Last week, someone wrote to CurePSP asking if PSP was genetic. I took a look at what I had previously provided CurePSP on that topic to post on its website, and decided it wasn’t nearly detailed enough. So I decided to write up the following. A version of it appears, or will soon appear, at http://www.curepsp.org.

PSP only very rarely runs in families.  Fewer than one in 20 people with PSP knows of even one other family member with PSP, even counting distant cousins. 

But when multiple genetic variants confer only small risks of developing a disease and some sort of non-genetic factor is also necessary, it will be rare for more than one member of a family to have the unlucky co-occurrence of enough of those factors to produce outward signs of the disease. 

That’s basically how PSP works, but then things get a little more complicated:

The gene on chromosome 17 that encodes the tau protein is called MAPT, for “microtubule-associated protein tau.”  The MAPT gene has two variants that are more common in PSP than in the rest of the population.  One of them is called the H1 haplotype and actually consists of a section of the chromosome that is reversed relative to adjacent sections.  About 95 percent of people with PSP have this variant on both of their copies of chromosome 17, while this is true for only about 60 percent of the rest of the population.  So the H1 haplotype is (nearly) necessary but far from sufficient to cause the disease. 

We’re still not quite sure how the H1 haplotype increases PSP risk.  It may simply increase the amount of tau produced, which causes that protein to stick together, even if it’s structurally normal.  But more recent work shows that it causes too many methyl groups to stick to the MAPT gene, altering its function. This is exciting because drugs can be developed to alter DNA methylation. Other recent evidence supports the idea that the H1 haplotype reduces the fraction of tau molecules that include the fragment encoded by the MAPT gene’s exon 2. 

The other MAPT variant associated with PSP is statistically independent of the H1 haplotype and its function is unknown.

Over the past two decades a handful of other gene variants not on chromosome 17 have been found to be slightly more common in people with PSP than in those without PSP.  These genes help control a variety of critical processes such as disposal of damaged proteins, inflammatory mechanisms, operation of synapses, and integrity of the brain cells’ insulating sheaths.  However, the effect of these genes, individually or together, is too small to serve as a diagnostic test for the disease or to produce more than one case in a family.   

A gene called LRRK2 has been found to influence (in a rough way) not the likelihood of PSP, but the age at which it starts.  CurePSP is presently supporting a project to pursue this clue to try to find a blood test that might predict the individual’s rate of progression.  As it happens, mutations in LRRK2 are the most common cause of familial Parkinson’s disease and the occasional person with that mutation will have the pathology of PSP at autopsy despite having had the outward appearance of PD during life.  Wonders never cease.  Drugs that suppress the action of abnormal (and normal) LRRK2 are in trials for Parkinson’s.

Despite all I’ve said about the genetic component of PSP being subtle, a small fraction of people with PSP do have a relative with the same diagnosis, raising questions about the risk to their siblings and children.  A few points of advice about that:

• When a disease occurs in several members of a family in a pattern consistent with either a dominant or a recessive mechanism, it’s easy nowadays to identify that gene.  Despite the dozens of families alleging multiple members with PSP, such a gene has never been reported in the literature. 
• False-positive diagnoses of PSP are common.  This may account for most of the reports of multiply-affected families, even if one of them had autopsy confirmation.  However, in most situations where two or more relatives have been diagnosed with PSP, there have been no autopsies.
• A strongly familial disorder called frontotemporal dementia with parkinsonism (FTDP) can mimic PSP, even at autopsy, but the special features of PSP such as balance loss and trouble with downgaze are mild or absent.  Many of the mutations causing this disorder are in the MAPT gene, but those mutations do not occur in non-familial PSP.  Furthermore, FTDP is associated with the MAPT’s H2 rather than H1 haplotype.  Both of these points cast additional doubt on FTDP being real PSP.  The FTDP-associated mutations can be detected by a commercially available blood test with a doctor’s prescription, but they are very rare, with only about 100 such families having been reported in the medical literature world-wide.
• Despite those caveats, there actually are two or three families world-wide having several members with ordinary PSP (i.e., not FTDP) both during life and at autopsy, with no mutations in the MAPT gene.  Such families can be highly valuable for PSP research, as the gene causing their disease could be encoding a protein that might be key to all PSP.

Bottom line: 

Familial PSP is so rare that people with that condition need not be concerned for their children or siblings.  This advice even accounts for the possibility that what has been diagnosed as PSP may in fact be its rare, familial imitator, FTD with parkinsonism.  Most PSP experts advise their patients’ healthy relatives to make no changes to plans for career, children or finances because of one person with PSP in the family. 

However, when there is a clear indication of two or more close relatives with PSP, one should consider testing one affected person for FTDP by sequencing either the MAPT gene or a battery of genes associated with various dementing neurodegenerative diseases.  This should be done only with the guidance and participation of a genetics counselor or neurologist well-versed in interpreting genetic testing.  If the affected patient has one of those mutations, then another affected relative can be tested as confirmation and healthy relatives can be tested for the same specific mutation if they so choose.  However, a positive result would not predict the age of symptom onset, so there is little or no actionable information to be gained through testing healthy relatives.

Further research results in the near term could change these recommendations, so keep an eye on http://www.curepsp.org for updates.  But if you want me to speculate right now, take a look at the next post.