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Chapter 200S

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Important new data on free sialic acid storage diseases have emerged in the past few years. A number of new cases, illustrating both phenotypic variability and new mutations of the SLC17A5 (formerly AST) gene, have allowed a genotype-phenotype correlation to be drawn. Expression studies of the gene product, sialin, in somatic and neuronal cells have shed new light on the molecular mechanisms leading to central nervous system (CNS) manifestations of the disease. Recent work on an animal model for sialic acid storage disease, a sialin-deficient mouse, has revealed possible pathogenetic mechanisms behind free sialic acid storage diseases. In sialin-deficient animals, defective maturation of oligodendrocytic cells leads to apoptotic cell death and consequent decrease in myelin production in the CNS.

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Clinical Findings

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Number of Patients

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During recent years the number of new cases of Salla disease (SD) in Finland, where the highest gene frequency occurs, has decreased, probably due to outbreeding of the isolated subpopulation in the northeastern corner of the country. The possibility for prenatal diagnosis is also likely to contribute to the lower number of new cases. Ten years ago the adult type of free sialic acid storage disease, Salla disease, had been diagnosed in 108 patients from Finland,1 27 cases from Sweden,9 two siblings from Denmark,5 seven cases from central Europe,4,6,8,11,17,21,23 and twin sisters from North America.18 A minority of these cases presented with a phenotype more severe than that of the conventional Finnish Salla phenotype and are referred to as “intermediate”.13 The most severe end of the phenotypic continuum associated with free sialic acid storage in lysosomes, infantile sialic acid storage disease (ISSD), is less common and has no ethnic predilection. Recently 30 ISSD cases were reviewed,15 and a few additional patients have been reported since that review.12,13,24,25

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Developmental Pattern in Salla Disease
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A study of 41 Finnish patients, including four severely affected patients who were compound heterozygous for sialin mutations, described the neurocognitive development of SD in detail.27 All patients were severely intellectually disabled except a boy who at 11 months had a mental developmental age of 10 months (Bayley scale). Later, however, his development was clearly delayed. An age-related correlation of both mental and motor development was recorded using Bayley scales. Mental development was superior to motor skills until the second decade, but in later age groups the difference was no longer present.Fig. 200S-1 Both motor and mental developmental ages of four compound heterozygous patients were significantly lower than those of patients homozygous for the R39C SD mutation. Characteristic of the cognitive profile in SD is better verbal ability compared to nonverbal functioning. Spatial and visuoconstructive skills were particularly poorly developed, whereas visual perception and immediate visual memory scores were somewhat ...

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