References for this review were identified by searches of PubMed from 1990 until November 2005 with the terms “young onset”, “early onset”, “young”, “early” “Parkinson”, “Parkinson's”, “Parkinson's disease”, “parkinsonism”, “genetic”. Articles were also identified through searches of the authors’ own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the topics covered in the review.
ReviewEpidemiological, clinical, and genetic characteristics of early-onset parkinsonism
Introduction
Early-onset parkinsonism refers to patients presenting with a parkinsonian syndrome with onset before age 40 years,1, 2 although some authors include onset up to age 50 years.3 The incidence of early-onset parkinsonsism in the USA is 0·8 per 100 000 per year in those aged 0–29 years, rising to 3·0 per 100 000 per year in those aged 30–49 years.4 However, because of the long disease course of Parkinson's disease—particularly in those with early onset—of all patients with parkinsonism 3–5% have onset before age 40 years; this is as high as 10% in Japan.1, 5 Early-onset parkinsonism has been further subdivided into cases with onset before age 21 years (juvenile parkinsonism) and those with onset at or above age 21 years; within the latter group, patients with a primarily parkinsonian phenotype have usually been defined as having young-onset Parkinson's disease (YOPD). Several clinical, pathological, and genetic findings give support to the arbitrary division between juvenile parkinsonism and YOPD: juvenile parkinsonism is very rare, at least in Western societies, is commonly familial, and most patients have atypical features and pathology.6 By contrast, YOPD has a rising incidence with increasing age, is less commonly familial, and both the clinical picture and the pathology, with the exception of some of the genetic forms, usually resemble that of older-onset Parkinson's disease.7 Juvenile parkinsonism and YOPD will therefore be considered separately in this review (panel).
Section snippets
Juvenile parkinsonism
Although juvenile parkinsonism is rare, it seems to be more common in Japan than elsewhere;5, 8 this may be related to historically high rates of consanguinity in the Japanese population,9, 10, 11, 12 as the disorder is commonly familial2, 7, 8 and the proportion of patients with a genetic disorder in juvenile parkinsonism is high. In those patients with a pure parkinsonian syndrome without additional features, most cases are due to mutations in the parkin gene.13 The main differential
YOPD
Although the differential diagnosis of a patient with early-onset parkinsonism starting at or after age 21 years is similar to that for juvenile parkinsonism (table), secondary parkinsonism is much less common in this age group and becomes increasingly rare with increasing age at onset. Nevertheless, Wilson's disease, dopa-responsive dystonia, drug-induced parkinsonism, and structural causes must be excluded in any young patient presenting with parkinsonism—even in the absence of other
Monogenetically inherited early-onset parkinsonism
Several genetic mutations cause early-onset parkinsonism;34 in particular, mutations in the parkin (PARK2) gene cause a substantial proportion of juvenile parkinsonism and YOPD, particularly if the parkinsonism is relatively “pure”, and if there is positive family history. Several other genes cause Parkinson's disease (reviewed by Healy and colleagues34 and Gasser35), particularly early-onset parkinsonism, and new loci are still being identified.
Diagnosis
Investigations in YOPD must be guided by clinical presentation and presence or absence of a family history. In those with additional neurological features, detailed investigation is needed to exclude secondary causes of parkinsonism. However, even in patients with apparently typical Parkinson's disease, Wilson's disease, dopa-responsive dystonia, structural abnormalities, and drug-induced parkinsonism should be considered and excluded where appropriate. Thus, in all patients, a history of
Conclusion
Although alternative and potentially treatable causes of juvenile parkinsonism and YOPD need to be excluded, and some patients, particularly if there is a positive family history, have an underlying genetic cause, most patients with YOPD have idiopathic Lewy-body Parkinson's disease. The overall course of the disease in these patients is slower than in those who are older at onset, and particular attention needs to be paid to problems associated with longer disease duration, higher rate of
Search strategy and selection criteria
References (118)
- et al.
Multicenter genetic study of retinitis pigmentosa in Japan: II: prevalence of autosomal recessive retinitis pigmentosa
Jpn J Ophthalmol
(1997) - et al.
Progressive supranuclear palsy: where are we now?
Lancet Neurol
(2002) - et al.
Multiple system atrophy
Lancet Neurol
(2004) - et al.
Corticobasal degeneration
Lancet Neurol
(2004) - et al.
Consensus statement on the diagnosis of multiple system atrophy
J Neurol Sci
(1999) - et al.
PINK, PANK, or PARK? A clinicians’ guide to familial parkinsonism
Lancet Neurol
(2004) - et al.
Alpha-synuclein locus duplication as a cause of familial Parkinson's disease
Lancet
(2004) - et al.
Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease
Neuron
(2004) - et al.
Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology
Neuron
(2004) - et al.
A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease
Lancet
(2005)
Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations
Am J Hum Genet
Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease
Lancet
A common LRRK2 mutation in idiopathic Parkinson's disease
Lancet
Disease modification in Parkinson's disease
Lancet Neurol
Cross sectional prevalence survey of idiopathic Parkinson's disease and Parkinsonism in London
BMJ
Young onset Parkinson's disease
Mov Disord
Environmental antecedents of young-onset Parkinson's disease
Neurology
Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976–1990
Neurology
Young-onset Parkinson's disease: a clinical review
Neurology
Diagnostic considerations in juvenile parkinsonism
Mov Disord
Young-onset Parkinson's disease revisited–clinical features, natural history, and mortality
Mov Disord
Familial juvenile parkinsonism
Eur Neurol
A recent survey of consanguineous marriages in Japan
Clin Genet
An expected decrease in the incidence of autosomal recessive disease due to decreasing consanguineous marriages
Genet Epidemiol
Parental consanguinity as a cause for increased incidence of births defects in a study of 238,942 consecutive births
Ann Genet
Association between early-onset Parkinson's disease and mutations in the parkin gene: French Parkinson's Disease Genetics Study Group
N Engl J Med
Huntington's disease and other choreas
J Neurol
New pathologic observations in juvenile onset parkinsonism with dystonia
Neurology
Familial aggregation of Parkinson disease: a comparative study of early-onset and late-onset disease
Arch Neurol
Parkinson disease in twins: an etiologic study
JAMA
Epidemiology of Parkinson's disease
Adv Neurol
Sporadic rapid-onset dystonia-parkinsonism presenting as Parkinson's disease
Mov Disord
When is ataxia not ataxia?
Arch Neurol
Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach
J Neurol Neurosurg Psychiatry
Progression of motor impairment and disability in Parkinson disease: a population-based study
Neurology
Onset and progression of disease in familial and sporadic Parkinson's disease
Am J Med Genet
Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease
Neurology
Paroxysmal exercise-induced dystonia as a presenting feature of young-onset Parkinson's disease
Mov Disord
A comparison of clinical and pathological features of young- and old-onset Parkinson's disease
Neurology
[PET study of dopamine metabolism and dopamine D2 receptor in juvenile parkinsonism]
Nippon Rinsho
Young-onset Parkinson disease with and without parkin gene mutations: a fluorodopa F 18 positron emission tomography study
Arch Neurol
Normal dopamine transporter binding in dopa responsive dystonia
J Neurol
Genetics of Parkinson's disease
Curr Opin Neurol
Mutation in the alpha-synuclein gene identified in families with Parkinson's disease
Science
Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation
Ann Neurol
PET studies of parkinsonism associated with mutation in the alpha-synuclein gene
Neurology
A large kindred with autosomal dominant Parkinson's disease
Ann Neurol
Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease
Nat Genet
The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia
Ann Neurol
alpha-Synuclein locus triplication causes Parkinson's disease
Science
Cited by (312)
Genetics of Parkinson´s disease: Recessive forms
2024, Neurology PerspectivesAn overview about neurological diseases in India – A theranostics approach
2024, Aging and Health ResearchGut microbiome and Parkinson's disease: Perspective on pathogenesis and treatment
2023, Journal of Advanced ResearchAdmixture analysis to define late onset Parkinson's disease: Moderating effect of the APOE gene
2023, Psychiatry Research CommunicationsThe definition of precision medicine in neurodegenerative disorders and the one disease-many diseases tension
2023, Handbook of Clinical Neurology