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.

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.

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.

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.

Factitious torsion dystonia in rehabilitation: a singular new case and literature review.

We report a case of a 29-year-old woman suffering from chronic factitious disorder (FD) with torsion dystonia. For nearly five years, she traveled widely over the country, going from one hospital to another, taking serious medical risk in order to prolong her illness. After several admissions to Rehabilitation Units and multiple explorations, we find convincing evidence for factitious origin and the diagnosis of Munchausen syndrome was evoked. Such a clinical presentation is infrequent in Munchausen's syndrome. Indeed, most often the clinical picture is characterized by acute abdominal pain, fainting, hemoptysis, precordialgia, hematemesis or dermatological lesions. Physicians should be aware of this rare and potentially critical form of FD. Awareness in identifying these patients may lead to prevent unnecessary medical and/or surgical interventions.

Management of DYT1 dystonia throughout pregnancy.

A 30-year-old woman with generalised DYT1 dystonia, controlled with medication, presented at 9 weeks gestation with an unplanned pregnancy. A number of learning points were highlighted in management of the patient's dystonia alongside pregnancy including avoidance of excessive medication exposure to the fetus, while maintaining symptom control to a level acceptable and safe for the patient and prenatal diagnostic testing. In our case there was no overt ill effect to the newborn. This is a common worry among pregnant women with dystonia and as such the authors felt it important to report.

Status dystonicus a rare complication of dystonia.

A severe episode of dystonia refractory to standard drug therapy has been labeled as status dystonicus or dystonic storm. We report the development of this complication in a 10-year old boy with idiopathic torsion dystonia, the probable precipitating factor being either an infection or introduction of clonazepam.

Genetics and treatment of dystonia.

The torsion dystonias encompass a broad collection of etiologic subtypes, often divided into primary and secondary classes. Tremendous advances have been made in uncovering the genetic basis of dystonia, including discovery of a gene causing early onset primary torsion dystonia-a GAG deletion in exon 5 of the DYT1 gene that encodes torsinA. Although the exact function of torsinA remains elusive, evidence suggests aberrant localization and interaction of mutated protein; this may result in an abnormal response to stress or interference with cytoskeletal events and the development of neuronal brain pathways. Breakthroughs include the discovery of a genetic modifier that protects against clinical expression in DYT1 dystonia and the identification of the gene causing DYT6, THAP1. The authors review genetic etiologies and discuss phenotypes as well as counseling of patients regarding prognosis and progression of the disease. They also address pharmacologic and surgical treatment options for various forms of dystonia.

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.

Distonía focal del pie de inicio en el adulto / Adult-onset primary focal foot dystonia

Introducción. La distonía focal idiopática del pie de inicioen el adulto es una entidad rara de la que hasta la fechasólo se han encontrado siete casos publicados en la literatura.Dado que las formas idiopáticas en el adulto son excepcionales,su presentación obliga siempre a descartar formassecundarias. Caso clínico. Mujer de 51 años con distonía focal delpie de 3 años de evolución. La paciente presentaba posturaen flexión plantar e inversión del pie que empeoraba con laacción. Las exploraciones complementarias dirigidas a descartarcausas secundarias fueron negativas. A lo largo de suevolución el fenómeno distónico permaneció limitado al piey no desarrolló otra sintomatología neurológica. La pacientese benefició de tratamiento con toxina botulínica. Conclusiones. La distonía focal primaria idiopática delpie en el adulto es excepcional. El patrón más común es laflexión plantar y de los cinco dedos. El dolor asociado es unsíntoma relativamente frecuente. La patogenia es sólo parcialmenteconocida, los estudios neurofisiológicos y de resonanciafuncional demuestran que existe una pérdida delcontrol inhibitorio a nivel espinal y troncoencefálico, unaplasticidad cortical anómala y una integración sensitivomotoradefectuosa. La respuesta al tratamiento con fármacosorales es escasa, pero los pacientes pueden beneficiarsede la infiltración con toxina botulínica en los músculos implicados

Introduction. Adult-onset primary focal foot dystoniais a rare event. Up to now, only 7 cases have been reportedin the literature. Since the idiopathic-type fooddystonia is uncommon in adults, secondary types mustbe ruled out. Clinical report. We present the case of a 51 yearwoman with a 3 year history of focal food dystonia. Shehad abnormal posture of the foot with plantar flexionand inversion, which worsened with action. Complementarystudies aimed at ruling out secondary causes wereall negative. The dystonia remained limited to her foodand she did not develop any other neurological symptoms.She benefited from botulinum toxin treatment. Conclusions. Primary focal foot dystonia is uncommonin adults. The most common pattern is plantar andfive toes flexion. Associated pain is common. Its pathogenesisis only partially understood, the neurophysiologicstudies and functional resonance showing a loss ofinhibitory control at spine and brainstem levels, abnormalcortical plasticity and altered sensorimotor integration.The response of this disorder to drugs is poor, however,the patients may benefit from botulinum toxininfiltrations of the muscles involved

Dystonia, mental deterioration, and dyschromatosis symmetrica hereditaria in a family with ADAR1 mutation.

A family with dystonia associated with dyschromatosis symmetrica hereditaria (DSH), mental deterioration, and tissue calcification is described. The proband possessed an adenosine deaminase acting on the RNA 1 gene (ADAR1) mutation Gly1007Arg. This ADAR1 mutation could disturb RNA editing at Q/R sites of glutamate receptor in the brain and increase Ca(2+) influx into neurons, which is thought to induce dystonia and mental deterioration. The observations in our family raise the possibility that the ADAR1 mutation might be a direct cause or a predisposing factor for heredodegenerative dystonia. Further investigation of ADAR1 mutations will shed light on the genotype-phenotype correlation in DSH.

Atypical phenotypes and clinical variability in a large Italian family with DYT1-primary torsion dystonia.

The GAG deletion in the DYT1 gene usually causes a typical form of primary torsion dystonia (PTD) with early onset in a limb, rapid generalization, and sparing of cranial-cervical muscles, but atypical phenotypes have often been reported. Here, we describe a large DYT1 Italian family with phenotypically heterogeneous PTD that recapitulates all the atypical features associated with the DYT1 mutation, including late age at onset, focal or segmental phenotypes, onset or spreading of dystonia to the cranial-cervical muscles. Of 38 healthy family members, 15 also carried the DYT1 mutation, with an estimated penetrance of 21%. A literature review of atypical familial cases of DYT1-PTD showed that late onset, cervical involvement, and limited progression of dystonia are features frequently seen in DYT1 families. However, nearly all of these atypical patients fall within at least one of the clinical categories that best predict the DYT1 carrier status, namely, early onset, onset in a limb, and family history positive for early-onset dystonia.

Non-DYT1 early-onset primary torsion dystonia: comparison with DYT1 phenotype and review of the literature.

To investigate the clinical features of early-onset primary torsion dystonia (EO-PTD), 57 consecutive genetically characterized patients with onset before 21 years were studied. Sex, ethnic origin, family history of dystonia, age at onset, disease duration, site of dystonia onset and distribution at latest examination, dystonia progression, time to generalization, and motor disability were noted. The 14 patients (25%) with GAG deletion (904_906/907_909delGAG) in the DYT1 gene were compared with the remaining non-DYT1 patients. Cranial involvement was present in 49% of non-DYT1 cases, but only 14% of DYT1 cases; non-DYT1 patients were younger at time of generalization. DYT1 cases had features similar to sporadic non-DYT1 cases but differed markedly from familial non-DYT1 cases, the latter having later age at onset, less common limb onset, more frequent cervical involvement, and slower progression than DYT1 PTD. These findings indicate that non-DYT1 forms of EO-PTD differ clinically from those of DYT1 forms. Cranial involvement before 21 years of age is the strongest predictor of non-DYT1 status. Positive family history and cervical involvement are associated with less severe progression in non-DYT1 forms.

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.

Pisa syndrome without neuroleptic exposure in a patient with Parkinson's disease: case report.

We report on a patient affected by Parkinson's disease who developed over a period of a few weeks a tonic deviation of her head, neck, and trunk fitting the typical description of Pisa syndrome (PS). This patient was under stable levodopa and pramipexole treatment and had never been exposed to any psychotropic or antiemetic drugs before or at the time she developed the postural abnormality. Because dopamine transporter imaging revealed bilateral and symmetrical reduction of striatal uptake, we suggest that PS is not primarily related to side differences in dopaminergic denervation or drug exposure.