Diagnosis: Signs and symptoms
Despite the differences in progression of the MPS III subtypes, the clinical characteristics are more similar than different. In all patients, prenatal and infant development are typically normal. The initial signs of disease can be found in the newborn, such as neonatal tachypnea, through the early infancy period, such as macrocephaly. However, these are not commonly recognized until about age 1 or soon after in those with MPS IIIA and IIIB.3 Speech delay is the first developmental delay seen in most patients. In those with MPS IIIC, initial symptoms are typically detected at age 3 or later and progress more slowly.10,11 The same is likely to be true of MPS IIID, although this subtype is less well characterized than the other three.7
Although many organs can be involved, degeneration of the CNS is regarded as the most characteristic.3 In aggressive disease, this includes slower acquisition of and failure to meet developmental milestones with progressive intellectual disability, while behavioral difficulties are a more common initial compliant in children with milder disease.13,14 These behavioral changes include hyperactivity, inattention, autistic behaviors, worsening safety awareness, and in some cases aggressive behavior that can be destructive. Sleep disturbances are common.15Because of variability inherent in descriptions of relatively small numbers of patients, the characterization of each of the MPS III subgroups is based on a limited number of small studies, but most patients demonstrate behavior disorders, have coarse facial features, and develop speech delay, according to a survey conducted of published studies.7 Collectively, abnormal behavior was identified as an early symptom in 77% of those with MPS IIIA, 69% of those with IIIB, and 77% of those with IIIC.
For MPS IIIA, loss of speech was observed at a median age of 3.8 years and loss of walking ability at 10.4 years. The median survival has been reported to range between 13 and 18 years. In children with MPS IIIB, the median age of speech loss was reported to about the same age, while loss of walking ability occurred at 11 years. In one study of MPS IIIB, 24% of patients had developed dementia by age 6 years, and the reported median survival has ranged between 17 and 19 years. For MPS IIIC, the onset of clinical symptoms has been observed at a median age of 3.5 years with evidence of cognitive loss observed in 33% of children by the age of 6 years. The median survival has ranged from 19 to 34 years in three studies tracing the natural history of this MPS III subtype.
The differential diagnosis reasonably includes other types of mucopolysaccharidosis disorders with cognitive impairment, including Hurler, Hunter, or Sly syndromes, other neurodevelopmental disorders, and inborn errors of metabolism. The heterogeneity of the features makes definitive laboratory or genetic testing, rather than the effort to differentiate clinical features, appropriate for a definitive diagnosis.
Once the diagnosis is made, other examinations for the common complications of Sanfilippo syndrome are appropriate. Abdominal imaging is appropriate for detecting complications in the gastrointestinal tract, including hepatomegaly, which has been reported in more than half of patients with MPS IIIA and IIIB and in 39% of patients with IIIC.7 In patients with breathing concerns at night and/or sleep disturbance, polysomnography can be useful for identifying sleep apnea and nocturnal seizure activity. In children suspected of seizures, EEG is appropriate. In one study, 66% of patients with MPS IIIA developed seizure activity.16 This has been less commonly reported in MPS IIIB and IIIC, ranging from 8% to 13%.15
Formal hearing evaluation is indicated for any child with speech delays. Hearing loss typically develops after the newborn period in Sanfilippo and may affect peak language acquisition if not treated, according to Dr. O’Neill.
Radiographic studies for dysostosis multiplex or other skeletal abnormalities are also appropriate based on clinical presentation.
Treatment: Present and future
In the absence of treatments to improve the prognosis of Sanfilippo syndrome, current management is based on supportive care and managing organ-specific complications. However, several strategies have proven viable in experimental models and led to clinical trials. None of these therapies has reached approval yet, but several have been associated with attenuation of biomarkers of MPS III disease activity.
Of nearly 30 Sanfilippo clinical trials conducted over the past 20 years, at least 9 have now been completed.5 In addition to studying gene therapy and enzyme replacement therapy, these trials have included stem cell transplantation and substrate reduction therapy, for which the goal is to reduce synthesis of the heparan sulfate GAG to prevent accumulation.5 Of this latter approach, promising initial results with genistein, an isoflavone that breaks down heparan sulfate, reached a phase 3 evaluation.18 Although heparan sulfate levels in the CNS were non-significantly reduced over the course of the trial, the reduction was not sufficient to attenuate cognitive decline.
In other LSDs, several forms of enzyme replacement therapy are now approved. In Fabry disease, for example, recombinant alpha-galactosidase A has now been used for more than 15 years.19 Clinical benefit has not yet been demonstrated in patients with Sanfilippo syndrome because of the difficulty of delivering these therapies past the blood-brain barrier. Several strategies have been pursued. For example, intrathecal delivery of recombinant heparan-N-sulfatase reduced CNS levels of GAG heparan sulfate in one phase 2B study, but it approached but fell short of the statistical significance for the primary endpoint of predefined cognitive stabilization.20 The signal of activity and generally acceptable tolerability has encouraged further study, including an ongoing study with promising interim results of intracerebroventricular enzyme replacement in MPS IIIB, according to Dr. O’Neill.
Acceptable safety and promising activity on disease biomarkers have also been seen with gene therapy in clinical trials. In one study that showed attenuation of brain atrophy, there was moderate improvement in behavior and sleep in three of the four patients enrolled.21 Other studies using various strategies for gene delivery have also produced signals of activity against the underlying pathology, generating persistent interest in ongoing and planned clinical studies with this form of treatment.22Unmodified hematopoietic stem cell transplantation (HSCT), an approach that has demonstrated efficacy when delivered early in the course of other LSDs, such as Hurler syndrome,23 has not yet been associated with significant activity in clinical studies of MPS III, including those that initiated treatment prior to the onset of neurological symptoms.24 However, promising early results have been reported in a study of gene-modified HSCT, which overexpresses the MPS IIIA enzyme.
“The clinical trial landscape fluctuates quite a bit, so I always encourage clinicians and families to check back often for updates. Patient organizations can also be helpful for understanding the most up-to-date and emerging trial options,” Dr. O’Neill reported.
Although it is expected that the greatest benefit would be derived from treatments initiated before or very early after the onset of symptoms, based on the limited potential for reversing cognitive loss, Dr. O’Neill said that she and others are also striving to offer treatments for individuals now living with Sanfilippo syndrome.
“We have to be willing to test treatments that are symptomatic in nature. To that aim, the Cure Sanfilippo Foundation has sponsored a study of a CNS-penetrating anti-inflammatory agent in advanced-disease patients more than 4 years of age,” Dr. O’Neill said. This group of patients typically been ineligible for clinical trials in the past. Dr. O’Neill hopes to change this orientation.
“It is important to highlight that all patients deserve our efforts to improve their quality of life and alleviate suffering, regardless of how old they are or how progressed in the disease they happen to be,” she said.
However, whether the goal is enrollment before or early in disease or later in disease progression, the challenge of enrolling sufficient numbers of patients to confirm clinical activity has been and continues to be a hurdle to progress.
“Clinical studies in Sanfilippo enroll relatively small numbers of patients, often 20 or less,” said Dr. O’Neill, explaining one of the reasons why her organization has been so active in raising awareness and funding such studies. For patients and families, the Cure Sanfilippo Foundation can offer a variety of guidance and support, but information about opportunities for clinical trial participation is a key resource they provide for families and their physicians.
Conclusion
For most children with Sanfilippo syndrome, life expectancy is limited. However, the characterization of the genetic causes and the biochemistry of the subtypes has led to several viable therapeutic approaches under development. There has been progress in delivery of therapeutic enzymes to the CNS, and there is substantial optimism that more progress is coming. One issue for treatment development, is the last of a clear regulatory pathway addressing important biomarkers of pathology, such as heparan sulfate burden. Developing treatments that address this issue or impaired enzyme activity levels have promise for preventing progression, particularly if started in infancy. However, the effort to draw awareness to this disease is the first step toward accelerating the time to an early diagnosis and subsequent opportunities to enroll in clinical trials.