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With a growing list of monogenetic causes of Parkinson's disease (PD),1–3 prioritization of genetic testing is made on the presumed mode of inheritance. In patients with early-onset PD from consanguineous families, the most common mode of inheritance is autosomal recessive. Rarely, an individual may be homozygous for a mutation inherited in an autosomal dominant manner, complicating the diagnostic process.

The proband is a 36-year-old female from a consanguineous Pakistani family (Fig. 1A). She presented with a 5-year history of left-sided stiffness, micrographia, festinant gait, tremor, and falls. Past medical history included postpartum psychosis and severe depression. There were no symptoms of autonomic dysfunction. Neurological examination at the age of 35 years revealed severe bilateral bradykinesia, rigidity, worse on the left, and mild bilateral upper limb rest tremor. Gait was shuffling, with freezing and complete loss of postural reflexes. Bilateral ankle clonus was noted. Initially, there was a poor response to dopamine agonists. She responded well to 100/25 mg co-careldopa 3 times per day, but developed wearing offs and peak-dose dyskinesias after 4 months of treatment. There was no family history of parkinsonism. The proband's mother's neurological examination at the age of 72 years was normal. The proband's father, who died at age 64 years from a stroke, had no symptoms or signs of parkinsonism as described by his family. Her siblings and children were asymptomatic, but were unavailable for examination.

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Figure 1. A: Pedigree and clinical information on the family. A half filled symbol represents the proband (arrow), who is the only individual affected by parkinsonism. Clinically unaffected but confirmed mutation carrier (the proband's mother) is represented by a circle with a dot. Empty symbols represent clinically unaffected family members. B: MLPA result for the proband, shows triplication of exons 1, 3, 4, 5, and 6 of SNCA (exon 2 result not shown) using kit P052C, with an MLPA ratio of approximately 2.0 (normal MLPA ratio is 1.0, with 0.5 for each allele), indicating 4 copies of SNCA. C: The proband's array–comparative genomic hybridization (array-CGH) result shows a region of copy number gain on the long arm of chromosome 4 within band 4q22.1. The copy number gain is approximately 0.98 Mb and contains 5 genes including SNCA. A normal ratio plot score for any given gene is zero, the average ratio score in this region of copy number gain is 1.0, consistent with the MLPA finding of 4 copies of the SNCA gene region. SNP array (not shown) showed that the duplicated regions on 4q22 were homozygous. Supplemental Figure 1. FISH analysis of interphase chromosomes from EBV-transformed lymphocytes of the proband. There are two FISH probes shown, both from the critical region (4q22). The green probe (RP11-67M1) shows two pairs of signals for each chromosome 4 indicating a double duplication. The red probe (RP11-169K7) also shows two signals for each chromosome 4 and an additional two signals due to cross-hybridization to another chromosome.

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Investigations in the proband included routine blood work, copper studies, and white cell enzymes, and were all normal. Dopamine transporter scan (DAT-SCAN) showed bilateral reduction in tracer uptake in the striatum, more significant on the right. Formal neuropsychological examination revealed a mild degree of intellectual under-functioning from premorbid estimates, with anterior/subcortical dysfunction. Mutations in PARKIN, PINK1, and common LRRK2 mutations were excluded. Multiplex ligation-dependent probe amplification (MLPA) showed 4 copies of SNCA (Fig. 1B). Comparative genomic hybridization (Nimblegen 135 K array Roche-Niblegen) showed copy number gain of 0.928 Mb, containing 5 genes including SNCA (Fig. 1C). Single-nucleotide polymorphism (SNP) array showed this to be homozygous. Fluorescent in situ-hybridization demonstrated duplication of SNCA on both alleles (Supplemental Figure 1). The proband's mother's MLPA showed SNCA duplication. Considering the proband's homozygosity for SNCA duplication, her father is likely to have had an SNCA duplication. Less likely, de novo duplication (in addition to duplication inherited from mother) occurred in the proband.

SNCA multiplication is a rare cause of autosomal dominant PD.4,5 SNCA triplications (4 copies of SNCA) are fully penetrant; with early-onset and rapidly progressive parkinsonism associated with dementia, autonomic dysfunction, and psychiatric features.4 With SNCA duplications (3 SNCA copies), the disease clinically resembles idiopathic PD5 and reduced penetrance is recognized.6 Our patient has 4 SNCA copies and her clinical phenotype closely matches that of patients with SNCA triplications4 and is in keeping with the single previously described case of SNCA double duplication.7

Homozygous SNCA duplications are a rare cause of young-onset parkinsonism and should be considered in the patients with a family history compatible with recessive inheritance. Early cognitive dysfunction and depression are consistently reported in patients with 4 SNCA copies and may be regarded as “red flags” for SNCA multiplications.

Acknowledgements

This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme.

Author Roles:

1. Research project: A. Conception, B. Organization, C. Execution. 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique. 3. Manuscript: A. Writing of the first draft, B. Review and Critique.

Maja Kojovic: 1A, 1B, 1C, 3A.

Una-Marie Sheerin: 1B, 1C, 3B.

Anirban Saha: 2B, 3B.

Jose Bras: 1C, 3B.

Vaneesha Gibbons: 1C, 3B.

Rodger Palmer: 1C, 3B.

Henry Houlden: 1A, 1B, 3B.

John Hardy: 1A, 1B, 3B.

Nicholas W Wood: 1A, 1B, 3B.

Kailash P Bhatia: 1A, 1B, 3B.

Financial Disclosures: Maja Kojovic: No conflicts of interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria for conference travel from: EFNS, MDS, Ipsen and UCB; Grants: None. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Neurology, University of Ljubljana, Slovenia. Contracts: None. Royalties: None. Other: None.

Una-Marie Sheerin: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: None. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

Anirban Saha: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: None. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

Jose Bras: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: None. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

Vaneesha Gibbons: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: None. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

Rodger Palmer: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: None. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

Henry Houlden: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: Medical Research Council (UK) and Wellcome Trust. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

John Hardy: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: None. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

Nicholas W Wood: No conflicts of Interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: None. Partnerships: None. Honoraria: None. Grants: funded Medical Research Council (UK), Wellcome Trust and Parkinson's UK. Intellectual Property Rights: None. Expert Testimony: None. Employment: Department of Human Physiology, University of Milan, Italy. Contracts: None. Royalties: None Other: None.

Kailash P. Bhatia: No conflicts of interest to report. Stock Ownership in medically-related fields: None. Consultancies: None. Advisory Boards: Movement Disorders Society Scientific Advisory Board Member, Scientific advisory board for GSK and Boehringer Ingelheim. Partnerships: None. Honoraria to speak/attend meetings from GSK, Boehringer-Ingelheim, Ipsen, Merz, and Orion Corporation. Grants: Halley Stewart Trust through Dystonia Society UK, Wellcome Trust MRC strategic neurodegenerative disease initiative award (Ref. number WT089698), a grant from the Dystonia Coalition and a grant from Parkinson's UK (Ref. number G-1009). Intellectual Property Rights: None. Expert Testimony: None. Employment: University College London. Royalties: From Oxford University Press for book: Oxford Specialist Handbook of Parkinson's disease and Other Movement Disorders. Other: None.

References

  1. Top of page
  • 1
    Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 2010; 31: 763780.
  • 2
    Zimprich A, Benet-Pages A, Struhal W, et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet 2011; 89: 168175.
  • 3
    Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006; 38: 11841191.
  • 4
    Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science 2003; 302: 841.
  • 5
    Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 2004; 364: 11671169.
  • 6
    Nishioka K, Ross OA, Ishii K, et al. Expanding the clinical phenotype of SNCA duplication carriers. Mov Disord 2009; 24: 18111819.
  • 7
    Ikeuchi T, Kakita A, Shiga A, et al. Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Arch Neurol 2008; 65: 514519.

Maja Kojovic MD*, Una-Marie Sheerin MD†, Ignacio Rubio-Agusti MD*, Anirban Saha PhD‡, Jose Bras PhD†, Vaneesha Gibbons MD†, Rodger Palmer PhD§, Henry Houlden PhD†, John Hardy PhD¶, Nicholas W. Wood PhD† **, and Kailash P. Bhatia FRCP*, * Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, UCL, London, United Kingdom, † Department of Molecular Neuroscience, UCL Institute of Neurology, UCL, London, United Kingdom, ‡ Hurstwood Park Neurological Centre, Haywards Heath, United Kingdom, § Regional Cytogenetics Laboratory, North East Thames Regional Genetics Service, Great Ormond Street Hospital National Health Service (NHS) Trust, London, United Kingdom, ¶ Department of Molecular Neuroscience, and Reta Lila Weston Trust for Medical Research, UCL Institute of Neurology, London, United Kingdom, ** UCL Genetics Institute, UCL, London, United Kingdom.