Marked variation in clinical presentation and age of onset in a family with a heterozygous parkin mutation

Parkin gene mutations have been detected in families with early‐onset autosomal recessive parkinsonism. We report a novel heterozygous 40 base pair deletion in exon 3 of the parkin gene that increases the susceptibility of carriers to develop parkinsonism/dystonia and manifests remarkable variability in regard to age of onset and phenotype in a single family. After identifying the new mutation in the proband of this kindred, family members were contacted and evaluated by a movement disorders specialist using standardized protocols and prospectively set diagnostic criteria. Importantly, examining physicians and family members were blinded to the genetic testing. Five affected members in two generations carried the parkin mutation. The proband and one of his brothers had disease onset at 24 years of age while another brother had disease at age 44. One exhibited multi‐focal dystonia and parkinsonism of 17 years duration, another suffered a unilateral slowly progressive parkinsonism over 13 years while the third suffered dystonia–parkinsonism of recent onset. A sibling pair in the preceding generation had mild previously undiagnosed parkinsonism. Clinicians should be aware that patients carrying a parkin gene mutation may present with dystonia–parkinsonism or very subtle parkinsonism with a markedly varied age of onset. © 2003 Movement Disorder Society

[1]  P. Lansbury,et al.  The UCH-L1 Gene Encodes Two Opposing Enzymatic Activities that Affect α-Synuclein Degradation and Parkinson's Disease Susceptibility , 2002, Cell.

[2]  M. Farrer,et al.  Parkinson's genetics: molecular insights for the new millennium. , 2002, Neurotoxicology.

[3]  Karl Herholz,et al.  The striatal dopaminergic deficit is dependent on the number of mutant alleles in a family with mutations in the parkin gene: evidence for enzymatic parkin function in humans , 2002, Neuroscience Letters.

[4]  M. Farrer,et al.  The Tau H1 Haplotype is associated with Parkinson's disease in the Norwegian population , 2002, Neuroscience Letters.

[5]  D. Hernandez,et al.  Lewy bodies and parkinsonism in families with parkin mutations , 2001, Annals of neurology.

[6]  Matthew J. Farrer,et al.  α-synuclein gene haplotypes are associated with Parkinson’s disease , 2001 .

[7]  L. Golbe,et al.  The tau A0 allele in Parkinson's disease , 2001, Movement Disorders.

[8]  W D Heiss,et al.  Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene , 2001, Annals of neurology.

[9]  D. Hernandez,et al.  alpha-Synuclein gene haplotypes are associated with Parkinson's disease. , 2001, Human molecular genetics.

[10]  Hitoshi Takahashi,et al.  An autopsy case of autosomal‐recessive juvenile parkinsonism with a homozygous exon 4 deletion in the parkin gene , 2000, Movement disorders : official journal of the Movement Disorder Society.

[11]  S. Tsuji,et al.  Novel mutations, pseudo‐dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism , 2000, Annals of neurology.

[12]  X. Breakefield,et al.  Parkin deletions in a family with adult‐onset, tremor‐dominant parkinsonism: Expanding the phenotype , 2000, Annals of neurology.

[13]  Shinsei Minoshima,et al.  Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase , 2000, Nature Genetics.

[14]  Bonifati,et al.  Association between early-onset Parkinson's disease and mutations in the parkin gene. , 2000, The New England journal of medicine.

[15]  M. Farrer,et al.  Case-control study of the ubiquitin carboxy-terminal hydrolase L1 gene in Parkinson’s disease , 1999, Neurology.

[16]  S. Blumen,et al.  Autosomal-recessive juvenile parkinsonism in a Jewish Yemenite kindred: mutation of Parkin gene. , 1999, Neurology.

[17]  R. Krüger,et al.  Increased susceptibility to sporadic Parkinson's disease by a certain combined α‐synuclein/apolipoprotein E genotype , 1999, Annals of neurology.

[18]  Y. Agid,et al.  A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease. , 1999, Human molecular genetics.

[19]  Y. Agid,et al.  Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism , 1998, The Lancet.

[20]  M. Polymeropoulos,et al.  Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson’s disease , 1998, Human Genetics.

[21]  A. Brookes,et al.  Point Mutations (Thr240Arg and Ala311Stop) in theParkinGene , 1998 .

[22]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[23]  A. Ishikawa,et al.  Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism , 1996, Neurology.

[24]  T. Miyatake,et al.  A family with hereditary juvenile dystonia‐parkinsonism , 1995, Movement disorders : official journal of the Movement Disorder Society.

[25]  Y. Yamamura,et al.  Paralysis agitans of early onset with marked diurnal fluctuation of symptoms , 1973, Neurology.