Posted - June 2018 in Research Highlights
Limitations in classification and diagnosis
Here are three studies that suggest different approaches in classification and testing to more quickly and accurately identify overlapping movement disorders involving spasticity and ataxia.
Some HSPs and spinocerebellar ataxias overlap
Limitations of current disease classifications
Testing of larger gene panels that are now available earlier in the process of establishing a diagnosis for conditions showing symptoms of both ataxia and spasticity is suggested.
Increasing availability of next-generation sequencing technologies has revealed several limitations of diagnosis-driven traditional clinicogenetic disease classifications, particularly among patients with an atypical or mixed phenotype.
Hereditary spastic paraplegia (HSP) and spinocerebellar ataxia (SCA) are two such disease entities with an often overlapping presentation, in which next generation exome sequencing has played a key role in identification of genes causing disease along a continuum of ataxia and spasticity. We describe a patient who presented with features of both ataxia and spasticity, in whom initial diagnostic testing was inconclusive. Ultimately next generation exome sequencing identified homozygosity for a pathogenic variant in exon 13 of the CAPN1 gene c.1534C>T(p.Arg512Cys).
This case supports consideration of a less discriminatory classification system among such patients, potentially allowing for more expedient diagnosis through testing of a larger gene panel along the ‘ataxia-spasticity spectrum’.
SOURCE: Pract Neurol. 2018 Apr 20. pii: practneurol-2017-001842. doi: 10.1136/practneurol-2017-001842. [Epub ahead of print] PMID: 29678961
CAPN1 mutations broadening the hereditary spastic paraplegia/spinocerebellar ataxia phenotype.
1 Department of Neurology, St James’s Hospital, Dublin, Ireland.
Mixed ataxia-spasticity condition
VPS13 gene linked to range of movement disorders
OBJECTIVE: To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias and spastic paraplegia.
METHODS: In an international collaboration, we independently performed exome sequencing in seven families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knock-out model and investigated mitochondrial function in patient-derived fibroblast cultures.
RESULTS: Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all seven families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4, SCAR4. Linkage to chromosome 1p36 was found in this family with a LOD score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but two patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knock-down or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production.
INTERPRETATION: Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. This article is protected by copyright. All rights reserved.
SOURCE: Ann Neurol. 2018 Mar 31. doi: 10.1002/ana.25220. [Epub ahead of print] PMID: 29604224 © 2018 American Neurological Association.
Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
Seong E1, Insolera R2, Dulovic M3, Kamsteeg EJ4, Trinh J3, Brüggemann N5, Sandford E1, Li S, Ozel AB6, Li JZ6,7, Jewett T8, Kievit AJA9, Münchau A3, Shakkottai V10, Klein C3, Collins C2, Lohmann K3, van de Warrenburg BP11, Burmeister M1,6,7,12.
1 Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, 48109, USA.
2 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA.
3 Institute of Neurogenetics, University of Lübeck, Germany.
4 Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
5 Department of Neurology, University of Lübeck, Germany.
6 Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
7 Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA.
8 Department of Pediatrics, Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
9 Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
10 Departments of Neurology and of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
11 Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
12 Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, USA.
HSP and cerebellar symptoms
CAPN1 gene mutation
Hereditary spastic paraplegias (HSPs) and ataxias are genetically heterogeneous disorders, with more than 70 genes implicated in each group. A smaller fraction of disorders from both groups manifest both with spastic paresis and ataxia, and recognizing this phenotype helps narrowing down the differential diagnosis.1 Recently, homozygous and compound heterozygous mutations in CAPN1, which encode for the neuronal cysteine protease calpain, have been described as a cause of HSP (SPG76, MIM#616907).2
Here, we report 3 patients from 2 families with homozygous CAPN1 mutations who are characterized with slowly progressive lower limb spasticity with mild ataxia. Review of all patients with CAPN1 mutations so far supports the strong association of cerebellar involvement with this disorder and delineates several additional disease characteristics.
We report 3 adult-onset patients from 2 families who have disease onset with spastic paraparesis, emergence of cerebellar symptoms during disease course, slow disease progression, and homozygous mutations in the CAPN1 gene. These characteristics are in accordance with the previous reports and point out to a characteristic phenotype.2,4,5 The first study reported 8 patients from 3 families with pyramidal signs starting during young adulthood (range 19–39 years). All except for 1 patient had cerebellar findings during follow-up, and 1 patient required walking aid at the age of 40.2 In the second study, 6 patients from 4 families had slowly progressive spastic ataxia starting at young adulthood. One patient was using a wheelchair at the age of 30, and 2 patients needed walking aid in their forties.4 In a third report, 2 patients had a similar spastic-ataxia phenotype with onset around thirties.5 It is important that the range of age at onset was expanded by a recent report of a 16-year-old patient with congenital onset and pure spastic paraplegia.6
Our study, together with the rapidly expanding number of reported cases, validates the observation that homozygous or compound heterozygous mutations in calpain-1 cause a spasticity-dominant phenotype and emphasize its association with cerebellar symptoms. Accordingly, calpain-1 deficiency in mice disrupts cerebellar development causing cerebellar ataxia, and missense mutations in CAPN1 are associated with spinocerebellar ataxia in Parson Russell Terrier dogs.4,7 The cerebellar findings in CAPN1 patients reported so far include ataxic gait, dysarthria, and mild dysmetria/dysdiadochokinesia. Slow saccades were remarkable in 2 patients.2,4,–6 In light of these observations, we suggest that CAPN1-based disease should be considered among the emerging group of ataxia-spasticity spectrum disorders, especially in adult patients.1
SOURCE: Neurol Genet. 2018 Feb; 4(1): e218. Published online 2018 Jan 18. doi: 10.1212/NXG.0000000000000218 PMID: 29379883 Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Homozygous CAPN1 mutations causing a spastic-ataxia phenotype in 2 families
Cemile Kocoglu, MSc, Asli Gundogdu, MSc, Gulsen Kocaman, MD, Pinar Kahraman-Koytak, MD, Kayihan Uluc, MD, Gunes Kiziltan, MD, Ahmet Okay Caglayan, MD, Kaya Bilguvar, MD, Atay Vural, MD, PhD, and A. Nazli Basak, PhD
From the Suna and Inan Kirac Foundation (C.K., A.G., A.N.B.), Neurodegeneration Research Laboratory (NDAL), Molecular Biology and Genetics Department, Bogazici University, Istanbul, Turkey; Department of Neurology (G. Kocaman), Medical Faculty, Bezmialem Vakif University, Turkey; Department of Neurology (P.K.-K., K.U.), Faculty of Medicine, Marmara University, Istanbul, Turkey; Department of Neurology (G. Kiziltan), Cerrahpasa Faculty of Medicine, Istanbul University, Turkey; Department of Medical Genetics (A.O.C.), School of Medicine, Istanbul Bilim University, Turkey; Yale Program on Neurogenetics (A.O.C.), Departments of Neurosurgery, Neurobiology and Genetics, Yale University School of Medicine, New Haven, CT; Department of Genetics (K.B.), Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT; and Department of Neurology (A.V.), Koc University Hospital, Istanbul, Turkey.
Correspondence Dr. Basak [email protected]