Which gene mutations may be related to Parkinson disease (PD)?

Updated: Aug 29, 2019
  • Author: Robert A Hauser, MD, MBA; Chief Editor: Selim R Benbadis, MD  more...
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The identification of a few families with familial Parkinson disease sparked further interest in the genetics of the disease. In one large family in Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein gene. [8] Termed PD-1, this mutation codes for a substitution of threonine for alanine at amino acid 53. These individuals were characterized by early age of disease onset (mean age, 47.5 years), rapid progression (mean age at death, 56.1 years), lack of tremor, and good response to levodopa therapy. [8] Five small Greek kindreds were also found to have the PD-1 mutation.

In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that mutations in the alpha-synuclein gene can cause Parkinson disease. [9] A few additional familial mutations in the alpha-synuclein gene have been identified and are collectively called PARK1. It is now clear that these mutations are an exceedingly rare cause of Parkinson disease.

A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations within 6 of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are well-validated causes of familial parkinsonism. [10] Inheritance is autosomal dominant for SNCA and LRRK2 (although LRRK2 mutations exhibit variable penetrance). Inheritance is autosomal recessive for PRKN, DJ1, PINK1, and ATP13A2. In addition, polymorphisms within SNCA and LRRK2, as well as variations in MAPT and GBA, are risk factors for Parkinson disease. [10]

(For more information on genes/loci underlying monogenic parkinsonism and susceptibility genes/loci for Parkinson disease, see Tables 1 and 2, respectively, in The Genetics of Parkinson Disease. [10] )

In one study of 953 patients with Parkinson disease with age at onset of 50 years or younger, 64 patients (6.7%) had a PRKN mutation, 1 patient (0.2%) had a DJ1 mutation, 35 patients (3.6%) had an LRRK2 mutation, and 64 patients (6.7%) had a GBA mutation. [11] . Mutations were more common in patients with age at onset of 30 years or younger (40.6%) than in those with age at onset between 31 and 50 years (14.6%); more common in patients of Jewish ancestry (32.4%) than in non-Jewish patients (13.7%); and more common in patients reporting a first-degree family history of Parkinson disease (23.9%) than in those without such a family history (15.1%). [11]

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