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Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2004
X-linked dystonia-parkinsonism (XDP) or “lubag” is an X-linked recessive disorder that afflicts Filipino men, and rarely, women. Genetic confirmation is performed through haplotyping or detection of disease-specific changes in the DYT3 gene.
To describe the phenotypes and molecular data of 8 symptomatic female patients with XDP from 5 kindreds.
The average age of onset of symptoms was 52 years (range, 26-75 years). Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and focal dystonia (cervical) in 1. Seven of 8 patients had slow or no progression of their symptoms and required no treatment. The patient with disabling parkinsonism was responsive to carbidopa/levodopa. Seven were heterozygous for the XDP haplotype, whereas 1 was homozygous.
The phenotypes of female patients with XDP may include parkinsonism, dystonia, myoclonus, tremor, and chorea. The dystonia, if present, is mild and usually nonprogressive. Similar to men with XDP, parkinsonism is a frequent symptom in women. In contrast to men, affected women have a more benign phenotype, older age of onset, and milder course. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.
X-linked dystonia-parkinsonism (XDP) is an adult-onset dystonia syndrome that afflicts Filipino men.1,2 In the local dialect, XDP is referred to as “lubag,” meaning “twisted.” The dystonia usually starts focally and becomes generalized or multifocal after the first 5 years in most patients.3 Frequently, parkinsonism is encountered as the initial symptom even before the onset of dystonia.1,4 Patients with XDP who present with predominant parkinsonism (with minor or late-onset dystonia) tend to have a more benign course.
Linkage analyses have assigned the disease locus (DYT3) in XDP to the proximal long arm of the X chromosome,5 and studies6,7 of allelic association have delineated this locus within Xq13.1. A disease-specific haplotype was established that spanned approximately 300 kb between DXS10016 and DXS559.8 This haplotype and the recently identified mutations in the disease gene, a multiple transcript system,9 facilitate the molecular diagnosis of the disorder. Since XDP is an X-linked recessive disorder, almost all affected individuals are men and inherit the disease from their unaffected mothers. Three reports, however, point to the occasional occurrence of XDP in women.3,10,11 We describe the phenotypic presentations of XDP in 8 women from 5 families and discuss the possible molecular mechanisms.
The phenotypes of the 8 female patients with XDP are summarized in Table 1. These symptomatic women are all relatives of genetically confirmed male patients with XDP previously seen by the investigators. All possible female relatives of men with XDP are routinely examined by one of the investigators (V.G.H.E.) and genetically tested. The 8 women in this report are the only women with symptoms or abnormal neurological findings, since most female relatives of male patients with XDP are healthy or asymptomatic.1,3 The average age of onset of symptoms for the 8 women was 52 years (range, 26-75 years). All patients had a family history of XDP in male relatives and hailed from the Panay Islands in the Philippines. Six of 8 patients had parkinsonism, whereas only 1 had dystonia. The initial symptom was focal tremor or parkinsonism in 4, chorea in 3, and dystonia (retrocollis with head tremor) in 1. Seven of 8 patients were not significantly bothered by their symptoms and did not require or want any treatment. Only 1 woman (patient 4) was treated symptomatically; her parkinsonism was responsive to levodopa, with no drug-induced dyskinesias after 1 year of therapy. Aside from the extrapyramidal symptoms, the neurological examination in all 8 patients was otherwise unremarkable. No patient had any other identifiable secondary cause for her dystonia, parkinsonism, or chorea. None had a family history of idiopathic Parkinson disease (PD). The 3 patients with chorea had no history of Huntington disease in their individual families.
The XDP-specific alleles have been observed at loci DXS8030 and DXS8101 in all patients with XDP tested to date. Recently, the disease gene DYT3, a multiple transcript system, was identified.9 The disease-specific single nucleotide-change 3 (DSC3) has been postulated to contribute to XDP. Patients with XDP carry an allele of 244 base pairs (bp) at DXS8030 and an allele of 271 bp at DXS8101. Locus DXS559 is a distal flanking marker of the XDP critical region.7 Most XDP patients carry an allele of 242 bp at this locus. Allele ranges in controls are 236 to 250 bp at DXS8030, 247 to 271 bp at DXS8101, and 224 to 252 bp at DXS559.
The haplotypes detected in the 8 women are given in Table 2. The XDP-specific alleles of 244, 271, and 242 bp were detected at DXS8030, DXS8101, and DXS559, respectively, whereas the normal allele sizes are specified in Table 2. The findings are consistent with heterozygosity in 7 of 8 patients for the XDP-specific haplotype. Since the disease-specific haplotype was detected in both chromosomes in patient 7, we also tested for the presence of DSC3 in DYT3. As expected, the patient was also homozygous for this mutation. Within the 5 families, 17 women tested positive for either the XDP haplotype or DSC3 in DYT3; 9 (53%) were either symptomatic or had abnormal neurological examination results and 8 (47%) were normal.
Patients 5, 6, and 7 had chorea and were therefore also tested for an expansion at the Huntington locus in the short arm of chromosome 4. For all 3 patients, a Huntington-specific CAG expansion was excluded.
Although more than 500 symptomatic men with XDP have been studied to date, reports on symptomatic female patients with XDP are scarce.3,10,11 Our series represents the largest number of affected female patients with XDP described so far. Of the 8 women we describe, only 1 had dystonia, which was focal and nondisabling. The others presented with various phenotypes, including tremor, myoclonus, parkinsonism, and chorea. The average age of onset for our female patients with XDP (52 years) is much older than that reported in men (39 years).3 Although the oldest age of onset of XDP reported in men is 64 years,3 our 2 oldest female patients had onset at the age of 75 years.
The phenomenology of XDP (particularly in men) was initially thought to consist mainly of dystonia of varying degrees, with parkinsonism being rare or late in onset.3 These earlier descriptions, however, lacked correlation with genetic information. Recently, with advances in genetic testing, the XDP phenotype was expanded to include myoclonus, chorea, focal tremor, pure parkinsonism, myorhythmia, and chorea-ballism.1 This current study shows that such phenotypic variability in XDP also applies to affected women. Dystonia, thought to be the hallmark of XDP in men, is relatively uncommon in women and, if present, remains mild, focal, or nondisabling.
Just as parkinsonism was almost universally noted in male patients with XDP,1 6 of the 8 women we describe exhibited parkinsonism. Typically, parkinsonism is an early feature in male patients with XDP1 and often precedes the onset of dystonia. It may improve with levodopa in the early stages but becomes less responsive or unresponsive as dystonia sets in and progresses. So far, patient 4 has not developed dystonia and has remained responsive to levodopa. Given that PD is relatively common in elderly people, the diagnosis of PD cannot be excluded in levodopa-responsive, parkinsonian, elderly patients with XDP, especially if the dystonia is minimal or absent.
Patient 5 was previously described in the report of 2 women with XDP by Waters et al.11 We include her in our series to show that her chorea has progressed slowly and now affects the upper limbs and facial region more prominently than before. Despite being generalized, her chorea remains mild and nondisabling (and, thus, untreated) 15 years after onset. Her older sister (not examined) reportedly has not had progression of her mild, intermittent left arm and leg dystonia since onset 14 years ago. Patient 7 in our series has had 2 years of nonprogressive, mild monolimbic chorea. In general, symptomatic women with XDP tend to have a more benign course and a milder phenotype. Of the 8 patients we describe, only 1 was sufficiently disabled to require medications.
Neuropathological data on XDP are scarce. Waters et al12 reported a patchy, mosaic pattern of neuronal loss and astrocytosis in the caudate and lateral putamen in a male XDP patient with generalized dystonia and parkinsonism. More recently, the patchy striatal gliosis in XDP was noted to exhibit dorsal-to-ventral, rostral-to-caudal, and medial-to-lateral gradients.13 Furthermore, gliotic changes were also observed in the globus pallidus and substantia nigra pars reticularis. Thus, the striatal and extrastriatal pathologic features in XDP may account for the phenotypic heterogeneity in both men and women.
Genetic molecular analyses of 7 of the 8 women we describe show that they are heterozygotes for the XDP-specific haplotype (ie, they carry both a wild-type and a mutated allele at DYT3). Since XDP is an X-linked recessive disorder, the symptoms in these women described can be due to an extreme X-inactivation mosaic, with the mutated X active in a significant number of neurons of the basal ganglia. Discrete symptoms in women carriers of X-linked recessive genes are not uncommon and have been ascribed to nonrandom X inactivation. One impressive example is a family with X-linked recessive Pelizaeus-Merzbacher disease described by Hodes et al.14 Interestingly, the affected woman (patient 7) was homozygous for the disease-specific haplotype and carried the mutation DSC3 in DYT3 on both chromosomes. Molecularly, she is thus comparable to affected men who also have disturbed DYT3 function.
In summary, female carriers of the XDP haplotype or DYT3 mutation can present with a movement disorder, including parkinsonism, tremor, chorea, dystonia, or myoclonus. Compared with male patients with XDP, affected women tend to have a more benign phenotype, older age of onset, and milder course. Dystonia, if present, remains mild, nonprogressive, and nondisabling. Similar to men, female patients with XDP often present with parkinsonism, which can be levodopa responsive. Extreme X-inactivation mosaic may be a cause of symptoms in women with XDP, but a homozygously affected woman has also been observed.
Correspondence: Virgilio Gerald H. Evidente, MD, Department of Neurology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259 (firstname.lastname@example.org).
Accepted for Publication: February 24, 2004.
Author Contributions:Study concept and design: Evidente and Natividad. Acquisition of data: Evidente, Nolte, Advincula, Mayo, and Müller. Analysis and interpretation of data: Evidente, Nolte, and Niemann. Drafting of the manuscript: Evidente and Niemann. Critical revision of the manuscript for important intellectual content: Evidente, Nolte, Niemann, Advincula, Mayo, Natividad, and Müller. Obtained funding: Evidente, Natividad, and Müller. Administrative, technical, and material support: Evidente, Advincula, Mayo, Natividad, and Müller. Study supervision: Evidente and Müller.
Funding/Support: This study was funded by the Mayo Clinic Foundation and St Luke’s Medical Center (Philippines). Dr Müller was supported by grant Mu668/6-3 from Deutsche Forschungsgemeinschaft, Bonn, Germany.
Acknowledgment: We thank Petra Happel and Christel Nohl for excellent technical assistance.
Evidente VGH, Nolte D, Niemann S, et al. Phenotypic and Molecular Analyses of X-linked Dystonia-Parkinsonism (“Lubag”) in Women. Arch Neurol. 2004;61(12):1956–1959. doi:10.1001/archneur.61.12.1956
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