Sa Schneider

THAP1 mutations (DYT6) are an additional cause of early-onset dystonia

Background: The clinical phenotype of DYT6 consists mainly of primary craniocervical dystonia. Recently, the THAP1 gene was identified as the cause of DYT6, where a total of 13 mutations have been identified in Amish-Mennonite and European families. Methods: We sequenced the THAP1 gene in a series of 362 British, genetically undetermined, primary dystonia patients (78 with focal, 186 with segmental, and 98 with generalized dystonia) and in 28 dystonia-manifesting DYT1 patients and 176 normal control individuals. Results: Nine coding mutations were identified in the THAP1 gene. Two were small deletions, 2 were nonsense, and 5 were missense. Eight mutations were heterozygous, and 1 was homozygous. The main clinical presentation of cases with THAP1 mutations was early-onset (<30 years) dystonia in the craniocervical region or the limbs (8 of 9 patients). There was phenotypic variability with laryngeal or oromandibular dystonia present in 3 cases. Four of 9 THAP1 cases developed generalized dystonia. Conclusions: The number of THAP1 mutations has been significantly expanded, indicating an uncommon but important cause of dystonia. Coding mutations account for 9 of 362 dystonia cases, indicating a mutation frequency of 2.5% of dystonia cases in the population that we have screened. The majority of cases reported here with THAP1 mutations had craniocervical- or limb-onset segmental dystonia, but we also identified 1 homozygous THAP1 mutation, associated initially with writers dystonia and then developing segmental dystonia. Three of our patients had a nonsense or frameshift THAP1 mutation and the clinical features of laryngeal or oromandibular dystonia. These data suggest that early-onset dystonia that includes the involvement of the larynx or face is frequently associated with THAP1 mutations.

Editorial: Metal-related neurological disorders: several new genes and better understanding. Preface.

It is a captivating era to be working in neurology as recent years have engendered fascinating developments. To illustrate, we have put together a special edition dedicated to metal-related neurological disease. Different topics are covered including disorders related to neural accumulation of iron (i.e., syndromes of neurodegeneration with brain iron accumulation), manganese, copper, or calcium. In recent years, neurogenetic workup has provided valuable insights with numerous genes characterized and yet more new genes on the threshold. The increasing number of genetic tests that have become commercially available (most recently as gene panels at more and more affordable costs) is of great clinical relevance and calls for an informed selection of the right test(s). Furthermore, new genetic approaches confirm that heritable factors underlie a larger proportion of patients than anticipated and genetic mutations should thus also be suspected in patients with a negative family history (i.e., due to de novo mutations). In parallel, there have been pathological advances, which can be correlated to molecular findings and which may challenge some of the previously held concepts for, for example, the presence of Lewy body pathology, and this link makes it clear that study of rare disorders may have ramifications and help in the understanding of more common conditions like Parkinsons disease (PD). Improved imaging techniques with higher resolution and new sequences with increased sensitivity to certain tissues lead to radiological-phenotypic-genotypic correlations. All these findings shed light on the complexity of metal-related diseases. However, their broader pathophysiology remains ill-understood. Mitochondrial dysfunction, abnormal lysosomal metabolism, and altered lipid pathways are all suspected to play a role in these Mendelian disorders; however, we have only just begun to unravel the complex puzzle of genes, the environment, and the aging brain. Improved scientific understanding will in the future hopefully provide the basis for the development of specific and even curative therapies for our patients.

SPG11 Presenting with Tremor.

Background Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurological diseases, which typically present with progressive lower extremity weakness and spasticity causing progressive walking difficulties. Complicating neurological or extraneurological features may be present. Case Report We describe a 19-year-old male who was referred because of an action tremor of the hands; he later developed walking difficulties. Callosal atrophy was present on his cerebral magnetic resonance imaging scan, prompting genetic testing for SPG11, which revealed homozygous mutations. Discussion The clinical features, differential diagnosis and management of SPG11, the most common form of autosomal recessive complicated HSP with a thin corpus callosum are discussed.