Biomedical subjects

Joseph Jankovic

Publications and source records attributed to Joseph Jankovic.

At least 19 recordsLinked to original sources

PubMed2026

Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analysed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer's disease metabolome. A PD acylcarnitine signature was further replicated in human post-mortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.

Humans↗

PubMed2007

G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy.

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in approximately 1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA.

Cerebellum↗

PubMed2007

Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders.

We sought to review the long-term tolerability of tetrabenazine (TBZ) and seek determinants of tolerability in the treatment of hyperkinetic movement disorders. A retrospective chart review was performed on patients treated with TBZ between 1997 and 2004. Efficacy of TBZ was assessed by a 1- to 5-point response scale (1 = marked reduction in abnormal movements, 5 = worsening). All adverse events (AEs) were captured according to their relationship with study drug. A total of 448 patients (42% male) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19). The mean age at onset of the movement disorder was 43.0 +/- 24.2 years, with TBZ starting at a mean age of 50.0 +/- 22.3 years. Patients remained on treatment for a mean of 2.3 +/- 3.4 years. An efficacy response rating of 1 or 2 was sustained in the majority of patients between the first and last visit. Common AEs included drowsiness (25.0%), Parkinsonism (15.4%), depression (7.6%), and akathisia (7.6%). Comparison of log-likelihood ratios revealed that age was a reliable predictor of Parkinsonism (P < 0.0001). TBZ is a safe and effective drug for the long-term treatment of hyperkinetic movement disorders.

Adult↗

PubMed2007

Short-term effects of tetrabenazine on chorea associated with Huntington's disease.

We sought to assess the short-term clinical effects of tetrabenazine (TBZ) on choreic movements in Huntington's disease patients. A total of 10 patients on stable doses of TBZ were enrolled in this observational study. Patients took their evening dose of TBZ and presented the next day to the Baylor College of Medicine Movement Disorders Clinic without taking the usual morning dose. They were assessed using the Unified Huntington's Disease Rating Scale (UHDRS) motor assessment and Beck Depression Inventory. The usual morning dose of TBZ was then administered and patients were followed with serial UHDRS motor examinations approximately every 2 hours until choreic movements subsided and then returned. TBZ decreased the UHDRS chorea score on average 42.4% +/- 17.8%. The duration of effect varied from a minimum of 3.2 hours to a maximum of 8.1 hours (mean = 5.4 +/- 1.3). No patient experienced an adverse event related to TBZ or its withdrawal. During short-term follow-up after a single dose, TBZ improves chorea for approximately 5 hours.

Adult↗

PubMed2007

Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families.

Mutations in the leucine-rich repeat kinase-2 gene (LRRK2) are responsible for some forms of familial as well as sporadic Parkinson's disease (PD). The purpose of this study was to examine the frequency of a single pathogenic mutation (6055G > A) in the kinase domain of this gene in United States and Tunisian familial PD and to compare clinical characteristics between patients with and without the mutation. Standardized case report forms were used for clinical and demographic data collection. We investigated the frequency of the most common substitution of LRRK2 (G2019S, 6055G>A) and its impact on epidemiological and phenotypic features. The frequency of mutations in Tunisian families was 42% (38/91) and in U.S. families 2.6% (1/39), with the unique opportunity to compare homozygous (n = 23) and heterozygous (n = 109) Tunisian carriers of G2019S substitutions. Individuals with G2019S substitutions had an older age at onset but few other differences compared with families negative for the substitution. Patients with LRRK2 mutations had typical clinical features of PD. Comparisons between individuals with heterozygous and homozygous LRRK2 mutations suggested that gene dosage was not correlated with phenotypic differences; however, the estimated penetrance was greater in homozygotes across all age groups.

Adult↗

PubMed2007

Autopsy-proven Huntington's disease with 29 trinucleotide repeats.

Huntington's disease (HD) is a neurodegenerative disorder associated with expansion of CAG trinucleotide repeats in the huntingtin gene. A minimum of 36 CAG repeats is usually reported in patients with clinical features of HD; 30 to 35 repeats represent an intermediate range. Here we report a 65-year-old male with autopsy-proven HD and 29 CAG repeats.

Autopsy↗

PubMed2007

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.

Disability Evaluation↗

PubMed2006

Comparing knowledge and attitudes towards genetic testing in Parkinson's disease in an American and Asian population.

INTRODUCTION: Recent discoveries of disease-causing genes in Parkinson's disease (PD) have generated considerable interest regarding genetic testing in PD. The attitudes toward genetic testing are largely influenced by knowledge and preconceived notions. OBJECTIVE: We investigated the relationship between knowledge of and attitude towards predictive genetic testing of PD in two independent centers in America and Asia involving PD patients and caregivers. METHODS: In a prospective study involving 515 subjects comprising of PD patients and their caregivers in two independent centers in America and Asia, the level of knowledge about genetic testing and patients' attitudes towards such testing were evaluated using a standardized questionnaire. RESULTS: American PD patients had a higher level of knowledge of PD genetics than Asian PD (31.1% vs. 12.3%, p=0.0002). A greater number of American PD patients and caregivers reported a positive attitude towards the potential medical benefits of genetic testing compared to their Asian counterparts (85.4% vs. 42.2%, 92.2% vs. 32.1%, p<0.00005), but a more negative attitude towards potential compromise in getting health and life insurance (43.7% vs. 25.8%, p=0.0002). However, in the Asian cohort, multivariate analysis revealed that a high level of genetics knowledge was associated with a positive attitude response regarding the potential medical benefits of testing (p<0.0005), but a negative attitude towards compromises in healthcare and life insurance, getting a job and starting a family (p<0.0005). These associations were not observed amongst American subjects. CONCLUSIONS: The relationship between level of genetic knowledge and attitude towards potential risks and benefits of predictive genetic testing in PD was distinctly different in two independent, racially and culturally different PD populations and caregivers. These observations have clinical implications in the development of PD genetic counseling programs.

Adult↗

PubMed2006

Runner's dystonia.

Adult-onset focal dystonia in the upper limbs is well characterized whereas such dystonia has been rarely reported in the lower limbs, especially in proximal parts. When such focal dystonia occurs in an athlete it is often wrongly attributed to an orthopedic disorder. We present five cases, three female and two male with mean age of 44.6+/-10.43 years, mean age at onset of 37.4+/-10.33 years, and mean duration of symptoms for 7.2+/-4.44 years, who initially noted dystonia of one leg during long-distance running. The clinical features of dystonia in these long-distance runners overlap with those of more recognizable forms of focal dystonia including relief with sensory or motor "tricks". They also share features with paroxysmal dyskinesia and carbamazepine markedly ameliorated the symptoms at least in one patient. One patient benefited from an oral anticholinergic, one from levodopa, and another two patients benefited from repeat botulinum toxin injections. Our patients differed from the typical childhood-onset leg dystonia, such as the DYT1 dystonia, in that there was no family history of dystonia and the leg dystonia remained focal without spreading to other body parts. Two of our patients had prior injury to the affected leg within 1 year prior to the onset of the dystonia, raising the possibility of peripherally-induced dystonia. We draw attention to this rare, disabling, adult-onset focal dystonia involving proximal lower limbs. When recognized early, it may be treated effectively with either anticholinergic drugs, anticonvulsants, levodopa, or botulinum toxin injections.

Adult↗

PubMed2006

Genetic analysis of LRRK2 mutations in patients with Parkinson disease.

In addition to the G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2), which is particularly frequent in patients of Ashkenazi Jewish and Northern African origin, three amino acid substitutions (R1441C, R1441G, and R1441H), all at the same residue (R1441), have been identified as important genetic causes of Parkinson disease (PD). To evaluate the frequency of R1441C/G/H and G2019S mutations in the LRRK2 gene in North American patients with PD and to explore genotype-phenotype correlations, we screened 496 PD patients from North America. One Hispanic female was heterozygous for the LRRK2 R1441G mutation, and six other cases including 2 non-Jewish/non-Hispanic whites, 3 Ashkenazi Jewish, and 1 Hispanic, were found to be heterozygous for the LRRK2 G2019S mutation. G2019S mutation in the LRRK2 gene is a common mutation associated with PD in a North American population, especially in Jewish PD patients (10.7%), while the R1441C/G/H mutation occurs at a relatively low frequency in North Americans except possibly in Hispanics for R1441G. All six G2019S carriers shared a common haplotype with that observed in Europeans and North Africans. The clinical features of all seven cases with LRRK2 mutation were quite broad and included early and late disease onset. These finding may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.

Adult↗

PubMed2006

Botulinum toxin injection for congenital muscular torticollis presenting in children and adults.

Congenital muscular torticollis may present in late childhood or adulthood with cervical contractures, limited range of motion, pain, and muscular hypertrophy. Seven of eight pediatric and adult patients with congenital muscular torticollis were injected with botulinum toxin type A. Only two patients had a modest benefit with improved range of motion. Early recognition and treatment of congenital muscular torticollis is crucial to prevent subsequent contractures and other complications.

Adolescent↗

PubMed2006

The LRRK2 I2012T, G2019S and I2020T mutations are not common in patients with essential tremor.

Several mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified both in familial and sporadic cases of Parkinson's disease (PD). G2019S, located at a kinase (MAPKKK) domain, is the most common mutation in the LRRK2 gene in PD, Two adjacent mutations (I2012T and I2020T) were mapped to the same domain suggesting shared pathogenic mechanism of these mutations. Since phenotypes of PD overlap with essential tremor (ET), we investigated LRRK2 G2019S, I2012T, and I2020T mutations in a cohort of 272 patients with ET. No mutations were found in our ET cohort and, therefore, we conclude that LRKK2 I2012T, G2019S and I2020T variants are rare causes of Caucasian ET.

Adolescent↗

PubMed2006

Exploring the relationship between essential tremor and Parkinson's disease.

Although essential tremor (ET) and Parkinson's disease (PD) are considered distinct disorders, there is overlap in some clinical features. In some PD patients, a long-standing postural tremor in the hands may precede the onset of parkinsonian features by several years or decades. Furthermore, large families with both ET and PD phenotypes have been described and autopsy studies have demonstrated Lewy body pathology in brains of ET patients. Functional neuroimaging suggests that some ET patients have dopaminergic deficit. We examine here the evidence for and against an association between ET and PD, and critically review data supporting the notion that a subset of ET patients is predisposed to developing PD.

Essential Tremor↗

PubMed2006

A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor.

Familial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D(3) receptor gene (DRD3), localized on 3q13.3, is associated and cosegregates with familial ET in 23 out of 30 French families. Sequencing revealed no other nonsynonymous variants in the DRD3-coding sequence and in the first 871 bp of the 5' flanking region. Moreover, Gly-9 homozygous patients presented with more severe and/or earlier onset forms of the disease than heterozygotes. A replication study comparing 276 patients with ET and 184 normal controls confirmed the association of the Gly-9 variant with risk and age-at-onset of ET. In human embryonic kidney (HEK) 293-transfected cells, the Gly-9 variant did not differ from the Ser-9 variant with respect to glycosylation and to anterograde and retrograde trafficking, but dopamine had an affinity that was four to five times higher. With the Gly-9 variant, the dopamine-mediated cAMP response was increased, and the mitogen-associated protein kinase (MAPK) signal was prolonged, as compared with the Ser-9 variant. The gain-of-function produced by the Gly-9 variant may explain why drugs active against tremor in Parkinson's disease (PD) are usually not effective in the treatment of ET and suggests that DRD3 partial agonists or antagonists should be considered as novel therapeutic options for patients with ET.

Adolescent↗

PubMed2006

Long-term prognosis of patients with psychogenic movement disorders.

Psychogenic movement disorders (PMD) are hyper- or hypokinetic movement disorders associated with underlying psychological or psychiatric disorders. Structured telephone interview was administered to 228 patients with PMD seen in our clinic between 1990 and 2003. The mean age of the subjects was 42.3+/-14.3 years (range 14-70 years), mean duration of symptoms was 4.7+/-8.1 years (range 2-14 years), and mean duration of follow-up was 3.4+/-2.8 years (6 months-12 years). Improvement of symptoms was noted in 56.6% patients; while 22.1% were worse, and 21.3% remained the same at the time of follow-up. In this longitudinal study of patients with PMD we found that indices of strong physical health, positive social life perceptions, patient's perception of effective treatment by the physician, elimination of stressors, and treatment with a specific medication contributed to a favorable outcome.

Adolescent↗

PubMed2006

Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23.

Essential tremor (ET) is the most prevalent adult-onset movement disorder showing evidence of non-random accumulation in some families. ET has previously been mapped to genetic loci on chromosomes 2p and 3q, but no causative genes identified. We conducted genomewide linkage screening with subsequent fine mapping in seven large North American families comprising a total of 325 genotyped individuals that included 65 patients diagnosed as definite ET. Linkage analysis was based on methodology implemented in SimWalk2 and LINKAGE programs. A multigenerational family revealed suggestive linkage to a locus on chromosome 6p23 with maximal nonparametric linkage (NPL) multipoint score 3.281 (P = 0.0005) and parametric multipoint log of the odds (LOD) score 2.983. A second family showed positive linkage to the same 6p23 region with a maximal NPL score 2.125 (P = 0.0075) and LOD score 1.265. Haplotype analysis led to the identification of a 600 kb interval shared by both families. Sequencing of coding regions of 15 genes located in the linked region detected numerous sequence variants, some of them predicting a change of the encoded amino acid, but each was also found in controls. Our findings provide evidence for linkage to a novel susceptibility locus on chromosome 6p23. Analysis of additional ET-affected families is needed to confirm linkage and identify the underlying gene.

Adult↗

PubMed2006

Mapping of the regions on the heavy chain of botulinum neurotoxin A (BoNT/A) recognized by antibodies of cervical dystonia patients with immunoresistance to BoNT/A.

The purpose of this work was to map the entire recognition profile of the H chain of botulinum neurotoxin A (BoNT/A) by Abs in sera that have protective anti-BoNT/A Abs by the mouse protection assay (MPA) from cervical dystonia (CD) patients who had been treated with botulinum neurotoxin, serotype A (BOTOX). In previous studies we found that human anti-tetanus neurotoxin (TeNT) Abs cross-react with BoNT/A and BoNT/B. In the present work we devised an assay procedure for measuring specific anti-BoNT/A Abs in human sera by absorbing out or inhibiting the anti-TeNT Abs with TeNT before analyzing the sera for the anti-BoNT/A Abs. The sera were obtained from 28 CD patients who had become unresponsive to treatment with BoNT/A and the sera were found to protect mice against a lethal dose of BoNT/A. For localization of the Ab-binding regions on the H chain we employed a set of sixty, 19-residue synthetic peptides (except for peptide C31 which was 22 residues) that encompassed the entire H chain sequence 449-1296 and overlapped consecutively by five residues. The pattern of Ab recognition varied from patient to patient, but a very limited set of peptides were recognized by most of the patients. These were, in decreasing amounts of Ab binding, peptide N25 (H chain residues 785-803), C9/C10 (967-985/981-999), C31 (1275-1296), C15 (1051-1069), C20 (1121-1139), N16 (659-677), N22 (743-761), and N4 (491-509). But not every serum recognized all these peptides. The finding that the binding profile was not the same for all the patients is consistent with previous observations that immune responses to protein antigens are under genetic control and that the response to each epitope within a protein is under separate genetic control. Except for the region within C9/C10, the other regions either coincided (N16 and C31), or overlapped (N4, N22, N25, C15 and C20), with the recently mapped synaptosomes (snps)-binding regions on the H chain. The molecular and clinical implications of these findings are discussed.

Amino Acid Sequence↗

PubMed2006

Genetic analysis of the GABRA1 gene in patients with essential tremor.

The gamma-aminobutyric acid A (GABA-A) receptor mediates inhibitory neurotransmission in the brain and as such may be involved in certain neurological movement disorders, such as tremor. GABA-A receptor alpha 1 (Gabra)(-/-) mice have been reported to exhibit postural and kinetic, alcohol-responsive, tremor that is characteristic of essential tremor (ET), the most common form of tremor. To determine whether ET is associated with the GABRA1 gene mutation, we screened 76 patients with familial ET and found a novel nucleotide variant: IVS8+24 G>T (nt 6119289) in a male patient, and a known 156T>C polymorphism (nt 6090903) in exon 4 in 41% patients, which results in a silent mutation (G52G). No significant association between 156T>C variant and disease risk was found (adjusted OR=0.95, 95% CI=0.57-1.61; p=0.858) by further analysis of 121 familial ET patients and 114 normal controls, except a novel 96A>G (Q32Q; nt 6090743) variant, found in a normal control. Since the 156T>C variant appears to be not pathogenically relevant, our results suggest that missense, nonsense or splice site mutation in the coding region of the GABRA1 gene is not a major genetic cause of ET in Caucasian subjects.

Adult↗