Second edition

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Table 8.1 Genetic forms related to Parkinson’s disease
Although the mechanism or mechanisms underlying cell
loss and Lewy body formation are not known, it is theorized
that, perhaps related to mitochondrial respiratory chain
dysfunction, there is an increased formation of free radicals
with subsequent cell damage. Genetic factors and environmental
factors may both be involved. Although idiopathic
Parkinson’s disease has long been thought to be sporadic,
recent epidemiologic work strongly suggests familial factors
(Sveinbjornsdottir et al. 2000). Furthermore, fluorodopa
positron emission tomography has demonstrated not only
reduced dopamine uptake in the striatum of patients but
also a reduced uptake in their clinically unaffected co-twins,
suggesting that the co-twins had asymptomatic disease
(Piccini et al. 1999). Environmental toxins have long been
suspected, and suspicion has focused on exposure to pesticides
(Ascherio et al. 2006). Of interest, it also appears that
cigarette smoking appears to reduce the risk of developing
Parkinson’s disease (Thacker et al. 2007).
Interest in genetic factors has recently been stimulated
by the investigation of cases having a clear-cut, unequivocal
familial basis (Feany 2004; Klein 2006; Tan and
Jankovic 2006). These constitute only a small percentage of
cases, no more than 10 percent, and the pattern of inheritance
may be either autosomal dominant or autosomal
recessive. Table 8.1 lists the various forms that have been
discovered, grouping them according to whether they
are dominantly or recessively inherited. As noted these
cases may be either early (under 40 years) or late onset, and
the parkinsonism may be typical or have atypical aspects.
Two of the more common forms are PARK8, due to mutations
in LRRK, and PARK2, due to mutations in PRKN.
PARK8 cases may be clinically indistinguishable from
idiopathic Parkinson’s disease (Gaig et al. 2007;
Papapetropoulos et al. 2006); PARK2 cases may also be
indistinguishable or may present with a combination of
parkinsonism and foot dystonia (Khan et al. 2003; Lucking
et al. 2000). It is unclear at present how relevant these discoveries
are to an understanding of the overwhelming
8.5 Parkinson’s disease 347
Inheritance
pattern Chromosome Locus Gene Protein Onset Parkinsonism
AD 12p11-q13 PARK8 LRRK2 Leucine-rich repeat kinase 2 Late Typical
AD 4q21 PARK1 SCNA Alpha-synuclein Early to late Typical or atypical
AD 4q21 PARK4 SCNA Alpha-synuclein Early to late Typical or atypical
AD 4p14 PARK5 UCH-L1 Ubiquitin C-terminal hydrolase Late Typical
AD 2p13 PARK3 ? ? Late Typical
AD 1p PARK11 ? ? Late Typical
AR 6q25.2–27 PARK2 PRKN Parkin Early to late Atypical
AR 1p36 PARK6 PINK1 PTEN-induced putative kinase 1 Early to late Typical
AR 1p36 PARK7 DJ-1 DJ-1 Early Typical
AR 1p36 PARK9 ? ? Early Atypical
? 1p PARK10 ? ? Late Typical
AD, autosomal dominant; AR, autosomal recessive.
majority of cases that do not exhibit a clear-cut familial
basis, as they may not have the same pathology as that
described above. For example, although Lewy bodies, the
pathologic hallmark of Parkinson’s disease, are found in
some cases of PARK8 (Papapetropoulos et al. 2006) and
PARK2 (Farrer et al. 2001; Pramstaller et al. 2005), they are
not found in other cases, both of PARK8 (Funayama et al.
2002; Gaig et al. 2007) and PARK2 (Mori et al. 1998;
Takahashi et al. 1994).
The place of genetic testing, at present, is uncertain.
Where a strong family history exists, a case could be made
for testing to allow for genetic counselling; otherwise, such
testing is probably best reserved for research settings.
Differential diagnosis
Parkinson’s disease constitutes only one of many different
causes of parkinsonism, and the full differential for
parkinsonism is discussed at length in Section 3.8. Of the
disorders noted there, several should especially come to
mind when considering a diagnosis of Parkinson’s disease,
including diffuse Lewy body disease, multiple system atrophy,
progressive supranuclear palsy, corticobasal ganglionic
degeneration, and vascular parkinsonism.
Diffuse Lewy body disease may present with a classic
parkinsonism; however, within a year of onset of the
movement disorder, this disease also causes a dementia
marked by confusional episodes and visual hallucinations.
Although most patients with Parkinson’s disease will also
develop a dementia, this, as noted above, is a late occurrence,
appearing only many years after the onset of the
movement disorder, and it is this disparity in time of onset
of the dementia which is most helpful in distinguishing
these two disorders.
Multiple system atrophy may cause a fairly classic
parkinsonism; however, these patients will also typically
have evidence of either cerebellar degeneration with ataxia,