Free Sialic Acid Storage Disorders

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2021-01-18

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Summary

Clinical characteristics.

Free sialic acid storage disorders (FSASDs) are a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). The mildest type was Salla disease, characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures. Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term Salla has been used in the literature to refer to less severe FSASD. More severe FSASD is historically referred to as ISSD, and is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.

Diagnosis/testing.

The diagnosis of a FSASD is established in a proband by identification of biallelic pathogenic variants in SLC17A5 on molecular genetic testing.

Management.

Treatment of manifestations: Management is symptomatic and supportive: standard treatment of seizures; feeding therapy and provision of adequate nutrition; rehabilitation to optimize mobility and communication; supplementation of calcium and vitamin D for low bone density; family and social support.

Surveillance: Assessment of feeding, respiratory status, seizures, development, mobility, and nutrition with each visit. Regular evaluation by a rehabilitation specialist to identify potentially helpful interventions. Annual ECG and echocardiography for cardiomegaly.

Genetic counseling.

The FSASDs are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Molecular genetic carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.

Diagnosis

There are no consensus clinical diagnostic criteria for free sialic acid storage disorders (FSASDs).

Suggestive Findings

A FSASD should be suspected/considered in individuals with the following clinical, imaging, and laboratory findings.

Less Severe FSASD Including Salla Disease

Clinical findings

Truncal ataxia and hypotonia apparent at approximately one year of age
Developmental delay
Growth deficiency (short stature)
Intellectual disability
Spasticity
Facial coarsening (variable and not always present)

Imaging findings on brain MRI examination

Hypomyelination of the basal ganglia
Hypoplasia of the corpus callosum

Severe FSASD Including Infantile Free Sialic Acid Storage Disease (ISSD)

Clinical findings

Nonimmune hydrops fetalis (24%)
Hepatosplenomegaly
Failure to thrive
Severe developmental delay
Cardiomegaly
Club feet
Increasingly coarse facial features
Neurologic deterioration
Early death

Imaging findings on skeletal survey (ISSD) include skeletal dysostosis (e.g., irregular enlarged metaphyses, short femurs, diffuse hypomineralization with fractures, hip dysplasia, anterior beaking of the dorsal vertebrae, and hypoplasia of the distal phalanges).

FSASD Including Less Severe and Severe Forms

Laboratory findings

Free sialic acid. Sialic acids are a family of negatively charged sugars, one of which, N-acetylneuraminic acid, is elevated in lysosomes in free sialic acid storage disorders.
Urinary excretion of free sialic acid, measured by the fluorimetric thiobarbituric acid assay, thin-layer chromatography or mass spectrometry, is elevated about tenfold in individuals with Salla disease and about 100-fold in individuals with ISSD. HPLC/tandem mass spectrometry is also able to detect free sialic acid in urine [Valianpour et al 2004].
Note: (1) In the thiobarbituric acid assay, interfering substances may lower the measurement and chromophores may contribute to absorbance, creating a false measurement. (2) In thin-layer chromatography, an elevation of free sialic acid may be overlooked.
Cultured fibroblasts from individuals with all forms of FSASD show increased concentration of free sialic acid [Renlund et al 1986].

Establishing the Diagnosis

The diagnosis of a free sialic acid storage disorder is established in a proband by identification of biallelic pathogenic variants in SLC17A5 on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of free sialic acid storage disorders is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited neurodegenerative disorders are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of free sialic acid storage disorders, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

Single-gene testing. Sequence analysis of SLC17A5 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
Note: Targeted analysis for pathogenic variant p.Arg39Cys can be performed first in individuals of Finnish or Swedish ancestry [Aula et al 2000].
A multigene panel that includes SLC17A5 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of free sialic acid storage disorders some panels for developmental delay may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, comprehensive genomic testing (which does not require the clinician to predetermine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Free Sialic Acid Storage Disorders

Gene ¹	Method	Proportion of Pathogenic Variants ² Detectable by Method
SLC17A5	Sequence analysis ³	90%-95% ^4, 5
SLC17A5	Gene-targeted deletion/duplication analysis ⁶	5%-10% ^4, 7

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: The p.Arg39Cys variant, known as the "FIN" variant, is common in the Finnish and other Nordic populations; therefore, a higher detection rate by sequencing is expected in those populations [Peltonen et al 1999, Aula et al 2000].
5.: Aula et al [2000], Froissart et al [2005], Zielonka et al [2019]
6.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
7.: Tarailo-Graovac et al [2017], Žigman et al [2018]

Clinical Characteristics

Clinical Description

To date, approximately 80 individuals have been identified with biallelic pathogenic variants in SLC17A5 [Alajoki et al 2004, Zielonka et al 2019]. (~300 individuals with free sialic acid storage disorders (FSASDs) are reported in the literature, but many reports do not include molecular data.) The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Select Features of Free Sialic Acid Storage Disorders

Feature ¹		% of Persons w/Feature
Developmental delay / cognitive impairment		75%
Facial dysmorphism / coarse facies ²		50%-68% ²
Hepatosplenomegaly		54%
Truncal hypotonia		54%
Skeletal abnormalities		50%
Spasticity		48%
Ataxia		44%
Failure to thrive		42%
Short stature		27%
Hydrops fetalis		24%
Epilepsy		22%
Neurodegenerative course		20%
Neonatal ascites		19%
Cardiomegaly		19%
Hernias		19%
Microcephaly		18%
Recurrent airway infections		16%
Nystagmus		12%
Nephropathy		10%
Optic atrophy		7%
Athetosis		6%
Ptosis		3%
Hoarse voice		2%
Corneal clouding		1%
Brain MRI findings	Brain atrophy	23%
	Hypomyelination	22%
	Hypoplasia of the corpus callosum	16%

: Adapted from Zielonka et al [2019]
1.: Includes features reported in entire spectrum of phenotype (less-severe to severe FSASD)
2.: Coarse facies are more frequent in severe FSASD.

The FSASDs comprise a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term Salla has been used in the literature to refer to less severe FSASD in general. Less severe FSASD is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor delay, spasticity, athetosis, and epileptic seizures. More severe FSASD, also known as ISSD, is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.

Less Severe FSASD (Salla Disease)

Salla disease, which serves as a model for less severe FSASD, has the mildest phenotype [Varho et al 2002]. It is characterized by a normal appearance and normal neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delay [Renlund et al 1983, Alajoki et al 2004]. Muscular hypotonia is often first recognized at approximately age six months. One third of affected children learn to walk. Expressive language development can be limited to single words but receptive speech is good. Slow developmental progress often continues until the third decade, after which regression can occur.

Some individuals with Salla disease present later in life with spasticity, athetosis, and epileptic seizures, becoming nonambulatory and nonverbal. Affected individuals are characterized as good-humored and sociable [Varho et al 2002].

T₂-weighted bright cerebral white matter changes on brain MRI are typical but variable. Abnormal myelination of the basal ganglia and hypoplasia of the corpus callosum are constant and early findings [Sonninen et al 1999]. Cerebellar white matter changes are also present and can explain the ataxia [Linnankivi et al 2003, Biancheri et al 2004]. In addition to the central dysmyelination, a peripheral dysmyelination with the clinical picture of a polyneuropathy occurs with variable neurologic presentations [Varho et al 2000, Varho et al 2002].

Affected individuals do not have organomegaly, skeletal dysostosis, or abnormal eye findings. Growth hormone and gonadotropin deficiencies were observed in one individual [Grosso et al 2001].

Life expectancy appears to be shortened, although affected individuals up to age 72 years have been observed.

Intermediate Severe FSASD

Since the advent of molecular studies, phenotypes with a severity between those of Salla disease and ISSD [Aula & Gahl 2001] have been attributed to compound heterozygosity for the Salla disease-causing common pathogenic variant p.Arg39Cys and another SLC17A5 pathogenic variant [Kleta et al 2003]. Thus, the term "intermediate severe Salla disease" was proposed [Aula et al 2000].

Severe FSASD (Infantile Free Sialic Acid Storage Disease; ISSD)

ISSD, the most severe phenotype, is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly. Additional reported features include early truncal hypotonia with later spasticity and ataxia, skeletal abnormalities, and seizures (see Table 2). No single feature occurs in all individuals.

ISSD can present prenatally and in the neonatal period with nonimmune hydrops fetalis (24% of individuals) [Lemyre et al 1999, Stone & Sidransky 1999, Froissart et al 2005, Zielonka et al 2019]. Some affected infants are born prematurely. Other affected infants appear normal at birth but lose developmental milestones during infancy [Kleta et al 2003, Kleta et al 2004].

Skeletal abnormalities can include irregular metaphyses, diffuse hypomineralization, club feet, short femurs, enlarged metaphyses, fractures, hip dysplasia, anterior beaking of the dorsal vertebrae, and hypoplasia of the distal phalanges [Froissart et al 2005].

Dysmorphic facial features are nonspecific and generally fall into the spectrum of "coarsened" features (e.g., epicanthal folds, ptosis, anteverted nose, gum hypertrophy).

Reported ocular findings include nystagmus, exotropia, optic atrophy, and albinoid fundi. Corneal clouding has been rarely reported.

Additional reported features include nephropathy and/or nephrotic syndrome and hernias [Lemyre et al 1999, Ishiwari et al 2004].

Death usually occurs in early childhood, typically from recurrent respiratory infections.

Genotype-Phenotype Correlations

Correlations between the type of SLC17A5 pathogenic variant and the severity of the lysosomal free sialic acid storage disease have been identified [Aula et al 2000, Varho et al 2000, Kleta et al 2003]:

Homozygosity for the pathogenic missense variant p.Arg39Cys, a single Finnish founder variant, leads to Salla disease, with its slow clinical course of neurologic deterioration.
Compound heterozygosity for the p.Arg39Cys pathogenic variant and another SLC17A5 pathogenic variant leads to intermediate severe FSASD, as does homozygosity for the p.Lys136Glu pathogenic variant [Biancheri et al 2005].
Compound heterozygosity for pathogenic variants other than p.Arg39Cys leads to the severe phenotype of FSASD (ISSD), with early onset and multisystemic involvement.

Variable expression has been observed among affected family members [Landau et al 2004].

Penetrance

The FSASDs appear to be fully penetrant. However, Mochel et al [2009] reported two individuals with homozygous p.Lys136Glu pathogenic variants, no detectable urinary sialic acid abnormality, and elevated CSF free sialic acid, suggesting that penetrance based on urinary studies alone may be incomplete.

Nomenclature

Free sialic acid storage disorders (FSASDs) have been and continue to be labeled with different terms, mainly because of the different names used to denote N-acetylneuraminic acid. The term free sialic acid storage disorder refers to the entire spectrum of disease. The form of less severe FSASD historically known as Salla disease is specific to the Finnish founder mutation, but continues to be used colloquially to refer to mild forms of FSASD. Severe, infantile onset ISSD remains in usage to refer to disease at the more severe end of the FSASD spectrum.

Prevalence

Less severe FSASD (Salla disease), has been reported in approximately 150 individuals, mainly from Finland and Sweden [Aula et al 2000, Erikson et al 2002]. Individuals with molecularly proven less severe FSASD have been identified outside of Finland and Sweden [Martin et al 2003]. The prevalence of the SLC17A5 pathogenic variant p.Arg39Cys is high in the founder region of northeastern Finland, where the carrier frequency is in the range of 1:100 [Aula et al 2000]. Ninety-five percent of individuals of Finnish heritage with FSASD have the p.Arg39Cys pathogenic variant. The prevalence of other SLC17A5 pathogenic variants appears to be independent of the geographic origin or ethnicity of affected individuals; their presence has been documented in more than 30 individuals from several countries throughout the world [Lemyre et al 1999, Aula et al 2000, Kleta et al 2003, Martin et al 2003, Sønderby Christensen et al 2003, Kleta et al 2004].

Differential Diagnosis

Biochemical Findings

Increased urinary and cellular free sialic acid. The only disorders in which significantly elevated urinary and cellular free sialic acid are known to occur are sialuria (OMIM 269921) and the free sialic acid storage disorders (Salla disease and ISSD). The clinical course of sialuria involves developmental delay and hepatomegaly but does not include severe neurologic involvement or early death. In sialuria, elevation of free sialic acid occurs in the cytoplasm rather than in the lysosome.

Based on clinical suspicion and the finding of elevated free sialic acid in urine, one of two steps is taken to distinguish these conditions:

The cellular (cytoplasmic versus lysosomal) localization of free sialic acid can be documented; a predominantly lysosomal localization indicates a FSASD.
Molecular genetic testing of SLC17A5 (for FSASD) or GNE (for sialuria) can be performed.

Note: Other causes of mild elevation in urinary free sialic acid may exist.

Sialic acid bound to glycoproteins or glycolipids. If sialic acid bound to glycoproteins or glycolipids is stored, disorders such as sialidosis caused by sialidase (neuraminidase) deficiency (OMIM 256550) and galactosialidosis (OMIM 256540) caused by combined sialidase and galactosidase deficiency should be considered (see Table 3). These enzyme deficiencies involve lysosomal storage of sialic acid-containing glycoconjugates. These disorders both have features typical of lysosomal storage diseases, but they vary widely in their manifestations.

Clinical Findings

See Table 3 for other lysosomal storage disorders that are associated with the clinical manifestation of coarse facial features and developmental delays and other causes of nonimmune hydrops fetalis. Note: All disorders included in Table 3 are inherited in an autosomal recessive manner.

Table 3.

Other Genes of Interest in the Differential Diagnosis of Free Sialic Acid Storage Disorders (FSASDs)

Clinical Finding(s) Overlapping w/FSASDs	Gene	Disorder	Associated Enzyme
Coarse facial features & developmental delays	AGA	Aspartylglucosaminuria (OMIM 208400)	N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase
	ARSB	MPS VI (OMIM 253200)	Arylsulfastase B
	FUCA1	Fucosidosis (OMIM 230000)	Tissue alpha-L-fucosidase
	GLB1	GM1 gangliosidosis (see GLB1-Related Disorders)	Beta-galactosidase
	GNPTAB	Mucolipidosis II (I-cell disease; see GNPTAB-Related Disorders)	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta
	IDS	MPS II	Iduronate 2-sulfatase
	IDUA	MPS I	Alpha-L-iduronidase
	MAN2B1	Alpha-mannosidosis	Lysosomal alpha-mannosidase
	NEU1	Sialidosis type II (OMIM 256550)	Sialidase-1
Nonimmune hydrops fetalis	CTSA	Galactosialidosis (OMIM 256540)	Lysosomal protective protein
	GALC	Krabbe disease	Galactocerebrosidase
	GBA	Gaucher disease	Lysosomal acid glucosylceramidase
	GBA2	Beta-glucosidase deficiency (OMIM 614409)	Non-lysosomal glucosylceramidase
	GNPTAB	I-cell disease (Mucolipidosis II)	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta
	GUSB	MPS VII (OMIM 253220)	Beta-glucuronidase
	IDUA	MPS I	Alpha-L-iduronidase
	LIPA	Lysosomal acid lipase deficiency	Lysosomal acid lipase/cholesteryl ester hydrolase
	NEU1	Sialidase deficiency (OMIM 256550)	Sialidase-1
	SMPD1	Acid sphingomyelinase deficiency	Sphingomyelin phosphodiesterase

: From Saudubray & Charpentier, Chapter 86, Table 42, Online Metabolic and Molecular Bases of Inherited Disease. Accessed 1-8-20 (Registration required).
: MPS = mucopolysaccharidosis

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a free sialic acid storage disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Free Sialic Acid Storage Disorders

System/Concern	Evaluation	Comment
Neurologic	Neurologic evaluation	To incl brain MRI Consider EEG if seizures are a concern.
Development	Developmental assessment	To incl motor, adaptive, cognitive, & speech/language evaluation Evaluation for early intervention / special education
Musculoskeletal	Orthopedics / physical medicine & rehabilitation / PT / OT evaluation	To incl assessment of: Gross motor & fine motor skills; Mobility, activities of daily living, & need for adaptive devices; Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Gastrointestinal/ Feeding	Gastroenterology / nutrition / feeding team evaluation	To incl evaluation of aspiration risk & nutritional status Consider evaluation for gastric tube placement in patients w/dysphagia &/or aspiration risk.
Miscellaneous/ Other	Biochemical genetics FindZebra contact@findzebra.com