Gene mutations known to cause dominant PD associated with dementia

In 2011, vacuolar protein sorting 35 (VPS35) was the first PD gene identified using a direct next-generation sequencing strategy [4, 5]. Only one mutation (p.D620N) has been shown to be unequivocally pathogenic, with a frequency ranging from 0.1 to 1% in familial cases with autosomal dominant PD [6]. From the clinical descriptions of the 35 unrelated PD cases reported in the literature, dementia seems to be a very rare event in this type of PD, with only one Asian patient reported to have mild cognitive impairment [6, 7]. Dementia is also an uncommon event in LRRK2-associated PD, but is much more common when SNCA mutation is the cause of disease.

SNCA (previously PARK1, PARK4; encoding the protein a-synuclein)

The first key advance that occurred in the genetics of PD was closely related with PD-D. A study of a large kindred with early onset, Lewy body-positive autosomal dominant PD [8] identified a missense mutation (p.A53T) in the gene encoding a-synuclein [9].

Although mutations in SNCA are very rare in patients with PD, they did provide the first clue that this protein is involved in the molecular pathway leading to the disease. The advantage of studying a rare familial form of the disease for understanding the more common, apparently sporadic forms became evident when Lewy bodies and Lewy neurites present in sporadic PD were found to contain aggregates of a-synuclein [10]. This work neatly demonstrated a link between familial and sporadic disease and placed a-synuclein at the centre of scientific research into PD. Five missense mutations have been identified in a-synuclein to date (p.A30P, p.E46K, p.H50Q, p.G51D, and p.A53T) [9, 11-14]. Furthermore, several families have now been described where the cause of PD lies in the genetic burden of a-synuclein: patients presenting with one or two extra copies of this gene (locus duplication and triplication, respectively) [15]. PD-D and dementia with Lewy bodies (DLB) were explicitly described as the presenting diseases in the family carrying the p.E46K mutation. However, it is clear that dementia occurs as a common feature of families linked to a-synuclein mutation, both missense and copy number mutations (see Table 13.1).

It is also worth noting that within those families where disease is caused by multiplication of the a-synuclein locus, the genetic load appears to be correlated with both the severity of disease and the presence/absence of dementia. Thus, patients who carry two additional copies of a-synuclein tend to present in their 30s and the disease progresses to include severe dementia, whereas patients who carry only one additional copy of a-synuclein tend to get the disease a decade or so later and dementia is not as frequent a feature (although it does still occur) [15-17]. The prevalence of dementia in these families argues strongly that this is truly a facet of the disease process and not simply coincidental. This notion is supported by neuropathological examination of patients who carry these mutations, which reveals a widespread and severe a-synuclein pathology involving neocortical as well as archi-cortical systems [18]. Table 13.1 summarizes the main features of PD families where a genetic mutation in SNCA has been associated with the disease [11-17, 19-44].

Table 13.1 Main features of Parkinson's disease families where a genetic mutation in SNCA has been associated with the disease

SNCA mutation








No. of cases (families)

4 cases; 1 family

5 cases; 1 family

  • 3 cases;
  • 2 families

8 cases (2 families; 1 case apparently sporadic)

70 cases; 22 families

36 cases; 25 10 families, triplications sporadic cases, and 2 unaffected homozygous carriers duplications reported

Age at onset (years)

60 ± 11

60 ± 7

62 ± 8

36 ± 12

47 ± 12

50 ± 11

40 ± 14


2 of 4 (50%)

  • 4 of 5
  • (80%)


3 of 6 (50%)

  • 9 of 23
  • (39%)
  • 12 of 24
  • (50%)

All (n = 13)



At ages 52 and 76

  • 2 within 4 years,
  • 1 after 14 years

2 within 3 years, third case after 9 years

2 and 9 years after onset; not known for the third case

51 ±13 years (n = 57)

57 ± 11 years (n = 11)

39 ± 4 years


[11, 19]


[13, 20]

[14, 21, 22]

[9, 23-27]

[16, 28-39]

[15, 17, 40-43]

AAO dementia, age at onset of dementia.

Kasten, M. and C. Klein, Mov Disord, The many faces of alpha-synuclein mutations, 28, 6, 697-701 ©2007 [44].

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