Milder and Slow-progressing Forms of Sanfilippo Syndrome Arise Differently Later in Life, Study Finds

Physicians should be aware that milder and slow-progressing forms of Sanfilippo syndrome may not be associated with severe cognitive impairments and may emerge differently later in life, a study has found.

The research, “The attenuated end of the phenotypic spectrum in MPS III: from late-onset stable cognitive impairment to a non-neuronopathic phenotype,” was published recently in the Orphanet Journal of Rare Diseases.

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare genetic lysosomal storage disorder that can be caused by mutations in one of four genes — GNS, HGSNAT, NAGLU, and SGSH — that provide instructions for making enzymes necessary to break down complex sugar molecules called heparan sulfate.

When genetic mutations reduce the activity of any of these four enzymes, heparan sulfate starts to accumulate inside lysosomes — the cell compartments responsible for digesting and recycling different types of molecules — causing brain atrophy (shrinkage) and gradual cognitive decline.

“Classical MPS III is clinically divided in three disease phases. After an initial symptom-free phase, a developmental delay is generally noted at the age of 2–6 years. During the second phase, progressive loss of cognition, behavioral and sleeping problems manifest. During the third phase, generally starting in their teens, progressive motor deterioration results in complete dependency (…). Most patients demise in their second or third decade of life,” the researchers wrote.

However, over the last decades, there have been reports of people in whom MPS III progressed at a slower pace, and was not associated with the severe intellectual disabilities that normally accompany the disease.

In this study, investigators from the University of Amsterdam, Netherlands, and their collaborators described the cases of adults with slow-progressing forms of MPS III.

In the study, researchers analyzed data from 12 adults with MPS III (11 with MPS IIIA and one with MPS IIIB, median age at diagnosis 43 years) from six families who had either mild or non-neuronopathic forms of the disease, and had been followed at three specialized centers of lysosomal storage disorders.

Non-neuronopathic disease was defined as a form of MPS III that did not interfere with patients’ abilities to complete regular secondary education and being independent adults (living independently or being able to hold a paid job).

From the 12 people included in the study, four experienced symptoms that led to diagnostic tests — whole exome sequencing (WES) and metabolomics — that confirmed the diagnosis of MPS III. These symptoms included retinal dystrophy (vision loss), heart disease associated with heart enlargement, and neurocognitive decline.

(Of note, WES is a technique that examines the DNA sequence of all genes that instruct the creation of proteins (exome); metabolomics is the study of metabolism and all its key players.)

The remaining eight patients included in the study were diagnosed with MPS III following family genetic screening.

Metabolomic studies confirmed the levels of complex sugar molecules in the urine were high in all individuals, and the activity of enzymes involved in the breakdown of heparan sulfate was low, confirming the diagnosis of MPS III in all patients included in the study.

Genetic analyses identified a total of seven missense genetic mutations in the SGSH gene, including five that had previously been reported as pathogenic (mutations that can cause the disease) and two of unknown significance (those whose relation to the disease is not well understood). Two missense mutations also were identified in the NAGLU gene, both of which had been previously reported as pathogenic. (A missense mutation is a single nucleotide — the building blocks of DNA — mutation that alters protein composition.

“At last follow-up, at a median age of 47 years, only three patients had a mild neurocognitive impairment, including one with a slow decline after the age of 41 years. All other patients have a normal cognitive functioning. Only one patient has mild facial coarsening which is characteristic for MPS III; all others patients have normal features,” the researchers wrote.

Altogether, these findings indicate that in certain cases MPS III may be milder, progress at a slower pace, and not be associated with severe neurocognitive impairments that compromise individuals’ independence. In such cases, it is possible that heart disease and retinal dysfunction are the only signs of MPS III.

“Awareness of this phenotype [disease manifestation] is essential as patients and families can benefit from diagnosis as this leads to appropriate diagnostic strategies, monitoring, family counseling and, hopefully within the next decades, treatment. We strongly advise to add MPS III genes as a second diagnostic panel in targeted gene panels for retinal dysfunction and cardiomyopathy [heart disease],” they concluded.