Screening for mutations of the ferritin light and heavy genes in Parkinson's disease patients with hyperechogenicity of the substantia nigra

Felletschin, B; Bauer, Peter; Walter, Uwe; Behnke, Stephanie; Spiegel, Jörg; Csóti, Ilona; Sommer, Ulrike; Zeiler, Björn; Becker, Georg; Rieß, Olaf; Berg, Daniela

doi:10.1016/j.neulet.2003.08.026

Cited by 42 publications

(26 citation statements)

References 14 publications

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“…Our finding of larger SN echogenic size in PMC with two mutated alleles, compared to PMC with one mutated allele, further suggests that this assumed early damage of dopaminergic cells is influenced by genetic factors such as parkin mutation. To confirm and to specify the contribution of the parkin mutation in concurrence with other possible genetic factors generating SN hyperechogenicity (e.g., ferritin mutations), 8 further BPS and genetic studies of this family, including members without parkin mutation, and of other families with PMC are warranted.…”

Section: Figmentioning

confidence: 95%

“…[3][4][5][6][7][8] The finding of SN hyperechogenicity in 9% of young healthy subjects corresponds to decreased striatal 18 F-dopa uptake on PET scanning and was proposed as a marker for susceptibility to nigrostriatal injury. 9 Recently, homozygous, heterozygous, and compound-heterozygous mutations in the parkin gene were reported to cause hereditary adult-onset parkinsonism, in some families clinically indistinguishable from idiopathic PD.…”

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confidence: 99%

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Brain parenchyma sonography detects preclinical parkinsonism

et al. 2004

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Substantia nigra (SN) hyperechogenicity on brain parenchyma sonography (BPS) is highly characteristic for idiopathic PD. We studied 7 symptomatic and 7 asymptomatic parkin mutation carriers (PMC) from a large kindred with adult-onset parkinsonism. BPS revealed larger SN echogenic sizes in PMC with parkin mutations on both alleles (homozygous, compound-heterozygous), compared to PMC with only one mutated allele (Mann-Whitney U test, P = 0.007). In symptomatic PMC, larger SN echogenic size was correlated with younger age at onset of the disease (Spearman rank correlation, Rho = -0.937, P = 0.002) but not with age, disease duration, or disease severity. BPS demonstrated SN hyperechogenicity, in concordance with abnormal nigrostriatal (18)F-dopa positron emission tomography (PET), in all symptomatic and 3 asymptomatic PMC. In 2 asymptomatic PMC, PET and BPS were normal. However, in another 2 asymptomatic PET-normal PMC, SN hyperechogenicity could be detected. Data suggest SN hyperechogenicity as an early marker to detect preclinical parkinsonism.

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Section: Figmentioning

confidence: 95%

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confidence: 99%

Brain parenchyma sonography detects preclinical parkinsonism

et al. 2004

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“…Since the first description of SN hyperechogenicity in idiopathic PD (Becker et al, 1995), a number of studies have shown that this ultrasound feature is typical for this neurodegenerative disorder (Berg et al, 2001a;Walter et al, 2003). In more than 90% of PD patients an area of SN hyperechogenicity is displayed, well beyond the standard deviation of an age-matched control group.…”

Section: Hyperechogenicity Of the Sn In Pdmentioning

confidence: 99%

“…and HFE) were screened for mutations in patients with PD and increased SN echogenicity (Felletschin et al, 2003;Deplazes et al, 2004, Hochstrasser et al, 2004Akbas et al, Table II). All genes investigated so far, play an important role in different aspects of iron metabolism (FIG.…”

Section: Variations Of Genes Involved In Brain Iron Metabolism and Pdmentioning

confidence: 99%

Disturbance of iron metabolism in Parkinson’s disease — ultrasonography as a biomarker

et al. 2006

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A central role of iron in the pathogenesis of Parkinson's disease (PD) has been discussed for many years. So far, however, a biomarker indicating increased iron levels in the substantia nigra (SN) in PD patients has been missing. Performing transcranial ultrasound we detected an increased area of SN echogenicity as a typical echofeature in PD, visible already in the early stages of the disease and in subjects with subclinical impairment of the nigrostriatal system. Animal studies and post mortem analyses of human brain tissue revealed that this echofeature is associated with increased iron levels of the substantia nigra as well as a reduced neuromelanin content. The apparently autosomal dominant inheritance of this echofeature in relatives of patients with idiopathic PD indicates a primary role of disturbances of iron metabolism in PD. Consequently performed mutation analyses in genes involved in brain iron metabolism lead to the discovery of specific mutations in the ferritin-H, IRP2 and HFE gene in single PD patients. Moreover, variations in the ceruloplasmin gene were found to be associated with PD or SN hyperechogenicity. Functional relevance of some of these mutations for iron metabolism could be proven. Therefore, SN hyperechogenicity can be regarded as biomarker for both: impairment of the nigrostriatal system and increased iron levels of the SN. Future studies aim at substantiating the hypothesis that healthy subjects with SN hyperechogenicity indeed represent a population at risk for nigrostriatal degeneration, which would have a significant impact on therapeutical options.

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“…The disorder is termed hereditary ferritinopathy. The fi rst published work failed to confi rm more frequent occurrence of these mutations in patients with PD or increased SN echogenicity 29 . Ferroxidase ceruloplasmin (Cp) is involved in iron metabolism.…”

Section: Echogenicity Of Substantia Nigra and Iron Metabolismmentioning

confidence: 99%