Home日本語

Congenital cerebral hypomyelination; network for Pelizaeus-Merzbacher disease and related disorders

  • Inherited white matter disorders
  • Congenital cerebral hypomyelination

MENU

Guidelines on Hereditary Leukodystrophies

Salla disease (SD; OMIM #604369)

Disease description: Salla disease (SD) is a rare autosomal recessive lysosome storage disease caused by a mutation in the SLC17A5 gene encoding sialin. The general term "free sialic acid storage disease" encompasses infantile sialic acid storage disease, a clinically severe form, and SD, a mild form. Brainstem motor ataxia, hypotonia, and nystagmus appear during infancy and delayed psychomotor development and growth retardation become obvious. Spasticity and athetosis, motor ataxia, and hypomyelination subsequently become evident into adulthood.

1. Overview

Definition

Free sialic acid storage diseases are neurodegenerative autosomal recessive inherited diseases caused by a SLC17A5 mutation, which results in the intralysosomal accumulation of free sialic acid. The general term "free sialic acid storage disease" encompasses infantile sialic acid storage disease (ISSD; OMIM #269920), a clinically severe form; Salla disease (SD), a mild form; and intermediate severe SD, a clinically intermediate form (1,2).

Epidemiology

Patients with SD are concentrated in northern Europe, primarily Finland but also Sweden, Denmark, and elsewhere. Approximately 200 cases have been reported to date, including 23 of intermediate severe SD (3). In Finland, >90% of patients have a p.Arg39Cys mutation of SLC17A5, and the frequency of carriers is 1 in every 100–200 people (4). Although it is rare in Japan, one case of ISSD and one of SD have been reported to date (5, 6).

Etiology and pathophysiology

Free sialic acid (N-acetylneuraminic acid), produced in lysosomes by the decomposition of glycoproteins or glycolipids by sialidase, is normally transported outside lysosomes by the lysosome membrane transporter protein sialin. In SD and other free sialic acid storage diseases, a mutation in the SLC17A5 gene encoding sialin impairs its function transporting free sialic acid away from lysosomes, causing the intralysosomal accumulation of sialic acid. It is unclear how the accumulation of free sialic acid impairs cellular function (1, 7).

Clinical symptoms

SD is asymptomatic at birth, but trunk ataxia and hypotonia typically become noticeable during infancy. Developmental delay and growth retardation are seen from early childhood, and although around one-third of patients become able to walk independently, motor ataxia, spasticity, athetosis, and cognitive and motor functional regressions gradually progress during adulthood. Epilepsy may also be present, particularly absence seizures. The symptoms of ISSD include severe developmental delay, coarse facial features, hepatosplenomegaly, skeletal deformity, and spasticity, whereas coarse facial features, hepatosplenomegaly, and skeletal deformity are not usually seen in SD (1, 3).

Imaging and other investigations

As the accumulation of intralysosomal free sialic acid (N-acethylneuraminic acid; NANA) increases its excretion in the urine (often to over 100 times its normal level), the urinary free sialic acid measurement is helpful for diagnosis (8). In many cases, free sialic acid is also elevated in the cerebrospinal fluid, and the localized intralysosomal accumulation of free sialic acid can be confirmed in cultured fibroblasts. Cranial magnetic resonance imaging may not reveal any abnormalities in patients with SD, but widespread hyperintensity of the white matter on T2-weighted imaging (hypomyelinating pattern) suggestive of cerebral dysmyelination is evident along with hypoplasia of the corpus callosum and cerebellar atrophy. N-acetylaspartate is high on magnetic resonance spectroscopy, and this finding is useful for diagnosis (1, 9).

Genetic diagnosis

If SD is suspected on the basis of increased free sialic acid in urine, cerebrospinal fluid, and fibroblasts, the diagnosis can be confirmed by identifying a pathogenic mutation of SLC17A5, the causative gene. In terms of the correlation between genotype and phenotype, patients who are homozygous for the founder mutation p.Arg39Cys reportedly develop SD, the mild form of free sialic acid storage disease (1, 10).

2. Treatment and care

SD is mainly treated with symptomatic therapy. This includes rehabilitation to maintain motor and communication abilities, appropriate nutritional management, and anti-epileptic drug treatment to control seizures.

3. Prognosis

SD gradually progresses even after patients have reached adulthood, and many end up unable to walk or become bedridden. Although the disease is believed to curtail the lifespan, a patient who lived to age 70 was reported. Patients with ISSD exhibit fetal hydrops, hepatosplenomegaly, underdevelopment, coarse facial features, seizures, and skeletal deformities, usually dying in early childhood.

4. Differential diagnosis

Patients with elevated urinary sialic acid levels may also suffer from sialuria, sialidosis, or galactosialidosis. Sialuria is caused by the accumulation of free sialic acid in the cytoplasm rather than in lysosomes. Like ISSD, it causes coarse facial features and hepatosplenomegaly, but it does not cause skeletal deformity or severe developmental delay (11). Sialidosis is caused by the absence of sialidase and galactosialidosis by the absence of β-galactosidase. This causes an increase in the level of conjugated sialic acid bound to glycoproteins and glycolipids and a mild elevation in urinary sialic acid. Both can be differentiated by measuring of the respective enzyme activities (12).

5. Recent topics

Genetic counseling, prenatal diagnosis

Because SD is an autosomal recessive inherited disease, if both parents are carriers, their next child has a 25% chance of inheriting the disease, a 50% chance of being a carrier, and a 25% chance of being unaffected. The prenatal diagnosis can be performed by measuring free sialic acid levels in amniotic cells or chorionic biopsy samples, or the preimplantation diagnosis may be used if the causative SLC17A5 mutation has been identified (1).

References

(Unless otherwise noted at the end, all are evidence level 6.)

  1. Adams D, Gahl WA. Free sialic acid storage disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA): University of Washington, Seattle; 1993-2017.
  2. Schleutker J, Leppänen P, Månsson JE, Erikson A, Weissenbach J, Peltonen L, et al. Lysosomal free sialic acid storage disorders with different phenotypic presentations--infantile-form sialic acid storage disease and Salla disease--represent allelic disorders on 6q14-15. Am J Hum Genet 1995; 57(4): 893-901.
  3. Barmherzig R, Bullivant G, Cordeiro D, Sinasac DS, Blaser S, Mercimek-Mahmutoglu S. A new patient with intermediate severe Salla disease with hypomyelination: a literature review for Salla disease. Pediatr Neurol 2017; 74: 87-91.
  4. Aula N, Salomäki P, Timonen R, Verheijen F, Mancini G, Månsson JE, et al. The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. Am J Hum Genet 2000; 67(4): 832-840.
  5. Nakano C, Hirabayashi Y, Ohno K, Yano T, Mito T, Sakurai M. A Japanese case of infantile sialic acid storage disease. Brain Dev 1996; 18(2): 153-156.
  6. Ishiwari K, Kotani M, Suzuki M, Pumbo E, Suzuki A, Kobayashi T, et al. Clinical, biochemical, and cytochemical studies on a Japanese Salla disease case associated with a renal disorder. J Hum Genet 2004; 49(12): 656-663.
  7. Havelaar AC, Mancini GM, Beerens CE, Souren RM, Verheijen FW. Purification of the lysosomal sialic acid transporter. Functional characteristics of a monocarboxylate transporter. J Biol Chem 1998; 273(51): 34568-34574.
  8. Valianpour F, Abeling NG, Duran M, Huijmans JG, Kulik W. Quantification of free sialic acid in urine by HPLC-electrospray tandem mass spectrometry: a tool for the diagnosis of sialic acid storage disease. Clin Chem 2004; 50(2): 403-409.
  9. Varho T, Komu M, Sonninen P, Holopainen I, Nyman S, Manner T, et al. A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla disease. Neurology 1999; 52(8): 1668-1672.
  10. Tarailo-Graovac M, Drögemöller BI, Wasserman WW, Ross CJ, van den Ouweland AM, Darin N, et al. Identification of a large intronic transposal insertion in SLC17A5 causing sialic acid storage disease. Orphanet J Rare Dis 2017; 12(1): 28.
  11. Enns GM, Seppala R, Musci TJ, Weisiger K, Ferrell LD, Wenger DA, et al. Clinical course and biochemistry of sialuria. J Inherit Metab Dis 2001; 24(3): 328-336.
  12. Gahl WA, Krasnewich DM, Williams JC. Sialidoses. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Vol 66, chapter 18. Amsterdam, Netherlands: Elsevier; 1996: 353-375.
Literature search

PubMed

  • "Salla disease"[MeSH Terms] OR ("Salla "[All Fields] AND "disease"[All Fields])
    279 results

Igaku Chūō Zasshi

  • "Salla病/AL " 
    22 results