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Genetic Causes of Sporadic Parkinson’s Disease

Posted in Leading Norwegian Scientific Discoveries on 31st Jan 2013


Krisztina Kunszt Johansen/Jan Olav Aasly

Krisztina Kunszt Johansen, MD is a Postdoc at the Department of Neuroscience, Norwegian University of Science and Technology, NTNU, Trondheim and resident at the Department of Neurology, St Olavs Hospital, Trondheim. She has been studying clinical and epidemiological aspects of genetic Parkinson’s disease. In 2007-2008 she spent 1 year at the Parkinson’s Institute in Sunnyvale, California. Her present research is focused on biomarkers in Park8 PD.

Jan Olav Aasly, MD is a Consultant Neurologist, Department of Neurology at St Olav’s hospital, Trondheim, Norway, and professor of Neurology, NTNU. Head of the Department of Neurology, St Olav’s Hospital, Trondheim, 1992-1999. He studied clinical neurophysiology at the University of Northern Sweden, 1983-1984. Since the 1990s he has been studying clinical and genetic aspects of Parkinson’s disease in close collaboration with colleagues at the Mayo Clinic, USA, and University of British Columbia, Vancouver, Canada. He was the first to describe clinical aspects of Park8 genetic PD gene.

Correspondence to:
Dr Jan Aasly, Department of Neurology, St Olav’s Hospital, Edvard Grieg’s gate 8, N-7030 Trondheim, Norway. Tel: + 47 7257 5071, Fax: + 47 73 86 75 81.
Email:Jan Aasly

Norwegian leading discoveries in neurology and neuroscience are presented in a series of short articles in ACNR, initiated by the journal. All the selected discoveries have links to ongoing research projects in leading groups. They span from clinical to more basic topics. The discoveries are all relevant for clinicians evaluating and treating patients with brain and nervous system disease. Neuroscience with a clinical focus has been a priority for Norwegian research. Further expansion is planned in cooperation between the universities, the university hospitals, the Research Council of Norway, and the Norwegian Brain Council. Although the discoveries in this series are presented as Norwegian, they all appear in an international context. They represent small pieces fitting into the bigger puzzle, but contribute in elucidating mechanisms for brain and neuromuscular function, thus laying foundations for improved treatment of human disease.

Familial occurrence of Parkinson’s disease (PD) has been observed ever since the disease was first described almost two centuries ago. In 1903 William Gowers reported that 15% of his patients had a positive family history of PD which is about the same percentage of familial occurance reported in most studies today. The first major genetic study in PD was performed by Henry Mjønes in the late 1940s. He found secondary cases of parkinsonism in up to 40% of his PD patients and concluded that PD was an autosomal dominant disease with 60% penetrance. David Marsden and colleagues came to similar conclusions when studying large multi-incident PD families in the late 1980s. Despite the convincing evidence of inheritance sporadic PD remained a disease in which the role of genetic factors in the cause of PD was ‘negligible’. In the early 1990s Duvoisin and colleagues studied multiple PD cases in the Contursi kindred originating from southern Italy and in 1997 they published the first gene for Parkinson’s disease which coded for alfa-synuclein.1 Although mutations in the alfa-synuclein gene are very rare causes of PD this was a major discovery for understanding PD pathology. Lewy body inclusions consist of aggregated α-synuclein and PD is pathologically classified as a synucleinopathy.1 In the following year the gene for autosomal recessive juvenile parkinsonism was located in the parkin gene.2 Over the next years several important PD genes were discovered. Mutations in the LRRK2 gene represent the most common causes for autosomal dominant PD and mutations in PTEN-induced putative kinase 1 (PINK1) are the second most common cause of recessive PD.3 A few more genes have recently been reported in some large PD families. These discoveries include mutations in vacuolar protein sorting 35 (VPS35),4 eukaryotic translation initiation factor 4 gamma 1 (eIF4G1),5 as well as dynactin p150Glued mutations in Perry syndrome patients (depression and parkinsonism with hypoventilation).

Most cases of Parkinson’s disease are sporadic and several susceptibility genes have been described. There is a documented association between parkinsonism and the gene encoding the lysosomal enzyme glucocerebrosidase (GBA), in Gaucher’s disease, and GBA heterozygotes have an increased incidence of PD.6 Genetic studies for new PD genes are possible only in relatives of patients with known diseases or in multi-incident PD families. In true sporadic PD cases where many rare mutations may be involved a very large number of cases are needed to demonstrate a correlation between rare genetic variants and a disease. There are other genetic diseases as well which may mimic parkinsonism and should not be misdiagnosed as PD. These include tremor and bradykinesia in spinocerebellar ataxia 2 and 3, (SCA2 and SCA3) whereas fragile X mental retardation 1 (FRM1) premutations may manifest as fragile X tremor/ataxia syndrome (FXTAS).

In Central Norway the reported frequency of familial PD is about the same as in other centers around the world which is around 15% with a mean age of onset around 60 years. The Norwegian population has been stable with low degree of mobility and until recent years also with a low rate of immigration. The movement disorder clinic at the University hospital in Trondheim has collected clinical data and DNA from more than 800 PD patients. This population has been extensively tested for genetic causes as part of a very good collaboration with the Farrer lab (Mayo clinic, Jacksonville, Fl, and recently Vancouver, University of British Columbia, Vancouver, Canada).

The PD material from Central Norway has been central in finding new genes in so-called sporadic PD. The clinical features of the LRRK2 G2019S PD was first described in this material.7 Although this is an autosomal dominant disease with high penetrance about one third of our LRRK2 cases appear to be so-called sporadic without any known relatives suffering from the same disease. The low mobility in the population became evident in the genealogical studies in LRRK2 families. All Norwegian LRRK2 G2019S cases were traced back to a relatively small geographical area in Central Norway and the pedigrees showed one common ancestor born around 1580.8 We suggest that the G2019S mutation was imported to Norway, probably through a tradesman from Europe in the late mediaeval time who travelled up to settlements along the Norwegian coast-line. Recently we reported a severe LRRK2 variant, the N1437N mutation, representing only a few kindreds.9 This gene was also found in familial cases located in a very small geographical area although quite distant to other LRRK2 families.

Clinical characteristics of the LRRK2 G2019S patients do not phenotypically differ from any other sporadic PD cases and studies in healthy LRRK2 mutation carriers has told us that the onset of PD is probably a rather slow process.

Carriers of PD mutations enter the pre-clinical phase defined by abnormal images, PET or SPECT scans, probably many years before onset of clinical symptoms. It may resemble that which is seen in PD twins. Although the age of onset in twins may vary considerably PET scans often show that the unaffected sibling has ongoing dopaminergic deficits, (Figure 1).


Figure 1: PET scan, Healthy LRRK2 mutation carrier, UPDRS: 0 (left), normal control (right). Dr. Vesna Stossi, UBC, Vancouver, Canada.

It is more likely a slowly progressing chronic disease which can be split in several phases, the pre-physiological, pre-clinical, the pre-motor and the pre-diagnostic phase.10 In healthy LRRK2 mutation carriers the initial part of the disease is characterised by an increased dopamine turnover and changes in cerebrospinal fluid markers.11,12 Biomarker studies using metabolomic techniques in blood samples are able to separate carriers from PD cases even in the pre-motor phase,13 (Figure 2).


Figure 2: Age effects on metabolomic profiles of IPD patients and LRRK2 PD patients. (A) PLS-DA scores plot showing lack of separation between younger (57.365.6 years old, n = 19, mean6SD) and older (71.463.3 years old, n = 22, mean6SD) idiopathic PD patients. (B) PLS-DA scores plot showing a significant separation between older idiopathic PD patients (71.463.3 years old, n = 22, mean6SD) and LRRK2 patients (72.8611.2 years old, n = 12, mean6SD). The analytes discriminating between all IPD patients and LRRK2 patients were used for this analysis. From Johansen et al. 2009.13

In the pre-motor phase neuronal inclusion bodies are found in the olfactory bulb and in the autonomic nervous system. Olfactory testing is easily obtainable and inexpensive but the results may be quite unspecific. There are wide overlaps between normal controls and individuals at risk and this tool is not suitable for pre-motor identification of PD. Autonomic disturbances may manifest as significant reduction of the frequency of bowel movements but is observed only in a minority of cases prior to PD onset. REM sleep behaviour disorder (RBD) may also be observed early in PD but like constipation and anosmia it is only of significance in those who report this disorder. In the pre-diagnostic phase which is the last phase before the patient develop PD bradykinesia and rigidity are easily detected when examining the patients14. Tremor is rarely observed because this often makes the patients aware of the symptoms and PD is readily diagnosed.

Genes for sporadic PD may sound like a contradiction. It implies that these genes have a low penetrance or an age of onset late in life which makes any familial occurrence less obvious. The PD biobank in Central Norway has a high number of cases from a homogenous population covering most of the PD cases in that area. This material will then also include many distant relatives. The reliability of family history information of PD in distant relatives of PD cases is low but may be considerably increased by longitudinal studies performed by a team of neurologists who are well informed on local kindreds. Distant relatives share less genetic material than first degree relatives and is optimal for next generation gene sequencing searching for genes with low penetrance and late onset of disease. Large cohorts in low mobility populations and thorough genealogical screening will reveal cases from kindreds where familial cases may be easily over-looked.
Genes for sporadic PD are biomarkers for early or pre-clinical PD. Low penetrance autosomal dominant late onset PD mutations may simulate sporadic cases and true family occurrence may only be detected in large genealogical studies. Large disease populations from multiethnic cohorts may preclude or mismanage rare genetic causes from being discovered. The Norwegian LRRK2 families have been thoroughly studied in terms of their premotor features. The LRRK2 carriers, as other PD patients, develop their symptoms over a long period, probably over many years.10,15

So far all studies with so-called neuroprotective agents have been negative. Many future neuroprotective agents will have to be started before the patients enter a more advanced stage of the disease. An inexpensive and non-toxic agent would be optimal for early treatment and subjects who never enter the clinical phase of PD need to be included in such studies.

Next generation sequencing in multi-incident PD families followed longitudinally by the Trondheim PD cohort team has recently found 3 more PD genes (Matt Farrer, personal communication). Family members at risk for developing PD are excellent candidates for developing biomarkers for PD. They should also be offered the possibility of testing new future neuroprotective drugs since this type of treatment probably should be initiated many years prior to disease onset. By identifying more genes for sporadic PD it will enhance our knowledge of PD and enable more cases to be included in trials for more efficient drugs which may delay the progression of the disease.


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