Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature.

Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme alpha galactosidase A, with consequent accumulation of globotrioasoyl ceramide in cells and tissues of the body, resulting in a multi-system pathology including end organ failure. In the classical phenotype, cardiac failure, renal failure and stroke result in a reduced median life expectancy. The current causal treatment for Fabry disease is the enzyme replacement therapy (ERT): two different products, Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), have been commercially available in Europe for almost 10 years and they are both indicated for long-term treatment. In fact, clinical trials, observational studies and registry data have provided many evidences for safety and efficacy of ERT in improving symptoms of pain, gastrointestinal disturbances, hypohidrosis, left ventricular mass index, glomerular filtration rate and quality of life. Few data are available on comparison of the two treatments and on the clinical course of the disease. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations.

Advances in the management of Anderson-Fabry disease: enzyme replacement therapy.

Anderson-Fabry disease (AFD) is a lysosomal storage disorder (LSD) due to alpha-galactosidase A (alpha-Gal A) deficiency and the resultant accumulation of incompletely metabolised glycosphingolipids (GSLs), primarily globotriosylceramide (Gb(3)), within various tissues. It is an X-linked multisystem disorder characterised by progressive renal insufficiency, with added morbidity from cardio- and cerebrovascular involvement, and associated with significant impact on quality of life and diminished lifespan. The disease manifests primarily in hemizygous males; however, there is increasing recognition that heterozygous (carrier) females may also develop disease-related complications, although onset among affected women may be delayed. Until recently, treatment has been limited to symptomatic management of pain and other measures to alleviate the problems associated with end-stage complications from renal, cardiac and nervous system involvement. The availability of the recombinant enzyme offers the potential of a safe and effective targeted treatment approach. At the moment, two distinct enzyme formulations are approved in Europe (and in other countries) and both continue to undergo FDA evaluation in the US. Increasing knowledge of the natural history of AFD and greater experience with enzyme therapy should enable optimal patient care. The relative rarity and complexity of AFD necessitates a multi-disciplinary team approach that may be facilitated by a centralised registry.

Lysosomal glycosphingolipid storage in chloroquine-induced alpha-galactosidase-deficient human endothelial cells with transformation by simian virus 40: in vitro model of Fabry disease.

Human umbilical venous endothelial cells were transformed with a temperature-sensitive mutant of simian virus 40, tsA640, and a cell line, subcultured for over 20 serial passages, was established at a temperature permissive for the virus. Treatment of transformed endothelium with 3 micrograms/ml chloroquine caused a specific reduction of alpha-galactosidase activity, without cell injury, and revealed several electron-dense materials surrounded by single unit membranes. Crystalline lamellae in lysosomes with a periodicity of 6.5 nm, which are typically seen in various tissues in Fabry disease, were produced in the presence of a glycosphingolipid mixture. These cells should be useful for in vitro pathophysiological studies on Fabry endothelium.

Angioqueratoma corporis diffusum por deficiencia de Alfa Galactosidasa "A" / Angiokeratoma corporis diffusum due to alpha-galactosidase \"A\" defficiency

Se comunica el caso de un paciente de sexo masculino de 24 años de edad, que presenta angioqueratomas múltiples en todo el tegumento y mucosas, con afectación oftalmológica típica. Se realizó ultramicroscopía de una lesión de piel, donde pudieron verse inclusiones citoplasmáticas en células endoteliales, fibroblastos, células periteliales y perineurales. Bioquímicamente se comprobó la deficiencia enzimática en plasma de la * galactosidasa "A". Se realiza una revisión histórica y se consideran además los aspectos clínicos, histopatológicos, ultramicroscópicos y enzimáticos, como así los distintos diagnósticos diferenciales. También se dan algunas pautas terapéuticas novedosas y otras paliativas. Para finalizar, sugerimos el estudio genético de los familiares directos del paciente para detectar posibles futuros casos y poder brindarles consejo genético adecuado

Angioqueratoma corporis diffusum por deficiencia de Alfa Galactosidasa "A" / Angiokeratoma corporis diffusum due to alpha-galactosidase "A" defficiency

Se comunica el caso de un paciente de sexo masculino de 24 años de edad, que presenta angioqueratomas múltiples en todo el tegumento y mucosas, con afectación oftalmológica típica. Se realizó ultramicroscopía de una lesión de piel, donde pudieron verse inclusiones citoplasmáticas en células endoteliales, fibroblastos, células periteliales y perineurales. Bioquímicamente se comprobó la deficiencia enzimática en plasma de la * galactosidasa "A". Se realiza una revisión histórica y se consideran además los aspectos clínicos, histopatológicos, ultramicroscópicos y enzimáticos, como así los distintos diagnósticos diferenciales. También se dan algunas pautas terapéuticas novedosas y otras paliativas. Para finalizar, sugerimos el estudio genético de los familiares directos del paciente para detectar posibles futuros casos y poder brindarles consejo genético adecuado

Effect of the microbial lactase (EC 3.2.1.23) activity in yoghurt on the intestinal absorption of lactose: an in vivo study in lactase-deficient humans.

Breath hydrogen excretion was measured in eight lactase (EC 3.2.1.108)-deficient volunteers ingesting 18 g lactose in the form of milk, yoghurt and heated yoghurt. Total excess hydrogen excretion (area under curve) was significantly lower after yoghurt and heated yoghurt, than after milk: 103 (SE 29), 191 (SE 32), and 439 (SE 69) respectively (P less than 0.001). The oro-caecal transit time of fermentable components from yoghurt and heated yoghurt (mainly lactose) was longer than that from milk: 165 (SE 17), 206 (SE 19), v. 103 (SE 19) min (P less than 0.01). An intestinal perfusion technique was used in the same subjects after ingestion on two consecutive days of 18 g lactose in yoghurt and heated yoghurt. Significantly less lactose was recovered from the terminal ileum after yoghurt than after heated yoghurt meals: 1740 (SE 260) v. 2825 (SE 461) mg (P less than 0.05), and approximately one-fifth of the lactase activity contained in yoghurt reached the terminal ileum. These findings indicate that more than 90% of the lactose in yoghurt is digested in the small intestine of lactase-deficient subjects and suggest that both the lactase activity contained in the viable starter culture and a slow oro-caecal transit time are responsible for this excellent absorption.

Hypolactasia and Crohn's disease: a myth.

A retrospective analysis was made of jejunal biopsies performed on 62 patients with Crohn's disease for disaccharidase levels and routine histology. Thirteen patients with irritable bowel syndrome acted as a control group. Two patients with Crohn's disease had hypolactasia. Two patients had marginally low sucrase levels, but all patients had normal maltase levels. Only one patient with irritable bowel syndrome had hypolactasia with normal histology. There were no significant differences between the two groups. Four patients with Crohn's disease had abnormal jejunal histology. The prevalence of hypolactasia in patients with Crohn's disease is not increased. Ideally lactase deficiency in patients with Crohn's disease should be confirmed before starting a lactose-free diet which can produce further restrictions on dietary intake.

Abnormal glycosphingolipid metabolism in the nervous system of galactosialidosis.

In an autopsy case of galactosialidosis, GM3, GM2, GM1, and GD1a were accumulated in sympathetic and spinal ganglia and grey matter of the spinal cord. Especially, the accumulations of GM3 and GM2 amounted to 41- and 86-fold increases in sympathetic ganglia, respectively, as compared to normal controls. In addition LacCer, GA2 and GA1 were accumulated in sympathetic and spinal ganglia. The accumulations of GM3 and GD1a are considered to be the result of defective lysosomal sialidase activity and the accumulation of GM1, LacCer and GA1 is also considered to be due to decreased beta-galactosidase activity in this disorder. To better understand the possible mechanism of GM2 accumulation, we determined the activity of GM2 synthesizing enzyme (GM3:UDP-GalNAc transferase), as well as hexosaminidase activity, in sympathetic ganglia, but they did not change. Abnormal ganglioside and neutral glycosphingolipid metabolism, as well as sialyloligosaccharide and sialylglycoprotein metabolism, may be involved in the pathogenesis of this disorder.

The neurological complications of Anderson-Fabry disease (alpha-galactosidase A deficiency)--investigation of symptomatic and presymptomatic patients.

Anderson-Fabry disease is an X-linked inborn error of metabolism characterized by subnormal activity of the lysosomal hydrolase, alpha-galactosidase A. We have assessed the incidence and nature of neuropathy in 12 patients (seven affected men and five carrier females). Abnormalities of cutaneous thermal sensation were common, even in asymptomatic carriers, with a unique predilection for cold sensitivity which suggests involvement of small myelinated nerve fibres. Intracranial abnormalities were frequently detected by magnetic resonance imaging (MRI) in males, both with and without overt cerebrovascular disease, and were more extensive in older patients. Such abnormalities were not detected in carriers. Auditory and vestibular abnormalities were present in six patients, only one of whom was symptomatic. Cranial MRI and assessment of cutaneous thermal thresholds are sensitive techniques which can identify neurological involvement in asymptomatic patients. They may be of benefit in monitoring the effectiveness of enzyme replacement therapy and excluding the carrier state for the defective gene.

[Relation of the outcome of disk epiphysectomy in dysplastic scoliosis and the biochemical composition of the vertebral body]. / Zavisimost' iskhoda disképifizéktomii pri displasticheskom skolioze ot biokhimicheskogo sostava tela pozvonka.

Pronounced changes in the content of collagen, non-collagen proteins and the activity of a number of lysosomic enzymes have been established in the bone tissue of the vertebral bodies obtained on diskepiphysectomy in the patients with dysplastic scoliosis. Numerous correlation links between the metabolic parameters and the spinal deformation a year after diskepiphysectomy have been determined.

Interspecific genetic complementation analysis of human and sheep fibroblasts with beta-galactosidase deficiency.

Interspecific somatic cell hybrids were analyzed by genetic complementation to determine if a lysosomal storage disease in sheep associated with deficiencies of beta-galactosidase and alpha-neuraminidase was homologous with any of four beta-galactosidase-deficient human diseases. Fibroblasts from beta-galactosidase-deficient sheep, cats, and human patients were fused and assayed histochemically for beta-galactosidase, with 5-bromo-4-chloro-3-indolyl beta-D-galactoside. We observed complementation in heterokaryons consisting of fibroblasts from beta-galactosidase-deficient sheep and fibroblasts from patients with galactosialidosis or mucolipidosis type II, but no complementation in heterokaryons consisting of fibroblasts from beta-galactosidase-deficient sheep and fibroblasts from human or feline GM1 gangliosidosis (type I) or from human mucopolysaccharidosis type IVB fibroblasts. We conclude that the ovine disease is due to a mutation at the genetic locus homologous with that of GM1 gangliosidosis and mucopolysaccharidosis type IVB, suggesting that the primary defect in the ovine disease is a mutation of the beta-galactosidase structural gene.

Lectin histochemistry of an ovine lysosomal storage disease with deficiencies of beta-galactosidase and alpha-neuraminidase.

Lectin histochemistry is a useful technique to identify and to localize in cells and tissues the terminal carbohydrate moieties of glycoproteins and glycolipids. The specific diagnosis of some glycoprotein storage diseases was accomplished using lectin staining patterns, and such methods of diagnosis have been attempted for some glycolipid storage diseases. This technique was applied to formalin-fixed paraffin-embedded and frozen neural, hepatic, and renal tissues of sheep with an inherited lysosomal storage disease with deficiencies of beta-galactosidase and alpha-neuraminidase. The cytoplasm of central nervous system neurons of affected sheep in paraffin-embedded sections stained with peanut agglutinin (PNA), Ricinus communis agglutinin-I (RCA-I), Dolichos biflorus agglutinin (DBA), and soybean agglutinin (SBA). The cytoplasm of neurons in frozen sections of these tissues stained with PNA, RCA-I, wheat germ agglutinin (WGA), and Ulex europaeus agglutinin-I (UEA-I). The cytoplasm of frozen and paraffin-embedded sections of liver and kidney of affected sheep stained with PNA, whereas paraffin-embedded sections also stained with RCA-I. These results suggest the stored material in this disease has terminal saccharide moieties consisting of beta-galactose, N-acetylneuraminic acid, and N-acetylgalactosamine. Paraffin processing altered lectin staining patterns. Although the staining pattern in this glycolipid storage disease was complex, lectin histochemistry may prove to be a useful technique for the characterization of storage products and for the diagnosis of lysosomal storage diseases.

Calcium absorption from milk in lactase-deficient subjects.

Intestinal calcium absorption from milk containing lactose (+) and from another containing glucose (-) was studied in eight patients with normal lactase (NL) and seven lactase-deficient (LD) subjects to determine if lactase deficiency is implicated in Ca absorption. The results were compared with data obtained from Ca ingestion in a water solution. Ca absorption was measured by a double-isotope technique and the kinetic indices were obtained by a deconvolution method. With (-), Ca absorption was identical in NL and LD subjects and slightly higher than with water solution (15%, NS). With (+), Ca absorption in NL subjects was identical with that from water solution; in LD subjects it increased (23%, p less than 0.02). These data indicate that: Ca is absorbed equally well from milk as from water solution; (+) favors Ca absorption in LD subjects, which suggests that milk ingestion might be encouraged in LD subjects to avoid Ca deficiency; and (-) should be a valuable alternative for lactose-intolerant patients.