Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein.

Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen idependently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.

Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia.

DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of approximately 30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms. In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia. We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%. Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.

Human gene for torsion dystonia located on chromosome 9q32-q34.

Torsion dystonia is a movement disorder of unknown etiology characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Dystonic movements can be caused by lesions in the basal ganglia, drugs, or gene defects. Several hereditary forms have been described, most of which have autosomal dominant transmission with variable expressivity. In the Ashkenazi Jewish population the defective gene frequency is about 1/10,000. Here, linkage analysis using polymorphic DNA and protein markers has been used to locate a gene responsible for susceptibility to dystonia in a large, non-Jewish kinship. Affected members of this family have a clinical syndrome similar to that found in the Jewish population. This dystonia gene (ITD1) shows tight linkage with the gene encoding gelsolin, an actin binding protein, and appears by multipoint linkage analysis to lie in the q32-q34 region of chromosome 9 between ABO and D9S26, a region that also contains the locus for dopamine-beta-hydroxylase.

Genetics of dystonia.

Primary torsion dystonia (PTD) has a broad clinical spectrum, with earlier onset of symptoms associated with more generalized muscle involvement. The causes for most dystonia are unknown although several monogenic subtypes have been identified. One important genetic cause of PTD is DYT1; a three base pair deletion in this gene is a major cause for early-onset dystonia. Its identification has allowed the development of cellular and animal models; it has also permitted studies that identify both "manifesting" and "non-manifesting" DYT1 mutation carriers. These studies have expanded our understanding of clinical expression to include psychiatric symptoms and also have enabled imaging studies of endophenotypes. These advances provide a widened platform for future research.

The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.

GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.

Acetylcholinesterase activity in patients with torsion dystonia. Measurement in erythrocyte membranes.

Anticholinergic therapy provides symptomatic relief in many patients with dystonia. The mechanism underlying this therapeutic action is poorly understood; however, one possibility is that the degradation of acetylcholine is perturbed in these conditions. To investigate this possibility, acetylcholinesterase activity was measured in erythrocyte membranes from healthy volunteers and patients with torsion dystonia. Enzyme activities in erythrocytes from 14 patients with adult-onset, childhood-onset idiopathic, and childhood-onset familial dystonias did not differ significantly from activities measured in erythrocyte membranes from 17 healthy volunteers. Moreover, when blood samples from several members of a family with dominant inheritance of dystonia were assayed simultaneously, similar enzyme activities were found in the affected and unaffected individuals. The data suggest that a generalized acetylcholinesterase deficiency is not involved in the pathogenesis of torsion dystonia.

Delayed-onset cerebellar syndrome.

BACKGROUND: Delayed-onset involuntary movements, including dystonia and myoclonus, have been reported after stroke or head trauma. Moreover, there have been reports of delayed-onset isolated intention tremor and, in several of these cases, gait ataxia. OBJECTIVE: To further define the clinical features of a delayed-onset cerebellar syndrome. DESIGN: Subjects with cerebellar tremor and either head trauma or stroke were identified using a computerized database, providing detailed demographic and clinical information of 4002 patients with involuntary movements other than Parkinson's disease seen at our center between 1983 and 1995. Medical records and videotaped neurological examinations were retrospectively reviewed. SETTING: The Center for Parkinson's Disease and Other Movement Disorders at Columbia-Presbyterian Medical Center, New York, NY. PATIENTS: Five patients with delayed-onset cerebellar syndromes. RESULTS: Five patients with stroke or head trauma developed a cerebellar syndrome 3 weeks to 2 years after the initial insult. The syndrome, characterized by intention tremor, ataxic dysarthria, nystagmus, dysmetria, dysdiadochokinesis, and gait ataxia, was progressive in at least one patient. In four patients, lesions were present on neuroimaging in the thalamus or brain stem (especially in the midbrain). CONCLUSIONS: A delayed-onset cerebellar syndrome may follow head trauma or stroke. The syndrome is sometimes progressive and often disabling. The delayed onset implies that the syndrome is not caused by the initial lesion itself but may be caused by development of post-synaptic supersensitivity or secondary reorganization of involved pathways.

Use of intrathecal baclofen in the treatment of patients with dystonia.

BACKGROUND: Continuous infusion of intrathecal (IT) baclofen is a highly effective standard therapy for severe spasticity of spinal origin. By contrast, there is limited clinical experience regarding the use of IT baclofen in treating patients with dystonia, and little is known regarding the indications for treatment, efficacy, and safety of IT baclofen in this disorder. OBJECTIVE: To study retrospectively the effects of IT baclofen in treating 25 patients with severe segmental or generalized dystonia. SETTING: Neurological Institute, Columbia-Presbyterian Medical Center, New York, NY. PATIENTS: Twenty-five patients with severe segmental or generalized dystonia that was refractory to oral medications underwent IT baclofen test dosing. In addition to dystonia, 17 patients had spasticity or painful spasms. Thirteen of 25 patients responded to the test doses of IT baclofen, according to unblinded neurological assessments that included the patient's subjective report; all 13 underwent implantation of a pump for continuous IT baclofen infusion. RESULTS: In contrast to reports of patients with spasticity of spinal origin, those with dystonia in the present series had a lower response rate to bolus IT baclofen doses and a smaller degree of clinical improvement. For 10 of the 13 responders to the test doses of IT baclofen, dystonia rating scale scores of videotaped examinations by blinded observers detected no significant change (P < .07) in severity of dystonia. Retrospective data from 11 of 13 patients with implantable pumps, followed up for a mean interval of 21 months after pump insertion, showed continuing efficacy in 6 individuals (55%), based on a determination of patient satisfaction; however, only 3 patients (27%) reported a sustained improvement in functional capacity. Five (38%) of the 13 patients with implantable pumps experienced severe complications that required hospitalization. CONCLUSIONS: Despite recent reports that have described the benefit in small numbers of patients with dystonia, we concluded that the role of IT baclofen in treating severe dystonia remains uncertain. Intrathecal baclofen may be more effective when dystonia is associated with spasticity or pain. In the present series, we detected no significant difference in the response to IT baclofen in patients with or without spasticity or pain, perhaps owing to the small sample size.

The clinical manifestations of pontine hemorrhage.

The survival rate was 40% in 10 patients suffering hemorrhage into the pons who were admitted to an acute care facility. This rate is higher than previously reported. In addition to the "classic" pontine hematoma syndrome characterized by coma, quadriparesis, and eventual demise, two more benign syndromes arising from hemorrhage confined to one side of the pons were also recognized. In one of these hemipontine syndromes, hematoma involved both the basis pontis and tegmentum and was associated with hemiparesis, brainstem signs, and preserved consciousness. In the other, hemorrhage was confined to the tegmentum and was associated with gaze paresis, motor sparing, and preserved consciousness. All patients suffering hemipontine hemorrhage survived. An impressive degree of functional recovery occurred in these survivors.

Subcortical neglect.

Unilateral neglect is usually caused by lesions of the right cerebral cortex, especially parietal. Neglect after subcortical lesions has been reported rarely in thalamic or striatal hemorrhage, and after infarction of thalamus or striatum and internal capsule shown by CT. In these patients, there may have been compression or ischemia of overlying cerebral cortex and white matter. We report a patient with sensory hemineglect, asomatognosia, and anosognosia caused by infarction of striatum and deep white matter, with involvement of neither cortex nor thalamus and without mass effect. This is the first autopsy-confirmed example of human neglect with involvement of only the striatum and deep white matter.

Validity and reliability of a rating scale for the primary torsion dystonias.

For quantitative assessment of the primary torsion dystonias, a rating scale is proposed that has two sections--a Movement Scale, based on examination, and a Disability Scale, based on the patient's statements about seven activities of daily living. We assessed the validity of the Movement Scale by comparing scores with a ranking of patients according to dystonia severity and with ratings of the patients on the Disability Scale. In addition, we assessed the inter-and intra-rater reliability of the scale by comparing independent scorings of patients by four examiners and by comparing scorings by the same examiners performed at different times. We found that the Movement Scale was a valid and reliable indicator of the severity of primary torsion dystonia.

Genetic linkage analysis in primary torsion dystonia.

We studied five families, each containing two siblings affected with torsion dystonia and having phenotypically normal parents, for linkage of dystonia to 18 marker systems, including HLA. Analysis assumed an autosomal recessive mode of inheritance. Linkage was not found. Two markers, HLA and MN, were excluded from tight linkage, and evidence against tight linkage to ABO, Rh, GC, and GLO was obtained.

Delayed-onset dystonia due to perinatal or early childhood asphyxia.

We report 10 patients with delayed-onset dystonia associated with perinatal asphyxia and 2 associated with asphyxia in childhood. In the perinatal group, the mean age of onset was 12.9 years. Among these patients, dystonia continued to progress for a mean of 7 years, and as long as 28 years. These patients had moderate motor disability; none was wheelchair-bound, and thus their prognosis was better than that of the childhood-onset idiopathic torsion dystonias. The most frequently beneficial drugs were anticholinergics. Since some of these patients closely resembled cases of idiopathic torsion dystonia, the prior occurrence of asphyxia should be used as a criterion of exclusion for that diagnosis.

Rapid-onset dystonia-parkinsonism in a second family.

Rapid-onset dystonia-parkinsonism (RDP), first described in a large Midwestern family, is now reported in a second, apparently unrelated, family in which four individuals have this same syndrome. All four developed sudden onset of dysarthria, dysphagia, severe dystonic spasms, bradykinesia, and postural instability over less than 1 hour to a few days. Three of the four had stable limb dystonia for several years preceding the onset of combined dystonia-parkinsonism. Treatment with levodopa/carbidopa provided little benefit. We propose diagnostic criteria for RDP and further define the spectrum of this unusual disease.

The effect of estrogen replacement on early Parkinson's disease.

OBJECTIVE: To determine the effect of estrogen in postmenopausal women with early PD. BACKGROUND: The role of estrogen in PD is highly disputed, with some studies suggesting a prodopaminergic effect and others suggesting an antidopaminergic effect. Owing to controversy and the small sample sizes of prior studies, further investigation is warranted. METHODS: A retrospective chart review was carried out from a computerized database of patients at Columbia-Presbyterian, including only women who had symptoms of presumed PD for less than 5 years and who had not yet been on L-dopa at their first visit. Multiple regression was performed to assess the effects of estrogen on disease, measured by total Unified Parkinson's Disease Rating Scale (UPDRS) score, as a function of symptom duration, age at onset, education, smoking, dopamine agonist, and deprenyl use. RESULTS: Of the women who were not on L-dopa and had PD for less than 5 years at their first visit, 34 were found to have received estrogen at some time and 104 had never received estrogen. Excluding the women who had taken dopamine agonists, analysis yielded a multiple regression coefficient of 0.52 (p < 0.001). Estrogen use was negatively correlated with UPDRS score; age at onset and symptom duration were positively correlated (p < 0.05). CONCLUSIONS: We found a positive association between estrogen use and lower symptom severity in women with early PD not yet taking L-dopa. These results indicate that estrogen therapy should not be avoided and may be beneficial in early PD, at least prior to the initiation of L-dopa.

Diagnostic criteria for dystonia in DYT1 families.

Family studies of primary torsion dystonia have used the diagnostic categories of definite, probable, and possible dystonia for gene mapping and identification, but the validity of this hierarchical classification is not known. The authors assessed 147 DYT1 GAG deletion carriers and 113 blood-related noncarriers from 43 families. Only the category of definite dystonia was 100% specific. Probable dystonia, but not possible, was increased in carriers compared with noncarriers. The authors recommend that only those with definite signs of dystonia be considered affected in linkage and other genetic studies.

Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations.

BACKGROUND: Early onset PD has been associated with different mutations in the Parkin gene, including exon deletions and duplications. METHODS: The authors performed an extensive mutational analysis on 50 probands with onset of PD at younger than 50 years of age. Thirteen probands were ascertained from a registry of familial PD and 37 probands by age at onset at younger than 50 years, blind to family history. Mutational analysis was undertaken on the probands and available family members and included conventional techniques (single strand conformation polymorphism analysis and sequencing) and a newly developed method of quantitative duplex PCR to detect alterations of gene dosage (exon deletions and duplications) in PARKIN: RESULTS: Using this new technique, the authors detected eight alterations of gene dosage in the probands, whereas 12 mutations were found by conventional methods among the probands and another different mutation in an affected family member. In total, the authors identified compound heterozygous mutations in 14%, heterozygous mutations in 12%, and no Parkin mutation in 74% of the 50 probands. We expanded the occurrence of Parkin mutations to another ethnic group (African-American). CONCLUSION: The authors systematically screened all 12 Parkin exons by quantitative PCR and conventional methods in 50 probands. Eight mutations were newly reported, 2 of which are localized in exon 1, and 38% of the mutations were gene dosage alterations. These results underline the need to screen all exons and to undertake gene dosage studies. Furthermore, this study reveals a frequency of heterozygous mutation carriers that may signify a unique mode of inheritance and expression of the Parkin gene.

Symmetric sarcoid polyneuropathy: analysis of a sural nerve biopsy.

A 20-year-old woman with sarcoidosis had uveitis, subacute symmetric sensorimotor neuropathy, and noncaseous granulomas in biopsies of gastrocnemius muscle and sural nerve. Morphologic studies of the nerve confirmed the electrodiagnostic impression of an acute axonal and demyelinating neuropathy. Of 100 teased myelinated nerve fibers, 15% contained myelin ovoids and 24% demonstrated segmental demyelination. Quantitative analysis showed a reduction in the numerical density of myelinated fibers. By electronmicroscopy, unmyelinated fibers were largely spared. The exact mechanism of nerve fiber damage was not determined, but a local effect of the granuloma seemed likely, because most lesions were found in the endoneurium.

Clinical findings of a myoclonus-dystonia family with two distinct mutations.

Myoclonus-dystonia has recently been associated with mutations in the epsilon-sarcoglycan gene (SCGE) on 7q21. Previously, the authors reported a patient with myoclonus-dystonia and an 18-bp deletion in the DYT1 gene on 9q34. The authors have now re-evaluated the patient harboring this deletion for mutations in the SGCE gene and identified a missense change. In the current study, the authors describe the clinical details of this family carrying mutations in two different dystonia genes. Further analysis of these mutations separately and together in cell culture and in animal models should clarify their functional consequences.