Mucopolysaccharidosis type 3 (ORPHA:581)
A group of rare lysosomal storage diseases characterized by progressive neurocognitive decline, loss of functional abilities and premature death. There are four etiological subtypes of mucopolysaccharidosis type 3 (MPS III, Sanfilippo syndrome) called Sanfilippo syndrome type A, B, C, and D. Each subtype is caused by deficiency of a particular enzyme involved in the degradation of heparan sulfate leading to substrate accumulation and cellular dysfunction.
Epidemiology
The total number of patients with Sanfilippo syndrome is most likely underestimated due to delayed or missed diagnoses. The combined prevalence of Sanfilippo syndrome is estimated as 1:50,000 to 1:250,000 depending on the population studied. Sanfilippo syndrome type A is the most common subtype globally; however, the prevalence of subtypes can vary depending on the geographic region. Sanfilippo syndrome types C and D are much less common.
Clinical description
The age at onset, severity of symptoms and rate of disease progression vary greatly in Sanfilippo patients. The behavioral, cognitive, and physical findings present as a clinical spectrum from early-onset, rapidly progressive disease with death in late childhood and adolescence, to slower progressing forms that present in later childhood with survival into adulthood. After a period of normal development typical disease manifests between 1 and 4 years of age with mild global developmental or speech delay. Behavioral disturbances include but are not limited to hyperactivity, attention deficit, loss of impulse control, unawareness of dangerous situations, autistic-like behavior, hyperorality and unresponsiveness to discipline. Furthermore, patients frequently present with severe sleep disturbances. Physical manifestations are often less pronounced and might include musculoskeletal, respiratory, gastrointestinal, cardiovascular symptoms and hearing loss. In later stages of the disease patients show a decline in engagement with their environment, dementia, and progressive loss of motor function. Patients may develop seizures, dysphagia, and become fully bedridden.
Etiology
Deficiencies in one of the four enzymes required for heparan sulfate (HS) degradation are responsible for each of the subtypes: heparan-N-sulfatase for Sanfilippo syndrome type A (SGSH gene), alpha-N-acetylglucosaminidase for type B (NAGLU gene), alpha-glucosaminide N-acetyltransferase for type C (HGSNAT gene), and N-acetylglucosamine-6-sulfate sulfatase for type D (GNS gene). Numerous pathogenic variants have been identified in corresponding genes.
Diagnostic methods
In individuals with clinical features suggestive of Sanfilippo syndrome confirmation of diagnosis requires at least two biochemical or genetic tests. Diagnosis is based on detection of increased levels of HS in urine, demonstration of one of the four enzyme deficiencies and/or evidence of pathogenic or likely pathogenic variants in the corresponding genes. For types A and D, the measurement of the activity of another sulfatase is compulsory for exclusion of multiple sulfatase deficiency.
Differential diagnosis
Sanfilippo syndrome should be included in the differential diagnosis of children with behavioural disorders, attention deficit syndrome and autism spectrum disorders. Furthermore, other neuropathic types of mucopolysaccharidoses (e.g. neuropathic Hunter syndrome) do present with a similar phenotype.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variants have previously been identified.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
There is currently no approved disease-modifying therapy for patients with Sanflippo syndrome. However, disease-specific therapies are being studied within clinical trials including but not limited to enzyme replacement therapies accessing the central nervous system as well as in vivo and ex vivo gene therapies. Patient care requires a multidisciplinary team with experience in the management of Sanfilippo syndrome focusing on supportive interventions to maintain function, optimize ability, and maximize quality of life. Consensus guidelines for clinical care are available.
Prognosis
The prognosis is poor with death usually occurring within the second decade of life in severe cases (> 80% of cases). Patients with attenuated phenotypes have a more variable life span, in rare cases surviving into the seventh decade of life.

                            Last update: 
                            June 2024


                            - Expert reviewer(s): 
                            Dr Nicole MUSCHOL | MetabERN*


                                * European Reference Network