Sanfilippo syndrome is a rare inherited neurodegenerative metabolic disorder for which there are no approved therapies. Symptoms of the more severe subtypes typically begin within the first years of life, rapidly producing serious and progressive physical and cognitive deficits. The underlying pathophysiology is targetable, but the delay in diagnosis of this as well as other lysosomal storage disorders (LSDs) is slowing progress toward effective therapies.
“Lack of awareness and the delays to diagnosis have been a real challenge for us. There is reason for cautious optimism about treatments now in or approaching clinical studies, but to evaluate efficacy on cognitive outcomes we need to enroll more children at a very young age, before loss of milestones,” according to Cara O’Neill, MD, a co-founder and chief science officer of Cure Sanfilippo Foundation.
Epidemiology and description
Sanfilippo syndrome, like the more than 50 other LSDs, is caused by a gene mutation that leads to an enzyme deficiency in the lysosome.1 In the case of Sanfilippo syndrome, also known as mucopolysaccharidosis (MPS III), there are hundreds of mutations that can lead to Sanfilippo by altering the function of one of the four genes essential to degradation of heparan sulfate.2 Lysosomal accumulation of heparan sulfate drives a broad spectrum of progressive and largely irreversible symptoms that typically begin with somatic manifestations, such as bowel dysfunction and recurrent ear and upper respiratory infections.
Dr. Cara O'Neill
Impairment of the central nervous system (CNS) usually occurs early in life, halting physical and mental development. As it progresses, accumulation of heparan sulfate in a variety of cells leads to a cascade of abnormal cellular signaling and dysfunction. Disruption of these processes, which are critical for normal neurodevelopment, result in loss of the developmental skills already gained and eventually loss of brain tissue.3 Although life expectancy has improved with supportive care, survival into adulthood is typically limited to milder forms.4
Over the past several years, progress in this and other LSDs has yielded therapeutic targets, including those involving gene repair and enzyme replacement. Already approved for use in some LSDs, these therapies have also shown promise in the experimental setting for Sanfilippo syndrome, leading to several completed clinical trials.5
So far, none of these treatments has advanced beyond clinical trials in Sanfilippo syndrome, but there have been favorable changes in the markers of disease, suggesting that better methods of treatment delivery and/or more sensitive tools to measure clinical change might lead to evidence of disease attenuation. However, the promise of treatment in all cases has been to prevent, slow, or halt progression, not to reverse it. This point is important, because it indicates that degree of benefit will depend on enrolling patients early in life. Even if effective therapies are identified, few patients will benefit without strategies to accelerate diagnosis.
In fact, “one study6 reported that the average age of diagnosis for Sanfilippo syndrome has not improved over the past 30 years,” according to Dr. O’Neill. She indicated that this has been frustrating, given the availability of clinical trials on which progress is dependent. There is no widely accepted protocol for who and when to test for Sanfilippo syndrome or other LSDs, but Dr. O’Neill’s organization is among those advocating for strategies to detect these diseases earlier, including screening at birth.
Almost by definition, the clinical diagnosis of rare diseases poses a challenge. With nonspecific symptoms and a broad range of potential diagnoses, diseases with a low incidence are not the first ones that are typically considered. In the case of Sanfilippo syndrome, published studies indicate incidence rates at or below 1 per 70,000 live births.7 However, the incidence rates have been highly variable not only by geographical regions but even across neighboring countries where genetic risk would be expected to be similar.
In Europe, for example, epidemiologic studies suggest the lifetime risk of MPS IIIA is approximately two times greater in Germany and the Netherlands relative to France and Sweden.7 It is possible that the methodology for identifying cases might be a more important factor than differences in genetic risk to explain this variability. Many experts, including Dr. O’Neill, believe that prevalence figures for Sanfilippo syndrome are typically underestimates because of the frequency with which LSDs are attributed to other pathology.
“For these types of rare disorders, a clinician might only see a single case over a career, and the symptoms can vary in presentation and severity with many alternatives to consider in the differential diagnosis,” Dr. O’Neill explained. She cited case reports in which symptoms of Sanfilippo syndrome after a period of initial normal development has been initially attributed to autism, which is a comorbid feature of the disease, idiopathic developmental delay, or other nonprogressive disorders until further clinical deterioration leads to additional testing. The implication is that LSDs must be considered far earlier despite their rarity.
For the least common of the four clinical subtypes, MPS IIIC and MPS IIID, the median ages of diagnosis have ranged from 4.5 to 19 years of age.7 This is likely a reflection of a slower progression and a later onset of clinical manifestations.
For the more rapidly progressing and typically more severe subtypes, MPS IIIA and MPS IIIB, the diagnosis is typically made earlier. In one review of epidemiologic studies in different countries, the earliest reported median age at diagnosis was 2.5 years,7 a point at which significant disease progression is likely to have already occurred. If the promise of treatments in development is prevention of disease progression, disability in many patients might be substantial if the time to diagnosis is not reduced.