ORPHA: 2828; DO: 0060370;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.23 | Parkinson disease 7, autosomal recessive early-onset | 606324 | Autosomal recessive | 3 | DJ1 | 602533 |
A number sign (#) is used with this entry because autosomal recessive early-onset Parkinson disease-7 (PARK7) is caused by homozygous or compound heterozygous mutation in the DJ1 (PARK7) gene (602533) on chromosome 1p36.
A digenic form of Parkinson disease (see 605909) resulting from a mutation in the DJ1 gene and a mutation in the PINK1 gene has been reported.
For general phenotypic information and a discussion of genetic heterogeneity of Parkinson disease, see 168600.
Van Duijn et al. (2001) reported a consanguineous family from a genetically isolated community in the southwestern region of the Netherlands in which 4 individuals had a form of early-onset Parkinson disease. Onset of symptoms was before the age of 40 years with resting tremor, postural tremor, bradykinesia, loss of postural reflexes, and an asymmetric onset of symptoms. Three of the 4 patients also showed psychiatric symptoms, including psychotic episodes. In all patients, the progression of disease was slow, and there were no atypical features or signs of involvement of additional neurologic systems.
Abou-Sleiman et al. (2003) reported 2 unrelated patients with early-onset Parkinson disease. They presented at ages 36 and 39 years with rigidity, bradykinesia, and tremor, with a good response to L-DOPA therapy. Both patients had psychologic disturbances early in the disease, particularly an anxiety disorder.
Clinical Variability
Annesi et al. (2005) reported 3 affected sibs from a consanguineous southern Italian family in which 3 sibs had early-onset parkinsonism at ages 36, 35, and 24 years, respectively. One sib also had features of amyotrophic lateral sclerosis with upper and lower limb weakness, fasciculations, and EMG evidence of denervation. He later developed severe, bulbar involvement, muscle atrophy, and hyperreflexia with extensor plantar responses, as well as marked cognitive impairment and parkinsonism. He died from respiratory failure at age 43 years. The other 2 sibs had prominent parkinsonism, hyperreflexia, urinary incontinence, and behavioral abnormalities, such as aggression and bulimia. Annesi et al. (2005) noted that the phenotype was reminiscent of that reported in Guam (105500).
In a family with early-onset parkinsonism from a genetically isolated community in the Netherlands, van Duijn et al. (2001) found linkage to chromosome 1p36. Using a multiple marker spanning a disease haplotype of 16 cM, they found a multipoint linkage lod score of 4.3. On the basis of several recombination events, the region defining the disease haplotype was clearly separated, by 25 cM or more, from the more centromeric PARK6 locus. Therefore, the authors concluded that this was a distinct form of the disease from PARK6.
Among 4 families with autosomal recessive early-onset parkinsonism analyzed, Bonifati et al. (2002) found that 2 supported linkage to PARK7, 1 with conclusive evidence.
The transmission pattern of PARK7 in the families reported by Bonifati et al. (2003) was consistent with autosomal recessive inheritance.
In the family reported by van Duijn et al. (2001) and in 1 of the families reported by Bonifati et al. (2002), Bonifati et al. (2003) identified homozygous mutations in the DJ1 gene that cosegregated with the disease (602533.0001-602533.0002).
Among 185 unrelated patients with early-onset Parkinson disease, Abou-Sleiman et al. (2003) identified 2 patients with mutations in the DJ1 gene (602533.0003-602533.0004). The authors estimated that the frequency of DJ1 mutations in early-onset Parkinson disease is very low, at approximately 1%.
Among 118 familial patients and 7 sporadic patients with early-onset Parkinson disease (range of age at onset, 12 to 78 years), Ibanez et al. (2003) did not identify any mutations in the DJ1 gene, suggesting that PARK7 is not a common locus for early-onset autosomal recessive Parkinson disease. The patients came from Europe, South America, Lebanon, Asia, Turkey, and North Africa.
In 3 affected sibs from a consanguineous southern Italian family with early-onset parkinsonism, amyotrophic lateral sclerosis, and cognitive impairment, Annesi et al. (2005) identified double homozygosity for 2 mutations in the DJ1 gene (602533.0006).
Alcalay et al. (2010) identified a mutation in the DJ1 gene in 1 (0.2%) of 953 patients with early-onset PD before age 51, including 77 and 139 individuals of Hispanic and Jewish ancestry, respectively.
Burbulla et al. (2017) studied dopaminergic neurons derived from patients with idiopathic and familial (homozygous for DJ1 c.192G-C, 602533.0005) Parkinson disease. The authors identified a time-dependent pathologic cascade beginning with mitochondrial oxidant stress, leading to oxidized dopamine accumulation, and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and alpha-synuclein (SNCA; 163890) accumulation. This toxic cascade was observed in human, but not in mouse, Parkinson disease neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or alpha-synuclein amounts in mouse midbrain neurons recapitulated pathologic phenotypes observed in human neurons. Thus, Burbulla et al. (2017) concluded that dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in Parkinson disease pathogenesis.
Ramsey et al. (2010) noted that several in vitro studies had suggested that DJ1 could inhibit the formation and protect against the deleterious effects of SNCA (163890) aggregation. They crossbred transgenic mice (M83) expressing the human pathogenic SNCA A53T mutation (163890.0001), which causes PARK1 (168601), on a DJ1-null background (M83-DJ-null mice) to determine the effects of the lack of DJ1 in these mice. M83 and M83-DJ-null mice displayed a similar onset of disease and pathologic changes, and none of the analyses to assess for changes in pathogenesis revealed any significant differences between M83 and M83-DJ-null mice. The authors suggested that DJ1 may not function to modulate SNCA directly and does not appear to play a role in protecting against the deleterious effects of A53T in vivo. Ramsey et al. (2010) speculated that SNCA and DJ1 mutations may lead to Parkinson disease via independent mechanisms.
Abou-Sleiman, P. M., Healy, D. G., Quinn, N., Lees, A. J., Wood, N. W. The role of pathogenic DJ-1 mutations in Parkinson's disease. Ann. Neurol. 54: 283-286, 2003. [PubMed: 12953260] [Full Text: https://doi.org/10.1002/ana.10675]
Alcalay, R. N., Caccappolo, E., Mejia-Santana, H., Tang, M. X., Rosado, L., Ross, B. M., Verbitsky, M., Kisselev, S., Louis, E. D., Comella, C., Colcher, A., Jennings, D., and 21 others. Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the Consortium on Risk for Early Onset Parkinson Disease study. Arch. Neurol. 67: 1116-1122, 2010. [PubMed: 20837857] [Full Text: https://doi.org/10.1001/archneurol.2010.194]
Annesi, G., Savettieri, G., Pugliese, P., D'Amelio, M., Tarantino, P., Ragonese, P., La Bella, V., Piccoli, T., Civitelli, D., Annesi, F., Fierro, B., Piccoli, F., Arabia, G., Caracciolo, M., Canadiano, I. C. C., Quattrone, A. DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex. Ann. Neurol. 58: 803-807, 2005. [PubMed: 16240358] [Full Text: https://doi.org/10.1002/ana.20666]
Bonifati, V., Breedveld, G. J., Squitieri, F., Vanacore, N., Brustenghi, P., Harhangi, B. S., Montagna, P., Cannella, M., Fabbrini, G., Rizzu, P., van Duijn, C. M., Oostra, B. A., Meco, G., Heutink, P. Localization of autosomal recessive early-onset parkinsonism to chromosome 1p36 (PARK7) in an independent dataset. Ann. Neurol. 51: 253-256, 2002. [PubMed: 11835383] [Full Text: https://doi.org/10.1002/ana.10106]
Bonifati, V., Rizzu, P., van Baren, M. J., Schaap, O., Breedveld, G. J., Krieger, E., Dekker, M. C. J., Squitieri, F., Ibanez, P., Joosse, M., van Dongen, J. W., Vanacore, N., van Swieten, J. C., Brice, A., Meco, G., van Duijn, C. M., Oostra, B. A., Heutink, P. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299: 256-259, 2003. [PubMed: 12446870] [Full Text: https://doi.org/10.1126/science.1077209]
Burbulla, L. F., Song, P., Mazzulli, J. R., Zampese, E., Wong, Y. C., Jeon, S., Santos, D. P., Blanz, J., Obermaier, C. D., Strojny, C., Savas, J. N., Kiskinis, E., Zhuang, X., Kruger, R., Surmeier, D. J., Krainc, D. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357: 1255-1261, 2017. [PubMed: 28882997] [Full Text: https://doi.org/10.1126/science.aam9080]
Ibanez, P., De Michele, G., Bonifati, V., Lohmann, E., Thobois, S., Pollak, P., Agid, Y., Heutink, P., Durr, A., Brice, A., French Parkinson's Disease Genetics Study Group. Screening for DJ-1 mutations in early onset autosomal recessive parkinsonism. Neurology 61: 1429-1431, 2003. [PubMed: 14638971] [Full Text: https://doi.org/10.1212/01.wnl.0000094121.48373.fd]
Ramsey, C. P., Tsika, E., Ischiropoulos, H., Giasson, B. I. DJ-1 deficient mice demonstrate similar vulnerability to pathogenic ala53-to-thr human alpha-syn toxicity. Hum. Molec. Genet. 19: 1425-1437, 2010. [PubMed: 20089532] [Full Text: https://doi.org/10.1093/hmg/ddq017]
van Duijn, C. M., Dekker, M. C. J., Bonifati, V., Galjaard, R. J., Houwing-Duistermaat, J. J., Snijders, P. J. L. M., Testers, L., Breedveld, G. J., Horstink, M., Sandkuijl, L. A., van Swieten, J. C., Oostra, B. A., Heutink, P. PARK7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am. J. Hum. Genet. 69: 629-634, 2001. [PubMed: 11462174] [Full Text: https://doi.org/10.1086/322996]