SCA3 Presenting as an Isolated Axonal Polyneuropathy

Objectives  To highlight an unexpected clinical presentation and to review the associated polyneuropathy phenotypes of SCA3.

Design  Clinical follow-up.

Setting  Neurological referral center.

Patient  Middle-aged man with no family history for SCA3.

Results  Presentation with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy for 6 years before developing a cerebellar syndrome prompting genetic testing for SCA3.

Conclusion  SCA3 can present with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy.

SCA3 (or Machado-Joseph disease) is an autosomal dominant cerebellar ataxia (ADCA I) due to CAG repeat expansions in ataxin3. Patients with SCA type 3 have the latest onset and slowest progression with cerebellar ataxia and polyneuropathy, with or without progressive external ophthalmoplegia or pyramidal signs.¹ We describe a patient with a unique presentation of an axonal distal sensorimotor polyneuropathy for 6 years before developing a cerebellar syndrome leading to the diagnosis of SCA3. We also review SCA3 -associated polyneuropathy phenotypes.

A 52-year-old man had leg weakness for 6 months and no family history for SCA3. His mother had diabetes mellitus and died at 86 years. His father's age of death and details were unknown. The facial and cranial nerves were normal. He had distal lower limb weakness. Arm reflexes were sluggish, the knee jerks were brisk, ankle jerks were absent, and plantar responses were mute. Results of the sensory examination were unremarkable. Results of the following tests were either negative or normal: complete blood cell count, erythrocyte sedimentation rate, liver and thyroid function, VDRL, human T-lymphotrophic virus 1, serum protein electrophoresis, rheumatoid factor, antinuclear antibody, Kveim, chest radiograph, and levels of glucose, urea, electrolytes, vitamin B₁₂, folate, extractable nuclear antigen, antineutrophil cytoplasmic antibody, and cerebrospinal fluid. Electrophysiology showed absent (medians, ulnars, and surals) or small (radial, 4.6 μV) sensory nerve action potentials, absent soleus H-reflexes, normal motor conduction velocities and F-wave latencies (medians, ulnars, and common peroneal nerves), no conduction block, small lower limb compound muscle action potentials, and distal denervation in the upper and lower limbs consistent with an axonal sensorimotor polyneuropathy.

Six months later he reported cramps in his hands and legs. He had fasciculations in the biceps, triceps, thighs, and calves. There was now distal weakness in the upper and lower limbs. Reflexes were brisk with absent ankle jerks, an extensor right plantar, and no sensory signs. A year later, he reported worsening weakness of the upper and lower limbs. Reflexes were now diminished with flexor plantar responses. Sensory examination results remained normal. A sural nerve biopsy specimen confirmed a moderately severe axonal neuropathy affecting myelinated and unmyelinated axons, with some regeneration and secondary demyelination and remyelination. There was no vasculitis, abnormal infiltrates, or Schwann cell hyperplasia.

Two years later he walked with a cane. There was more distal weakness of the upper and lower limbs. All reflexes were absent except for the knee jerks. The right plantar was again extensor; the left plantar was equivocal. There was impaired pin-prick sensation in the left foot. A second autoimmune screen, including the levels of antigliadin, antiendomysial, antineuronal antibodies, and vitamin E were normal. Magnetic resonance imaging of the lumbosacral spine disclosed no abnormality. Three years later he reported poor balance resulting in falls. He had an ataxic gait out of proportion to the polyneuropathy and used a walker. There were broken smooth-pursuit eye movements, no nystagmus, and a mild intention tremor of the limbs. Computed tomography of the brain showed atrophy of the cerebellar hemispheres with preservation of the pons and olives. Magnetic resonance imaging showed no cervical cord pathology. Genetic analysis revealed an expanded CAG trinucleotide repeat (62) in ataxin3. A year later, nerve conduction study results showed a more severe polyneuropathy with absent sensory nerve action potentials in the upper and lower limbs, unrecordable lower limbs, and smaller upper limbs, compound muscle action potentials, and more severe distal denervation in the limbs.

Our patient presented with a progressive axonal, distal, symmetric, sensorimotor polyneuropathy. A cerebellar syndrome developed 6 years later. We have not found a similar presentation of SCA3 in the literature. Chronic idiopathic axonal polyneuropathy, considered initially, is a diagnosis of exclusion²; the earlier onset and progression of the severe polyneuropathy in our patient also argue against this diagnosis.² The known association of polyneuropathy and SCA3, long follow-up, and low incidence of SCA3 make a chance association between these 2 unlikely. In retrospect, the right extensor plantar response recorded 1 year after presentation signaled a multiple system disorder. It was not confirmed 1 year later. After a further 2 years, it was extensor again. However, the patient returned for follow-up 3 years later; by then he also had ataxia.

Patients with SCA3 who develop a polyneuropathy may present with a late-onset ataxic syndrome.³ Patients with symptoms or signs of a polyneuropathy may have electrophysiological evidence of an axonal sensorimotor polyneuropathy, a motor or sensory neuropathy, or normal findings.⁴ Reduced sensory nerve action potentials were seen in 13 of 17 patients with SCA3 ; only 56% had absent or reduced reflexes and vibration sense.⁵ Myelinated and unmyelinated fibers are decreased in number and relatively hypomyelinated with a smaller mean axon size, consistent with distal axonopathy.⁶

There is an inverse correlation between CAG trinucleotide repeat length and onset of disease in SCA3.⁷ The polyneuropathy appears late and correlates with shorter CAG trinucleotide repeat length. There is an inverse correlation between age and compound muscle action potentials or sensory nerve action potentials in SCA3, with decline at a more rapid rate than in normal aging.⁸ Conduction velocity slowing was not correlated with CAG repeat length.⁸ CAG repeat expansions in ataxin3 have a bimodal distribution, with populations of normal (<41) and disease-causing expansions (>62).⁹

A male with a progressive, severe, asymmetric proximal polyneuropathy from age 50 years with no central nervous system or cerebellar signs, a family history of SCA3, and a 54-repeat trinucleotide expansion is recorded.¹⁰ He had non–insulin dependent diabetes, and IgG-κ monoclonal gammopathy. Two relatives with ataxia and peripheral neuropathy or pyramidal signs had SCA3 CAG trinucleotide repeat expansions within the pathogenic range.¹⁰ The proband's intermediate-range 54 repeats may not be unequivocally related to his isolated polyneuropathy, particularly with its predominantly proximal and asymmetrical phenotype. There are no reports of such a phenotype in the 116 other cases of polyneuropathy and SCA3 (Table). CAG repeats within the intermediate range (53-54) have only been reported to be associated with disease in 4 members of 1 other pedigree¹¹; 2 had a polyneuropathy plus other features but without data excluding other causes of polyneuropathy.

SCA3 published polyneuropathies are sensorimotor in 85.3% (99 of 116 patients) and sensory in 7.8% (9 of 116 patients). All those with polyneuropathy and a pathologically expanded CAG repeat had distal symmetrical presentations (Table).

SCA3 should be considered a rare differential diagnosis of an axonal, distal, symmetric, sensorimotor polyneuropathy of unknown etiology in a middle-aged patient despite the absence of a positive family history. However, genetic investigation of such an unusual occurrence would be impractical unless it had clear therapeutic or genetic counseling implications.

Correspondence: Roberto J. Guiloff, MD, FRCP, Neuromuscular Unit, West London Neurosciences Centre, Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, United Kingdom (r.guiloff@imperial.ac.uk).

Accepted for Publication: September 22, 2010.

Author Contributions: Drs Graves and Guiloff had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Graves and Guiloff. Acquisition of data: Guiloff. Analysis and interpretation of data: Graves and Guiloff. Drafting of the manuscript: Graves and Guiloff. Critical revision of the manuscript for important intellectual content: Graves and Guiloff. Administrative, technical, and material support: Graves and Guiloff. Study supervision: Guiloff.

Financial Disclosure: None reported.