Machado-Joseph Disease Presenting As Severe Asymmetric Proximal Neuropathy

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534 Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:534–536 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.4.534 on 1 October 1997. Downloaded from

SHORT REPORT

Machado-Joseph disease presenting as severe asymmetric proximal neuropathy

I N van Schaik, G J Jöbsis, M Vermeulen, H Keizers, P A Bolhuis, M de Visser

Abstract far, and seemed to have a relatively short CAG Despite much eVort, a 74 year old man repeat expansion.4 with progressive proximal weakness and Recently, a new subtype has been proposed sensory disturbances due to axonal neu- based on a report of two patients with spastic ropathy remained a diagnostic problem. paraplegia without cerebellar ataxia.13 Whether Investigation of his family disclosed an these cases really represent a new subtype or additional patient with a cerebellar syn- just an atypical presentation of Machado- drome and a family member with mainly Joseph disease type I is disputable. However, pyramidal features. Analysis of DNA they illustrate that ataxia need not necessarily showed a CAG repeat expansion in the be the main feature and that cerebellar Machado-Joseph disease gene in all three symptoms may be masked by other neurological signs. Here we describe a patient patients. Although not conclusively with severe asymmetric proximal motor- proved, we think that the neuropathy of sensory neuropathy without apparent cerebel- the index case is linked to the CAG repeat lar features. Examination of family members expansion. Machado-Joseph disease prompted a diagnosis of Machado-Joseph should be considered in progressive ax- disease. Subsequent DNA analysis disclosed a onal neuropathy. CAG expansion in the Machado-Joseph disease gene in all three patients. (J Neurol Neurosurg Psychiatry 1997;63:534–536)

Keywords: neuropathy; Machado-Joseph disease; Case summaries SCA3; trinucleotide repeat expansion The proband, patient A (ﬁgure), a 74 year old man of Dutch descent developed diYculty walking at the age of 50 due to buckling of his

Machado-Joseph disease comprises four diVer- left knee. Subsequently, in the course of two http://jnnp.bmj.com/ ent clinical types depending on the age of decades, weakness spread to his left arm, right onset.1–3 Patients with Machado-Joseph disease leg, and finally his right arm. At the age of 73 type I have a mean age at onset of 23 years and he became confined to a wheelchair and display predominantly pyramidal and extrapy- needed assistance for normal daily activities. ramidal signs. Most patients with Machado- He experienced pins and needles with numb- Joseph disease have type II, presenting with ness of the left arm and altered temperature Department of sensation of the lower limbs with periods of Neurology, Academic ataxia as the dominant symptom and a mean Medical Center, age at onset of 35 years. In patients with type burning feet. Medical history disclosed non- on October 1, 2021 by guest. Protected copyright. insulin dependent diabetes mellitus for the past University of III, with a mean age at onset of 53 years, the two years, hypertension, myocardial infarction, Amsterdam, clinical features are those of peripheral neu- Amsterdam, The a left-sided total hip replacement, and menis- ropathy with muscle atrophy with fascicula- Netherlands cectomy. Medication consisted of metoprolol, I N van Schaik tions in addition to ataxia. Patients with the triamterene, hydrochlorothiazide, tolbutamide, G J Jöbsis rare type IV have parkinsonism variably and calcium carbasalate. M Vermeulen combined with ataxia, muscle atrophy, and H Keizers On examination there were cold, bluish dis- P A Bolhuis sensory loss, and have a later onset than type coloured legs with pitting oedema; absence of 4 M de Visser III. abnormal cranial nerve signs except for sac- The genetic defect of Machado-Joseph cadic eye movement on pursuit; fasciculations Correspondence to: disease consists of an expanded trinucleotide Dr G J Jöbsis, Department of of arm muscles; generalised atrophy, especially Neurology, H2-214, repeat within the coding region of a novel gene of the proximal muscles and more severe on the Academic Medical Center, on chromosome 14q.5 Normal alleles vary from left; severe paresis of the left leg (grade 2-3 on PO box 22700, 1100 DE 13 to 36 CAG repeats whereas mutated alleles MRC scale); and paresis of the other limbs, Amsterdam, The 56 Netherlands. contain between 61 and 84 repeats. Repeat proximal grade 3-4 and distal grade 4. Sensory numbers are related to age of onset,3 7–12 and to deficit consisted of diminished sensation to Received 31 January 1997 clinical phenotype (I, II, and III).371012 Of the pain and light touch in the left arm and dimin- and in revised form 6 April 1997 rare Machado-Joseph disease type IV, only two ished vibration and position sense of the entire Accepted 2 May 1997 patients have been characterised genetically so lower limbs. There was areflexia except for the Machado-Joseph disease presenting as severe asymmetric proximal neuropathy 535 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.4.534 on 1 October 1997. Downloaded from

III Pedigree structure with filled symbols designating patients with Machado-Joseph disease. Examined subjects are indicated by the crosses above the pedigree symbol. Arrow indicates proband. tendon reflexes of the right arm and plantar inflammation. Ten months after examination responses were flexor. he died at home during his sleep due to an Extensive laboratory investigation was unre- unknown cause. Permission for necropsy was markable except for an IgG-ê paraproteinae- not given by his family. mia which was classified as a monoclonal gam- A younger brother of the proband (patient mopathy of undetermined significance B), a 72 year old man with progressive walking (MGUS). Antibodies against myelin associated diYculty for at least 10 years, displayed on glycoprotein and GM1-gangliosides were ab- examination cerebellar features such as gait sent. Magnetic resonance imaging showed ataxia, dysarthria, and saccadic eye movements slight atrophy of the cerebellum, cerebrum, and on pursuit. Except for diminished vibration cervical spinal cord but not of the brainstem sense of the feet, there were no sensory signs or and was otherwise normal. Electrophysiologi- upper motor signs. The ankle and knee jerks cal studies disclosed decreased compound were absent. Brain MRI showed atrophy of muscle action potentials (CMAPs), decreased cerebellum and brainstem. Eye movement sensory nerve action potentials (SNAPs), and recording showed spontaneous nystagmus, slightly delayed nerve conduction velocities in abnormal smooth pursuit, and diminished the upper and lower limbs (table). The vestibulo-ocular and caloric nystagmus. peroneal CMAP and left sided sural SNAPs Patient C, a 29 year old son of patient B with were absent. Electromyography showed signs symptoms of clumsiness and stiVness, had of severe denervation and reinnervation. These spasticity in addition to nystagmus, saccadic findings were considered to be consistent with eye movements, and dysdiadochokinesia. axonal motor-sensory neuropathy. Visual and The figure shows additional family members brainstem auditory evoked potentials were neurologically examined. normal, eye movement recording showed square wave jerks and saccadic pursuit. With Methods and results of genetic analysis magnetic stimulation no central conduction DNA was obtained by extraction from leuco- disturbance of motor neurons was found. cytes using standard methods. The Machado-

Biopsy of the quadriceps muscle showed Joseph disease CAG repeat was ampliﬁed by http://jnnp.bmj.com/ chronic and active denervation atrophy with polymerase chain reaction from genomic DNA some rimmed vacuoles and sarcoplasmic gly- as described elsewhere.5 The size of the CAG cogen masses. An ischaemic forearm test repeat was determined by polyacrylamide/urea/ disclosed a normal increase of lactate after formamide gel electrophoresis using a se- exercise. Sural nerve biopsy showed chronic quence ladder as a length marker. Determina- axonal degeneration with signs of regeneration tions of CAG repeat length showed a repeat and extensive loss of both myelinated and number (including one interspersed CAA) of

unmyelinated ﬁbres. The large myelinated 22 and 54 for patient A, 22 and 62 for patient on October 1, 2021 by guest. Protected copyright. ﬁbres were nearly absent in the unimodal B, and 22 and 68 for patient C. histogram. Immunohistochemical techniques did not show IgG or complement deposits. Discussion Staining for leucocyte markers showed some Although the index case with severe, asymmet- cells scattered throughout the epineurium and ric, proximal motor-sensory neuropathy is not perineurium. There were no signs of active suggestive of Machado-Joseph disease, this

Neurophysiological ﬁndings in the index patient

Motor Sensory

Amplitude (mV) Amplitude (µV)

Dlt (ms) Distal ProximalNCV (m/s) Dlt (ms) Distal Proximal NCV (m/s) F response

R median nerve 5.7 2.7 6.8 52 3.9 1.0 46 38.4-40.5 R ulnar nerve 3.2 18.3 13.6 39 5.3 16.2 9.8 49 29.3-29.8 R peroneal nerve 4.4 A A A L peroneal nerve 3.5 A A A 9.9 A R posterior tibial nerve 12.1 36.5 L posterior tibial nerve 3.8 0.5 0.8 38

Dlt = Distal latency time; NCV = nerve conduction velocity; A = absent. 536 van Schaik, Jöbsis, Vermeulen, Keizers, Bolhuis, de Visser J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.4.534 on 1 October 1997. Downloaded from

diagnosis was finally considered most likely. tion are taken to constitute suYcient grounds to The family contained additional members with distinguish it from SCA3, our kindred shows longstanding neurological complaints; these that Machado-Joseph disease is also present in relatives were either unavailable or clinical patients of Dutch descent. Whatever the out- investigation or DNA analysis showed that they come of the nosological debate, Machado- did not have Machado-Joseph disease. The Joseph disease/SCA3 should be considered in index patient had had non-insulin dependent severe, progressive proximal axonal neuropathy, diabetes mellitus for two years which was well especially if the family history shows relatives regulated with an oral antidiabetic drug. His with a cerebellar syndrome. In a heterogeneous neurological symptoms started long before the group of disorders with a highly variable presen- diabetes was diagnosed. Moreover, the type of tation like ADCA I, DNA analysis will help to neuropathy, distribution of signs and symp- delineate the nosological boundaries. The range toms, and the neurophysiological and patho- of phenotypes in Machado-Joseph disease could logical findings are not consistent with any of become larger when CAG repeat expansions are the known diabetic neuropathy syndromes. systematically sought in families with neurode- The same holds true for the IgG monoclonal generative diseases of unknown origin. gammopathy of undetermined significance (MGUS). Neuropathies associated with IgG This work was supported in part by grants from the Schuhmacher-Kramer foundation and the Prinses Beatrix MGUS are normally symmetric, slowly pro- Fonds. INvS and GJJ contributed equally to this study. We are gressive, and never lead to complete paralysis grateful to Dr AAWM Gabreëls-Festen for assessment of the sural nerve biopsy and Dr R Witteveen for referral of the index or respiratory failure. Neurophysiological stud- patient. ies show segmental demyelination and nerve biopsies often show deposits of immunoglobu- 1 Rosenberg RN. Machado-Joseph disease: an autosomal dominant motor system degeneration. Mov Disord lins in the peripheral nerve; both features were 1992;7:193–203. absent in the index case. 2 Barbeau A, Roy M, Cunha L, et al. The natural history of The repeat length of 54 CAGs of patient A is Machado-Joseph disease. An analysis of 138 personally examined cases. Can J Neurol Sci 1984;11:510–25. below the smallest repeat expansion reported 3 Sasaki H, Wakisaka A, Fukazawa T, et al. CAG repeat expansion of Machado-Joseph disease in the Japanese: for Machado-Joseph disease so far—that is, analysis of the repeat instability for parental transmission, 413 61. In view of the correlation between repeat and correlation with disease phenotype. J Neurol Sci 1995; 371012 133:128–33. number and phenotype, it is tempting to 4 Tuite PJ, Rogaeva EA, St George-Hyslop PH, Lang AE. speculate that the atypical presentation of the Dopa-responsive parkinsonism phenotype of Machado- index case is related to the short repeat expan- Joseph disease: confirmation of 14q CAG expansion. Ann Neurol 1995;38:684–7. sion. 5 Kawaguchi Y, Okamoto T, et al. CAG expansions in a novel Machado-Joseph disease has been consid- gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet 1994;8:221–8. ered to be distinct from autosomal dominant 6 Maruyama H, Nakamura S, Matsuyama Z, et al. Molecular features of the CAG repeats and clinical manifestation of cerebellar ataxia type I (ADCA I, reviewed by Machado-Joseph disease. 1995; :807–12. 14 Hum Mol Genet 4 Junck and Fink ). Characteristics that seemed 7 Dürr A, Stevanin G, Cancel G, et al. Spinocerebellar ataxia to separate Machado-Joseph disease included 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 199639:490–9. clinical signs (faciolingual contraction fascicu- 8 Ranum LPW, Lundgren JK, Schut LJ, et al. Spinocerebellar ataxia type I and Machado-Joseph disease: incidence of lations and pseudoexophthalmus), distribution CAG expansions among adult-onset ataxia patients from of pathology (sparing of the inferior olivary 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 1995;57:603–8. nuclei and Purkinje cells but substantial 9 Matilla T, McCall A, Subramony SH, Zoghbi HY. Molecu-

involvement of the dentate nuclei and substan- lar and clinical correlations in spinocerebellar ataxia type 3 http://jnnp.bmj.com/ tia nigra), and the nearly exclusive occurrence and Machado-Joseph disease. Ann Neurol 1995;38:68–72. 10 Maciel P, Gaspar C, DeStefano AL, et al. Correlation in people of Portuguese or Azorean descent. between CAG repeat length and clinical features in Recently, the genetic defect of Machado- Machado-Joseph disease. Am J Hum Genet 1995;57:54–61. 11 Cancel G, Abbas N, Stevanin G, et al. Marked phenotypic Joseph disease was found to be identical to a heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph subset of ADCA I—that is, spinocerebellar disease locus. 1995; :809-16. 8 9 11 15–18 Am J Hum Genet 57 ataxia type 3 (SCA3). Several hypo- 12 Takiyama Y, Igarashi S, Rogaeva EA, et al. Evidence for inter-generational instability in the CAG repeat in the thetical mechanisms could account for a muta- MJD1 gene and for conserved haplotypes at ﬂanking mark-

tion giving rise to two disorders or various phe- ers amongst Japanese and Caucasian subjects with on October 1, 2021 by guest. Protected copyright. 14 Machado-Joseph disease. Hum Mol Genet 1995;4:1137–46. notypes within one disorder. Alternatively, 13 Sakai T, Kawakami H. Machado-Joseph disease: a proposal contrary to previous classiﬁcation systems the of spastic paraplegic subtype. Neurology 1996;46:846–7. most common type of Machado-Joseph disease 14 Junck L, Fink JF. Machado-Joseph disease and SCA3: the genotype meets the phenotypes. Neurology 1996;46:4–8. with mainly cerebellar features might be 15 Schols L, Vieira-Saecker AMM, Schols S, Przuntek H, Epplen JT, Riess O. Trinucleotide expansion within the identical to SCA3. Other types of Machado- MJD1 gene presents clinically as spinocerebellar ataxia and Joseph disease should be present in ADCA occurs most frequently in German SCA patients. Hum Mol Genet 1995;4:1001–5. I/SCA3 families as well. 16 Haberhausen G, Damian MS, Leweke F, Muller U. Spinoc- This Dutch family has three presentation erebellar ataxia, type 3 (SCA3) is genetically identical to Machado-Joseph disease (MJD). J Neurol Sci 1995;132:71– forms: amyotrophy with neuropathy, cerebellar 5. ataxia, and spasticity. Our ﬁndings sustain the 17 Higgins JJ, Nee LE, Vasconcelos O, Ide SE, Lavedan C, Goldfarb LG, Polymeropoulos MH. Mutations in Ameri- presence of an age related presentation in can families with spinocerebellar ataxia (SCA) type 3: west European, non-Portuguese/non-Azorean SCA3 is allelic to Machado-Joseph disease. Neurology ADCA I with the Machado-Joseph disease/ 1996;46:208–13. 18 Silveira I, Lopes-Cendes I, Kish S, et al. Frequency of SCA3 repeat expansion. If, despite a shared spinocerebellar ataxia type 1, dentatorubropallidoluysian mutation, the particular features of Machado- atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology 1996;46: Joseph disease such as the age related presenta- 214–8.