SNCA duplications: ordinary-looking Parkinson's, partial penetrance

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Marie-Christine Chartier-Harlin (INSERM, Lille), Matthew Farrer, Alain Destée and colleagues (Lancet 2004). P. Ibáñez, Alexandra Dürr, Alexis Brice and colleagues (Pitié-Salpêtrière, Paris; Lancet 2004). O. A. Ross, Farrer and colleagues (Ann Neurol 2008, funded in part by NINDS and NIA). K. Nishioka, Nobutaka Hattori and colleagues (Movement Disorders 2009; Japanese families).

What happened

Landmark 14 showed that a family with four copies of the synuclein gene (SNCA; triplication) developed early, severe disease. Two groups asked whether one extra copy (duplication) also causes disease.

• Chartier-Harlin. They screened nine families with dominant parkinsonism and found one with a duplication, confirmed by fluorescent in-situ hybridisation. The illness looked like ordinary Parkinson's: late onset, slow progression, and neither cognitive decline nor dementia was prominent. They concluded there is a direct relation between gene dose and disease progression.
• Ibáñez. They screened 119 individuals from dominant families and found two patients with duplications. Their illness was indistinguishable from ordinary Parkinson's, unlike the triplication families. They concluded that SNCA is more often involved in familial disease than thought and that disease differs clearly with the number of extra copies.
• Ross 2008. Five families with SNCA multiplication; severity of parkinsonism, autonomic dysfunction and dementia tracked with dose. Apart from the Lister kindred, each multiplication appeared to be new in that family, and two different DNA mechanisms (including recombination) produced duplications and triplications.
• Nishioka 2009. Four new families and one sporadic case. Eleven symptomatic patients had parkinsonism, three of whom later developed dementia. Lifetime penetrance was estimated at 43.8% (the share of carriers who get ill). One asymptomatic carrier aged 79 had normal tests, so a carrier "may escape" disease.

Why it moved us toward a cure

A copy-number ladder (two copies: healthy; three: ordinary-looking Parkinson's; four: severe early disease) links dose to severity. It supports lowering synuclein by modest amounts (landmark 29), since one extra copy, a 50% rise in gene dose, can be enough to cause disease. Incomplete penetrance means other genes or the environment modify the effect. Those modifiers are leads for protection.

Outcome

Advanced. The dosage principle is established, and it motivates the antisense and siRNA trials.

Sources

• Chartier-Harlin et al., Lancet 2004;364:1167–1169, DOI 10.1016/S0140-6736(04)17103-1, PMID 15451224
• Ibáñez et al., Lancet 2004;364:1169–1171, DOI 10.1016/S0140-6736(04)17104-3, PMID 15451225
• Ross et al., Ann Neurol 2008;63:743–750, DOI 10.1002/ana.21380, PMID 18571778
• Nishioka et al., Mov Disord 2009;24:1811–1819, DOI 10.1002/mds.22682, PMID 19562770
• Not yet verified: all numbers are from abstracts (full texts not read); the age-dependence of penetrance beyond Nishioka's one 79-year-old carrier; protein levels in duplication carriers (the 50% figure is gene dose, not measured protein); later penetrance estimates; whether the antisense and siRNA trials cited as the outcome were designed on this evidence (the link is the map's inference).