Disease relevance of Sialic Acid Storage Disease

• Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease) [1].
• The pivotal function of lysosomal membrane proteins is also highlighted by the recent identification of disease-causing mutations in cystine and sialic acid transporter proteins, leading to nephropathic cystinosis and Salla disease [2].
• Nephrosis in two siblings with infantile sialic acid storage disease [3].
• Mutations associated with sialuria are located in the epimerase domain, and those associated with IBM2 are in the epimerase or the kinase domain or both, whereas the mutations we observed in the Nonaka myopathy patients were located in the sugar kinase domain of the gene [4].
• Severe emphysema is reported in a patient with Salla disease, a recessively inherited disorder of sialic acid metabolism that leads to intralysosomal accumulation of free sialic acid in cells of various tissues [5].

Psychiatry related information on Sialic Acid Storage Disease

• OBJECTIVE: To evaluate the degree of possible peripheral nervous system (PNS) involvement in addition to CNS manifestations in Salla disease, a free sialic acid storage disorder leading to severe mental retardation with a wide clinical variation [6].

High impact information on Sialic Acid Storage Disease

• We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins [1].
• Fibroblast granular fractions of patients with Salla disease exhibited negligible egress of sialic acid, whether endogenous or derived from N-acetylmannosamine exposure [7].
• Studies on the defect underlying the lysosomal storage of sialic acid in Salla disease. Lysosomal accumulation of sialic acid formed from N-acetyl-mannosamine or derived from low density lipoprotein in cultured mutant fibroblasts [8].
• "French type" sialuria, a presumably dominant disorder that, until now, had been documented in only five patients, manifests with mildly coarse facies, slight motor delay, and urinary excretion of large quantities (>1 g/d) of free N-acetylneuraminic acid (NeuAc) [9].
• We report the cloning and characterization of human UDP-GlcNAc 2-epimerase cDNA, with mutation analysis of three patients with sialuria [10].

Chemical compound and disease context of Sialic Acid Storage Disease

• Since neurological symptoms predominate in Salla disease, our results suggest that sialin is rate-limiting to specific sialic acid-dependent processes of the nervous system [11].
• Sialuria is a rare inborn error of metabolism characterized by cytoplasmic accumulation and increased urinary excretion of free N-acetylneuraminic acid (NeuAc, sialic acid) [10].
• Cytidine feeding (5 mM, 72 h) reduced the NeuAc content of sialuria cells, initially 112, 104, and 266 nmol/mg protein, by 63-71 nmol/mg protein; CMP-NeuAc concentrations, initially 4, 2, and 5 nmol/mg protein, increased by 14-33 nmol/mg protein [12].
• Feeding sialuria cells up to 5 mM D-glucosamine for 72 h increased free sialic acid content 20-60%, but normal cells were unaffected by this treatment [12].
• With this technique, the basic defect in sialuria has been identified unequivocally as the loss of feedback control of uridine diphosphate N-acetylglucosamine 2-epimerase by cytidine monophosphate N-acetylneuraminic acid with resultant overproduction of sialic acid [13].

Biological context of Sialic Acid Storage Disease

• Interestingly, while two missense mutations and one small, in-frame deletion associated with ISSD abolished transport, the mutation causing Salla disease (R39C) slowed down, but did not stop, the transport cycle, thus explaining why the latter disorder is less severe [11].
• The approach was applied to the sialic acid metabolic pathway in human cells, yielding novel mutants with phenotypes related to the inborn metabolic defect sialuria and metastatic tumor cells [14].
• This represents the first successful prenatal identification of a patient with Salla disease and indicates that both free sialic acid and free/total sialic acid ratio should be monitored in pregnancies at risk for the disease [15].

Anatomical context of Sialic Acid Storage Disease

• Sialic acids cleaved off from degraded sialoglycoconjugates are exported from lysosomes by a membrane transporter, named sialin, which is defective in two allelic inherited diseases: infantile sialic acid storage disease (ISSD) and Salla disease [11].
• While phase microscopy and immunochemical studies demonstrated abnormal storage within intracellular inclusions in ISSD cells, no morphological evidence of storage within any subcellular organelles was found in the sialuria cells [16].
• The body fluids of a patient with sialuria contain the same O-acylated and unsaturated N-acetyl neuraminic acid derivatives as mentioned above, but the total amounts of free acylneuraminic acids in these materials are significantly higher than found for normal persons [17].
• The method has been applied to normal and pathological sera from patients with breast, stomach, colon, ovarian and cervix cancers, to normal urine and urine from patient with sialuria and to normal saliva [18].

Gene context of Sialic Acid Storage Disease

• However, in Salla disease the high NA signal may have a contribution from accumulated lysosomal NANA, which offsets the possible loss of NAA [19].
• Report on two patients with Costello syndrome and sialuria [20].
• Nakano et al. have recently reported a Japanese case of infantile sialic acid storage disease [C. Nakano, Y. Hirabayashi, K. Ohno, T. Yano, T. Mito, M. Sakurai, Brain Dev., 18 (1996) 153-156] [21].
• Single allelic mutations of codons 263-266 of GNE have been implicated as the cause of French type sialuria (MIM: 269921) [22].

Analytical, diagnostic and therapeutic context of Sialic Acid Storage Disease

• Prenatal diagnosis and confirmation of infantile sialic acid storage disease [23].
• Amniocentesis was performed in a pregnancy at risk for infantile sialic acid storage disease [23].

References