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1/11. Clinical course and biochemistry of sialuria.

    Sialuria is a rare inborn error of metabolism in which excessive free sialic acid (n-acetylneuraminic acid, NeuAc) is synthesized. A defect in the feedback inhibition of UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase by the end-product of the sialic acid synthetic pathway, CMP-NeuAc, is the mechanism underlying this overproduction. Recent evidence suggests that sialuria is an autosomal dominant disorder. Only five patients have been documented to have such an enzymatic defect. We report a longitudinal study of one of the original sialuria patients, to age 11 years. Although he has coarse features and massive hepatomegaly, he has shown normal growth and relatively normal development. Pulmonary function testing showed minimal small airway obstruction. At 11 years, he developed intermittent abdominal pain and transient transaminase elevation above his baseline. Sialuria should be considered in the differential diagnosis of a patient with a phenotype suggestive of a mucopolysaccharidosis or oligosaccharidosis in the absence of developmental regression or prominent dysostosis multiplex. We recommend close monitoring of liver and pulmonary function in sialuria patients. ( info)

2/11. Multiple neuroendocrine disorder in Salla disease.

    Salla disease represents the slowly progressive adult form of the sialic acid storage diseases, a group of autosomal-recessive neurodegenerative disorders in which psychomotor development, ataxia, axial hypotonia, and spasticity in the lower limbs occur. No skeletal dysostosis or organomegaly is present, and life expectancy is normal. Short stature can also be observed. Progressive cerebral and cerebellar atrophy associated with dysmyelination and corpus callosum hypoplasia have been shown by magnetic resonance imaging studies. We report the first patient with Salla disease in whom combined growth hormone and gonadotropin deficiencies, hypothalamic pituitary in origin, have been demonstrated by neuroendocrine studies. We believe that the multiple neuroendocrine disorder may be the consequence of the abnormalities of common neuronal pathways regulating growth hormone and gonadotropin synthesis or secretion related to the brain storage of free sialic acid and/or to the neurodegenerative process occurring in Salla disease. Therefore, a complete endocrinologic evaluation of these patients is both warranted and useful. ( info)

3/11. An Italian severe Salla disease variant associated with a SLC17A5 mutation earlier described in infantile sialic acid storage disease.

    The present study reports two Italian brothers affected by severe Salla disease (sialic acid storage disease), a slowly progressive autosomal recessive neurodegenerative disorder prevalent in the Finnish population. Mutations of the SLC17A5 gene, which encodes a protein called sialin, are the primary cause of both Salla disease and infantile sialic acid storage disease (ISSD), a clinically distinct severe disorder. All Finnish patients with Salla disease show a R39C mutation. Both patients showed moderate intellectual disability, spastic ataxic syndrome, hypomyelination and cerebellar atrophy on magnetic resonance imaging (MRI), and lysosomal storage, all typical of Salla disease. mutation analysis of the SLC17A5 gene in the younger brother revealed no R39C mutation, but a 15-bp deletion in exon 6 on one of the alleles. This mutation is the same described in French-Canadian patients with ISSD. Salla disease must be suspected in patients with unexplained psychomotor retardation associated with ataxia and/or pyramidal symptoms, and MRI findings consistent with cerebral hypomyelination, irrespective of the patient's ethnic origin. A mutation screening based on R39C change does not exclude Salla disease outside finland. Conversely, mutations found in ISSD can be expected, even in patients showing the Salla phenotype (e.g. symptoms at the milder end of the spectrum). ( info)

4/11. A case of Salla disease with involvement of the cerebellar white matter.

    Salla disease (SD) is a lysosomal disorder manifesting in infancy with hypotonia, nystagmus, ataxia and retarded motor development. MRI typically shows hypomyelination confined to the cerebral white matter. We describe a patient with two MRI studies in addition to repeated urine examinations. This case was problematic because the first urine examination did not show the elevation of free sialic acid typical of SD and MRI was also atypical, with abnormal signal intensity in cerebellar white matter. We recommend repeated urinary examinations and a search for SLC17A5 mutations in patients with cerebral signal intensity abnormalities typical of SD and emphasise that cerebellar white-matter involvement on MRI does not exclude the diagnosis. ( info)

5/11. sialic acid storage disease of the Salla phenotype in American monozygous twin female sibs.

    Salla disease, one of three disease phenotypes that manifest increased urinary excretion of unconjugated sialic acid, is an autosomal recessive condition caused by a mutation in SLC17A5. This gene encodes sialin, a lysosomal membrane transporter for sialic acid. Salla disease is rare outside of individuals of Finnish ancestry. In this report we describe the disorder in non-Finnish monozygous twin siblings, the first reported American cases of Salla disease. ( info)

6/11. Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children.

    The differential diagnosis of developmental delays and growth retardation in early childhood includes the allelic lysosomal sialic acid storage disorders, Salla disease and infantile free sialic acid storage disease (ISSD). These diseases, due to defective free sialic acid transport out of lysosomes, derive from mutations in the SLC17A5 gene coding for the protein sialin. We present two patients with clinical, biochemical, and molecular data indicative of lysosomal free sialic acid storage disorders. One patient, with a severe clinical course typical of ISSD, had 86-fold elevated levels of fibroblast free sialic acid, with 62% in the lysosomal fraction. His SLC17A5 mutations include a 148-bp deletion of exon 9, due to a G >A splice site mutation in position 1 of intron 9, and a 15-bp deletion (del 801-815) in exon 6. Another patient, with "intermediate severe" Salla disease, had 9-fold elevated levels of free sialic acid in cultured fibroblasts, of which 87% resided in the lysosomal fraction. This girl is compound heterozygous for the SLC17A5 mutation commonly found in Finnish Salla disease patients (R39C) and a 15-bp deletion found in ISSD patients (del 801-815). These observations emphasize the importance of considering free sialic acid disorders in infants with developmental delays and growth retardation, regardless of whether they are of Finnish ancestry. ( info)

7/11. 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. ( info)

8/11. 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. ( info)

9/11. A novel mutation in the SLC17A5 gene causing both severe and mild phenotypes of free sialic acid storage disease in one inbred Bedouin kindred.

    Four members of an extended consanguineous Bedouin family presented with different phenotypic variants of an autosomal recessive lysosomal free sialic acid storage disease. One affected individual had congenital ascites followed by rapid clinical deterioration and death, a presentation concordant with the clinical course of infantile free sialic acid storage disorder. His three first cousins had a more slowly progressive neurodegenerative disease, in line with the clinical phenotype of the milder form (Salla type) of this lysosomal disorder. diagnosis of free sialic acid storage disease was based on clinical findings, histology, and biochemical assays of sialic acid. Molecular studies showed that all four affected individuals were homozygous for the same novel 983G > A mutation in exon 8 of the SLC17A5 gene, replacing glycine with glutamic acid at position 328 of the sialin protein. This family demonstrates the significant phenotypic variability of the disease in affected members of a single inbred kindred with precisely the same mutation, suggesting a role for modifier genes or environmental factors. It also highlights the need to consider this rare disorder in the differential diagnosis of congenital ascites and of unexplained psychomotor retardation, ataxia, and hypomyelination in infancy. ( info)

10/11. Homozygosity for the p.K136E mutation in the SLC17A5 gene as cause of an Italian severe Salla disease.

    Lysosomal free sialic acid storage diseases are recessively inherited allelic neurodegenerative disorders that include Salla disease (SD) and infantile sialic acid storage disease (ISSD) caused by mutations in the SLC17A5 gene encoding for a lysosomal membrane protein, sialin, transporting sialic acid from lysosomes. The classical form of SD, enriched in the Finnish population, is related to the p.R39C designed Salla(FIN) founder mutation. A more severe phenotype is due both to compound heterozygosity for the p.R39C mutation and to different mutations. The p.R39C has not been reported in ISSD. We identified the first case of SD caused by the homozygosity for p.K136E (c.406A>G) mutation, showing a severe clinical picture, as demonstrated by the early age at onset, the degree of motor retardation, the occurrence of peripheral nerve involvement, as well as cerebral hypomyelination. Recently, in vitro functional studies have shown that the p.K136E mutant produces a mislocalization and a reduced activity of the intracellular sialin. We discuss the in vivo phenotypic consequence of the p.K136E in relation to the results obtained by the in vitro functional characterization of the p.K136E mutant. The severity of the clinical picture, in comparison with the classical SD, may be explained by the fact that the p.K136E mutation mislocalizes the protein to a greater degree than p.R39C. On the other hand, the presence of a residual transport activity may account for the absence of hepatosplenomegaly, dysostosis multiplex, and early lethality typical of ISSD and related to the abolished transport activity found in this latter form. ( info)
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