Screening and testing
Independent of the potential to enroll children in clinical trials, early diagnosis also advances the opportunities for supportive care to lessen the burden of the disease on patients and families. Perhaps even more important, early diagnosis is vital to family planning. Since the American pediatrician Sylvester Sanfilippo, MD, first described this syndrome in 1963,7 the genetic profile and many of the features of the disease have become well characterized.8
Glenn O'Neill
“One reason to emphasize the importance of early diagnosis is the heritability of this disorder. With prompt diagnosis, genetic counseling can be offered to families to provide them with critical information for future family planning and for cascade testing of other potentially affected siblings,” Dr. O’Neill reported. The inheritance pattern of Sanfilippo syndrome is autosomal recessive.3 In families with an affected child, the risk for any subsequent child to have the same disorder is 25%. The chance of a sibling to be unaffected and not a carrier is also 25%. There is a 50% chance of a sibling to be a carrier but asymptomatic. Of priorities, spreading awareness has been a critical mission of the Cure Sanfilippo Foundation since it was founded 8 years ago, according to Glenn O’Neill, the president. He and his wife, Dr. O’Neill, who is a pediatrician, founded the organization after their own child’s diagnosis of Sanfilippo syndrome. Creating awareness is fundamental to the mission of attracting funds for research, but support to patients and their families as well as early enrollment in clinical trials are among other initiatives being pursued by the foundation to improve care and prognosis.
These strategies include some novel ideas, including an algorithm based on artificial intelligence (AI) that can accelerate suspicion of Sanfilippo syndrome in advance of laboratory or genetic testing, according to Dr. O’Neill. She reported that the facial phenotype, which is observed in a high proportion of but not in all Sanfilippo patients, includes coarse facial features such as puffiness around the eyes, heavy eyebrows, full lips, and macrocephaly.9 Interpretation of photos for AI-based analysis is enhanced when combined with other clinical symptoms.
The facial phenotype, which is observed in a high proportion of but not in all Sanfilippo patients, includes coarse facial features such as puffiness around the eyes, heavy eyebrows, full lips, and macrocephaly.
“The Foundation was involved in honing such a tool by submitting the photos that were used to teach the AI to recognize the Sanfilippo syndrome phenotype,” Dr. O’Neill said. The AI-based tool (Face2Gene.com) is available from FDNA, a company that has been involved in analyzing complex phenotypic and genomic information to guide diagnosis and therapeutic strategies for an array of diseases, not just Sanfilippo syndrome.
The preferred method for diagnosis is biochemical or genetic testing. Of these, urine testing for elevated levels of heparan sulfate glycosaminoglycans (GAG) can be useful for screening, although false-negative tests occur. Analysis of the blood can be performed to detect abnormal levels or activity of the enzymes that break down this GAG. In addition, genetic testing can be performed on blood, fibroblast, buccal swab, or saliva samples. Genetic testing of the blood is the most frequently performed.
For the four MPS III subtypes – MPS IIIA, IIIB, IIIC, and IIID – the presence of two pathogenic mutations in the SGSH (17q25.3), NAGLU (17q21.2), HGSNAT (8p11.21), and GNS (12q14.3) genes, respectively, are likely diagnostic, but enzymatic testing or GAG analysis should be performed to confirm disease status, according to Dr. O’Neill, who said that global consensus based clinical care guidelines led by the Foundation were recently accepted for publication and also include a section on the approach to diagnosis.
While laboratory testing is sensitive, urinary excretion of GAG can be variable, with the potential for ambiguous results. Typically, biochemical and genetic testing provide more reliable results for the diagnosis. They can be readily performed in utero or at the time of birth. In addition, gene panels can permit the diagnosis of multiple types of LSDs, not just Sanfilippo, making screening a cost-effective strategy to consider multiple diseases with overlapping symptoms when an LSD is suspected. Dr. O’Neill said clinical guidelines recommend confirmation of enzyme deficiency or evidence of GAG substrate accumulation as confirmatory tests when genetic testing is positive.
“Ultimately, our goal is to promote universal screening at birth for these serious genetic disorders affecting children,” Dr. O’Neill said.
“We are in a catch-22 when it comes to newborn screening. Currently our federal system requires there be an available treatment before recommending routine screening for a disease. However, it is extremely difficult to power trials with patients who are most likely to show benefit in a trial setting without that very early diagnosis. Universal newborn screening would pave the way for accelerated drug development for children,” she added.
In the meantime, Dr. O’Neill suggests that clinicians should employ a low threshold of suspicion to pursue diagnostic studies of LSDs in infants and children with developmental delays or otherwise unexplained progressive disorders.
Importantly, clinicians can now act quickly on their suspicions and order testing without concern for delays or denial by insurers through a special program, according to Dr. O’Neill. Free genetic testing, offered by the Invitae Corporation, evaluates a panel of 58 genes associated with lysosomal disorders, permitting detection of Sanfilippo syndrome and other LSDs, according to Dr. O’Neill. The Invitae testing is typically performed on 3 mL of whole blood delivered to a central testing facility.
“Results can be obtained within a few weeks or sooner. This can seem like a long wait for families, but it is much more efficient than ordering tests sequentially,” Dr. O’Neill said.