Sanfilippo Syndrome (Mucopolysaccharidosis Type III) is a rare, progressive, neurodegenerative genetic disorder. It is caused by the body’s inability to break down heparan sulfate, a complex sugar molecule. The accumulation of heparan sulfate, especially in the central nervous system, leads to cellular damage, dysfunction, and neurological and physical symptoms. Early identification is important for timely supportive care and access to emerging clinical trials.
Typical Age of Symptom Onset
Infants with Sanfilippo Syndrome typically appear normal at birth and during their first year. Initial signs usually become apparent between the ages of one and four years, though timing and severity vary across the four subtypes (A, B, C, and D). The earliest indicators are often subtle and primarily neurological or behavioral.
A common first sign is delayed speech and language acquisition, sometimes noticeable by age two. Children may struggle to learn new words or fail to meet expected language milestones, prompting a medical evaluation.
Following this initial developmental delay, behavioral issues and hyperactivity often emerge between ages three and ten. These can include sleep disturbances, aggression, destructiveness, and a lack of fear of danger.
Physical signs are generally less pronounced than in other mucopolysaccharidoses, making early clinical diagnosis difficult. While some children may exhibit mildly coarse facial features or excessive body hair, these signs are often not specific enough to suggest Sanfilippo Syndrome. The disease progresses with a slow-down in mental development after the toddler years, followed by a progressive loss of skills.
Factors Leading to Diagnostic Delays
The time between symptom onset and definitive diagnosis is often significantly delayed, frequently extending until age four or later. This delay occurs because the condition is rare, and primary care physicians may not immediately consider it. Furthermore, neurological symptoms like speech delay and hyperactivity frequently overlap with far more common childhood conditions.
Many children are initially misdiagnosed with conditions such as autism spectrum disorder, general developmental delay, or attention deficit/hyperactivity disorder (ADHD). Sanfilippo symptoms closely mimic features of these other disorders, leading to a focus on non-genetic explanations.
The subtlety of physical signs also contributes to the diagnostic challenge, as coarse facial features and skeletal changes are much milder in MPS III than in other forms of mucopolysaccharidosis. Even somatic signs like an enlarged liver or spleen can be overlooked when a child presents primarily with behavioral issues. The mean age of diagnosis for the more severe Type A and Type B subtypes is typically between 3.5 and 4.9 years, while diagnosis for the slower-progressing Type C and Type D can be delayed until mid-childhood or later adolescence.
Steps for Confirmatory Diagnosis
The definitive diagnosis of Sanfilippo Syndrome requires a sequence of specific laboratory tests. The initial screening test often involves a urine analysis to measure heparan sulfate levels. An elevated amount of heparan sulfate suggests a mucopolysaccharidosis, but this test cannot distinguish between the four Sanfilippo subtypes.
The gold standard for confirmation is the enzyme assay, which measures the activity of the four specific lysosomal enzymes involved in heparan sulfate breakdown. A deficiency in one of these four enzymes pinpoints the exact subtype of Sanfilippo Syndrome. For example, a deficiency in the sulfamidase enzyme indicates Type A, while a deficiency in alpha-N-acetylglucosaminidase indicates Type B.
The final step is molecular genetic testing, performed by sequencing the relevant genes to identify the specific mutation. This testing identifies pathogenic variants in one of the four genes: SGSH (Type A), NAGLU (Type B), HGSNAT (Type C), or GNS (Type D). Genetic testing confirms the diagnosis, informs genetic counseling, and determines eligibility for clinical trials.
Current and Future Early Screening Methods
The earliest possible diagnosis, before irreversible neurodegeneration begins, can be achieved through proactive screening methods. For families with a known history of Sanfilippo Syndrome, prenatal diagnosis is available via procedures like chorionic villus sampling or amniocentesis.
Carrier screening is also an option for couples to determine if they both carry a mutated gene, as Sanfilippo Syndrome is inherited in an autosomal recessive pattern. If both parents are carriers, they have a one-in-four chance of having an affected child with each pregnancy.
Sanfilippo Syndrome is not currently included on routine, mandated newborn screening panels in every region. However, efforts are underway to add it, with pilot programs testing newborns for Type A and Type B using dried blood spots. Widespread newborn screening would allow for diagnosis before symptoms appear, offering the greatest benefit for future therapeutic interventions.