Transcript The Genetics of Parkinson A version for the interested lay

Genetics of Parkinson
Carlos Singer MD
Professor of Neurology
Chief, Division of Parkinson and Movement
Disorders
University of Miami
Leonard M. Miller School of Medicine
May 20, 2010
For more information, please call the National
Parkinson Foundation at 800-327-4545 or visit
www.parkinson.org.
Genetics and Parkinson
 Family
history of PD is seen in 10-15% of
patients with classic PD
A
small percentage of these have a well
defined mutation.
Genetics and Parkinson
 We
have the technology to make this
diagnosis in the majority of this small
group of patients as their relatives.
 We have no additional treatment even if
the tests are “positive”
Genetics and Parkinson
 Why
bother making the diagnosis of
genetic Parkinson?
Genetics and Parkinson

For the patient:
Prognosis

For the unaffected relative who discover he or she is
positive for the gene:
Personal Planning:




Financial: life, disability, medical, long-term care
Family planning
Existential: change of profession, life style, “I wish I had …”
Anything else?
Genetics and Parkinson
 There
are 13 different genetic mutations,
some confirmed, some suspected.
 We will talk about two of them.


Parkin mutation
LRRK2 mutation
 We
will talk about one additional mutation
that is considered a “risk” gene

The “Gaucher’s disease” gene (GBA gene)
PARK1/PARK44q21.3 –synuclein
Autosomal dominant
PARK2 6q25.2-27
Parkin
Autosomal recessive
PARK3 2p13
Unknown
Autosomal dominant
PARK5 4p14
UchL1
Autosomal dominant
PARK6 1p35-p36
PINK1
Autosomal recessive
PARK7 1p36
DJ-1
Autosomal recessive
PARK8 12p11q13.1
LRRK2/Dardarin
PARK9 1p36
ATP13A2
PARK10 1p32
Unknown
Autosomal dominant
Autosomal recessive
(Kufer-Rakeb Syndrome)
Late-onset susceptibility gene
PARK11 2q36-37
PARK12X q21-q25
PARK13 2p13.1
Unknown
Unknown
Omi/HtrA2
Late-onset susceptibility gene
X-Linked
Autosomal dominant
Gene related to Gaucher’s disease
Dawson TM,
Dawson VL.
Mov Disord
2010;25
PARK 2: Parkin Mutation

No ethnic predisposition
 Early age : < 40 years

If age of first symptoms is less than 30, there is
a 25 % chance that person has the parkin
mutation

After age 30 but before age 40 it is somewhere
between 6 and 10%
PARK 2: Parkin Mutation

The way the patient presents:





Young age of Onset
Similar tremor, rigidity and slowness
Some patients have an additional problem:
dystonia
They respond well to L-dopa (Sinemet)
They have more of a tendency to develop similar
problems with “wearing off” and involuntary
movements (dyskinesias)
PARK 2: Parkin Mutation

PARK 2 is autosomal recessive.
 If both genes are affected, the individual will
develop the disease at a young age, usually
before age 40.
 If only one gene is affected, there is the
possibility – still unclear – that there is a
PREDISPOSITION to develop the disease.
Cautionary Note
 Predisposition
is not the same as
predestination
 Someone
predisposed to a disease is at
higher risk to develop the disease but
MAY NOT develop it.
PARK 2: Parkin Mutation


One DEFECTIVE GENE
 No Early-Onset Parkinson
 Late onset Parkinson? Not clear
Defective gene from mother
 Defective gene from father
 Early-Onset Parkinson
PARK 2: Parkin Mutation
 Issues
more likely to be considered with
relatives of PARK 2 patients by virtue of
the young age of onset:



Family planning
Prenatal diagnosis
Pre-implantation genetic diagnosis
Uncertainties and Speculations

If a patient has early onset PD but is parkin negative, the
person may have a mutation in a so far undiscovered genetic
address.

The patient may have gotten PD because of a combination of
one or more of genetic “predispositions” (theoretical)

The patient may have gotten Parkinson because of a
combination of one or more genetic predispositions and some
unknown environmental exposure

The patient may have been exposed to one or more
environmental exposures we do not yet understand.
LRRK2 Mutation PARK 8
 LRRK2:


Leucine Rich Repeat Kinase 2
Protein encoded: dardarin
Chromosome 12
 Autosomal

Dominant
Susceptible Populations
• North African Berber Arabs, Ashkenazi Jews
LRRK2 Mutation PARK 8


The way the patient presents:
Indistinguishable from sporadic PD
 Age of onset: 50’s-60’s
 Levodopa responsive
LRRK2 Mutation PARK 8

PARK 8 is autosomal dominant
 All you need is for one gene to be affected
 As the patient becomes older the chances to
come down with symptoms of Parkinson
increase


at 50 there is a 25 % chance of having the symptoms
at 80 the chances increase up to 80%
Gaucher’s disease
•
is not Parkinson’s Disease
•
is an ENZYME deficiency
•
a substance is accumulated in excess
•
affects liver, bone, blood in some people and the
nervous system in others BUT IT IS NOT
PARKINSONS’ DISEASE.
Gaucher’s Disease
 It
is a lysosomal storage disorder
 Caused by accumulation of material that is
not being normally recycled with the
accumulation causing problems in a
variety of organs: liver, spleen, bone,
brain.
The Gaucher’s Disease Gene
 One
DEFECTIVE GENE
 No Gaucher’s Disease
 Defective
gene from mother
 Defective gene from father
 Gaucher’s Disease
The Parkin Gene


One DEFECTIVE GENE
 No Early-Onset Parkinson
 Late onset Parkinson? Maybe
Defective gene from mother
 Defective gene from father
 Early-Onset Parkinson
Gene for Gaucher’s Disease = GBA
In Parkinson disease
GBA mutation in one of the two genes

Ashkenazi Jewish Parkinson patients
10.7%-31.3% have one GBA mutation
 Non-Ashkenazi Jewish Parkinson patients
2.3%- 9.4% have one GBA mutation
Velayati et al. Curr Neurol Neurosci Rep 2010; 10:190-198
 Predisposition
is not the same as
predestination
 Someone
predisposed to a disease is at
higher risk to develop the disease but
MAY NOT develop it.
 Having
ONE defective GBA gene is a risk
factor for developing Parkinson’s disease.
 Hypertension
is a risk factor for stroke.
 Should
a patient then be tested for the
GBA gene, especially if he or she is
Ashkenazi Jewish, even if there are no
other affected relatives?
 It
will make no difference in terms of
treatment. It will make no difference to
relatives since having the mutation does
not mean that they will develop Parkinson.







gauchers at NINDS
Gauchers News
European Gaucher Alliance
GeneReview/UW/NIH entry on Gaucher disease
National Gaucher Foundation
Children's Gaucher Research Fund
Hide & Seek Foundation For Lysosomal Disease
Research
Conclusions

The clearly genetic forms of Parkinson represent
a small group of Parkinson patients
 Most sporadic cases of Parkinson or even cases
of people with family history of Parkinson have
an unknown cause
 The performance of genetic testing has at
present no immediate significance to the
affected person.
 Depending on the case, it may have significance
to the relatives of the affected person.