VLDL was undetectable whereas the different Apo C isoforms were in the normal proportion. Patients with severe biliary cirrhosis showed high levels of total cholesterol and triglycerides, elevated LDL-cholesterol, and decreased HDL-cholesterol and total esterified cholesterol. Apo C-IIO in VLDL was proportionally increased as related to both Apo E and Apo C-III. Lipoprotein X was detected in all these patients and in half of the patients with severe hepatic cirrhosis. CONCLUSIONS: Severe chronic liver disease is associated with a decrease of the concentration of hepatic lipoproteins and the absence of Apo E in VLDL, probably as a result of a defect in their synthesis. The lipid profile found in patients with biliary cirrhosis delineates the pattern of chronic cholestasis, which is characterized by the presence of lipoprotein X, a significant increase of free-cholesterol and a decrease of HDL-cholesterol; VLDL, which are increased, are rich in Apo C-II. Data show the distinct apolipoprotein composition of VLDL in the different hepatic diseases.

Effect of postnatal hypoxia on the energy homeostasis of the newborn rat during the early neonatal period.

Newborn rats breathing a low-oxygen mixture showed similar rates of glycogenolysis to newborns breathing air. However, hypoxia prevented the decrease of plasma glucose and lactate concentrations which occurred in newborns breathing air immediately after delivery. The time-course of plasma alanine was not affected by experimental hypoxia. The decrease in the liver lactate/pyruvate ratio observed in control newborns immediately after delivery was prevented by hypoxia. Lower blood oxygen concentrations were observed in hypoxic animals throughout the observation period. Lower ATP concentrations were observed in hypoxic newborns during the first hour after delivery but similar values were observed in both groups thereafter.

The offspring of a phenylketonuric couple.

Biochemical studies carried out in seven members of a family with five phenylketonuric subjects are described. The concentration of phenylalanine and the phenylalanine/tyrosine ratios in the blood, together with the values obtained from the L-phenylalanine loading tests, were the criteria used to establish the diagnosis. The results suggest that the non-consanguineous parents, the children and their maternal aunt are homozygous for classical phenylketonuria; the paternal grandmother, as expected, was found to be heterozygous for this metabolic disorder. The mother, diagnosed in the fifth month of her last pregnancy, was treated with a low phenylalanine diet until delivery. Nevertheless, the girl who was born from that pregnancy showed some symptoms resulting from "maternal phenylketonuria", being diagnosed as phenylketonuric at one week of age and treated with a low phenylalanine diet thereafter.