PRNP P105L

Why is the illness often called something else first?

Because the legs are often affected before the mind. In the family reported by Ishizawa and colleagues, two sisters began with a stiff, spastic walk, and both were given an initial clinical diagnosis of familial spastic paraparesis, which is a different group of inherited conditions affecting the nerve pathways to the legs. The prion diagnosis came later.

That is important for counselling in two ways. A family history may exist and be recorded under another name, so a relative who says there is no prion disease in the family may still be describing it. And the early course can look unlike the picture most people have of Creutzfeldt-Jakob disease, where rapid memory change and jerky movements come early.

How much can the illness differ between relatives?

A good deal, within one family carrying one change. In the three relatives autopsied by Ishizawa and colleagues, two sisters began at 38 and 44 with spastic legs and later developed slurred speech, strong swings of emotion and dementia, lasting about 6 and 12 years. The son of one sister began at 47 with repetitive behaviour and speech, then clumsy walking, tremor and brief myoclonus, which is a sudden involuntary muscle jerk. He had no leg weakness at all, and his illness lasted a little over two years.

The woman described by Kawai and colleagues began at about 41 with a spastic walk, low mood and emotional lability, and had cerebellar signs, stiff legs and parkinsonian features on examination. Her father had similar symptoms from 45 and died at 62.

The practical point for a counselling conversation is that age at onset and first symptoms in one relative predict little about another. Goldman and Vallabh, writing on genetic counselling for prion disease, make the same point in general terms: someone who tests positive may have an age at onset and a presentation that differ from other family members, and for the slower variants the spread in duration is wide enough that individual predictions are not meaningful.

Why were the usual tests negative?

The tests that support a Creutzfeldt-Jakob disease diagnosis were designed around the rapid forms. In the case reported by Kawai and colleagues, spinal fluid 14-3-3 and total tau were not raised, RT-QuIC, the seeded conversion test that detects misfolded prion protein, was negative, the EEG showed no periodic sharp waves, and MRI showed shrinkage at the front of the brain without the bright signal on diffusion-weighted images that is typical of sporadic disease. The authors state that this bright signal is always absent in P105L, and link it to spongiform change in brain tissue, which this variant does not produce.

So a negative RT-QuIC result does not count against this diagnosis. In families where P105L is already known, the gene result is what identifies it. Where it is not yet known, the combination of a slow spastic course, frontal changes on imaging and normal prion markers is what leads a neurologist to ask for PRNP sequencing. This is one reason tests explained treats a negative result as a limited piece of information rather than a conclusion.

Is it Gerstmann-Straussler-Scheinker syndrome or genetic prion disease?

Both terms are used, and the difference is historical. Gerstmann-Straussler-Scheinker syndrome, usually shortened to GSS, is the name given to the slower forms with plaques of prion protein in the brain, and P105L sits in that group. Goldman and Vallabh argue that the single term genetic prion disease now serves clinicians better than the three historical subtype names, because the link between a particular variant and a particular named syndrome has weakened as more patients have been described. A report may therefore say GSS, GSS105 or genetic prion disease and mean the same gene result.

If a letter uses one name and a clinic uses another, the laboratory that issued the report is the place to confirm what was found. The variants hub explains how variant names are written.

What does a relative do with this information?

The first step is genetic counselling, not a test. Counselling comes first describes what those appointments involve: what is known in the family, what a test could and could not show, and what you would do with either answer. Testing is voluntary. The Australian national registry states that plainly for PRNP testing, and recommends consultation with a genetic service.

Three practical points come up often in these conversations and are worth raising early.

A result reaches other people too. Brothers, sisters and children learn something about themselves from your answer, whether or not they asked.

Not testing is a settled position, not a delay. Counsellors see people who hold it for years.

There are options between testing and not testing. Goldman and Vallabh describe banking DNA from an affected relative for possible later use, and holding a result in reserve rather than receiving it. Those options exist precisely because the decision is rarely all or nothing.

Choosing or declining a test is a personal decision, and this page cannot help with your own circumstances. A genetic counsellor and the laboratory that issued the report can.

What is not known

No series large enough to give rates with confidence intervals has been published for this variant, and no reliable count of reported families exists in the sources opened here. Whether the illness looks the same in families outside Japan is untested, because so few have been reported.

Penetrance means the proportion of carriers who become ill during a lifetime. Goldman and Vallabh group P105L with E200K, P102L, D178N, A117V and the longer octapeptide repeat insertions as the variants classified as highly penetrant, on the basis that they are enriched in patients compared with population controls. That classification is a statement about the variant, not a percentage for a person, and no study has followed P105L carriers from a young age to measure it directly.

For neighbouring pages, see P102L, which is the commoner variant in the same slow group, and protective variants, which covers changes in the same gene that appear to lower risk.