Clinical Guidance

Correlations between the type of SLC17A5 pathogenic variant and the severity of FSASD have been identified [, , , , , ]:

• Homozygosity for the Finnish founder pathogenic 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 pathogenic variant .

Variable phenotypic expression has been observed among affected family members , suggesting involvement of additional genetic or environmental factors.

Source: GeneReviews — "Free Sialic Acid Storage Disorder"

Penetrance

FSASD appears to be fully penetrant. However, two individuals homozygous for SLC17A5 pathogenic variant had no detectable urinary sialic acid abnormality and elevated cerebrospinal fluid free sialic acid, suggesting that penetrance based on urinary studies alone may be reduced .

Source: GeneReviews — "Free Sialic Acid Storage Disorder"

Diagnostic Criteria

There are no consensus clinical diagnostic criteria for free sialic acid storage disorder (FSASD).

Suggestive Findings

FSASD should be suspected 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 age one year

• 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

Source: GeneReviews — "Free Sialic Acid Storage Disorder"

Differential Diagnosis

Biochemical Findings Increased urinary and cellular free sialic acid. The only disorders in which significantly elevated urinary and cellular free sialic acid is known to occur are sialuria (OMIM 269921), N-acetylneuraminate pyruvate lyase (NPL) deficiency, and free sialic acid storage disorder (FSASD) . Of note, in both sialuria and NPL deficiency, elevated free sialic acid is localized in the cytoplasm rather than the lysosome as in FSASD. The clinical course of sialuria involves developmental delay and hepatomegaly. NPL deficiency is associated with progressive cardiac myopathy and mild skeletal myopathy. Neither disorder is associated with the severe neurologic involvement that occurs in FSASD. 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 FSASD. • Molecular genetic testing of SLC17A5 (for FSASD), GNE (for sialuria), or NPL (for NPL deficiency) 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 . These enzyme deficiencies involve lysosomal storage of sialic acid-containing glycoconjugates. Neuraminidase deficiency and galactosialidosis both have features typical of lysosomal storage diseases but vary widely in their manifestations. Clinical Findings See for other lysosomal storage disorders that are associated with the clinical manifestations of coarse facial features and developmental delays as well as other causes of nonimmune hydrops fetalis. Table 3. Other Genes of Interest in the Differential Diagnosis of Free Sialic Acid Storage Disorder

Management Guidelines

No clinical practice guidelines for free sialic acid storage disorder (FSASD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FSASD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Free Sialic Acid Storage Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval | • To incl brain MRI

• Consider EEG if seizures are a concern.

Developmental

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

Musculoskeletal

| Orthopedics/ physical medicine rehab/ PT OT eval | 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 eval

• Assess for hernia in those w/intermediate severe or severe FSASD.

| • To incl eval of aspiration risk nutritional status

• Consider eval for gastrostomy tube placement in those w/dysphagia /or aspiration risk.

Source: GeneReviews — "Free Sialic Acid Storage Disorder"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Free Sialic Acid Storage Disorder"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. Free Sialic Acid Storage Disorder: Recommended Surveillance

Source: GeneReviews — "Free Sialic Acid Storage Disorder"