Authors of a review article have discussed whether the proposed disease ‘Sanfilippo type E’ should be recognised in patients. While they conclude the current evidence suggests it shouldn’t be recognised, the debate shows how difficult it can be to classify and diagnose rare genetic disorders like Sanfilippo.
Currently, people with Sanfilippo may be diagnosed with one of four subtypes: types A, B, C, and D. Each is caused by the deficiency of a different enzyme dedicated to the breakdown of heparan sulfate (HS), a complex sugar produced by the body. However, a fifth enzyme, known as arylsulfatase G, is also dedicated to this task. There is debate about what disease this enzyme deficiency is linked to, and whether arylsulfatase G deficiency may cause Sanfilippo type E.
Although researchers have proposed a ‘type E’ subtype, no person has been diagnosed with Sanfilippo type E. Instead, arylsulfatase G deficiency has been linked to another disease in humans called Usher syndrome type IV, or USH4. This is a recently described disease, caused by variants in the arsg gene, and first reported in 2018 in five patients with late-onset retinal degeneration and hearing loss.
Since then, people with arsg genetic variants have been diagnosed with USH4. While the enzyme associated with USH4 is involved in HS degradation like other enzymes associated with Sanfilippo, people with USH4 do not develop many hallmark Sanfilippo symptoms such as behavioural symptoms or cognitive decline. Also, their levels of the complex sugars collectively referred to as GAGs remain in the normal range.
To better understand the function of the arsg gene, researchers previously developed a mouse model with no arylsulfatase G activity. This mouse model shows symptoms similar to other Sanfilippo mouse models albeit milder.
Importantly, symptoms in this mouse model do not appear to correlate with symptoms seen in the patients so far described with variants in the arsg gene. This may mean that more cell and animal models are needed to better understand the impacts of different genetic variants of arsg. Or, it may mean the disease in mice is simply different to that seen in humans.
Getting diagnosed with a rare disease can be a long process for the individual and their family, but the correct diagnosis is essential to inform the best treatment options and care. In this case, as the authors of the article note, patients with arylsulfatase G deficiency described so far do not fit the criteria for a typical diagnosis with Sanfilippo (or any MPS disorder).
As stated in the Clinical Consensus Guidelines for Sanfilippo, a diagnosis of Sanfilippo types A, B, C, or D requires at least two of the following: 1) high levels of complex sugar (e.g. heparan sulfate, HS) in blood or urine; 2) a deficiency of one of four enzymes associated with Sanfilippo; and 3) genetic testing that shows changes in genes associated with Sanfilippo.
