Infantile sialic acid storage disorder (ISSD) represents the most severe form of free sialic acid storage disease (FSASD), a rare lysosomal storage disorder caused by mutations in SLC17A5, which encodes the lysosomal sialic acid transporter sialin. These mutations lead to the accumulation of free sialic acid within lysosomes, resulting in multisystemic involvement. Through a case report and literature review, we explored the phenotypic spectrum of FSASD, with a particular focus on neurological manifestations and characteristic neuroimaging findings of ISSD. Our patient exhibited severe hypotonia shortly after birth, dysmorphic features, and hyporegenerative anemia, a clinical presentation that has not previously described in ISSD. Brain MRI revealed hypomyelination, periventricular white matter T1-hyperintensity and T2-hypointensity, callosal thinning, and optic atrophy, providing critical diagnostic clues. MR spectroscopy showed an elevated NAA-like peak, further supporting the suspicion of ISSD. Laboratory tests demonstrated increased chitotriosidase activity and elevated urinary excretion of free sialic acid. Next-generation sequencing identified compound heterozygosity for a known pathogenic variant and a previously unreported SLC17A5 variant (c.709G>A), affecting a highly conserved transmembrane domain residue and predicted to be pathogenic. Our findings underscore the role of neuroimaging in the early diagnosis of ISSD and suggest a potential link between sialic acid metabolism and erythropoiesis, suggesting further investigation. Despite the lack of targeted therapies, recognizing FSASD remains essential for patient management and genetic counselling, ensuring appropriate clinical care and family support. Free sialic acid storage disorder (FSASD) is a spectrum of neurodegenerative phenotypes resulting from increased lysosomal storage of free sialic acid. Less severe FSASD (historically called Salla disease) is 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. Severe FSASD (historically referred to as infantile free sialic acid storage disease, or ISSD) is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood. The diagnosis of FSASD is established in a proband by identification of biallelic pathogenic variants in SLC17A5 by molecular genetic testing. Treatment of manifestations: Management is symptomatic and supportive: standard treatment of seizures; developmental and educational support; rehabilitation to optimize mobility; supplementation of calcium and vitamin D for low bone density; feeding therapy and provision of adequate nutrition; treatment of ophthalmologic manifestations per ophthalmologist with low vision services as needed; treatment of cardiomegaly per cardiologist; treatment of nephropathy / nephrotic syndrome per nephrologist; surgical treatment of hernia as needed; family and social support. Surveillance: Assessment of seizures, other neurologic manifestations, development, mobility, growth, nutrition, feeding, respiratory status, and family needs at each visit. Annual ophthalmology exam in those with intermediate or severe FSASD. Annual EKG and echocardiography to assess for cardiomegaly. Annual urinalysis for proteinuria. FSASD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC17A5 pathogenic variant, each sib of an affected individual has at conception 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. Once the SLC17A5 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing and prenatal/preimplantation genetic testing are possible.

Lysosomal storage disorders (LSDs) are a group of inherited metabolic diseases caused by dysfunction of the lysosomal system, with subsequent progressive accumulation of macromolecules, activation of inflammatory response, and cell death. Neurologic damage is almost always present, and it is usually degenerative. White matter (WM) involvement may be primary or secondary. Diseases with primary WM involvement are leukodystrophies, demyelinating (Krabbe disease and metachromatic leukodystrophy), and hypomyelinating leukodystrophies (free sialic acid storage disease, fucosidosis, and mucolipidosis type IV). LSDs with secondary WM involvement are classified as leukoencephalopathies and include gangliosidosis, mucopolysaccharidosis (MPS), ceroid neuronal lipofuscinosis, multiple sulfatase deficiency, alpha-mannosidosis, Pompe disease, and Fabry disease. Neurologic manifestations may overlap among LSDs and include developmental delays, motor, cognitive and speech impairments, seizures, visual failure, ataxia, and extrapyramidal signs. Most of LSDs are typically present in early or late infancy, but juvenile and adult forms also exist and are associated with predominantly neuropsychiatric and behavioral symptoms. The outcome of these disorders is generally poor and specific treatments (enzyme replacement therapy, hematopoietic stem cell transplantation, or gene therapy) are only available in a small number of them.

Free sialic acid storage disorders (FSASDs) result from pathogenic variations in the SLC17A5 gene, which encodes the lysosomal transmembrane protein sialin. Loss or deficiency of sialin impairs FSA transport out of the lysosome, leading to cellular dysfunction and neurological impairment, with the most severe form of FSASD resulting in death during early childhood. There are currently no therapies for FSASDs. Here, we evaluated the efficacy of CRISPR-Cas9-mediated homology directed repair (HDR) and adenine base editing (ABE) targeting the founder variant, SLC17A5 c.115C>T (p.Arg39Cys) in human dermal fibroblasts. We observed minimal correction of the pathogenic variant in HDR samples with a high frequency of undesired insertions/deletions (indels) and significant levels of correction for ABE-treated samples with no detectable indels, supporting previous work showing that CRISPR-Cas9-mediated ABE outperforms HDR. Furthermore, ABE treatment of either homozygous or compound heterozygous SLC17A5 c.115C>T human dermal fibroblasts demonstrated significant FSA reduction, supporting amelioration of disease pathology. Translation of this ABE strategy to mouse embryonic fibroblasts harboring the Slc17a5 c.115C>T variant in homozygosity recapitulated these results. Our study demonstrates the feasibility of base editing as a therapeutic approach for the FSASD variant SLC17A5 c.115C>T and highlights the usefulness of base editing in monogenic diseases where transmembrane protein function is impaired.

Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease, intermediate-severe Salla disease, and infantile free sialic acid storage disease. Intermediate-severe Salla disease is the most recently described form. Here, we report a longitudinal characterization of intermediate-severe Salla disease progression in two sisters carrying the following biallelic variants in SLC17A5: c.406A>G (p.Lys136Glu) and c.819+1G>A. A retrospective review of medical records was performed. A developmental questionnaire was completed to obtain further clinical information. For functional characterization of the predicted splice site variant, RNA was extracted from patient blood samples and sequenced. Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence. Functional studies confirmed the pathogenicity of the c.819+1G>A variant, resulting in a frameshift and deletion of exon 6. We present a detailed study describing the clinical course of intermediate-severe Salla disease with over 15 to 20 years of evolution and demonstrate the pathogenicity of the c.819+1G>A splice site variant.

A boy, aged 3 hours, was admitted due to a prenatal diagnosis of fetal hydrops at 3 hours after resuscitation for birth asphyxia. Prenatal examination at 5 months of gestation showed massive ascites in the fetus, and after birth, the boy had the manifestations of systemic hydroderma, massive ascites, coarse face, and hepatomegaly. Genetic testing revealed heterozygous mutations in the SLC17A5 gene, and there was a significant increase in urinary free sialic acid. Placental pathology showed extensive vacuolization in villous stromal cells, Hofbauer cells, cytotrophoblast cells, and syncytiotrophoblast cells in human placental chorionic villi. The boy was finally diagnosed with free sialic acid storage disorders (FSASDs). This is the first case of FSASDs with the initial symptom of fetal hydrops reported in China. The possibility of FSASDs should be considered for cases with non-immune hydrops fetalis, and examinations such as placental pathology and urinary free sialic acid may help with early diagnosis and clinical decision making. 患儿，男，生后3 h，因产前诊断胎儿水肿、出生窒息复苏后3 h入院。患儿母亲孕5个月产检提示胎儿有大量腹水，患儿生后表现为全身皮肤水肿、大量腹水、面容粗糙、肝大。基因检测提示SLC17A5基因杂合变异，尿游离唾液酸显著升高，胎盘病理回报绒毛间质细胞、霍夫鲍尔细胞、细胞滋养层细胞和合体滋养层细胞广泛空泡化，该患儿最终诊断为唾液酸贮积症。该例患儿为国内首次报道以胎儿水肿为首发症状的唾液酸贮积症新生儿。对非免疫性胎儿水肿病例需考虑唾液酸贮积症可能，胎盘病理、尿游离唾液酸等检查有助于早期诊断和指导临床决策。.