Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders

Scholz, Sonja W.; Brás, José

doi:10.3390/ijms161024629

Cited by 24 publications

(17 citation statements)

References 209 publications

(265 reference statements)

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“…This observation illustrates an emerging concept in neurodegenerative diseases of late adulthood: namely, the absence of a family history does not exclude a genetic cause/predisposition (Scholz and Bras, 2015; Shulman, et al, 2011). Possible explanations for lack of a family history include death of relatives prior to manifesting symptoms, phenotypic heterogeneity, somatic mutations, spontaneous mutations, reduced penetrance, or non-paternity.…”

Section: Discussionmentioning

confidence: 71%

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Geiger

Ding

Crain

et al. 2016

Neurobiology of Disease

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Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia.

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Section: Discussionmentioning

confidence: 71%

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Geiger

Ding

Crain

et al. 2016

Neurobiology of Disease

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“…Among them, endocrine diseases are often ignored due to the heterogeneous of clinical manifestations, such as hyperparathyroidism, hypothyroidism, and pseudohypoparathyroidism (PHP). [2] …”

Section: Introductionmentioning

confidence: 99%

Pseudohypoparathyroidism with basal ganglia calcification

Song

Zhao²,

Li³

et al. 2017

Medicine

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Rationale:Parkinsonism can be secondary to many internal diseases, in some certain conditions, it seems that the clinical manifestations of parkinsonism presenting reversible. We report a case of patient with parkinsonism secondary to pseudohypoparathyroidism, who improved markedly after the supplement of serum calcium.Patient concerns and diagnoses:A 52-year-old woman with acute parkinsonism was diagnosed as pseudohypoparathyroidism after the conducting of brain computed tomography, laboratory examinations, and gene detection. The son of the patient was also examined and was diagnosed as pseudohypoparathyroidism, who had ever complained of the history of epilepsy. The clinical manifestations of parkinsonism of the patient was reevaluated after the supplement of serum calcium according to the diagnosis.Interventions and outcomes:The brain computed tomography revealed the basal ganglia calcification of the patient, accompanying by serum hypocalcemia and hyperphosphatemia. Loss of function mutation also confirmed the diagnosis. Five days after the therapy targeting at correction of serum hypocalcemia, the patient improved greatly in dyskinesia.Lessons:This study reported a patient presenting as acute reversible parkinsonism, who was finally diagnosed as pseudohypoparathyroidism. It indicated us that secondary parkinsonism should be carefully differentiated for its dramatic treatment effect. And the family history of seizures might be an indicator for the consideration of pseudohypoparathyroidism.

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“…[2] The molecular mechanism of DLB is largely unknown, although a genetic component has been proposed. [3]…”

Section: Introductionmentioning

confidence: 99%

<b><i>C9orf72</i></b> Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

Geiger

Arthur

Dawson³

et al. 2016

Neurodegener Dis

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Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. Objective: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. Methods: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. Results: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. Conclusion: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

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Genetics Underlying Atypical Parkinsonism and Related Neurodegenerative Disorders

Cited by 24 publications

References 209 publications

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies

Pseudohypoparathyroidism with basal ganglia calcification

<b><i>C9orf72</i></b> Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies

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