Excretion Of Free Sialic Acid Research Articles

A cross-sectional quantitative analysis of the natural history of free sialic acid storage disease—an ultra-orphan multisystemic lysosomal storage disorder

PurposeQuantitative definition of the natural history of free sialic acid storage disease (SASD, OMIM 604369), an orphan disorder due to the deficiency of the proton-driven carrier SLC17A5. MethodsAnalysis of published cases with SASD (N = 116) respecting STROBE criteria. Main outcome parameters: survival and diagnostic delay. Phenotype, phenotype–biomarker associations, and geographical patient distribution were explored. ResultsMedian age at disease onset was 0.17 years. Median age at diagnosis was 3 years with a median diagnostic delay of 2.5 years. Median survival was 11 years. The biochemical phenotype clearly predicted the disease course: patients with a urinary free sialic acid excretion below 6.37-fold or an intracellular free sialic acid storage in fibroblasts below 7.37-fold of the mean of normal survived longer than patients with biochemical values above these thresholds. Cluster analysis of disease features suggested a continuous phenotypic spectrum. Patient distribution was panethnic. ConclusionCombination of neurologic symptoms, visceromegaly, and dysmorphic features and/or nonimmune hydrops fetalis should prompt specific tests for SASD, reducing diagnostic delay. The present quantitative data inform clinical studies and may stimulate and accelerate development of specific therapies. Biomarker–phenotype association is particularly important for both counseling parents and study design.

Clinical, biochemical, and cytochemical studies on a Japanese Salla disease case associated with a renal disorder

We report the first Japanese case of Salla disease. A 5-year-old male patient developed unique proteinuria with other clinical manifestations, including coarse facies, dysostosis multiplex, mild mitral valve regurgitation, umbilical and inguinal herniation, and mild developmental delay. Pathological analysis of biopsied kidney tissues showed marked vacuolation of podocytes, mesangial cells, capillary endothelial cells, and tubular cells. Biochemical studies involving thin-layer chromatography and mass spectrometry revealed increased excretion of free sialic acid (N-acetylneuraminic acid) into the patient's urine. Immuno- and lectin staining of the patient's cells demonstrated the accumulation of sialyl and asialyl glycoconjugates in lysosomes and late endosomes. A defect in sialyl glycoconjugate metabolism is thought to have occurred in the patient's cells, besides impairment of the lysosomal transport of free sialic acid residues. A renal disorder should be considered as an important manifestation, not only in infantile free sialic acid storage disease but also in Salla disease.

Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity

The allelic autosomal recessive lysosomal storage disorders Salla disease and infantile free sialic acid storage disease (ISSD) result from mutations in SLC17A5. This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes. ISSD has a severe phenotype with infantile onset, while the Finnish variant, Salla disease, has a milder phenotype with later onset. Both disorders cause developmental delay, and ISSD is generally fatal in early childhood. We describe a 30-month old non-Finnish, Caucasian child with global developmental delay of postnatal onset, language, and motor skills stagnant at a 3–4 month level, hypotonia, and mild but progressive coarsening of facial features. Urinary excretion of free sialic acid was elevated 4.5 times above control. EM of a skin biopsy revealed enlarged secondary lysosomes consistent with oligosaccharide storage. Free sialic acid in fibroblasts was 3.8 ± 0.9 nmol/mg protein (concurrent normal controls, 0.5 ± 0.1); differential centrifugation indicated a lysosomal location. Genomic analysis revealed compound heterozygosity for two new SLC17A5 mutations. This child’s clinical manifestations of a lysosomal free sialic acid storage disease are consistent with her sialin mutations and biochemical findings. The differential diagnosis of postnatal developmental delay should include free sialic acid storage disorders such as ISSD and Salla disease.

Infantile sialic acid storage disease and protein-losing gastroenteropathy

We report on a boy who presented at birth with gastroschisis and thereafter developed the characteristic clinical symptoms of infantile sialic acid storage disease within the first two months of life. Measurements of free sialic acid excretion (tenfold increase) in the urine and a 15-fold elevation of free sialic acid in cultured fibroblasts proved the diagnosis. The clinical course was complicated by hypertrophic cardiomyopathy, recurrent infections, hypothyroidism, and intestinal protein losses, which had never been described before in an infantile sialic acid storage disease patient. The child died at the age of 10 months. Clinical and laboratory findings are discussed and compared with other cases described in the literature.

Magnesium may help patients with recessive hereditary inclusion body myopathy, a pathological review

Recently, bi-allelic mutations in the gene coding for the bi-functional enzyme UDP- N-acetylglucosamine 2-epimerase/ N-acetylmannosamine kinase (GNE/MNK), symbol GNE or GLCNE (MIM: 603824), were associated with the recessively inherited phenotype of IBM2 (MIM: 600737). All patients tested so far have bi-allelic missense mutation(s) of epimerase and/or kinase domains of GNE gene, which clearly explains the recessive inheritance pattern of this phenotype. Single allelic mutations of codons 263–266 of GNE have been implicated as the cause of French type sialuria (MIM: 269921). The dominantly inherited French type sialuria seems to result from defective allosteric feedback inhibitory regulation of GNE/MNK by cytidine monophosphate– N-acetylneuraminic acid (CMP-NANA), resulting in overproduction of cytosolic N-acetylneuraminic acid, and massive urinary excretion of free sialic acid. Because GNE is relatively weakly expressed in skeletal muscle cells, and involvement of other organs are not clinically evident in patients affected with IBM2, it is likely that the missense mutation(s) found in these patients cause a partial reduction of the efficiency of either the epimerase or the kinase activity of this enzyme. Therapeutic dietary modifications are recommended including reduction of ethanol consumption, avoidance of excess selenium, copper, and zinc, and dietary promotion of magnesium (Mg 2+), which is an essential co-factor for this enzyme.

Proton Nuclear Magnetic Resonance Spectroscopic Detection of Sialic Acid Storage Disease

Sialic acid storage disease (SASD) is a rare autosomal recessive lysosomal storage disorder characterized by excessive urinary excretion of free sialic acid and an accumulation of free sialic acid in skin fibroblasts (1). Clinically, two major forms exist: an infantile type with severe progression leading to early death (2), and a milder form (Salla disease) with a protracted course (3). The basic defect in both forms is a malfunction of a sialic acid transporter in the lysosomal membrane (4). Because the clinical characteristics of SASD are very similar to those of other lysosomal storage diseases, differential diagnosis relies on detection of increased urinary sialic acid excretion by thin-layer chromatography of urine (5) and quantification by colorimetric analysis (6) or ion-exchange HPLC (7). However, each method has disadvantages. Colorimetric assays suffer from interference by 2-deoxyglucose, whereas HPLC methods require lengthy sample preparation. Proton nuclear magnetic resonance (1H-NMR) spectroscopy is a powerful tool for the structural elucidation and characterization of body fluid metabolites in inherited metabolic disorders (8)(9)(10)(11). The technique is rapid, requiring minimal sample treatment. Sialic acid (free and as a conjugate) has been extracted from the urine of individuals with SASD and sialidoses, respectively, and characterized by 1H-NMR spectroscopy (12)(13)(14); however, the technique has not been used for direct diagnosis from unextracted urine. We carried out 1H-NMR analysis of urine from five patients with SASD (two with the infantile form, one with the intermediate form, and two patients with Salla disease) and compared the urinary sialic acid excretion determined by colorimetric analysis and 1H-NMR spectroscopy. Urine samples from patients with SASD were obtained as part of a selective screening program for inborn errors of metabolism. Clinical and diagnostic data on three patients have been described …

Molecular Pathology, Abstract 169–176, Posters

We report on a boy who presented at birth with gastroschisis and thereafter developed the characteristic clinical symptoms of infantile sialic acid storage disease within the first two months of life. Measurements of free sialic acid excretion (tenfold increase) in the urine and a 15-fold elevation of free sialic acid in cultured fibroblasts proved the diagnosis. The clinical course was complicated by hypertrophic cardiomyopathy, recurrent infections, hypothyroidism, and intestinal protein losses, which had never been described before in an infantile sialic acid storage disease patient. The child died at the age of 10 months. Clinical and laboratory findings are discussed and compared with other cases described in the literature.

Age-related reference values for urinary excretion of sialic acid and deoxysialic acid: application to diagnosis of storage disorders of free sialic acid

We have established by HPLC age-related reference intervals for sialic acid urinary excretion in 364 control individuals to assist in evaluating the clinical significance of the free sialic acid concentration in urine. In addition, an HPLC method for quantitative analysis of free deoxysialic acid was developed, and age-related reference intervals for excretion of this compound in urine were established. In patients with storage disorders of free sialic acid (n = 11) the sialic acid excretion was increased 2- to 35-fold, compared with the mean value of the control subjects in the corresponding age group, and exceeded the interval in each case. The excretion of deoxysialic acid was within the reference interval in all of the patients, indicating that its metabolism was not affected in the disorders. The age-related reference values assist in evaluating the excretion of free sialic acid in the diagnosis of storage disorders of free sialic acid, especially in young children.

Phenotypic variation and magnetic resonance imaging (MRI) in Salla disease, a free sialic acid storage disorder.

Salla disease (SD) is a recessively inherited lysosomal storage disorder particularly common in the Finnish population. Patients with SD are normal at birth, but develop psychomotor delay and ataxia during the first year of life. Phenotypic variation of SD is wide, ranging from severely disabled children to mentally retarded adults capable of living under sheltered conditions. In the present study four unusually severely affected patients were investigated by detailed clinical examination, magnetic resonance imaging (MRI) and analysis of the excretion of free sialic acid in urine. MRI study, reported here for the first time, revealed a similarly defective myelination pattern in seven patients. The myelination process seemed to cessate at the level of an infant of a few months of age. Genetic linkage study of the families of the severely affected patients suggested linkage to the recently discovered SD locus on the long arm of chromosome 6. Locus heterogeneity therefore is an unlikely explanation of the phenotypic variation in SD.

Infantile free sialuria without lysosomal storage

Except for two reported patients, increased free sialic acid excretion has been associated with lysosomal storage. This is a report of a child with progessive neurologic deterioration and increased excretion of free sialic acid. Although lysosomal storage was absent, nuclear invagination or inclusions were present.

Sialuria: a second case

AbstractA case of sialuria is described in a girl who presented in the neonatal period with hepatosplenomegaly, and who has moderate developmental delay at the age of 2 years. There was massive urinary excretion of free sialic acid (N‐acetylneuraminic acid). The clinical, biochemical and ultramicroscopical features were distinct from those described in Salla disease and in infantile sialic acid storage disorder.

Familial Lysosomal Storage Disease with Generalized Vacuolization and Sialic Aciduria. Sporadic Salla Disease

Two eight- and sixteen-year-old children with severe progressive neurologic disease revealed an ultrastructural finding of lysosomal vacuolization in mesenchymal or parenchymal cells of different organ biopsies (skin, muscle, nerve and liver), which may be very suggestive of mucolipidosis. However, in our patients biochemical tests available for these diseases yielded negative results, except for increased excretion of free sialic acid in urine and sialic acid storage in cultured fibroblasts. The clinical picture and the ultrastructural and biochemical findings were compatible with Salla disease, a rare lysosomal storage disease originally observed in Finland.

Salla disease: a new lysosomal storage disorder with disturbed sialic acid metabolism.

Salla disease is a lysosomal storage disorder associated with increased urinary excretion of free sialic acid. The main clinical features in 34 patients were severe psychomotor retardation of early onset, ataxia, athetosis, rigidity, spasticity, and impaired speech. Growth retardation, thick calvarium, and exotropia were present in about half the patients. The amplitude of EEG decreased progressively with increasing age. Life span appears to be normal; the age range of the patients was 3 to 63 years. Genealogic studies suggest an autosomal mode of inheritance. A thin-layer method is described for the detection of increased urinary free sialic acid excretion. The basic defect is so far unknown.