Reliability of Low-dose Biplanar Radiography in Assessing Pediatric Torsional Pathology.

BACKGROUND: Low-dose biplanar radiographs (LDBRs) significantly reduce ionizing radiation exposure and may be of use in evaluating lower extremity torsion in children. In this study, we evaluated how well femoral and tibial torsional profiles obtained by LDBR correspond with 3-dimensional (3D) computed tomography (CT) and magnetic resonance axial imaging (MRI) in pediatric patients with suspected rotational abnormalities. METHODS: Patients who had both LDBR and CT/MRI studies performed for suspected lower extremity rotational deformities were included. Unlike previous publications, this study focused on patients with lower extremity torsional pathology, and bilateral lower extremities of 17 patients were included. CT/MRI torsion was measured using the Reikerås method, after conversion to 3D reconstructions. The LDBRs were deidentified and sent to the software division of EOS imaging, who created 3D reconstructions and evaluated each reconstruction for the torsional quantification of the femurs and tibiae. These imaging modalities were compared using correlation statistics and Bland-Altman analyses. RESULTS: The mean age of the cohort was 12.1±1.7 years old. Torsional values of the femur were significantly lower in LDBRs versus 3D CT/MRIs at 17.7±15.1 and 23.3±17.3, respectively (P=0.001). Torsional values of the tibia were similar in LDBRs versus 3D CT/MRIs at 23.6±10.6 and 25.3±11.2, respectively (P=0.503). There was a good intermodality agreement between LDBR and 3D CT/MRI torsional values in the femur (intraclass correlation coefficient=0.807) and tibia (intraclass correlation coefficient=0.768). Bland-Altman analyses showed a fixed bias with a mean difference of -5.6±8.8 degrees between femoral torsion measurements in LDBRs versus 3D CT/MRIs (P=0.001); 15% (5/34) of femurs had a clinically significant measurement discrepancy. Fixed bias for LDBR measurements compared with 3D CT/MRIs for the tibia was not observed (P=0.193), however, 12% (4/34) of tibias had a clinically significant measurement discrepancy. CONCLUSION: Although we found strong correlations between torsional values of the femur and tibia measured from LDBRs and 3D CT/MRIs, torsional values of the femur produced from LDBRs were significantly lower than values obtained from 3D CT/MRIs with some notable outliers. LEVEL OF EVIDENCE: Level III.

Unraveling cellular phenotypes of novel TorsinA/TOR1A mutations.

A three-nucleotide (GAG) deletion (ΔE) in TorsinA (TOR1A) has been identified as the most common cause of dominantly inherited early-onset torsion dystonia (DYT1). TOR1A encodes a chaperone-like AAA+-protein localized in the endoplasmic reticulum. Currently, only three additional, likely mutations have been reported in single dystonia patients. Here, we report two new, putative TOR1A mutations (p.A14_P15del and p.E121K) that we examined functionally in comparison with wild-type (WT) protein and two known mutations (ΔE and p.R288Q). While inclusion formation is a characteristic feature for ΔE TOR1A, elevated levels of aggregates for other mutations were not observed when compared with WT TOR1A. WT and mutant TOR1A showed preferred degradation through the autophagy-lysosome pathway, which is most pronounced for p.A14_P15del, p.R288Q, and ΔE TOR1A. Notably, blocking of the autophagy pathway with bafilomycin resulted in a significant increase in inclusion formation in p.E121K TOR1A. In addition, all variants had an influence on protein stability. Although the p.A14_P15del mutation affects the proposed oligomerization domain of TOR1A, this mutation did not disturb the ability to dimerize. Our findings demonstrate functional changes for all four mutations on different levels. Thus, both diagnostic and research genetic screening of dystonia patients should not be limited to testing for the ∆E mutation.

Network biomarkers for the diagnosis and treatment of movement disorders.

Functional brain networks provide a set of useful biomarkers for the assessment of movement disorders such as Parkinson's disease (PD). Spatial covariance analysis of imaging data from PD patients has led to the identification of abnormal metabolic patterns associated with the motor and cognitive features of this disease. Measurements of pattern expression have been used for diagnosis, assessment of rates of disease progression, and objective evaluation of the efficacy of therapeutic interventions. For instance, the recent identification of new disease-specific patterns for Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) has improved diagnostic accuracy in patients with parkinsonian syndromes. Further, disease-related networks have been found to be modulated by novel treatment strategies such as gene therapy. Finally, the application of network analysis to the study of inherited movement disorders such as Huntington's disease can aid in the assessment of disease-modifying therapies in pre-symptomatic gene mutation carriers.

[Case of DYT1 dystonia (early-onset torsion dystonia) showing long-term focal dystonia in the arm].

DYTI dystonia (DYT1-D, early-onset torsion dystonia) is caused by a GAG deletion in the DYTI gene. Here we report a girl with child-onset familial DYT1-D showing localized arm involvement. The patient developed postural and action dystonia in the right and left arms at 7 and 9 years, respectively. She was misdiagnosed as hysteria due to lack of abnormalities on laboratory tests. At 11 years of age she was introduced to our clinic. Increased muscle tonus and dystonic discharges seen on surface electromyogram in the right arm and the sternocleidomastoid muscle led to the diagnosis of dystonia. A GAG deletion in the DYTI gene was confirmed in the patient, her healthy father and paternal grandfather with torsion dystonia. Titration of levodopa resulted in the fluctuation of her arm dystonia. Combined therapy by levodopa and trihexyphenidyl relieved postural dystonia in the right arm but not action dystonia in the left. Both types of dystonia in the right and left arms were well ameliorated by the additional increase of levodopa. Somatosensory evoked potentials demonstrated abnormal premovement gating. The latency and accuracy of the amplitude were disturbed in visually guided saccadic eye movement. Now at more than 11 years after onset, the patient has not shown torsion or involvement of the lower extremities. Most DYT1-D patients are refractory to medication and early surgical intervention is recommended. However, the presence of DYT1-D patients showing a milder disease course should also be considered.

Genetic Aspects of Myoclonus-Dystonia Syndrome (MDS).

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder with onset in the first two decades of life. Mutations in the epsilon-sarcoglycan gene (SGCE, DYT11) on chromosome 7q21-q31 represent the major genetic cause of M-D in some populations. The syndrome was related with mutations in two other genes (DRD2 and DYT1). A second locus has been reported in one large M-D family (DYT15, 18p11), but no gene has been identified yet. In this review, we discuss genetic aspects of myoclonus-dystonia.

Clinical and genetic features of DYT1 and DYT5.

Dystonia is a syndrome which is characterized by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. According to genetic basis, dystonia is classified into 13 subtypes. We mainly discussed two subtypes, DYT1 and DYT5, in this review. Early-onset primary dystonia is caused by the mutation of DYT1 gene, which leads to TORSINA abnormal. GTP cyclohydrolase 1 (GTPCH1)-deficient DRD (DYT5) is caused by the mutations of GCH1 gene. By genetic testing, we can confirm clinical diagnosis of each subtype and develop prenatal diagnosis for it.

Dystonia: a disorder often misdiagnosed as a conversion reaction.

The authors studied the records of 84 patients who had idiopathic torsion dystonia. Thirty-seven cases had originally been misdiagnosed as primarily psychiatric illness. Only 1 patient presented with dystonic movements that were clearly part of a more general psychiatric disorder. The authors believe her to be the first reported patient whose dystonia is undeniably of psychogenic origin.

Polysomnography of torsion dystonia.

Nocturnal EEG, electro-oculograms, and electromyograms were studied in nine patients with dystonia musculorum deformans and in nine healthy controls. Electrodes were placed over frontal, central, and occipital regions in accordance with the international 10-20 system of electrode placement. A standard bipolar montage was used for the recordings, and records were scored independently in accordance with the manual of Rechtschaffen and Kales. All patients were found to sleep poorly. Patients in advanced stages of dystonia all displayed an EEG pattern characterized by pronounced, high-amplitude (greater than 150 microV) spindles that were continuous for all stage 2 and portions of stage 3 sleep. Other sleep parameters were also disturbed. Sleep spindles become less frequent and diminish in amplitude with advancing age. The spindle activity of patients with advanced dystonia presents a stark contrast to this pattern and may underscore their clinical significance.

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.

A study of idiopathic torsion dystonia in a non-Jewish family: evidence for genetic heterogeneity.

A gene (DYT1) for idiopathic torsion dystonia (ITD) was mapped to chromosome 9q34 in non-Jewish and Jewish families; the dystonia in these families usually began in childhood, with the limb muscles affected first. The role of the DYT1 gene in adult-onset and cervical- or cranial-onset ITD is unknown. We examined 53 individuals from four generations of a non-Jewish North American family with adult-onset ITD. There were seven affected family members, with a mean age at onset of 28.4 years (range, 7 to 50 years). In six of the seven, the neck was affected first. All seven developed cervical dystonia, and dysarthria or dysphonia occurred in five. Linkage data excluded the region containing the DYT1 locus, indicating that DYT1 was not responsible for ITD in this family. This study provides evidence that a gene other than DYT1 is responsible for some cases of adult cervical-onset dystonia.

The DYT1 phenotype and guidelines for diagnostic testing.

OBJECTIVE: To develop diagnostic testing guidelines for the DYT1 GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary torsion dystonia (PTD) populations and to determine the range of dystonic features in affected DYT1 deletion carriers. METHODS: The authors screened 267 individuals with PTD; 170 were clinically ascertained for diagnosis and treatment, 87 were affected family members ascertained for genetic studies, and 10 were clinically and genetically ascertained and included in both groups. We used published primers and PCR amplification across the critical DYT1 region to determine GAG deletion status. Features of dystonia in clinically ascertained (affected) DYT1 GAG deletion carriers and noncarriers were compared to determine a classification scheme that optimized prediction of carriers. The authors assessed the range of clinical features in the genetically ascertained (affected) DYT1 deletion carriers and tested for differences between AJ and NJ patients. RESULTS: The optimal algorithm for classification of clinically ascertained carriers was disease onset before age 24 years in a limb (misclassification, 16.5%; sensitivity, 95%; specificity, 80%). Although application of this classification scheme provided good separation in the AJ group (sensitivity, 96%; specificity, 88%), as well as in the group overall, it was less specific in discriminating NJ carriers from noncarriers (sensitivity, 94%; specificity, 69%). Using age 26 years as the cut-off and any site at onset gave a sensitivity of 100%, but specificity decreased to 54% (63% in AJ and 43% in NJ). Among genetically ascertained carriers, onset up to age 44 years occurred, although the great majority displayed early limb onset. There were no significant differences between AJ and NJ genetically ascertained carriers, except that a higher proportion of NJ carriers had onset in a leg, rather than an arm, and widespread disease. CONCLUSIONS: Diagnostic DYT1 testing in conjunction with genetic counseling is recommended for patients with PTD with onset before age 26 years, as this single criterion detected 100% of clinically ascertained carriers, with specificities of 43% to 63%. Testing patients with onset after age 26 years also may be warranted in those having an affected relative with early onset, as the only carriers we observed with onset at age 26 or later were genetically ascertained relatives of individuals whose symptoms started before age 26 years.

Neurologic genetic diseases of Jewish people.

Three important dominantly-inherited neurological diseases were discovered to be particularly common among various Jewish ethnic groups. For idiopathic torsion dystonia (ITD), previously thought to be recessively transmitted among Ashkenazi Jews, we have established an autosomal dominant mode of inheritance. This finding resulted from a country-wide survey of ITD in Israel and its subsequent genetic analysis. In Creutzfeldt-Jakob disease (CJD) the focus among Libyan Jews was previously thought to be related to culinary habits; a point mutation of the prion-protein gene was first described by us. The factors leading to the preservation of these disadvantageous genes in the communities are however unknown. Genetic analysis shows reduced penetrance in ITD and age-related expression in CJD. Factors leading to the expression of the genes were looked for. Data for ITD suggest that laterality of onset depends on motor dominance. Data on anticipation are presented. Factors possibly involved in the expression of the CJD codon 200 mutation are also discussed. A focus of myotonic dystrophy was documented among Yemenite Jews. The preservation of this disadvantageous, dominantly-inherited gene (which leads to diminished reproductive abilities), was found to be social rather than biological, related to reduced age of marriage and number of offspring in this ethnic group. These data show an interaction between genetic and other biological and external factors in the expression of these three diseases.

Multidisciplinary management of dystonia misdiagnosed as hysteria.

Dystonia in the pediatric age group can be confused with hysteria, particularly when it occurs in an emotionally disturbed child with a negative family history of dystonia. A 20-year-old girl with a 12 year history of DMD is described. From age 12 to 17 she was housed in a mental institution after a misdiagnosis of hysteria was made. The progressive nature of DMD and the important emotional components are stressed. The multidisciplinary management model is discussed as a valuable method in the treatment of this chronic neurological disorder.

The varied clinical expressions of dystonia.

This article describes the myriad clinical appearances of dystonic movements. The phenomenology of the movements varies according to the region of the body affected, but even within the same region there is a wide variation. Arguments were presented that dystonic movements consists of both slow, sustained contractions, and rapid, repetitive, twisting movements, especially in the earlier stages of the disease called "dystonia musculorum deformans," also known as primary torsion dystonia.

Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans.

A 17-year-old Russian male with a 9-year diagnosed history of dystonia musculorum deformans manifested as severe tortipelvis, lordosis, and axial and appendicular spastic dystonia, refractory to medical therapy, is reported. This patient underwent a simultaneous bilateral pallidoansotomy with dramatic results. Postoperative evaluation revealed sustained alleviation of all dystonic symptoms and abnormal movements. Rapid recovery of useful strength in all limbs as well as dramatic improvement in coordination occurred. Bilateral posteroventral pallidotomy and pallidoansotomy in the past have proven effective in alleviation of all parkinsonian symptoms, including dyskinesia and dystonia, without the concurrent risk of intransigent side effects associated with bilateral thalamotomy or other stereotactic surgical procedures. Pallidoansotomy may prove to be the treatment of choice for idiopathic torsion dystonia and merits further investigation.

The idiopathic dystonias. A note on their orthopaedic presentation.

Eight patients suffering from various forms of idiopathic dystonia are described whose initial referral was for an orthopaedic opinion. The diagnoses of these patients, who were seen over a two-year period, comprised dystonia musculorum deformans, dystonia of the foot, spasmodic torticollis and occupational cramps. Although various musculoskeletal sequelae often occur, the primary underlying neurological cause of these unusual conditions is emphasised.

[Movement disorders: dystonias which are apparently psychosomatic. Torsion dystonias]. / Movimientos anormales: distonías aparentemente psicosomáticas. Distonías de torsión.

In neuropediatric clinical practice, disorders of movement include a wide diversity of conditions, amongst which the dystonias are uncommon in our practice, although they have to be considered amongst the possible diagnoses in some cases. The great variety of clinical symptoms and age of onset together with the nonspecific, erratic clinical course make diagnosis difficult. Some clinical pictures of genuine torsion disorders may be confused with hysterical conversion disorders, somatizations or Munchausen's syndrome. Diagnosis requires clinical knowledge of both conditions--torsion dystonia as opposed to hysteria or a conversion reaction--and considerable ability and experience. Genetics and molecular studies have helped to clarify some difficult diagnostic problems and facilitated both diagnosis and treatment. In a diagnostic video session we show the case of a seven year old boy who initially presented with a dystonic disorder. There was some doubt as to the aetiology and different types of treatment were given by different specialists. The true diagnosis was reached after molecular genetic studies.

Does neurology inform psychoanalysis? A case report.

In these days of malpractice suits it has become increasingly important that the psychoanalyst make correct diagnoses and institute appropriate treatment. The significance of this statement is enhanced by the fact that the opinion is being increasingly enunciated that there is no such disorder as conversion hysteria. Accordingly the psychoanalyst needs to keep up to date about relevant neurological matters. The present article reports a case of a young women who had been treated psychoanalytically for many years without the organic nature of her disorder being grasped. Appropriate pharmacological therapy produced prolonged remission of her symptoms.

Deep brain stimulation in DYT1 dystonia: a 10-year experience.

BACKGROUND: Globus Pallidus Interna (GPi) deep brain stimulation (DBS) is an effective treatment for DYT1-associated dystonia, but long-term results are lacking. OBJECTIVE: To evaluate the long-term effects of GPi DBS in patients with DYT1 dystonia. METHODS: A retrospective chart review (cohort study) of 47 consecutive DYT1+ patients treated by a single surgical team over a 10-year period and followed for up to 96 months (mean, 46 months) was performed. Symptom severity was quantified with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor (M) and disability (D) sub-scores. RESULTS: As measured with the BFMDRS (M), symptom severity was reduced to less than 20% of baseline after 2 years of DBS therapy (P = .001). The disability scores were reduced to <30% of baseline (P = .001). Symptomatic improvement was durable throughout available follow-up. Sixty-one percent of patients had discontinued all dystonia-related medications at their last follow-up. Ninety-one percent had discontinued at least 1 class of medication. Infections requiring removal and later reimplantation of hardware occurred in 4 of 47 patients (8.5%). Hardware malfunction including lead fractures occurred in 4 of 47 cases (8.5%). Lead revision to address poor clinical response was performed in 2 of 92 implanted leads (2.2%). CONCLUSION: GPi DBS is an effective therapy for DYT1-associated torsion dystonia. Statistically significant efficacy is maintained for up to 7 years. Neurologic complications are rare, but long-term hardware-related complications can be significant.