Salla Disease and Free Sialic Acid Storage Disorders

SLC17A5-related free sialic acid storage disorder (FSASD): Salla disease, the intermediate form and the infantile form (ISSD), together with the other free sialic acid disorders

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

Free sialic acid storage disorder (FSASD) is an autosomal recessive lysosomal disease caused by biallelic variants in the SLC17A5 gene, which encodes sialin, the transporter that exports free sialic acid from the lysosome to the cytosol [1, 2]. The historical designations Salla disease, intermediate severe Salla disease and infantile free sialic acid storage disease (ISSD) correspond to points on a continuous spectrum of severity [1–3]. The following table identifies each entity in the class and the disorders with which it shares the biochemical marker (raised free sialic acid) or the name (sialidosis, with bound sialic acid).

1. Introduction

1.1 Original description and historical milestones

Salla disease was delineated in Finland at the end of the 1970s, from patients in Finnish Lapland, and was named after the municipality of Salla, where most of the first families lived and where the founder variant is relatively frequent [1, 2]. Secondary sources differ on the year of the first report, which Huizing and colleagues place in 1978 and Zielonka and colleagues in 1979 [2, 3]. In the 1979 description by Aula and colleagues, four adults from two related sibships in north-eastern Finland (with a further 27 possible cases in ten sibships) had intellectual disability, onset at 12–18 months, deterioration in the second decade, 4–15% vacuolated lymphocytes and increased urinary excretion of sialic acid; the disease was detected during screening for aspartylglucosaminuria based on the search for cytoplasmic vacuoles [6]. The reference clinical series was published by Renlund and colleagues in 1983, with 34 Finnish patients aged 3 to 63 years: severe psychomotor delay of early onset, ataxia, athetosis, rigidity, spasticity and impaired speech, with growth retardation, thickened calvaria and exotropia in about half, electroencephalogram (EEG) amplitude decreasing with age, apparently normal life expectancy and increased urinary excretion of free sialic acid, detected by thin-layer chromatography [27]. The severe infantile form was described in 1982 by Tondeur and colleagues in two siblings born to Yugoslav parents, with coarse facies, hepatosplenomegaly, fair skin and severe psychomotor delay, and in the same year by Hancock and colleagues in an infant who died at 5 months with urinary excretion far higher than in Salla disease [2, 3, 7]. French-type sialuria, with massive excretion of free sialic acid, had been described in 1968 [22].

In 1986, Renlund, Tietze and Gahl showed that lysosome-rich fractions from fibroblasts of patients with Salla disease virtually failed to release free sialic acid, whether endogenous or generated from N-acetylmannosamine, which made Salla disease the first human disease attributed to a defect in the transport of a monosaccharide out of the lysosome [28]. Mancini and colleagues demonstrated in 1991 a single proton-coupled lysosomal transporter for acidic monosaccharides (sialic acid and glucuronic acid), defective in the various clinical forms and with transport velocity reduced to about half in obligate heterozygotes, the first human defect of lysosomal transport of several physiological compounds [1, 4, 29]. Linkage studies in Finnish families placed the locus on the long arm of chromosome 6 (Haataja and colleagues, 1994), in a region of about 200 kb; Schleutker and colleagues showed in 1995, in 50 Finnish and 26 non-Finnish families, that Salla disease, the intermediate forms and ISSD were linked to the same locus, with a common ancestral haplotype on Finnish chromosomes, a different haplotype in ISSD and the Finnish haplotype on only one chromosome in the intermediate forms [6, 7]; in 1999, Verheijen and colleagues identified the SLC17A5 gene (then also called AST), which encodes a transporter of the anion/cation symporter family that they named sialin, and found the R39C variant in the homozygous state in five Finnish patients with Salla disease and six different variants in six patients with ISSD of various origins [29]. The following year, Aula and colleagues described the exon-intron boundaries of the gene and showed that all 80 Finnish patients studied carried R39C, 91% in the homozygous state, and that compound heterozygosity with another variant was accompanied by a more severe phenotype [30].

1.2 Nomenclature and reclassification

For decades the literature used several designations for the same disease: Salla disease, Finnish-type sialuria (to distinguish it from French-type sialuria, which is not lysosomal), sialic acid storage disease (SASD), intermediate severe Salla disease and ISSD [2, 31]. The term «Salla» came to designate any mild form, regardless of the variant or geographical origin [1, 2]. In 2021, the international consortium of researchers on the disease (FSASD Consortium) proposed the single designation «free sialic acid storage disorder» (FSASD) for the whole spectrum, arguing that the multiplicity of names confused clinicians, laboratories, databases and the pharmaceutical industry and hindered both prevalence estimation and therapeutic research [2]. GeneReviews adopted this terminology in its 2025 update, keeping the historical names as descriptors of the less severe, intermediate and severe forms [1], and Orphanet treats the disease as a single entity (ORPHA:834) with three clinical subtypes [8]. A quantitative analysis of 116 published cases found no clinically separable subtypes: the three statistical clusters shared the same manifestations, which supports the notion of a continuous spectrum [3].

1.3 Definition of the entities in this article

The less severe form (Salla disease, OMIM 604369) is characterised by normal appearance and neurological examination at birth, hypotonia and ataxia in the first year, mild to moderate psychomotor delay and slow progression over decades, with survival into adulthood [1, 14]. The intermediate form, proposed by Aula and colleagues in 2000, has onset in the first six months, severe global delay and neurological regression in adolescence, and is associated with compound heterozygosity for p.(Arg39Cys) with another variant or with homozygosity for p.(Lys136Glu) [1, 15]. The severe form (ISSD, OMIM 269920) presents in the prenatal or neonatal period, often with fetal ascites or non-immune hydrops, visceromegaly, cardiomegaly, dysostosis and nephrotic syndrome, and usually leads to death in early childhood [1, 17].

The class of free sialic acid disorders also includes two cytoplasmic diseases, in which the excess free sialic acid is not inside the lysosome: French-type sialuria (GNE, autosomal dominant; biallelic loss of function of the same gene causes GNE myopathy) and N-acetylneuraminate pyruvate lyase deficiency (NPL) [1, 2]. The sialidoses (neuraminidase deficiency, NEU1) and galactosialidosis (CTSA) store sialic acid bound to glycoproteins and oligosaccharides, not free sialic acid [1, 31]; sialidosis is treated here as a differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1 The SLC17A5 gene and sialin

SLC17A5 lies at 6q13, has 11 exons, and the main transcript (NM_012434) encodes a protein of 495 amino acids and about 54 kDa (NP_036566); eight additional splice variants are listed in databases, with no established biological relevance [2, 32]. The MANE Select transcript is NM_012434.5, and the variants in this article are described on it [5]. Sialin is a proton-coupled protein with 12 transmembrane domains that exports N-acetylneuraminic acid (Neu5Ac) and other acidic hexoses, such as glucuronic acid, from the lysosomal lumen to the cytosol [2, 33]. The newly synthesised protein passes through the plasma membrane and is internalised into the endolysosomal compartment through an N-terminal dileucine motif (DRTPLL) [2]. Beyond its lysosomal function, sialin transports glutamate, aspartate and N-acetylaspartylglutamate (NAAG) into synaptic vesicles by a membrane potential-dependent mechanism, and transports nitrate in the acinar cells of the salivary glands [2, 33]. The cryo-electron microscopy structures of human sialin published in 2024 showed cytosol-open and lumen-open conformations, a positively charged cytosolic vestibule that accommodates NAAG or the inhibitor Fmoc-Leu-OH and a luminal cavity that can bind sialic acid, and identified the residues essential for binding of the two substrates [34].

2.2 Sialic acid in cellular metabolism

Sialic acids are negatively charged nine-carbon sugars that occupy the terminal positions of the glycan chains of glycoproteins and gangliosides; Neu5Ac is the most abundant in mammals and the precursor of the others [2, 31]. Free sialic acid metabolism has three components: de novo biosynthesis, mainly cytosolic, initiated by the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) and regulated by feedback inhibition by CMP-sialic acid; lysosomal salvage, in which neuraminidase 1 releases sialic acid from degraded glycoconjugates and sialin returns it to the cytosol; and cytosolic degradation by N-acetylneuraminate pyruvate lyase (NPL) into N-acetylmannosamine (ManNAc) and pyruvate [2, 13]. Each of these steps has its own disease: loss of GNE feedback inhibition causes sialuria, loss of sialin causes FSASD and loss of NPL causes NPL deficiency; in the first two and in the third there is urinary excess of free sialic acid, but only in FSASD is the excess lysosomal [1, 2].

2.3 Disease mechanism

The mechanism is loss of function [1]. Variants associated with FSASD reduce or abolish transport, and some cause retention in the Golgi apparatus or the endoplasmic reticulum; missense variants associated with severe forms have no measurable activity, whereas p.(Arg39Cys) and p.(Lys136Glu) retain residual activity [2]. Heterozygotes, with about 50% activity, have no phenotype, and certain missense variants with about 10% activity (p.Arg39Cys, p.Lys136Glu, p.Gly409Glu) are associated with mild disease, which suggests that a partial increase in function would be therapeutic [2]. Transport activity, protein localisation and the amount of stored free sialic acid correlate with severity and with survival [2, 3].

How stored sialic acid damages the nervous system has not been elucidated [1, 31]. The hypotheses include alteration of lysosomal pH (sialin is a proton-coupled transporter), secondary accumulation of sialoglycoproteins and gangliosides (free sialic acid competitively inhibits lysosomal neuraminidases), hyposialylation of gangliosides and of myelin-associated glycoprotein (MAG), and changes in polysialylated neural cell adhesion molecule (PSA-NCAM), which is required for myelination [2]. p.(Arg39Cys) completely loses vesicular transport of aspartate and glutamate while retaining residual sialic acid transport (34% of normal proton–sialic acid cotransport in the murine protein) [6], which led to the proposal of a neurotransmission defect; this hypothesis lost ground because aspartatergic neurotransmission is normal in the knockout mouse [2]. The Slc17a5−/− mouse, which survives to about three weeks, shows growth retardation, central and peripheral lysosomal vacuolation, accumulation of free sialic acid and glucuronic acid and progressive leukoencephalopathy with fewer myelinated axons and apoptosis of the oligodendrocyte lineage, with normal precursors [2]. The Slc17a5 R39C knock-in model, published in 2026, reproduces the accumulation of free sialic acid, ataxia, tremor, seizures and reduced survival, with diffuse hypomyelination of the central nervous system (CNS) and relatively preserved peripheral myelin, suppression of myelin genes, astrogliosis, progressive degeneration of Purkinje cells and increased serum neurofilament light chain (NfL) [19]. In the same model, glycosphingolipids accumulate mainly in the brain, glucosylceramide decreases in all brain regions and the activity of neuraminidases 1, 3 and 4 and of β-hexosaminidase increases [35]. In neural cells derived from patients' induced pluripotent stem cells (iPSC) (lines described from one patient with a mild form and another with an intermediate form [36]), free sialic acid is raised in all cell types and glycosphingolipid changes predominate in mature astrocytes [37]. In patients' cerebrospinal fluid (CSF), total glycosphingolipids and the gangliosides GM1a, GM3, GD3, GD1a and GD1b are increased [38].

MRI and proton magnetic resonance spectroscopy (1H-MRS) in the prospective National Institutes of Health (NIH) cohort showed that myelin is laid down in the normal sequence, although greatly delayed, without demyelinating lesions, and that choline is low in white matter, which is interpreted as delayed myelination rather than demyelination or inflammation [39]. In peripheral nerves there is dysmyelination with polyneuropathy in some patients [1, 40].

2.4 Variant spectrum

In December 2020, the Human Gene Mutation Database (HGMD) listed more than 55 pathogenic variants: 27 missense, 6 nonsense, 7 splicing, 8 small deletions and 8 large deletions or insertions [2]. Sequencing detects 90–95% of the described pathogenic variants and targeted deletion/duplication analysis the remaining 5–10%; these percentages refer to the proportion of variants detected by each method, not to the clinical sensitivity of the test [1]. Structural events that escape the usual methods have also been described: a homozygous 6040 bp insertion of a LINE-1 retrotransposon in intron 9 [41], a homozygous deletion of exons 8–9 identified from a region of homozygosity on a single nucleotide polymorphism (SNP) array [18] and a 184 bp intragenic deletion in tissue mosaicism [32]. The table summarises clinically relevant variants, described in Human Genome Variation Society (HGVS) nomenclature and normalised in VariantValidator on the MANE transcript.

In table 1 of Wolfenson and colleagues, the c.116G>A variant of one patient appears associated with p.(Arg39Cys); validation in VariantValidator shows that c.116G>A corresponds to p.(Arg39His) and that p.(Arg39Cys) corresponds to c.115C>T [5, 39]. The case of Cappozzo and colleagues was described on transcript NM_001382633.1; the c.709G>A variant occupies the same genomic position and has the same designation on the MANE transcript [5, 13].

2.5 Genotype-phenotype correlation, penetrance and modifiers

Homozygosity for p.(Arg39Cys) produces the less severe, slowly progressive form [1, 30]. Compound heterozygosity for p.(Arg39Cys) with a more severe variant produces the intermediate form, as does homozygosity for p.(Lys136Glu) [1]. Truncating variants on both alleles are associated with ISSD, and intermediate forms have at least one non-truncating variant [13]. In the Finnish series of Varho and colleagues, 90% of the 41 patients had the conventional phenotype and all but two were homozygous for R39C, whereas the four patients with profound disability probably had compound genotypes [48]; in Paavola's follow-up, the four patients aged 16–34 years with developmental ages far below those of the others were compound heterozygotes with R39C on only one allele [14]. The correlation is partial. In a consanguineous Bedouin family, of four homozygotes for p.(Gly328Glu), one had congenital ascites with rapid death and three cousins had slowly progressive neurodegenerative disease [44]. Two Dominican siblings homozygous for p.(Lys136Glu) had intellectual disability and mild hypomyelination with almost no motor deficit, whereas an Italian patient with the same genotype had a severe form [43] and five Irish siblings who were homozygous had a disease with adult progression, with dystonia, myoclonus and death in the fifth decade in two [49]. These discordances point to additional genetic or environmental factors [1, 2].

FSASD appears to have complete penetrance, but penetrance assessed by urine alone may appear reduced, because the two siblings homozygous for p.(Lys136Glu) had normal urinary free sialic acid and raised CSF levels [1, 43]. In the tissue mosaicism described by Shinawi and colleagues, the proportion of cells carrying the second variant explains an atypical phenotype and mildly altered biochemistry [32].

2.6 Allelic disorders and proposed associations

No phenotypes caused by germline SLC17A5 variants outside the FSASD spectrum are known [1]. The ClinGen consortium (Clinical Genome Resource) classifies the SLC17A5–FSASD relationship as definitive, with autosomal recessive inheritance (assessment of 30 October 2023), and has no actionability assertion for the gene [33]. SLC17A5 variants, including p.(Arg39Cys), were once suggested as risk factors for Parkinson's disease [2], but an analysis of 7184 cases and 51,650 European controls, with genome and exome data and genome-wide association statistics, found no association of rare variants, of p.(Arg39Cys) or of common variants with the risk of Parkinson's disease [50]; in mice heterozygous for R39C, gangliosides do not change significantly [51]. In a Slc17a5+/− mouse model, a selective working memory deficit with hippocampal changes was described [52]; in humans, GeneReviews considers heterozygotes asymptomatic and not at risk of disease [1].

3. Clinical Spectrum and Manifestations by System

3.1 Overview and frequency of manifestations

By 2025, about 260 individuals with biallelic SLC17A5 variants and about 50 without molecular data had been described [1]. All forms share neurodevelopmental delay, cognitive impairment and hypomyelination on MRI [39]; severity increases with the amount of stored free sialic acid [3]. The frequency of manifestations across the spectrum, compiled by Zielonka and colleagues from published cases and adapted by GeneReviews, is shown in the table; these are cases described in the literature, subject to publication and ascertainment bias, and not a population sample [1, 3].

Source: GeneReviews, adapted from Zielonka et al. 2019 [1, 3].

In the analysis by Zielonka and colleagues (116 patients from 94 families, published between 1976 and 2015), 10 were diagnosed prenatally and 106 after birth; in the postnatal group, the median age at onset was 0.17 years (about 2 months; interquartile range 0–0.58), the median age at diagnosis 3 years and the median diagnostic delay 2.5 years [3]. Fetal hydrops was the first sign in 20.7% of cases [3].

3.2 Less severe form (Salla disease)

Pregnancy and the first months are normal. The first signs (nystagmus, hypotonia, ataxia and motor delay) usually appear between 3 and 12 months, and hypotonia is often recognised at around 6 months [1, 14]. One third of children achieve walking; expressive language may be limited to single words, with relatively preserved comprehension [1]. In the cross-sectional series of 41 Finnish patients, 90% had the so-called conventional phenotype (including seven with relatively mild symptoms) and four, aged between 15 and 28 years, a severe form with profound intellectual disability [48]. In four Finnish patients with an unusually severe form, described by Haataja and colleagues, hypotonia and delay appeared at 2–4 months, there were generalised tonic-clonic seizures, unlike the absence-type epilepsy of the usual form, and MRI showed subcortical hyperintensity with sparing of the U-fibres and cerebellar atrophy [6]. The neurocognitive profile is characteristic: non-verbal performance (mean developmental age of 13 months) is lower than language performance (17 months), there are spatial and visuoconstructive deficits and poor tactile and visual shape discrimination, eye-hand coordination, visual attention and short-term visual memory are relatively preserved, comprehension is far better than expression, and interactive and non-verbal communication skills are strong [53]. Patients are described as good-humoured and sociable [1].

The 13-year follow-up of 24 Finnish patients (aged 16–65 years at reassessment; 19 homozygous for R39C and 5 compound heterozygotes) defined the long-term trajectory [14]. Motor developmental age improved until about 20 years and then declined; mental developmental age increased in most until the end of the third decade and then remained stable until the beginning of the sixth decade [14]. Ataxia, severe in childhood, disappears between 10 and 15 years and is replaced by athetosis; spasticity becomes more evident with age, especially in the more disabled patients [14]. At reassessment, 11 patients walked independently (all with impaired coordination), 7 with a walking aid and 6 did not walk; all had lower limb spasticity, brisk knee jerks, severe pes planovalgus and absent ankle jerks, 10 had a Babinski sign, 22 mild or moderate athetosis and 2 severe athetosis; none had nystagmus and all had moderate to severe strabismus [14]. The maximum developmental age was 27 months on the motor scale and 42 months on the mental scale [14]. Verbal comprehension was maintained, but speech production worsened through dyspraxia and dysarthria, without aphasia; patients with the conventional phenotype used at least two words appropriately, and those with the severe phenotype did not imitate words [14].

Source: Paavola et al. 2015 [14]. NEPSY: developmental neuropsychological assessment battery for children.

Epilepsy is frequent in adulthood: in the Finnish follow-up, 12 of the 24 patients had seizures (primary and secondary generalised), with a median age at onset of 29 years; 8 were on monotherapy and 4 on polytherapy, and 3 had startle reactions to auditory stimuli [14]. Psychiatric symptoms were recorded in 10 of 24 patients followed in Oulu between 1982 and 2015 (42%), with psychosis in adolescence in two, sleep disorders in 8, aggressive behaviour or agitation in 6 and off-label antipsychotics in 4 [54]. An Irish family with five affected siblings, homozygous for p.(Lys136Glu), shows the course of this variant in adulthood: hypotonia and delay in infancy, walking at 6 years in the proband, stimulus-sensitive myoclonus, dystonia and ataxia from early childhood, epilepsy in the third decade in two siblings, motor regression requiring a walking aid between the third and fifth decades in four, spastic dysarthria and dysphagia; two died at 43 and 47 years from aspiration pneumonia secondary to bulbar dysfunction [49]. MRI showed hypomyelination in all, bilateral posterior putaminal hypointensity on susceptibility sequences and, in two siblings, stable putaminal cysts, a finding not previously described; dystonia had been reported in only ten patients [49].

The peripheral nervous system is also affected: in 22 Finnish patients, nerve conduction was abnormal in 10 of 21, and the four most disabled and the oldest had markedly reduced velocities and prolonged distal latencies, consistent with demyelinating polyneuropathy; somatosensory evoked potentials were abnormal in most, unlike visual and auditory evoked potentials [40]. On MRI, cerebral white matter is hyperintense on T2 relative to grey matter (except in the internal capsules), myelination of the basal ganglia is abnormal and the corpus callosum is always thin; atrophy, when present, is mild and may involve the cerebellum and brainstem; an asymptomatic 1-month-old child had normal MRI [1, 55]. The cerebellar white matter changes described in some patients account for the ataxia [1].

3.3 Intermediate form

The intermediate form begins in the first six months with hypotonia and developmental delay, followed by slow acquisition of skills with a plateau at the end of childhood and, in adolescence, slow progressive neurological regression [13, 15]. Two sisters with p.(Lys136Glu) and c.819+1G>A, followed for 15–20 years, had cerebellar signs in the second year, loss of head control and of cognitive skills in the second decade and dystonia of discordant onset (at 19 months in one and at 14 years in the other); both developed coarse facial features and one had synophrys, epicanthic folds, low hairline and a high-arched palate [1, 15]. A 5-year-old girl with c.291G>A and c.819+1G>A had normal development in the first 6 months, then severe global delay, axial hypotonia and generalised dystonia, with marked hypomyelination and a thin corpus callosum at 19 and 28 months [16]. In five Central European patients heterozygous for R39C, Salla disease was of unusual severity [30].

The prospective NIH cohort (eight children aged 3 to 9 years assessed in 2022–2023, from the USA, Norway, the Dominican Republic and Brazil) documents this form in detail; urinary excretion placed these patients in the intermediate severity category [39]. Initial concerns arose between 3 and 10 months, mainly because of motor delay, and only one patient had dysmorphism at birth (bilateral club feet); four walked (with delay) and four did not [39]. All had intellectual disability or global delay, and the Vineland composite score was 52 ± 11, with socialisation (59 ± 12) higher than daily living skills, communication and motor skills [39].

Source: Wolfenson et al. 2026 [39].

In the same cohort, MRI showed markedly delayed myelination and a very thin corpus callosum in all, with predominantly central atrophy in five; at 7–9 years, myelination corresponded to that of an infant aged 4–6 months [39]. Nerve conduction was abnormal in five, with the oldest patient having an axonal and demyelinating sensorimotor neuropathy; the three youngest had normal or near-normal studies [39]. The most frequent ophthalmological findings were early myopia (5/8), exotropia (5/8), reduced visual acuity (6/8) and astigmatism (5/8), with mild optic atrophy in 2 and proposed cortical visual impairment in 4; auditory brainstem responses (ABR) were abnormal in 7 of 8, with a pattern of retrocochlear dysfunction [39]. The echocardiogram was normal in 7 (one with mitral thickening and regurgitation), polysomnography showed obstructive apnoea in 2 and periodic limb movements in 2, the skeletal survey was abnormal in 6 (coxa valga in 4, hip subluxation in 3, mild scoliosis in 3, diffuse osteopenia in 3) and bone age was delayed in 4 [39]. Endocrine, haematological, immunological and protein glycosylation assessments (transferrin and apolipoprotein CIII) were essentially normal [39].

3.4 Severe form (ISSD)

ISSD begins in utero or at birth. In a review of 27 cases, the presentation was fetal or neonatal ascites or hydrops in 13 of 21 (60%); coarse facies, fair skin, hepatosplenomegaly and severe psychomotor delay were present in all; nephrotic syndrome occurred in 4 of the 7 assessed; cardiomegaly in 9 of 12; the corneas were clear and albinoid fundi were reported in 5 of 7; dysostosis multiplex was not prominent; death occurred in early childhood, between 1 month and 3.3 years (mean 13.1 months; n = 20), always from respiratory infection [7, 17]. In a French series of 12 patients with very early manifestations, including eight fetuses diagnosed in utero, ascites predominated, rarely progressing to complete hydrops, and bone disease was severe from early on [47]. GeneReviews adds non-immune hydrops in 24%, prematurity in some, loss of acquired skills in infants who appeared normal at birth, club feet, short femurs, irregular and widened metaphyses, diffuse hypomineralisation with fractures, hip dysplasia, anterior beaking of the thoracic vertebrae and hypoplasia of the distal phalanges; the facial features (epicanthic folds, ptosis, anteverted nose, gingival hypertrophy) are non-specific and the ocular changes include nystagmus, exotropia, optic atrophy and albinoid fundi [1]. Huizing and colleagues describe hypertelorism, a flat nasal bridge, a broad nasal tip, a long philtrum and a broad forehead as typical facial features [2]. Radiographs show the dysostosis multiplex pattern common to lysosomal diseases with storage of complex carbohydrates (oar-shaped ribs, ovoid or hook-shaped vertebrae, iliac constriction, dysplasia of the femoral epiphyses, shortening and irregular modelling of the long bones, osteoporosis with coarse trabeculation) [56]. Neonatal MRI shows hypomyelination with periventricular changes hyperintense on T1 and hypointense on T2, and optic atrophy [13]. Persistent isolated hypogammaglobulinaemia and hyporegenerative anaemia have also been described [13], as well as capillary dilatations of the bulbar conjunctiva and, in a 10-year-old boy, mild corneal clouding [7].

3.5 Atypical forms

Two siblings homozygous for p.(Lys136Glu) had intellectual disability with mild supratentorial hypomyelination, almost no motor deficit, normal urinary free sialic acid and raised CSF levels [43]. A Swedish adolescent homozygous for a LINE-1 insertion had psychomotor delay, spasticity and rigidity without ataxia, with subtle hypomyelination; a small fraction of normal transcript would explain the mild phenotype [41]. A northern European adolescent girl with tissue mosaicism for an intragenic deletion had coarse facies, periorbital oedema, gingival hypertrophy, aortic and mitral valve disease, dilatation of the ascending aorta, progressive joint contractures, surgically treated scoliosis, short stature and mild to moderate intellectual disability, with normal brain MRI at 14 years [32].

3.6 Manifestations by system

ID: intellectual disability; ABR: auditory brainstem responses.

4. Clinical Recognition and Warning Signs

4.1 Prenatal and neonatal period

FSASD should be considered in the presence of non-immune fetal hydrops or isolated fetal ascites once alloimmunisation has been excluded, because one in five reported patients had hydrops as the first sign [3]. Lysosomal diseases account for between 1–15% and 5–16% of non-immune hydrops depending on the series [3, 13, 18], and in a retrospective study cited by the consortium FSASD accounted for 18% (5 of 28) of cases of hydrops of lysosomal cause [2]. Other prenatal signs are reduced fetal movements, breech presentation, club feet, short femurs and cardiomegaly [13, 39]. In the newborn, the combination of coarse facies, hepatosplenomegaly, ascites, nephrotic syndrome, dysostosis and vacuolated lymphocytes suggests a lysosomal disease of the oligosaccharidosis and mucolipidosis group [13, 17, 57]. When hydrops is present, it is recommended to store fibroblasts, frozen amniotic fluid and DNA, and to examine the placenta, because these allow diagnosis after death; some centres perform lysosomal screening for hydrops in cultured amniocytes [58].

4.2 Infancy and childhood

In infants, the warning signs are axial hypotonia with motor delay in the first year, nystagmus and ataxia; significant motor delay in the first year, in a context of global delay, justifies genetic testing [14, 39]. Several patients in the NIH cohort initially received a diagnosis of cerebral palsy [39], and Salla disease is among the metabolic diseases that mimic cerebral palsy [57]. Consensus of the FSASD Consortium and GeneReviews: suspect the disease in the presence of global delay or cognitive impairment (especially of speech) and regression, associated with coarse facies, faltering growth, organomegaly, axial hypotonia, ataxia, spasticity, bone anomalies or short stature [1, 2]. Zielonka and colleagues summarise the practical rule: neurological signs with visceromegaly and dysmorphism, or non-immune hydrops, should prompt the specific tests [3].

MRI is often the investigation that points the way: hypomyelination with a thin corpus callosum in a child with developmental delay should include FSASD in the differential diagnosis of hypomyelinating leukodystrophies [39, 59, 60]. The history should include ancestry: Finnish or Swedish, Mennonite, Inuit or Bedouin [1, 61, 62].

4.3 Adolescence and adulthood

In undiagnosed patients, the less severe form may present as intellectual disability with spasticity, athetosis and adult-onset epilepsy [1, 14]. FSASD without sialuria and the mosaic form show that adults with intellectual disability and mild hypomyelination, or with the appearance of a storage disease without a molecular diagnosis, may have the disease [32, 43].

4.4 Signs of severity

Signs of severity are hydrops and neonatal ascites, cardiomegaly, nephrotic syndrome and recurrent respiratory infections, which are the usual cause of death in the severe form [1, 17]. Dysphagia with aspiration, respiratory failure and refractory epilepsy require clinical reassessment [1].

4.5 Newborn screening

There is no newborn screening for FSASD. The consortium advocates the inclusion of SLC17A5 in future molecular newborn screening, once treatment exists, by analogy with the German cystinosis pilot [2].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no consensus clinical diagnostic criteria [1]. The diagnosis is established by identification of biallelic pathogenic or likely pathogenic variants in SLC17A5 [1]. According to the standards of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), the pathogenic and likely pathogenic classes are equivalent for clinical decision-making; two variants of uncertain significance (VUS), or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis [1].

5.2 Urinary biomarker

Urinary free sialic acid is the first-line biochemical test. It is raised about 10-fold in the less severe form and about 100-fold in ISSD; it is measured by the fluorimetric thiobarbituric acid assay, by thin-layer chromatography (TLC), by mass spectrometry or by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) [1]. Huizing and colleagues cite a 10–100-fold increase and Zielonka and colleagues a 2–100-fold increase [2, 3]; in Salla disease, Mochel and colleagues report 5–20-fold [43]. Excretion is highest shortly after birth, already detectable at three days of life, and decreases with age, so results are interpreted against age-specific reference values [39, 43].

The limitations are known. In the thiobarbituric acid assay, interfering substances may lower the value and chromophores may increase absorbance, producing false results; on TLC, a real elevation may go unnoticed [1, 3]. TLC is not always available and can miss cases, and tandem mass spectrometry improves detection [31]. Semi-quantitative oligosaccharide tests on a single void from an infant require confirmation [13]. Urinary excretion may be normal or borderline in confirmed patients (FSASD without sialuria due to homozygous p.(Lys136Glu); intermediate forms with borderline values), so a normal result does not exclude the disease [16, 39, 43]. Heterozygotes have normal values, and biochemical carrier testing is not feasible [1, 2].

5.3 Other biomarkers and supporting tests

Free sialic acid in cerebrospinal fluid (CSF) was slightly raised in all seven children of the NIH cohort in whom it was measured (25–31 µmol/L; reference 4–22), with normal protein, cells, IgG index, oligoclonal bands, neopterin, neurotransmitters and pterins [39]. In the siblings without sialuria, the CSF value by 1H-NMR was 28 and 29 µmol/L, about three times the mean of 250 neurological patients (8.9 ± 4.1 µmol/L) [43]. Plasma free sialic acid, measured on a research basis by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS), was on average 5.7 times the upper limit of normal, with normal total sialic acid [39]. In leucocytes, free sialic acid was 12.81 ± 3.31 nmol/mg protein in three children with the intermediate form, 36 times that of the parents, 22 times that of controls without lysosomal disease and 49 times that of patients with other lysosomal diseases; the authors propose it as a minimally invasive biomarker, but its value in the sialurias has not been studied and molecular confirmation remains indispensable [46].

Cultured fibroblasts from all forms have increased free sialic acid; demonstration that the excess is lysosomal, and not cytoplasmic, was the historical confirmatory standard and distinguishes FSASD from sialuria and from NPL deficiency [1, 2, 63]. This is a confirmatory test, not a screening test [43]. Electron microscopy of a skin biopsy shows cytoplasmic vacuolation in several cell types [2, 32]. Raised chitotriosidase and vacuolated lymphocytes on the blood film pointed a neonatal case towards lysosomal disease [13]. MRI with hypomyelination, a thin corpus callosum and atrophy supports the diagnosis; 1H-MRS shows low choline in white matter and raised N-acetylaspartate (NAA) in several regions [39], and in a newborn with ISSD a raised peak at the NAA position was described [13]. In the severe form, the skeletal survey shows dysostosis [1]. Glycosylation of transferrin and apolipoprotein CIII is normal and helps to exclude congenital disorders of glycosylation [39].

5.4 Genetic tests

GeneReviews proposes two pathways [1]. When the phenotype and biochemistry suggest FSASD, SLC17A5 sequencing is performed (or a multigene panel including the genes in the differential diagnosis) and, if only one variant or none is found, targeted deletion/duplication analysis; in at-risk ancestries, testing may start with the founder variants (p.(Arg39Cys) in Finns, Nordic populations and Mennonites; c.526-2A>G in Canadian Inuit; p.(Gly328Glu) in Bedouins). When the picture is indistinguishable from other neurodegenerative diseases, exome or genome sequencing is preferred [1]. Zielonka and colleagues recommend that, if the exome identifies biallelic variants, functional relevance be confirmed by biochemistry [3]. The consortium advocates early genetic testing in suspected cases, given the lack of validated blood biomarkers [2].

Source: GeneReviews [1], with the cases of Hasnain, Tarailo-Graovac and Shinawi [18, 32, 41].

A negative result does not exclude the disease. A homozygous deletion of exons 8–9 was suspected only when sequencing failed to amplify those exons, after an SNP array on amniocytes had shown a region of homozygosity on chromosome 6 that included SLC17A5 [18]. The LINE-1 insertion in intron 9 was detected only by exome sequencing followed by study of RNA and genomic DNA [41]. In the adolescent with mosaicism, trio exome, genome, targeted sequencing and deletion analysis on blood identified only one maternal variant; the second variant, a 184 bp deletion at the end of exon 3 (chr6:73 641 566–73 641 749, hg38), was found after more than 15 years by RNA sequencing of fibroblasts (exon 3 skipping), targeted deep sequencing (about 15% of reads) and long-read sequencing, which showed the deletion on the paternal allele in 25% of paternal alleles in fibroblasts and 42% in muscle, without detecting it in blood or buccal mucosa [32]. When a parent is not a carrier and parentage is confirmed, a de novo variant in the proband or parental mosaicism must be considered; apparent homozygosity may result from an undetected deletion (false homozygosity) or from uniparental isodisomy [1].

The report should state the gene, the transcript with version (NM_012434.5), the HGVS nomenclature, zygosity, the phase of the variants (parental testing) and the ACMG/AMP class [1, 5]. Parental testing is recommended to confirm heterozygosity and estimate the recurrence risk [1].

5.5 Algorithm

5.6 Prenatal and preimplantation diagnosis

Once the familial variants are known, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing are possible [1, 2]. Before molecular diagnosis, prenatal diagnosis was made by free sialic acid and the free/total ratio in amniocytes (Renlund and Aula, 1987) and by microscopic and biochemical analysis of chorionic villi, which in a twin pregnancy identified the affected twin (Lake and colleagues, 1989); in recurrent hydrops, free sialic acid was raised in amniotic fluid and fetal cells and the placenta showed vacuoles in the trophoblast and in Hofbauer cells [7]. In Zielonka's series, ten patients were diagnosed prenatally (two because of a previously affected sibling and eight because of ultrasound signs); eight pregnancies were terminated and two fetuses died later in pregnancy or at birth [3]. The distribution of storage in the placenta and fetal organs distinguishes FSASD from other lysosomal diseases, but not from sialidosis or galactosialidosis [47].

6. Differential Diagnosis

6.1 Other causes of raised free sialic acid

Only three known diseases markedly raise free sialic acid in urine and cells: FSASD, sialuria and NPL deficiency [1, 2]. Other causes of mild elevation may exist [1].

French-type sialuria (OMIM 269921) is autosomal dominant and results from heterozygous missense variants in the allosteric site of GNE, which abolish feedback inhibition by CMP-sialic acid; free sialic acid is overproduced in the cytoplasm and excreted in gram quantities, 100–1000 times normal [2, 64, 65]. On the MANE transcript of GNE (NM_005476.7), the described variants affect Arg263 and Arg266, for example c.788G>T p.(Arg263Leu) and c.797G>A p.(Arg266Gln); the recent literature uses the numbering of another isoform (Arg294 and Arg297) [5, 64, 66]. By 2019, nine patients had been described (eleven according to the 2021 review), with mild and variable developmental delay, mildly coarse features, hepatomegaly and prolonged neonatal jaundice, without regression or prominent dysostosis [2, 64, 67]. The patient followed by Enns and colleagues until 11 years of age had normal growth, near-normal development, massive hepatomegaly, mild small airway obstruction and transient elevation of transaminases, and the authors advise hepatic and pulmonary surveillance [67]. GeneGuidance mentions, as an unestablished hypothesis, intrahepatic cholangiocarcinoma in an adult with sialuria and in a relative [65]. Neuraminidase is normal or increased [22, 31]. In fibroblasts, free sialic acid is increased 70–200-fold and is located mainly in the cytosol (88% in one patient), and mother-to-child transmission of an Arg266 variant confirmed dominant inheritance [22]. The other GNE disorders (GNE myopathy, autosomal recessive, and thrombocytopenia 12) do not present with sialuria [65].

NPL deficiency results from biallelic variants in NPL; it was described in a sibship of two brothers with progressive cardiomyopathy and mild skeletal myopathy, with urinary free sialic acid about 10 times and erythrocyte free sialic acid 50–100 times normal, without accumulation in fibroblasts [2, 31]. In mice with the human p.Arg63Cys variant, the deficiency reduces muscle strength and regeneration and alters dystroglycan sialylation, and oral ManNAc corrects the myopathy [68]. NPL catabolises several sialic acids, and deficient erythrocytes accumulate Neu5Ac and 3-deoxy-D-glycero-D-galacto-nonulosonic acid (KDN) [69].

Cerebellar ataxia with raised free sialic acid in CSF (CAFSA) was described in 2009 in five adults with ataxia, peripheral neuropathy and cognitive decline, normal free sialic acid in urine and fibroblasts and hyposialylation of CSF transferrin, which is absent in Salla disease [70]. Later studies found biallelic POLG variants in two sisters and a metabotype shared with Kearns-Sayre syndrome, and concluded that CAFSA is a heterogeneous entity linked to mitochondrial DNA changes, not a transporter disease [71].

6.2 Diseases of bound sialic acid

In sialidosis (neuraminidase deficiency, NEU1, OMIM 256550) and galactosialidosis (combined neuraminidase and β-galactosidase deficiency due to lack of the protective protein cathepsin A, CTSA, OMIM 256540), what accumulates and is excreted is sialic acid bound to glycopeptides and oligosaccharides [1, 31]. Sialidosis ranges from fetal hydrops with multisystem disease to the cherry-red spot–myoclonus syndrome, and the cherry-red spot is common across the whole spectrum [31]. These diseases are distinguished by urinary oligosaccharides and enzyme assay; in hydrops, the placental histological pattern does not separate them from FSASD [47].

6.3 Other lysosomal diseases

In the presence of coarse facies with developmental delay, or of non-immune hydrops, the differential diagnosis includes the lysosomal diseases in the table, which are distinguished by urinary glycosaminoglycans and oligosaccharides, enzymes and genetic testing [1, 31]. In hydrops, the most frequent lysosomal diseases are mucopolysaccharidosis (MPS) VII, Gaucher disease, GM1 gangliosidosis and sialidosis [3]. Aspartylglucosaminuria, another disease of the Finnish heritage, has thalamic involvement on MRI (absent in FSASD), faster regression from adolescence and shorter survival (about 40 years in women and 35 in men) [14, 31].

6.4 Hypomyelinating leukodystrophies

FSASD is one of the hypomyelinating leukodystrophies of lysosomal cause, together with fucosidosis and mucolipidosis IV [60]. The MRI differential diagnosis includes Pelizaeus-Merzbacher disease (PLP1, X-linked), hypomyelination with congenital cataract (HYCCIN), 4H leukodystrophy (POLR3A, POLR3B, POLR1C), serine synthesis defects, MCT8 deficiency and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC, TUBB4A p.Asp249Asn), from the group of hypomyelinating leukodystrophies [59]. In FSASD, the clue is the combination of hypomyelination with a thin corpus callosum, systemic signs and raised free sialic acid [39, 57].

6.5 Differential diagnosis table

AR: autosomal recessive; AD: autosomal dominant; XL: X-linked.

7. Treatments and Risk Management Strategies

7.1 Framework and evidence base

There is no approved disease-modifying therapy for FSASD [1, 19]. No clinical practice guidelines have been published; the GeneReviews recommendations are based on the personal experience of the authors, who are involved in clinical and laboratory research on the disease, and constitute expert opinion [1, 33]. Management is symptomatic, supportive and multidisciplinary, preferably in specialised centres with access to all specialties and support services, as in the other oligosaccharidoses [1, 31]. In Europe, referral is made through MetabERN, whose lysosomal disorders subnetwork covers FSASD [20].

7.2 Initial evaluation after diagnosis

7.3 Treatment of manifestations

Epilepsy is treated with antiepileptic drugs chosen by an experienced neurologist according to the usual rules for the seizure type; many drugs may be effective, but none has been studied specifically in FSASD, and carers should be taught to recognise seizures [1]. In the Finnish follow-up, 8 of the 12 patients with epilepsy were on monotherapy and 4 on polytherapy [14]. Spasticity and dystonia are treated with physiotherapy and occupational therapy, stretching to prevent contractures and falls, positioning and mobility aids (wheelchair, walker, orthoses) and, when indicated, with baclofen, tizanidine, botulinum toxin (Botox®) or antiparkinsonian drugs, managed by the respective specialties, or with orthopaedic surgery [1]. These drugs are used according to the general indications and dosing of their labels for spasticity and dystonia; the sources consulted do not describe doses or outcomes specific to FSASD. Physiotherapy also aims to reduce late orthopaedic complications such as contractures, scoliosis and hip dislocation [1], which already appear in childhood (hip subluxation in 3 of 8 and scoliosis in 3 of 8 in the NIH cohort) [39].

Low bone mineral density and fractures justify ensuring adequate calcium and vitamin D intake, with supplementation if necessary [1]. Poor weight gain is treated with feeding therapy and gastrostomy when problems persist; the threshold for clinical swallowing assessment or radiological study should be low in the presence of choking, poor weight gain, frequent respiratory infections or food refusal; foods may be thickened or chilled, and severe dysfunction may require a nasogastric tube or gastrostomy [1]. Augmentative and alternative communication (AAC), from picture exchange systems to voice output devices, should be considered when there are expressive difficulties and does not hinder speech development [1]; the profile of Salla disease, with comprehension better than expression, makes this intervention relevant [14, 53]. Ophthalmological manifestations are managed with the ophthalmologist and low vision services; cardiomegaly with the cardiologist; nephropathy and nephrotic syndrome with the nephrologist; hernias surgically [1]. Psychiatric symptoms, including psychosis and sleep disorders, require psychiatric assessment, and in the Oulu series 4 of 24 patients were receiving off-label antipsychotics [54]. Obstructive sleep apnoea and recurrent otitis led to adenoidectomy, ventilation tubes and polysomnography in reported patients [32, 39].

In ISSD, reports describe neonatal intensive care with ventilation, repeated paracenteses, transfusions, erythropoietin for hyporegenerative anaemia, albumin infusions for nephrotic syndrome and nocturnal non-invasive ventilation [13, 18]. These measures are supportive and do not alter the course; in the Cappozzo case, the ethical appropriateness of starting parenteral nutrition was under discussion at 15 months [13]. Palliative care should be assessed on an ongoing basis [1, 31].

7.4 Development, education and family support

GeneReviews describes the North American model: early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech and feeding therapy, special education), developmental preschool from 3 to 5 years with an individualised education plan, developmental paediatrics follow-up and a transition plan in adolescence; recommendations vary between countries [1]. Support includes social services, respite care, care coordination, home nursing and adapted sport [1].

7.5 Transplantation, enzyme therapy and other interventions

There are no reports of haematopoietic stem cell transplantation (HSCT) in FSASD; in the lysosomal transporter diseases in which it has been tried, it did not correct the neurological symptoms, and the risks may outweigh the benefits [2]. Saudubray's table of HSCT indications in the mucopolysaccharidoses and oligosaccharidoses records zero transplanted patients with ISSD or Salla disease and classifies HSCT as not indicated, because the defect is in a membrane protein, which is not transferred from donor cells to the patient's cells as soluble hydrolases are [31]. None of the 116 patients in Zielonka's series underwent transplantation [3]. Among the oligosaccharidoses, HSCT has been performed in α-mannosidosis, aspartylglucosaminuria and fucosidosis, and enzyme replacement therapy is approved only in α-mannosidosis; the role of HSCT in the rest of the group is uncertain [31]. Protein replacement is more complex for a membrane transporter than for a soluble enzyme, which steers research towards gene therapy [2].

7.6 Special situations

In anaesthesia, facial dysmorphism, skeletal dysplasia and upper airway obstruction may make airway management difficult in the oligosaccharidoses, although generally less so than in the mucopolysaccharidoses [31]; the gingival hypertrophy, adenoid hypertrophy and sleep apnoea described in FSASD reinforce this precaution [32, 39]. No patients with FSASD are known to have reproduced, so there are no data on pregnancy or lactation in affected women [1]. GeneReviews does not list drugs to avoid. In the transition to adulthood, the Finnish trajectory (motor decline after 20 years, epilepsy with median onset at 29 years, stable cognition until the beginning of the sixth decade) defines the needs for rehabilitation and adult neurology [14].

7.7 Regulatory status and trials

There are no interventional trials, so there are no efficacy results to present; the studies listed do not test treatments. The absence of registrations does not prove the absence of preclinical or unregistered programmes.

7.8 Preclinical research and developments in the last 12 months

All known therapeutic advances are at the preclinical stage. Base editing with an adenine base editor corrected c.115C>T p.(Arg39Cys) in homozygous and compound heterozygous human fibroblasts, without detectable indels and with a significant reduction in free sialic acid, and the result was replicated in mouse fibroblasts carrying the same variant; homology-directed repair achieved little correction and generated many indels [74]. A virtual screen of chaperone molecules found a compound that partially corrected the trafficking of p.(Arg39Cys), without restoring transport [2]. ManNAc increases sialic acid biosynthesis in sialin-deficient cells, but does not fully restore ganglioside sialylation [75]. The consortium also proposes gene therapy with functional SLC17A5, gene editing of p.(Arg39Cys) and activation of transcription factor EB (TFEB) [2], and Zielonka and colleagues suggest channel potentiators and splice-switching antisense oligonucleotides [3].

Between October 2025 and October 2026 the following were published: the Slc17a5 R39C knock-in model, with central hypomyelination, Purkinje cell degeneration and raised serum NfL, proposed as a preclinical platform (preclinical) [19]; the characterisation of glycosphingolipids in that model (preclinical) [35]; the prospective NIH cohort, which proposes as outcomes for future trials myelination quantified by MRI and 1H-MRS, spectroscopic metabolites and the Vineland and cognition scales (human observational study) [39]; a case of ISSD with a novel variant and hyporegenerative anaemia (case report) [13]; and a family series of dystonia with putaminal cysts (report) [49]. A review of sialic acid-related diseases, published online in September 2025, proposes a structured diagnostic algorithm [76]. The patient association STAR Foundation funds the research consortium (about 40 researchers) and maintains a patient registry, with no clinical trial announced on its website in October 2026 [77].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

FSASD is autosomal recessive [1]. The parents of an affected individual are presumed to be heterozygous, and molecular testing of both is recommended to confirm this and to estimate the recurrence risk reliably [1]. If both are heterozygous, each sibling has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being neither affected nor a carrier [1]. Severity may vary between siblings with the same genotype, as in the Bedouin family in which one cousin had the fatal neonatal form and three others a slowly progressive form, so the phenotype of one child does not reliably predict that of the next [1, 44]. The parents' siblings have a 50% chance of being carriers [1]. No offspring of patients with FSASD are known [1].

If only one parent is a carrier and parentage is confirmed, the second variant may have arisen de novo in the proband or in a mosaic parent; if the proband appears homozygous, a deletion of one or more exons on the other allele (false homozygosity) and uniparental isodisomy should be excluded [1]. The case of somatic mosaicism described in 2025, in which the second variant arose on a paternal allele and is present in only some of the proband's tissues, illustrates a situation in which the recurrence risk for the parents is low, because neither of them carries that variant [32].

8.2 Carriers and cascade testing

Heterozygotes are asymptomatic and are not at risk of developing the disease [1]. Carrier testing in relatives requires the family variants to have been identified, and biochemical carrier testing is not feasible, because heterozygotes have normal urinary excretion [1, 2]. GeneReviews does not recommend routine testing of asymptomatic relatives at risk of being affected, because adult presentations are unusual and there are no early interventions [1]. Counselling should be offered to young adults who are carriers or at risk, and testing should be considered in the partners of known carriers, especially if they are of the same ancestry [1]. The carrier frequency of p.(Arg39Cys) is about 1 in 100 in the founder region of north-eastern Finland [1, 14], about 1 in 84 in the Finnish population of gnomAD [2] and, for c.526-2A>G, 1 in 129 in a sample of pan-Arctic Inuit controls [45]. For the world population, the estimate from gnomAD is 1 carrier in 286 individuals [2].

8.3 Prenatal and preimplantation diagnosis

Once the variants are known, prenatal diagnosis and preimplantation genetic testing are possible, and the ideal time to discuss the risk and the options is before pregnancy [1]. In pregnancies without a family history, ultrasound may show ascites, hydrops, short femurs, cardiomegaly or reduced fetal movements [13, 39, 47], and an SNP array on amniocytes may reveal a region of homozygosity pointing to SLC17A5 in couples from the same community [18]. Views on prenatal and preimplantation diagnosis vary between professionals and between families; it is a personal decision that benefits from informed discussion [1]. The sources consulted on FSASD do not specifically address carrier testing in minors; GeneReviews directs the offer of testing to young adults who are carriers or at risk [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Prevalence

The estimates are of different kinds and should not be confused. GeneReviews gives a worldwide prevalence of 1–3 per 1,000,000, calculated from variant frequencies in population databases, and of about 35 per 1,000,000 in Finland [1]. Huizing and colleagues applied the Hardy-Weinberg principle to SLC17A5 pathogenic variants in gnomAD (December 2020), excluding the 149 Finnish alleles with p.(Arg39Cys) and including the 79 non-Finnish ones, and obtained a conservative prevalence of at least 3 per 1,000,000 and a carrier frequency of 1 in 286; extrapolated, this would correspond to about 23,000 cases worldwide (about 13,000 in Asia, 2,000 in Europe and 1,700 in North America), without discounting the embryonic and infant lethality of the severe forms; for Finland, the carrier frequency of about 1 in 84 gives about 35 cases per million (about 190 patients) [2]. The gap between these figures and the roughly 260 patients described suggests underdiagnosis [2, 32].

Orphanet classifies the worldwide point prevalence of FSASD as less than 1 per 1,000,000 and records 130 cases [8, 78]. The only incidence figures based on a national registry are Swedish: between 1980 and 2009, the country's two diagnostic laboratories identified 433 lysosomal diseases (1 in every 6100 births), and Salla disease was the fourth most frequent, after Krabbe disease, Gaucher disease and metachromatic leukodystrophy, owing to immigration of carriers from the Salla region [12]. Orphanet derives from that study a birth prevalence of 1.59 per 100,000 for Salla disease and 0.14 per 100,000 for the infantile form [9, 11]. For sialuria, Orphanet records 5 cases and a prevalence of less than 1 per 1,000,000 [23].

9.2 Founder populations and geographical distribution

Finland accounts for most patients. Salla disease belongs to the so-called Finnish disease heritage, with p.(Arg39Cys) present in all 80 Finnish patients studied by Aula and colleagues, 91% in the homozygous state [30, 53]. The variant is also found in most Swedish patients with Salla disease and, in the heterozygous state, in Central European patients with intermediate forms [30]. Outside Scandinavia, homozygosity for p.(Arg39Cys) has been described in the Old Order Mennonite community of North America, where four patients (aged 8 months to 50 years) were identified through homozygosity mapping [42]. Other founder variants are c.526-2A>G in Canadian Inuit, with ISSD presenting with hydrops [45], and p.(Gly328Glu) in a Bedouin family from Israel [44]. The first Irish family was described in 2026 [49]. Patients have been described who were Dominican, French, Italian, Japanese, Kurdish, Polish, Saudi, Danish, Spanish and of Indian ancestry [1, 2, 39], and the global distribution is panethnic, with patients from all inhabited continents [3]. ISSD is rare in all populations studied [45]: the 2005 French series noted that, apart from Finland, only about 35 cases had been described worldwide [47].

In the USA, research is concentrated at the NIH, with prospective multinational cohorts [39, 46]. The 2022–2023 cohort included a 6-year-old Brazilian boy, compound heterozygous for p.(Arg39Cys) and p.(Leu144Arg), with epilepsy, ataxia and myoclonus [39]. The sources consulted contain no data from Portugal. These gaps reflect the sources analysed and do not demonstrate the absence of patients in those countries.

9.3 Special populations

Ancestry alters the pre-test probability and justifies testing the founder variants first in Finns, Swedes, Mennonites, Inuit and Bedouins [1]. In related couples or couples from the same community, regional homozygosity detected on SNP arrays may guide the diagnosis [18, 42]. Patients with FSASD have intellectual disability and are often non-verbal, which requires attention to pain, sleep disorders and psychiatric symptoms [14, 54].

9.4 European network and patient associations

MetabERN, the European Reference Network for hereditary metabolic disorders, includes a lysosomal disorders subnetwork (https://metab.ern-net.eu/) [20]. The Salla Treatment and Research (STAR) Foundation, founded in 2018 by an affected family, supports research, organises conferences and maintains a patient registry (https://www.star-foundation.io/) [39, 77]. GeneReviews also lists Metabolic Support UK, the National Tay-Sachs and Allied Diseases Association and the Myelin Disorders Bioregistry Project [1], the latter registered as NCT03047369 [73].

10. Illustrative Clinical Case

10.1 Severe infantile form with a novel variant and hyporegenerative anaemia

Cappozzo and colleagues described in 2025 a white girl, the second child of non-consanguineous parents, with no family history [13]. No invasive prenatal diagnostic procedures were performed and maternal infectious screening was negative. Third-trimester ultrasound showed oligohydramnios, reduced fetal movements, cardiomegaly and a femur on the 1st centile, without hydrops. She was born by caesarean section at 35 weeks and 6 days, because of breech presentation, with appropriate weight and length and head circumference at the upper limit of normal (+1.94 standard deviations). Minutes after delivery she developed respiratory distress requiring continuous positive airway pressure, and placement of a gastric tube revealed bleeding, with severe anaemia treated with transfusion, tranexamic acid and pantoprazole. On the second day, the echocardiogram showed right ventricular dilatation with mild hypokinesia, and transfontanellar ultrasound showed signs of lenticulostriate vasculopathy. Expanded newborn screening was normal. MRI at 4 days showed enlarged subarachnoid spaces, mild ventriculomegaly, absence of myelin in the posterior limbs of the internal capsules, frontal and parietal periventricular T2 hypointensity, small hyperintense lesions in the genu of the corpus callosum and small cavitations in the splenium [13].

At 2 months, she had coarse facies (hypertelorism, saddle nose, anteverted nares), sparse fair hair, gingival hypertrophy, fifth-finger clinodactyly, a thoracolumbar gibbus, bilateral adducted talipes equinovarus and faltering growth, with severe delay (no eye contact or social smile), global hypotonia, paucity of spontaneous movements and startle reactions; she had hepatomegaly and splenomegaly, an albinoid optic disc on fundoscopy and dysostosis multiplex [13]. Radiographs and spinal MRI showed anterior beaking of the vertebral bodies, anterior wedging of T12 and L1 with early thoracolumbar kyphosis and widened oar-shaped ribs (figure 2 of the article) [13]. Brain MRI at 2 months showed loss of white matter volume, worsening periventricular T2 hypointensity, now with T1 hyperintensity, no progression of myelination (figure 3), thinning of the corpus callosum, especially in the splenium, and a small optic chiasm with thin optic nerves (figure 4); spectroscopy in the right basal ganglia (echo time 288 ms) showed a raised peak at the NAA position [13].

Chitotriosidase was above 200 nmol/mL/h on three measurements (reference 20.3–66.7) and the peripheral blood film showed many vacuolated lymphocytes [13]. Leucocyte activities of β-glucosidase, acid sphingomyelinase, β-galactosidase, total β-hexosaminidase and arylsulfatase A and plasma activities of α-L-fucosidase and total β-hexosaminidase were normal, ruling out Gaucher disease type 2, Niemann-Pick disease type A, GM1 and GM2 gangliosidoses, multiple sulfatase deficiency, fucosidosis and mucolipidosis II; urinary glycosaminoglycans were normal and semi-quantitative oligosaccharide analysis showed increased excretion of free sialic acid [13]. A next-generation sequencing panel (GNE, NEU1, NPL, GNPTAB and SLC17A5) identified compound heterozygosity for c.1138_1139del p.(Val380SerfsTer8), of paternal origin and pathogenic, and c.709G>A p.(Gly237Arg), of maternal origin and not previously described, which affects a conserved residue in a transmembrane domain; initially classified as a VUS, it was reclassified as likely pathogenic by the multidisciplinary team on the basis of its phase in trans with a pathogenic variant and the concordance of the phenotype (PM3 and PP4 criteria) [13]. In the designations of the MANE transcript NM_012434.5, the two variants have the same notation [5].

Haemoglobin was 75 g/L (age reference 90–141) with reticulocytes at the lower limit, and normal indices and platelets; glucose-6-phosphate dehydrogenase activity was normal, the diepoxybutane test was inconclusive and the Fanconi anaemia genes were negative [13]. The anaemia persisted despite repeated transfusions and required weekly erythropoietin, with partial benefit. Hypoalbuminaemia and proteinuria developed, with a diagnosis of nephrotic syndrome, followed by renal failure (creatinine 0.7 mg/dL, urea 80 mg/dL). At 15 months, the patient was in a critical condition, on bilevel non-invasive ventilation during sleep, albumin infusions twice weekly and weekly erythropoietin to keep haemoglobin close to 90 g/L, with difficult oral feeding and an ethical discussion about parenteral nutrition [13].

The case brings together the elements that lead to the diagnosis of the severe form: prenatal signs without hydrops, a storage disease phenotype at birth, vacuolated lymphocytes, hypomyelination with periventricular changes and optic atrophy on MRI, enzymatic exclusion of other lysosomal diseases, raised urinary free sialic acid and molecular confirmation. Hyporegenerative anaemia had not previously been described in ISSD, and the link between sialic acid metabolism and erythropoiesis is the authors' hypothesis [13]. The supportive measures described (transfusions, erythropoietin, albumin, ventilation) are individual decisions, not a disease protocol, and did not modify the course [1, 13]. Figures 2, 3 and 4 are in the open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC12743418/).

10.2 Contrast: intermediate form in the NIH cohort

In the NIH cohort, a Norwegian girl aged 3 years and 1 month, compound heterozygous for c.115C>T p.(Arg39Cys) and c.507del p.(Leu170Ter), was born at 37 weeks and 5 days with asphyxia and bradycardia, had evident delay at 4 months, was diagnosed with cerebral palsy at 5 months and at 8 months had an MRI with markedly delayed myelination and atrophy of the brainstem, brain (including the corpus callosum) and optic nerves [39]. She required a gastrostomy for dysphagia and had bilateral optic nerve hypoplasia, scoliosis and kyphosis, hypotonia and ataxia. At the NIH assessment she had bilaterally abnormal auditory evoked potentials, progression of cerebral atrophy and progression of myelination, still markedly delayed, and a mental age equivalent to 4 months [39]. Figure 1 of the article compares this patient's MRI with that of the oldest patient in the cohort (9 years and 1 month) and shows that myelination advances in the normal order, albeit with great delay [39].

11. Prognosis and Long-Term Follow-Up

11.1 Survival and prognostic determinants

The prognosis depends on the position on the spectrum. In the series of 116 published cases, the estimated median survival of the 106 patients diagnosed after birth was 11 years, and 57.8% had died at last follow-up; patients with urinary free sialic acid excretion below 6.37 times the normal mean (p < 0.001; n = 54) or with fibroblast storage below 7.37 times (p = 0.014; n = 46) lived significantly longer, and higher excretion was associated with earlier onset [3]. These thresholds derive from aggregated laboratory data from several laboratories and must be confirmed prospectively; these are patients not treated with specific therapy, because none exists [3]. Survival of the ten cases diagnosed prenatally did not exceed one day, largely because of termination of pregnancy [3].

In ISSD, death usually occurs in early childhood (mean age 13.1 months in the review of 27 cases), almost always from respiratory infection [1, 17]; survival rarely exceeds 2 years [14, 18]. In the intermediate form, there are slow gains until the end of childhood and regression from adolescence, with documented courses of 15–20 years [15]. In Salla disease, life expectancy is shortened but there are patients aged 72 years [1]; in the Finnish cohort of 41 patients, mortality exceeded that of the population from 30 years of age (p = 0.00005), with mean survival of 57.2 years in women and 59.0 in men, and all eight who died had epilepsy [14]. Early development predicts the later course: developmental age at reassessment depended on the initial developmental age and not on age or sex [14]. Compound heterozygosity with R39C on only one allele is associated with much lower developmental ages [14].

11.2 Surveillance

Routine testing of asymptomatic relatives at risk is not recommended [1]. The biomarkers under study (leucocyte, plasma and CSF free sialic acid, CSF gangliosides, myelination quantified by MRI and 1H-MRS) do not yet have a role in clinical monitoring [38, 39, 46].

12. Summary and Final Considerations

Free sialic acid storage disorder is an autosomal recessive lysosomal disease caused by loss of function of sialin, encoded by SLC17A5, and forms a continuous spectrum ranging from Salla disease, which progresses slowly over decades, to the severe infantile form, which presents in utero and leads to death in early childhood [1–3]. The Finnish founder variant p.(Arg39Cys) is present in about 80% of reported patients and, in the homozygous state, determines the less severe form; its combination with more severe variants determines the intermediate forms, and biallelic truncating variants the severe form [1, 13]. The correlation is partial, with variability within families [43, 44].

The common picture is neurological: hypotonia and motor delay in the first year, intellectual disability with comprehension better than expression, ataxia giving way to athetosis, spasticity, adult-onset epilepsy in the less severe form and, in all forms, central hypomyelination with a thin corpus callosum, together with peripheral neuropathy and visual and auditory changes [14, 39, 53]. The severe form adds fetal hydrops or ascites, visceromegaly, cardiomegaly, dysostosis and nephrotic syndrome [17, 47]. Urinary free sialic acid is the initial biochemical test, with known limitations (analytical interference, age dependence, cases without sialuria), and the diagnosis is confirmed by biallelic variants; sequencing should be complemented by deletion analysis and, in difficult cases, by RNA studies, long reads and tissues other than blood [1, 32, 43]. The lysosomal excess distinguishes FSASD from sialuria (GNE) and NPL deficiency, in which the excess is cytoplasmic, and free sialic acid distinguishes it from the sialidoses, which store bound sialic acid [1, 2].

There is no specific treatment, clinical practice guideline, interventional trial or orphan designation in the European Union; management follows the GeneReviews expert recommendations, with multidisciplinary assessment, rehabilitation, epilepsy control, nutrition, educational support and annual surveillance of the eyes, heart and kidney [1, 72, 73]. Genetic counselling is based on the 25% recurrence risk, molecular carrier detection, prenatal and preimplantation diagnosis and knowledge of the Finnish, Mennonite, Inuit and Bedouin founder variants [1, 45]. Recent research, with the R39C mouse model, base editing of the founder variant, leucocyte biomarkers and the first prospective cohort, is preparing the outcomes for future trials, still without clinical application [19, 39, 46, 74].

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