Lillian V. Lee

The natural history of sex-linked recessive dystonia parkinsonism of Panay, Philippines (XDP)

Sex-linked dystonia parkinsonism (XDP) was reported by Lee et al. in 1975 occurring endemically in Panay, Philippines. It is an adult onset, sex-linked, predominantly male, severe, progressive movement disorder with high penetrance and a high frequency of generalization. The movement disorder is characterized by dystonic movements usually starting in the third or fourth decade, focal at the onset, spreading to generalization within 2-5 years. The dystonia co-exist or is replaced by parkinsonism usually beyond the 10th year of illness. As of June 2001, 376 XDP cases have been registered. One hundred and fifteen cases have died. The prevalence of XDP in the island of Panay is 5.24 per 100,000; 0.34/100,000 in the general population. The prevalence varies in the different provinces; it is highest in Capiz at 18.88/100,000, 7.46/100,000 in Aklan, 1.28 in Iloilo and 0.83 in Antique. The 376 cases are from 188 families and 92% of cases have positive family history. Ninety-nine percent of the cases are males. The mean age of onset is 39.48 years. Duration of illness is 12.95 years. Ninety-four percent of patients initially manifest with dystonic symptoms, while only 6% present with Parkinsonian traits. Among those presenting with dystonia, the initial presentation is in the lower extremities in 33%, craniofacial in 27%, cervical and shoulder in 25%, upper extremities in 14%, and trunk in 1%. Regardless of the site of onset, the dystonia spreads in 98% and generalizes within 5 years in 84%. Neuroimaging (magnetic resonance imaging, MRI) was done in 16 patients. In the patients who have just manifested the disease usually when dystonia predominates and parkinsonism is absent. MRI showed minimal atrophy of the caudate and putamen or subtle putaminal signal abnormality. In the late course, where Parkinsonism predominates, severe atrophy of the caudate and putamen as well as marked increase in signal abnormality are seen. There are six autopsied cases of XDP. Neuropathology revealed marked atrophy of the caudate and putamen mostly in the cases with longstanding illness. The sex-linked pattern of inheritance has been established. Genetic studies have located the affected gene (DYT3) to Xq13.1. Nemeths group has mapped the XDP gene to a <350 kb locus in the DXS 7117-DX 559 region. To date, no treatment has been proven consistently effective.

The Unique Phenomenology of Sex-Linked Dystonia Parkinsonism (XDP, DYT3, “Lubag”)

ABSTRACT Sex-linked dystonia parkinsonism (XDP, DYT3, “Lubag”) is an adult-onset, progressive, debilitating movement disorder first described in Filipino males from Panay Islands in 1975. XDP manifests predominantly as torsion dystonia, later combined with or sometimes replaced with parkinsonism. Within the Island of Panay, the prevalence rate is highest in the province of Capiz, where 1:4000 men suffer from the disorder. There is a high degree of penetrance and generalization. While women often serve as carriers, XDP is not limited to men. An updated XDP Philippine registry (as of January 2010) has identified 505 cases, with 500 males and 5 females. While some report that females may carry a milder form of the disorder, in our experience, both sexes generally follow a similar progressive clinical course.

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3)

X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.

Epidemiologic Investigation and Targeted Vaccination Initiative in Response to an Outbreak of Meningococcal Disease among Illicit Drug Users in Brooklyn, New York

BACKGROUND An outbreak of serogroup C meningococcal disease that involved illicit drug users and their contacts occurred in Brooklyn, New York, during 2005 and 2006. METHODS The objectives of this study were to identify the population at risk for meningococcal disease, describe efforts to interrupt disease transmission, and assess the impact of a vaccine initiative. Descriptive and molecular epidemiological analysis was used to define the extent of the outbreak and the common risk factors among outbreak-related cases. A vaccine initiative that used community-based service providers was targeted to illicit drug users and their close contacts. The vaccine initiative was assessed through cessation of outbreak-related cases and the reduction in carriage rate. RESULTS The investigation identified 23 outbreak-related cases of serogroup C meningococcal disease; 17 isolates were indistinguishable and 4 isolates were closely related according to pulsed-field gel electrophoresis. Two additional culture-negative cases had epidemiological links to laboratory-confirmed cases. The median age of patients with outbreak-related cases was 41 years, and 19 (83%) of 23 patients reported an association with illicit drug use. There were 7 outbreak-related deaths. Vaccination was administered to 2763 persons at 29 community locations, including methadone treatment centers, syringe-exchange programs, and soup kitchens. Three additional cases of meningococcal disease due to strains with the same pulsed-field gel electrophoresis pattern were identified after the vaccination initiative. CONCLUSIONS Community-based outbreaks of meningococcal disease are difficult to control, and the decision to vaccinate is not straightforward. Current national guidelines for implementing a vaccination campaign are not strict criteria and cannot be expected to accommodate the myriad of factors that occur in community-based invasive meningococcal disease outbreaks, such as the inability to enumerate the population at risk.

Understanding XDP Through Imaging, Pathology, and Genetics

ABSTRACT The X-linked dystonia-parkinsonism (XDP) is a severe, progressive, adult-onset, X-linked endemic disorder in Filipinos, which is characterized by dystonic movements that start in the third or fourth decade, and replaced by parkinsonism beyond the 10th year of illness. Understanding the pathophysiology of XDP and development of rational therapies will depend on observations from imaging, pathological, and genetic studies. In this paper we summarize the results of these studies on patients with XDP. The cranial magnetic resonance imaging shows hyperintense putaminal rim in both dystonic and parkinsonian stages, and atrophy of the caudate head or putamen in the parkinsonian stage. Neuropathological findings show atrophy of the caudate nucleus and putamen, with mild to severe neuronal loss and gliosis. In the neostriatum, the dystonic phase of XDP shows the involvement of striosomes and matrix sparing, while the later, i.e., parkinsonian phase, shows matrix involvement as well. In the dystonic phase, the loss of striosomal inhibitory projections lead to disinhibition of nigral dopaminergic neurons, perhaps resulting in a hyperkinetic state; while in the parkinsonian phase, severe and critical reduction of matrix-based projection may result in extranigral parkinsonism. Genetic sequencing of the XDP critical region in Xq13.1 has revealed an SVA retrotransposon insertion in an intron of TAF1. This may reduce neuron-specific expression of the TAF1 isoform in the caudate nucleus, and subsequently interfere with the transcription of many neuronal genes, including DRD2. Findings from imaging, pathology, and genetics studies are gradually shedding light on the pathophysiology of XDP, which hopefully will lead to more rational and directed therapies.

The Promise of Deep Brain Stimulation in X-Linked Dystonia Parkinsonism

ABSRACT X-Linked dystonia parkinsonism (XDP) is a rapidly progressive and disabling neurodegenerative disease affecting mainly male Filipinos with origins from Panay Island. We reviewed all the past neurosurgical ablative procedures done for XDP patients listed in the Philippine XDP registry. From 1960 to 1982, six patients had undergone bilateral chemopallidotomies or bilateral thalomotomies staged over time. Half of these patients had significant improvement in their symptoms but five of the six patients (83%) developed postoperative morbidities, mainly speech impairment or hemiparesis. All the five reported GPi deep brain stimulation (DBS) cases for XDP were also reviewed, showing consistently immediate improvement of symptoms (61.5%–88.3% decrease in the Burke-Marsden-Fahn Dystonia Rating Scale) lasting up to a year with no adverse effects noted. We also present the first Philippine case of GPi DBS done in the youngest XDP patient to date. This present case showed dramatic improvement (88.3% decrease of the Burke-Marsden-Fahn Dystonia Rating Scale) of his dystonic symptoms, without incurring any persistent adverse effects. The results of these early cases of pallidal DBS for XDP show that DBS is generally a safe and effective procedure for alleviating the disabling symptoms of XDP in contrast to previous ablative surgeries performed on these patients.

An outbreak of Klebsiella pneumoniae and Enterobacter aerogenes bacteremia after interventional pain management procedures, New York City, 2008.

Background and Objectives: In October 2008, an investigation was conducted into a cluster of gram-negative bloodstream infections after invasive pain management procedures at an outpatient facility to identify additional cases and determine the source of illness. Methods: We conducted a retrospective cohort study to determine exposures associated with illness. Eligible patients had an invasive procedure in the 4 days before or after the procedure date of the initial case-patients. Infection control assessments were made, and environmental specimens collected. Results: Four laboratory-confirmed case-patients (3 with Klebsiella pneumoniae and 1 with Enterobacter aerogenes) and 5 suspect case-patients were identified. In addition to the 9 confirmed and suspect case-patients, 45 patients were interviewed. All confirmed and suspect case-patients had a sacroiliac joint steroid injection procedure; injection into the sacroiliac joint was associated with illness (9/22 versus 0/31; P < 0.0001). Multiple breaches in infection control were noted including the reuse of single-use vials for multiple patients. The 3 K. pneumoniae with positive blood cultures were indistinguishable by pulse-field gel electrophoresis, and the E. aerogenes-positive blood culture was indistinguishable by pulse-field gel electrophoresis to the culture from an open vial of 100-mL iodixanol contrast solution. Conclusion: Infection was associated with pain management procedures, specifically those involving injection to the sacroiliac joint. Lapses in infection control likely led to the contamination of single-use vials that were then used for multiple patients. Reuse of medication vials should be restricted, and affordable single-dose vials should be made available.

Serving High-Risk Foods in a High-Risk Setting: Survey of Hospital Food Service Practices after an Outbreak of Listeriosis in a Hospital

BACKGROUND AND OBJECTIVES Prepared ready-to-eat salads and ready-to-eat delicatessen-style meats present a high risk for Listeria contamination. Because no foodborne illness risk management guidelines exist specifically for US hospitals, a survey of New York City (NYC) hospitals was conducted to characterize policies and practices after a listeriosis outbreak occurred in a NYC hospital. METHODS From August through October 2008, a listeriosis outbreak in a NYC hospital was investigated. From February through April 2009, NYCs 61 acute-care hospitals were asked to participate in a telephone survey regarding food safety practices and policies, specifically service of high-risk foods to patients at increased risk for listeriosis. RESULTS Five patients with medical conditions that put them at high risk for listeriosis had laboratory-confirmed Listeria monocytogenes infection. The Listeria outbreak strain was isolated from tuna salad prepared in the hospital. Fifty-four (89%) of 61 hospitals responded to the survey. Overall, 81% of respondents reported serving ready-to-eat deli meats to patients, and 100% reported serving prepared ready-to-eat salads. Pregnant women, patients receiving immunosuppressive drugs, and patients undergoing chemotherapy were served ready-to-eat deli meats at 77%, 59%, and 49% of hospitals, respectively, and were served prepared ready-to-eat salads at 94%, 89%, and 73% of hospitals, respectively. Only 4 (25%) of 16 respondents reported having a policy that ready-to-eat deli meats must be heated until steaming hot before serving. CONCLUSIONS Despite the potential for severe outcomes of Listeria infection among hospitalized patients, the majority of NYC hospitals had no food preparation policies to minimize risk. Hospitals should implement policies to avoid serving high-risk foods to patients at risk for listeriosis.

Assessment of Substantia Nigra Echogenicity in German and Filipino Populations Using a Portable Ultrasound System

Transcranial sonography of the substantia nigra for diagnosing premotor stages of Parkinson disease has been attracting increasing interest. Standard reference values defining an abnormal increased echogenic size (hyperechogenicity) of the substantia nigra have been established in several populations using high‐end stationary ultrasound systems. It is unknown whether a portable ultrasound system can be appropriately used and how the Filipino population would compare with the well‐studied white population.

Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism

The molecular dysfunction in X-linked dystonia-parkinsonism is not completely understood. Thus far, only noncoding alterations have been found in genetic analyses, located in or nearby the TATA-box binding protein-associated factor 1 (TAF1) gene. Given that this gene is ubiquitously expressed and is a critical component of the cellular transcription machinery, we sought to study differential gene expression in peripheral models by performing microarray-based expression profiling in blood and fibroblasts, and comparing gene expression in affected individuals vs. ethnically matched controls. Validation was performed via quantitative polymerase chain reaction in discovery and independent replication sets. We observed consistent downregulation of common TAF1 transcripts in samples from affected individuals in gene-level and high-throughput experiments. This signal was accompanied by a downstream effect in the microarray, reflected by the dysregulation of 307 genes in the disease group. Gene Ontology and network analyses revealed enrichment of genes involved in RNA polymerase II-dependent transcription, a pathway relevant to TAF1 function. Thus, the results converge on TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism, and provide evidence of altered expression of a canonical gene in this disease. Furthermore, our study illustrates a link between the previously described genetic alterations and TAF1 dysfunction at the transcriptome level.