<div id="ojsAbstract">Background:&nbsp;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:&nbsp;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:&nbsp;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.</div>&nbsp;</p

Catherine J. Mummery

Henry Houlden

Mohadeseh Mehrabian

Peter G. Bain

Susanne A. Schneider

PubMed

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

Schneider, Susanne A.

Mummery, Catherine J.

Mehrabian, Mohadeseh

Houlden, Henry

Bain, Peter G.

Columbia University Academic Commons

Case ReportSPG11 Presenting with TremorSusanne A. Schneider1,2, Catherine J. Mummery3, Mohadeseh Mehrabian4, Henry Houlden4& Peter G. Bain2*1 Schilling Section of Clinical and Molecular Neurogenetics, Department of Neurology, University Luebeck, Germany, 2Dementia Research Centre, Institute ofNeurology, London, United Kingdom, 3UCL Institute of Neurology, London, United Kingdom, 4Department of Clinical Neuroscience, Imperial College London,Charing Cross Hospital Campus, London, United KingdomAbstractBackground: Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurological diseases, which typically present withprogressive 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 atrophywas 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 thincorpus callosum are discussed.Keywords: Tremor, SPG11, hereditary spastic paraplegia, spatacsinCitation: Schneider SA, Mummery CJ, Mehrabian M, et al. SPG11 presenting with tremor. Tremor Other Hyperkinet Mov 2012;2: http://tremorjournal.org/article/view/104* To whom correspondence should be addressed. E-mail: p.bain@imperial.ac.ukEditor: Elan D. Louis, Columbia University, United States of AmericaReceived: May 4, 2012 Accepted: May 26, 2012 Published: September 14, 2012Copyright: ’ 2012 Schneider et al. This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License, whichpermits the user to copy, distribute, and transmit the work provided that the original author(s) and source are credited; that no commercial use is made of the work; and that the work is notaltered or transformed.Funding: Part of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’sNational Institute for Health Research Biomedical Research Centres funding scheme. Dr. Schneider was supported by the Bosch Foundation.Financial Disclosures: None.Conflict of Interest: The authors report no conflict of interest.IntroductionHere, we describe a case of hereditary spastic paraplegia (HSP) withtremor as the presenting feature. HSPs are a clinically and geneticallyheterogeneous group of diseases, which typically present with slowlyprogressive lower-extremity weakness and spasticity, causing progres-sive walking difficulties.1,2 Additional bladder dysfunction and mildsensory signs may be present. In contrast to these ‘‘pure’’ forms,‘‘complicated’’ variants with additional features occur, which mayinclude seizures, dementia, amyotrophy, or extrapyramidal dysfunc-tion. To date, at least 48 different subtypes of HSP have beenrecognized. Here we present a case of SPG11 due to mutations in thespatacsin gene, a major cause of complex phenotypes. The presence of athin corpus callosum is characteristic and its finding should be a redflag.Case reportThis 19-year-old right-handed male was born after an uneventfulpregnancy. He reached his early milestones for standing, walking, andspeech slightly late; he was a slow learner in school but passed severalexams and went on to a higher education college. He had no problemscompeting with his peers in sports. His problems began at age 14,when he noted a tremor of the hands, so that he required a scribe forhis school exams.His past medical history was unremarkable. He did not smoke ordrink alcohol. His parents had moved to the United Kingdom fromKenya only a few years earlier. There was no history of tremor orother movement disorder in the family; however, one distant paternalcousin was said to have some form of spastic paraplegia.When seen by a pediatric neurologist at age 16, there was an evidentmild action tremor. He had increased tone in his limbs, particularlythe legs, with brisk reflexes and flexor plantar responses. Power andsensory examination were normal and there were no cerebellar signs.Although he was noted to have a slightly stiff gait, initially a diagnosisof ‘‘anxiety related tremor’’ was made and propranolol prescribed.However, 6 months later he developed leg pain and difficulty climbingstairs. He noted problems getting on and off trains without holding aFreely available onlineTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services1bar for support. He also complained of leg stiffness in the morningsprompting further evaluation.Routine bloods, thyroid function tests, and ceruloplasmin werenormal. Genetic testing for Huntington’s disease (HD), dentatorubralpallidoluysian atrophy, and spinocerebellar ataxias were negative.Magnetic resonance imaging (MRI) of the spine was normal; inparticular, there was no spinal cord compression or lesion. An MRIscan of the brain was also reported to be normal, although on laterreview this was found to contain a key diagnostic clue.When he first presented to us at age 17 his symptoms hadprogressed. The action tremor was intrusive, affecting both hands,right more than left, and disturbing fine manual function (e.g. writingand doing up buttons). His parents noted that he had become moreanxious and prone to laughter. His appetite was normal and therewere no bladder or bowel symptoms. On examination there wasemotional lability. He had a moderate dysarthria, but cranial nerveexamination, including fundi and eye movements, was otherwisenormal. There were no abnormal signs in the upper limbs, except milddysdiadochkinesia. In particular, there was no tremor evident at rest,posture, or during intention, but mild tremor was present when tryingto pick up change, open a bottle, or draw (Figure 1). In the lowerlimbs, there was spastic paraparesis with increased tone, very briskreflexes, clonus at both ankles and extensor plantar responses. He worefoot splints because of bilateral upper motor neuron foot drop. Therewas no sensory deficit. His gait was narrow-based and there was atendency to drag his legs.Propanolol 80 mg/day proved unhelpful for this intermittenttremor. Baclofen 10 mg twice daily, however, relieved his musclespasms.His previous imaging studies were reviewed and the corpus callosumwas noted to be abnormally thin (Figure 2). This prompted genetictesting for SPG11, which revealed a homozygous c.5769delT spatacsinmutation, resulting in p.S1923RfsX1950 with a premature stop atcodon 1950.DiscussionHSPs are a clinically and genetically heterogeneous group ofneurological diseases. In practice ‘‘pure’’ manifestations are distin-guished from ‘‘complicated’’ HSP forms, as the latter have additionalneurological or extraneurological features, including mental retarda-tion, dysarthria, ataxia, peripheral neuropathy, or muscle atrophy.1Extrapyramidal features as presenting or main feature are rare.Inheritance of HSPs may be autosomal dominant, autosomal recessive,or X-linked. However, most cases follow an autosomal dominantpattern with SPG4 being most frequent, accounting for ,40% ofdominant HSPs. Among the autosomal recessive forms, mutations inthe spatacsin gene on chromosome 15q (SPG11, MIM610844)) are amajor cause of complex phenotypes, particularly when atrophy of thecorpus callosum is also present. Thus, in one study, the overallfrequency of SPG11 among patients with autosomal recessive early-onset complicated HSP was 14%, but this was considerably higher inpatients with a thin corpus callosum (42%).3Onset of SPG11 is early (during infancy or adolescence; age range1–31 years),4 in line with our case. Progressive leg stiffness and learningdisabilities are the commonest symptoms at onset. Although ourpatient had slightly delayed milestones, he presented with tremor,which was followed by the development of leg stiffness and walkingdifficulty. Patients may develop dysarthria, cerebellar ataxia, urinaryincontinence, or ophthalmological symptoms, including maculardegeneration, strabismus, or cataract. Peripheral neuropathy of theaxonal motor or sensorimotor type occur later in the disease course.However, with identification of the gene, unusual phenotypes areincreasingly recognized and include a juvenile, slowly progressive formof motor neuron disease associated with long-term survival,5 but notcognitive impairment and a thin corpus callosum (TCC). A predo-minantly parkinsonian phenotpye has also been reported recently.6,7Our patient was referred to us because of tremor, which is a rarepresenting sign (seen in one of 37 gene-proven cases8). There were nosigns of parkinsonism in our patient.However, while the clinical presentation of SPG11 can be complexand overlaps with cerebellar ataxias, leukodystrophies, and otherdisorders, certain features are usually not present in pure or com-plicated HSPs and should make the clinician suspicious of an alter-native diagnosis. This includes profound involvement of the upperextremity or bulbar muscles, or diurnal fluctuations and doparesponsiveness (as seen in dopa-responsive dystonia).Thinning of the corpus callosum and in most cases periventricularwhite matter alterations on MRI are characteristic of SPG11.9 Thisfinding prompted us to perform molecular testing for SPG11 in ourcase. However, a thin corpus callosum may also occur in othersubforms of HSP, including SPG15 (spastizin, 14q22), SPG21(maspardin, 15q22), SPG32 (14q12), SPG47 (AP4B1, 1p13) andHSP-TCC with epilepsy (8p12) and occasionally in SPG4 (SPAST,Figure 1. Ataxic-Tremor in a Spiral Drawing. A spiral drawn by thepatient when aged 17 years, showing mild ataxic (wavy rather than saw-tooth) typeaction tremor.Schneider SA, Mummery CJ, Mehrabian M, et al. SPG11 Presenting with TremorTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services22p22) and SPG7 (paraplegin, 16q24). Molecular testing can determinethe underlying HSP form for those with known gene defects. Thespatacsin gene (SPG11) has 40 exons and encodes a protein of 2443amino acids of unknown function, which is widely expressed in theadult cerebellum, cerebral cortex, hippocampus, and pineal gland.10The mutation identified in our case has previously been reported.11Neuropathologically, SPG11 is characterized by ‘‘dying-back’’axonal degeneration, maximal at the distal ends of the corticospinaltracts.1,2 Mild loss of anterior horn cells may occur. Demyelination, ifpresent, is consistent with the degree of axonal degeneration. Atrophymay also affect the brainstem, cerebellum, and deep gray matter,whereas the basal ganglia and spinal cord are usually spared. Thepathophysiological underpinnings of tremor in SPG11 may includecerebellar dysfunction and neuropathy.The treatment of HSPs remains symptomatic and should be tailoredto the individual symptoms, for example baclofen can alleviatespasticity. Patients may benefit from a multidisciplinary approach thatincludes physiotherapy, speech therapy, and occupational therapy.Genetic counseling should be offered and prenatal testing may beavailable for families in which a disease-causing mutation has beendetected.AcknowledgmentWe thank Dr Amrish Mehta, consultant neuroradiologist atImperial College Healthcare NHS Trust, Charing Cross Hospital,London, UK, for radiological advice.References1. Depienne C, Stevanin G, Brice A, et al. Hereditary spastic paraplegias: anupdate. Curr Opin Neurol 2007; 20:674–680, http://dx.doi.org/10.1097/WCO.0b013e3282f190ba.2. Salinas S, Poukakis C, Crosby A, et al. Hereditary spastic paraplegia:clinical features and pathogenetic mechanisms. Lancet Neurol. 2008; 7:1127–1138.3. Schule R, Schlipf NA, Synofzik M, et al. Frequency and phenotype ofSPG11 and SPG15 in complicated hereditary spastic paraplegia. J NeurolNeurosurg Psychiatry 2009;80:1402–1404, http://dx.doi.org/10.1136/jnnp.2008.167528.4. Stevanin G, Durr A, Brice A. Spastic Paraplegia Type 11. In:Genereviews [Internet]. Ed. Pagon RA, Bird JD, Dolan CR, Stephens K,Adam MP. Seattle (WA): University of Washington 1993.5. Orlacchio A, Babalini C, Borreca A, et al. SPATACSIN mutations causeautosomal recessive juvenile amyotrophic lateral sclerosis. Brain 2010;133:591–598, http://dx.doi.org/10.1093/brain/awp325.6. Anheim M, Lagier-Tourenne C, Stevanin G, et al. SPG11 spasticparaplegia. A new cause of juvenile parkinsonism. J Neurol 2009;256:104–108.7. Paisan-Ruiz C, Guevara R, Federoff M, et al. Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6,FBXO7 and spatacsin mutations. Mov Disord 2010;25:1791–1800, http://dx.doi.org/10.1002/mds.23221.8. Stevanin G, Azzedine H, Denora P, et al. Mutations in SPG11 arefrequent in autosomal recessive spastic paraplegia with thin corpus callosum,cognitive decline and lower motor neuron degeneration. Brain 2008;131:772–784, http://dx.doi.org/10.1093/brain/awm293.9. Stevanin G, Azzedine H, Denora P, et al. Mutations in SPG11 arefrequent in autosomal recessive spastic paraplegia with thin corpus callosum,cognitive decline and lower motor neuron degeneration. Brain 2008;131:772–784, http://dx.doi.org/10.1093/brain/awm293.10. Stevanin G, Santorelli FM, Azzedine H, et al. Mutations in SPG11,encoding spatacsin, are a major cause of spastic paraplegia with thin corpuscallosum. Nat Genet 2007;39:366–372, http://dx.doi.org/10.1038/ng1980.11. Paisan-Ruiz C, Dogu O, Yilmaz A, et al. SPG11 mutations are commonin familial cases of complicated hereditary spastic paraplegia. Neurology 2008;70:1384–1389, http://dx.doi.org/10.1212/01.wnl.0000294327.66106.3d.Figure 2. MR Brain Scan Showing a Thin Corpus Callosum. Sagittalbrain magnetic resonance imaging of the patients with an SPG11 mutationdemonstrating a thin corpus callosum (arrowed), a useful clue to this diagnosis(left, sagittal T1; center, axial T2, right, coronal T1 gradient echo).SPG11 Presenting with Tremor Schneider SA, Mummery CJ, Mehrabian M, et al.Tremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services3

English

SPG11 Presenting with Tremor

Background:&nbsp;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:&nbsp;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:&nbsp;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.&nbsp;</p

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