Is there a link between the gene mutations associated with Gaucher disease and Parkinson’s disease?

Mutations in the gene that encodes glucocerebrosidase (GBA1; The Human Gene Mutation Database [http://www.hgmd.cf.ac.uk/ac/index.php]), have been linked to Gaucher disease and Parkinson’s disease.1 Studies suggest that patients with Parkinson’s disease have a significantly higher frequency for the two most common GBA1 mutations, namely N370S (c.1226A>G; p.Asp409Ser) and L444P (c.1448T>C; p.Leu483Pro; see genetic inheritance of Gaucher disease).2-4

An international collaborative study of 16 centres (Europe, n=6; the Americas, n=5; Asia, n=3; Israel, n=2) investigated the frequency of GBA1 mutations in an ethnically diverse group of patients with Parkinson’s disease. Genotypic and phenotypic data were available for 5691 patients with Parkinson’s disease (including n=780 of Ashkenazi Jewish ethnicity) and 4898 individuals without Parkinson’s disease (including n=387 of Ashkenazi Jewish ethnicity).5

 

The N370S (c.1226A>G; p.Asp409Ser) and L444P (c.1448T>C; p.Leu483Pro) GBA1 mutations were detected in patients analysed at all 16 centres5:

  • 15% of patients with Parkinson’s disease who were of Ashkenazi Jewish ethnicity had either mutation, compared with 3% of unaffected healthy Ashkenazi Jews.
  • 3% of non-Ashkenazi Jewish patients with Parkinson’s disease had either mutation versus <1% of unaffected healthy individuals who were not of Ashkenazi Jewish ethnicity.

 

The odds ratio for any GBA1 mutation in patients with Parkinson’s disease versus controls was 5.43 (95% confidence interval [CI] 3.89‒7.57) across the 16 centres. Patients with these mutations were also more likely to present with the disease earlier, and were more likely to have affected relatives and atypical clinical manifestations.5

What is the risk of Parkinson’s disease in patients with Gaucher disease?

The adjusted lifetime risk ratio for Parkinson’s disease in patients with Gaucher disease Type 1 has been reported as 21.4 (95% CI 10.7‒38.3) compared with the general population. This finding indicates that patients with Gaucher disease have an approximate 20-fold increased lifetime risk of developing Parkinson’s disease.6

In this study, 11 of 444 patients with Gaucher disease developed Parkinson’s disease (male, n=7; female, n=4). The mean (standard deviation [SD]) age at diagnosis of Parkinson’s disease was 55 (8.8) years; for one patient, the diagnosis of Parkinson’s disease preceded that of Gaucher disease. The age at onset of Gaucher disease-related symptoms, age at Gaucher disease diagnosis, gender distribution, splenectomy rate and GBA1 genotype distribution between patients with Gaucher disease with and without Parkinson’s disease were similar. Except for one patient, all 11 patients with Gaucher disease and Parkinson’s disease had at least one N370S (c.1226A>G; p.Asp409Ser) mutation.6 

The overall mean (SD) severity score index for Gaucher disease (10.8 [0.8] vs 6.9 [3.7]; p=0.02) and the mean (SD) bone disease score (4.6 [0.5] vs 2.5 [1.5]; p=0.002) were significantly higher in patients with Parkinson’s disease versus those without Parkinson’s disease. The phenotype of Parkinson’s disease among patients with Gaucher disease was variable and ranged from mild disease to potentially life-threatening disease, requiring full-time nursing-home care.6

What is the phenotype of patients with Gaucher disease and Parkinson’s disease?

In a large Gaucher disease clinic in Israel, the disease characteristics of patients with Gaucher disease and Parkinson’s disease were assessed based on medical files (between 1990 and 2010) of 510 adult patients with Gaucher disease Type 1 (45.7% [n=233/510] males). Within this cohort, 11 (2.2%) patients with Parkinson’s disease were identified. Cognitive impairment was the most common clinical feature (n=7/11). Patients who had both Gaucher disease and Parkinson’s disease were significantly more likely to be male (81.8% vs 44.9%; p=0.027) and of an older mean age (62.8 years vs 47.1 years; p=0.004) than those without Parkinson’s disease. In this study, the severity of Gaucher disease was not significantly different between patients with and without Parkinson’s disease (7.7 vs 8.3; p>0.05).7

What other neurological disorders may patients with Gaucher disease experience?

In a study of 28 patients with Gaucher disease Type 1 (25.0% aged 18‒40 years; 39.3% aged 41‒55 years; 28.6% aged 56‒75 years), psychological functioning was assessed by the Minnesota Multiphasic Personality Inventory (MMPI-2) and a background questionnaire.8 Compared with a normative sample group, patients with Gaucher disease scored significantly higher on MMPI-2 scales for validity, hypochondriasis, depression, hysteria, psychasthenia (includes compulsions, obsessions and phobias)9 and schizophrenia.8 Patients with elevated scores for depression, hypochondriasis and hysteria tended to have somatic concerns and depressed mood, and were more likely to report physical symptoms. An elevation in psychasthenia and schizophrenia scales was suggestive of psychological turmoil and feelings of isolation. Higher scores for validity indicated that patients tended to deny or minimise psychopathology, as it is common for patients with chronic disorders to minimise the seriousness or significance of a disease to cope with upsetting feelings. Cohorts of patients with chronic heart disease and chronic pain have also shown elevations in depression, hypochondriasis and hysteria, suggesting that patients with Gaucher disease may exhibit moderate-to-severe psychiatric comorbidities, similar to those of other patients with long-term chronic conditions.8

In a different study, the presence of psychiatric comorbidities in 22 Egyptian patients with Gaucher disease (Type 1, n=13; Type 3, n=9) was determined using Arabic versions of the Mini-International Neuropsychiatric Interview (M.I.N.I) and the Mini-International Neuropsychiatric Interview for Children and Adolescents (M.I.N.I-KID) tools. In total, 41% of patients with Gaucher disease had psychiatric disorders, the most common being depression; however, no patients received any form of psychiatric treatment. There was no statistically significant association between the presence of psychiatric disorders and any clinical variable, genotype or phenotype of Gaucher disease. Overall, this study suggested that patients with Gaucher disease may also have psychiatric disorders.10 

C-ANPROM/INT//7566; Date of preparation: September 2020