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Biomedical subjects

Zbigniew K Wszolek

Publications and source records attributed to Zbigniew K Wszolek.

At least 19 recordsLinked to original sources
PubMed2026

Genetic Screening of Colombian Patients With Early-Onset Parkinson Disease.

BACKGROUND AND OBJECTIVES: Early-onset Parkinson disease (EOPD), defined as symptom onset before 50 years of age, accounts for approximately 10% of patients and is suggested to have a greater genetic component than typical late-onset forms of the disease. Recessive variants in PRKN, PINK1, and DJ-1, are the most common genetic cause of EOPD, however, most studies are in patients of white ancestry. This study aims to analyze genetic variants in PRKN, PINK1, and DJ-1 in Colombian patients to help address the gap in EOPD genetic research of South American populations. METHODS: We analyzed 43 unrelated patients with EOPD using Sanger sequencing for the PRKN, PINK1, and DJ-1 genes and employed multiplex ligation-dependent probe amplification to detect copy number variants. Additionally, long-read whole-genome sequencing was conducted on 3 unresolved patients with age at onset before 30 years of age (long-read sequencing [LRS] patient A-C). RESULTS: We identified known pathogenic single-nucleotide variants and copy number variants in the PRKN gene accounting for 2 patients' disease (4.6% of patients). We observed 2 pathogenic variants in PRKN (c.155delA; p.N52Mfs*29 and c.1083+1G>A) in patient 1, who reported an age at onset of 16 years. We further detected a homozygous duplication of PRKN exons 5-6 in an additional patient, age at onset of 18 years. DISCUSSION: Our study helps characterize genetic contributors to EOPD in Colombian patients, demonstrating genetic forms (PRKN, PINK1, and DJ-1) are rare. Our results highlight a need to include diverse populations in research to improve genetic understanding of disease.

Journal Article↗
PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗
PubMed2007

ELAVL4, PARK10, and the Celts.

Genetic variability in ELAVL4 located in the PARK10 locus was recently associated with age-at-onset (AAO) in a series of Parkinson's disease (PD) patients originating from the United States. We examined five markers spanning ELAVL4 in Norwegian, United States, and Irish PD case-control samples. No association was found between the examined markers and AAO or PD in Norwegian or US samples. However, ELAVL4 markers (rs967582 and rs3902720) were significantly associated with susceptibility to PD in our Irish series. Our data suggest that the association between ELAVL4 and PD previously observed might be explained by a Celtic-founder effect.

Adult↗
PubMed2007

Leucine-rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson's disease.

Leucine-rich repeat kinase 1 gene (LRRK1) on chromosome 15q26.3 is a paralog of LRRK2 in which multiple substitutions were recently linked to Parkinson's disease. We have examined the exon-intron structure of the gene and the expressed mRNA sequence in brain. LRRK1 sequencing analysis in 95 probands from families with autosomal dominant Parkinson's disease identified 23 variants, 14 of which are novel, with four resulting in non-synonymous amino acid substitutions. These four substitutions are rare and do not clearly segregate with disease within our families or associate with sporadic Parkinson's disease in a US case-control series. Subsequent sequencing of exon 26 encoding the kinase activation segment in an additional 360 probands identified one further synonymous variant, suggesting that LRRK1 variants are not a frequent cause of Parkinson's disease. The relative absence of substitutions within LRRK1 highlights a greater conservation of sequence than observed for LRRK2. Comparison of evolutionary interspecies sequences of LRRK1 and LRRK2 suggests they diverged from a common founder gene.

Alternative Splicing↗
PubMed2006

Clinical-pathologic study of biomarkers in FTDP-17 (PPND family with N279K tau mutation).

The objective of this clinical-pathologic study was to identify biomarkers for a pallidopontonigral degeneration (PPND) kindred of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) harboring the N279K tau mutation. Five affected subjects, one at-risk who later became symptomatic, and one at-risk asymptomatic mutation carrier, had abnormal (18)fluorodeoxyglucose PET demonstrating asymmetric temporal lobe hypometabolism. All except the asymptomatic mutation carrier had abnormal brain MRI. Parkinsonism, myoclonus, anosmia, insomnia, speech, and autonomic dysfunction were identified. Autopsy of six affected subjects showed frontotemporal degeneration with extensive tauopathy. Further studies of FTDP-17 patients are needed to replicate these findings.

Adult↗
PubMed2006

Pharmacologic management of seizures in organ transplant.

Seizures in a transplant candidate or recipient raise complicated management issues, but there are no results from controlled drug trials to guide their pharmacologic treatment. Most seizures in the transplant population are isolated events that do not require long-term antiseizure therapy. Short-term therapy, however, can reduce seizure recurrence. This review focuses on the pharmacologic management issues associated with acute and short-term therapy of seizures in this population. Phenytoin, fosphenytoin, and phenobarbital are current first-line therapies. The interactions between immunosuppressants and these antiepileptic drugs (AEDs) are of particular importance because the latter may reduce immunosuppressant blood levels. Other, newer agents are not subject to this interaction, and further studies are needed to define their role in the management of seizures in transplant patients.

Anticonvulsants↗
PubMed2006

Aprataxin (APTX) gene mutations resembling multiple system atrophy.

Mutations of the aprataxin (APTX) gene cause early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), also called ataxia with oculomotor apraxia type 1. Recent studies showed clinical heterogeneity in patients with EAOH. We describe 2 patients whose clinical features resembled those of multiple system atrophy of the cerebellar subtype (MSA-C) but without ocular motor apraxia and hypoalbuminemia. Each had a different nucleotide transition in the APTX gene (725G-->A and 457A-->G). These variants on the APTX gene exhibit phenotypic variability.

Adult↗
PubMed2006

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder, which has three cardinal features: behavioral and personality changes, cognitive impairment, and motor symptoms. FTDP-17 was defined during the International Consensus Conference in Ann Arbor, Michigan, in 1996. The prevalence and incidence remain unknown but FTDP-17 is an extremely rare condition. It is caused by mutations in the tau gene, which encodes a microtubule-binding protein. Over 100 families with 38 different mutations in the tau gene have been identified worldwide. The phenotype of FTDP-17 varies not only between families carrying different mutations but also between and within families carrying the same mutations. The pathogenetic mechanisms underlying the disorder are thought to be related to the altered proportion of tau isoforms or to the ability of tau to bind microtubules and to promote microtubule assembly. Definitive diagnosis of FTDP-17 requires a combination of characteristic clinical and pathological features and molecular genetic analysis. Genetic counseling should be offered to affected and at-risk individuals; for most subtypes, penetrance is incomplete. Currently, treatment for FTDP-17 is only symptomatic and supportive. The prognosis and rate of the disease's progression vary considerably among individual patients and genetic kindreds, ranging from life expectancies of several months to several years, and, in exceptional cases, as long as two decades.

Brain↗
PubMed2006

Effect of MAPT and APOE on prognosis of progressive supranuclear palsy.

To assess genetic influence on the clinical presentation of progressive supranuclear palsy (PSP), the genetic effect on disease course was examined for variants in the tau gene (MAPT) and the gene for apolipoprotein E (APOE) in 58 cases of pathologically confirmed PSP. Clinical indicators of disease course included age at symptomatic onset (AAO), age at death (AAD), and disease duration (DD) and the genetic effects examined included MAPT haplotypes and APOE genotypes. From linear regression analysis, the MAPT H1/H1 genotype was associated with significantly earlier AAO (P=0.038). The MAPT genotype did not significantly influence DD or AAD. The APOE epsilon4 allele did not significantly influence AAO, AAD, or DD. Male sex was a predictor for earlier AAO (P=0.015). The interaction between MAPT and APOE was not significant for AAD and DD, but a significant negative coefficient was found for AAO suggesting their combination does not have an additive effect. These results support the assertion that the H1/H1 genotype may contribute to the earlier occurrence of clinical symptoms.

Age of Onset↗
PubMed2006

Dopamine agonist therapy for Parkinson disease and pathological gambling.

We report 6 patients with pathological gambling during pharmacologic treatment for Parkinson disease (PD). Four patients were treated with levodopa/carbidopa and dopamine agonist (DA), and 2 patients received DA monotherapy. We reviewed several published reports regarding pathological gambling and antiparkinsonian therapy and suggest that more advanced PD and antiparkinsonian combination therapy (e.g., levodopa/carbidopa and DA) increases the risk for development of pathological gambling behavior compared with monotherapy with either DA or levodopa/carbidopa.

Carbidopa↗
PubMed2006

Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

Adult↗
PubMed2006

Absence of rapid eye movement sleep behavior disorder in 11 members of the pallidopontonigral degeneration kindred.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) is a parasomnia that is manifested by dream enactment behavior. The electrophysiologic substrate for RBD on polysomnography is rapid eye movement sleep without atonia. Rapid eye movement sleep behavior disorder likely stems from neuronal network dysfunction in the brainstem, although it is not yet clear which specific networks are involved. Rapid eye movement sleep behavior disorder is often associated with the sporadic synucleinopathies but rarely associated with the sporadic tauopathies. There are no reports on the possible association of rapid eye movement sleep without atonia and RBD with any familial tauopathy. OBJECTIVE: To characterize the clinical sleep and polysomnography features in a kindred with a familial tauopathy. METHODS: We performed standard polysomnography in 11 members of the pallidopontonigral degeneration kindred irrespective of any sleep-related complaints. Neuropathologic findings were analyzed in those who subsequently underwent autopsy. RESULTS: Six affected and 5 genealogically at-risk family members were studied. None of the 11 had a history of dream enactment behavior. Nine of the 11 members attained sufficient rapid eye movement sleep on polysomnography, and the electrophysiologic features of rapid eye movement sleep without atonia and behavioral manifestations of RBD were absent in all subjects. Neuropathologic examination of 4 affected individuals revealed marked nigral degeneration in 3 along with mild degenerative changes in the locus coeruleus, pontine nuclei and tegmentum, and medullary tegmentum. CONCLUSIONS: These findings argue against nigral degeneration being the primary cause of RBD. The absence of the historical, electrophysiologic, and behavioral manifestations of RBD in this kindred provides further evidence that RBD is rare in the sporadic and familial tauopathies. The difference in frequencies of RBD associated with the synucleinopathies compared with the tauopathies suggests differences in the selective vulnerability of brainstem circuits between the synucleinopathies and tauopathies.

Adult↗
PubMed2006

Phenotypic commonalities in familial and sporadic Parkinson disease.

BACKGROUND: Parkinson disease (PD) is a clinically well-documented neurodegenerative disorder. However, the mechanism or mechanisms of its phenotypic expressions are still unknown. OBJECTIVE: To compare phenotypes by examining demographic and clinical features of patients with familial PD and sporadic PD and with or without a family history of PD. DESIGN: Historical review of patients with sporadic PD in clinic-based samples and individual patients diagnosed with PD from families whose linkage to mutations or loci has been identified. SETTING: Movement disorder clinic in a referral center. PATIENTS: A total of 1277 patients with sporadic PD and 40 patients with familial PD. MAIN OUTCOME MEASURES: Clinical features, including distribution by sex, initial motor symptom, location of initial motor symptom, and frequency of asymmetric motor symptoms. RESULTS: Despite different etiologic backgrounds, both familial and sporadic PD exhibited several interesting commonalities, including a higher incidence in men, tremor as the initial motor symptom (predominantly involving the upper extremities), and asymmetric parkinsonism during disease course. CONCLUSIONS: The increased incidence of parkinsonism in men with familial PD suggests that the sex disparity is more likely the result of a protective effect against development of PD in women than of an increased risk in men that is associated with environmental factors. Phenotypic similarity among familial and sporadic PD indicates that a similar topographic distribution of the nigrostriatal lesion exists in patients with either form of PD regardless of apparent genetic influence.

Age Distribution↗
PubMed2006

Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations.

BACKGROUND: The G2019S mutation is the most common pathogenic substitution in the leucine-rich repeat kinase 2 (LRRK2) gene, which has recently been identified in familial and sporadic Parkinson disease (PD). OBJECTIVES: To report the clinical characteristics of PD patients with homozygous LRRK2 6055G>A (G2019S) mutations and to compare them with previously published descriptions of heterozygous patients. DESIGN: Descriptive clinical report from an international consortium of studies. Subjects Patients with familial PD and homozygous LRRK2 mutations included 23 Tunisians, 2 Algerians, 2 US patients, 1 Canadian, and 1 Moroccan. RESULTS: There were no observable differences between the homozygote and heterozygote phenotypes. CONCLUSIONS: Parkinson disease related to LRRK2 is characterized by typical clinical features, and the similarities between patients with homozygous and heterozygous mutations do not support a gene dosage effect.

Aged↗
PubMed2006

Lrrk2 and Lewy body disease.

OBJECTIVE: The Lrrk2 kinase domain G2019S substitution is the most common genetic basis of familial and sporadic parkinsonism. Patients harboring the G2019S substitution usually present with clinical Parkinson's disease. METHODS: Herein, we report that the most common neuropathology of G2019S-associated Parkinson's disease is Lewy body disease. RESULTS: Lrrk2 G2019S was observed in approximately 2% (n = 8) of our Parkinson's disease/Lewy body disease cases (n = 405). The mutation was also found in one control subject and one Alzheimer's disease patient, reflecting reduced penetrance. INTERPRETATION: Therapeutic strategies targeted at modulating Lrrk2 kinase activity may be important to treat patients with genetically defined familial or typical sporadic Parkinson's disease.

Aged↗