Sanfilippo type A: new clinical manifestations and neuro-imaging findings in patients from the same family in Israel: a case report

Abstract

IntroductionSanfilippo syndrome type A (mucopolysaccharidosis IIIA - MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by a deficiency in sulfamidase.Case presentationTwo daughters (13 and 11 years old) of a consanguineous Palestinian family from the Israeli Arab community were investigated clinically and genetically for the presence of progressive neurodegenerative disease, psychomotor retardation and behavioral abnormalities. Development was normal up to one year of age. Thereafter, progressive motor and speech delay started. Metabolic screening including glycosaminoglycans, karyotype testing and magnetic resonance imaging were normal. Later in the disease, they developed severe spasticity and intellectual disability with autistic features and incontinence. Magnetic resonance imaging revealed diffuse hypomyelination with thinning of the corpus callosum. Genetic examination through whole exome sequencing revealed a homozygous mutation c.416C >T (p.T139M) in the N-sulfoglucosamine sulfohydrolase (SGSH) gene. Repeated biochemical testing at age 11 and 13 revealed increased levels of glycosaminoglycans confirming the diagnosis of Sanfilippo syndrome type A.ConclusionThese cases were considered to be the first report of Sanfilippo syndrome in Israel. We recommend that if similar clinical features are present during childhood, it is preferred to go directly and primarily for a genetic diagnosis of Sanfilippo syndrome, then secondarily for other lysosomal storage disorders that may also be involved.

The role of innate immunity in mucopolysaccharide diseases

“…; Sharkia et al . ), demonstrating the phenotype variation in patients versus murine models. However, the functional role of neuronal cell death in MPSIII clinical disease onset and progression is neither well established, nor understood.…”

Diagnosis of Mucopolysaccharidoses

“…In this scenario, WES/WGS could be valuable diagnostic tools: (a) to find novel genes associated with rare conditions, as the newly discovered MPS like syndrome (MPSPS) [111,112]; (b) to expand the recognized phenotypic spectrum of a well-known disease [113][114][115][116]; (c) to elucidate complex phenotypes, as reported by the group of Kaissi et al, when the genetic confirmation of MPS genes involved in a pair of siblings adds to the obscure nature of the disease [117] and (d) as a first-tier diagnostic tool for MPS, with subsequent traditional biochemical testing (GAG quantification and enzyme assay) to confirm molecular diagnosis, in an inversion of the traditional diagnostic algorithm, which may be a trend for the future if the cost of sequencing and the number of laboratories that continue to perform sophisticated enzyme assays continues to decrease [118].…”

A novel mutation in the NAGLU gene associated with Sanfilippo syndrome type B (mucopolysaccharidosis III B)

“…Each enzyme deficiency segregates the disease as follows: deficiency of N ‐sulfoglucosamine sulfohydrolase due to a mutation of its gene on chromosome 17q25 results in Sanfilippo A, homozygous or compound heterozygous mutation in the gene encoding N ‐alpha‐acetylglucosaminidase (NAGLU) on chromosome 17q21 results in Sanfilippo B, mutations in the HGSNAT gene encoding heparan acetyl‐CoA:alpha‐glucosaminide N ‐acetyltransferase, on chromosome 8p11, leads to Sanfilippo C, and finally a mutation in the gene encoding N ‐acetylglucosamine‐6‐sulfatase on chromosome 12q14 results in Sanfilippo D . Above mutations result in accumulation of excessive intralysosomal glycosaminoglycans (mucopolysaccharides) in various tissues, causing distended lysosomes to accumulate in the cell and interfere with cell function, and these patients have an increased urinary excretion of GAG and show signs of deterioration of physical and mental status characterized by severe central nervous system degeneration with mild somatic involvement manifesting as intellectual disability, dementia, and a shortened lifespan of 20–30 years . Here, we wish to report a novel homozygous variant in a child with features of Sanfilippo syndrome B.…”