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Logo of neurologyNeurologyAmerican Academy of Neurology
Neurology. 2011 May 17; 76(20): 1768–1770.
PMCID: PMC3100132

AMACR mutations cause late-onset autosomal recessive cerebellar ataxia

David Dick, MD, Rita Horvath, MD, PhD, and Patrick F. Chinnery, FMedScicorresponding author

Progressive cerebellar disorders presenting in late middle age often have a structural, toxic, inflammatory, or endocrine basis. Having excluded these causes, many patients are given a clinical diagnosis of multiple systems atrophy type C, or idiopathic late-onset cerebellar ataxia, and not investigated further. Here we describe a sporadic cerebellar syndrome leading to the diagnosis of a rare metabolic disorder with important implications for treatment.

Case report.

A 58-year-old man presented with an 8-year history of gait unsteadiness, slurred speech, a few tonic/clonic seizures, and a decline in short-term memory. There was no relevant family history or consanguinity.

On examination, he had a cerebellar dysarthria with appendicular and gait ataxia. Deep tendon reflexes were preserved, and plantar responses flexor. His Mini-Mental State Examination test score was 19/23 at 51 years of age, and 21/30 at age 58, with an Addenbrooke cognitive assessment of 61/100.

Routine hematology, thyroid function, vitamin E, B12, and copper studies were normal. CSF examination revealed normal protein content, cell count, and no oligoclonal bands. Urinary amino and organic acids, hexosaminidase, and acylcarnitines were normal. Echocardiography was normal. An EEG showed a mild generalized increase in slow wave activity and occasional sharply contoured theta waves in the right frontotemporal region. Nerve conduction studies revealed a mild, length-dependent sensorimotor polyneuropathy. Genetic studies were negative for Friedreich ataxia, spinocerebellar ataxia 1, 2, 3, 6, 7, and 17, dentatorubropallidoluysian atrophy (DRPLA), and the fragile X tremor-ataxia syndrome.

Muscle biopsy showed occasional atrophic fibers, but no cytochrome oxidase deficient fibers or ragged red fibers. Long-range PCR detected full-length normal mitochondrial DNA in skeletal muscle. Electron microscopy revealed the presence of occasional subsarcolemmal clusters of enlarged mitochondria containing paracrystalline inclusions.

Brain MRI at age 51 (figure) showed high signal on T2-weighted images in the white matter of both hemispheres, thalami, midbrain, and pons with associated brainstem atrophy. There was also extensive cortical thickening in the right frontal lobe with abnormal enhancement after IV contrast. By 51 years of age, the cortical thickening had resolved, leaving frontal atrophy.

Images taken at 51 years old (51 y/o = A–D) and 57 years old (57 y/o = E–I). All images are axial T2 sequences, with the exception of (I), which is a sagittal fluid-attenuated inversion recovery image: (A) right frontal cortical thickening; ...

Very long chain fatty acids analysis revealed normal C22:0, C24:0, and C26:0 levels and ratios, but elevated levels of phytanic (14.7 μmol/L, normal 0.3–11.5 μmol/L) and pristanic (75.9 μmol/L, normal 0.0–1.5 μmol/L) acids, suggesting a disorder of peroxisomal fatty acid oxidation. Plasma bile acid analysis revealed normal levels of deoxycholic acid (undetectable, normal <4.4 μM), chenodeoxycholic acid (0.27, normal 0.22–12.4 μM), cholic acid (undetectable, normal <4.6 μM), ursodeoxycholic acid (undetectable, normal <2.1 μM), hyocholic acid (undetectable, normal <1.0 μM), varanic acid (undetectable), and C29 dicarboxylic acid (undetectable), but elevated levels of dihydroxycoprostanic acid (DHCA, 0.87, normally not detected), and trihydroxycoprostanoic acid (THCA, 0.17, normally not detected). Increased excretion of DHCA and THCA in the presence of an elevated pristanic acid suggested a diagnosis of α-methylacyl-CoA racemase (AMACR) deficiency, confirmed by the detection of the homozygous c.154T>C (p.S52P) AMACR mutation previously reported in patients with this defect.1


AMACR deficiency is a rare cause of relapsing encephalopathy, with only 4 previously published clinical descriptions.13 The case described here is unusual because of the predominant cerebellar presentation, with a dysarthria described as a late feature in only one other patient.1 Seizures are unusual in late-onset degenerative ataxias. Potential causes include DRPLA, spinocerebellar ataxia type 10, episodic ataxia type 2, and neurometabolic disorders including mitochondrial diseases. If we include the patient described here, seizures have now been described in 80% of patients of AMACR deficiency. In 2, the first seizure occurred after age 50. Our observations stress the importance of measuring phytanic and pristanic acid levels in patients with unexplained ataxia when there are additional features such as epilepsy, even when there is not an obvious retinopathy or deafness (which would be expected in Refsum disease). It is not clear how elevated phytanic acid levels cause neural cell death, but the mechanism may be mediated through an effect on oxidative phosphorylation, and the supply of ATP.4 This may explain why the clinical presentation and imaging findings in our patient are reminiscent of mitochondrial disorders, which underpin a growing group of recessive cerebellar ataxias.5 It is intriguing that there was no objective cognitive decline in our patient over a 7-year period, despite the progressive ataxia. This contrasts with other cases, where the cognitive decline was prominent and progressive. This emphasizes the importance of dietary modifications aimed at reducing phytanic acid and pristanic acid levels, which may prevent clinical progression.6


The authors thank Drs. H.R. Waterham and S. Ferdinandusse for providing the AMACR molecular diagnostic service.


Disclosure: Dr. Dick and Dr. Horvath report no disclosures. Dr. Chinnery serves as an Associate Editor for Brain and is a Wellcome Trust Senior Fellow in Clinical Science and a UK NIHR Senior Investigator who also receives funding from the Medical Research Council (UK), the UK Parkinson's Disease Society, Association Française contre les Myopathies, and the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust.


1. Ferdinandusse S, Denis S, Clayton PT, et al. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 2000;24:188–191 [PubMed]
2. Thompson SA, Calvin J, Hogg S, Ferdinandusse S, Wanders RJ, Barker RA. Relapsing encephalopathy in a patient with alpha-methylacyl-CoA racemase deficiency. J Neurol Neurosurg Psychiatry 2008;79:448–450 [PubMed]
3. McLean BN, Allen J, Ferdinandusse S, Wanders RJ. A new defect of peroxisomal function involving pristanic acid: a case report. J Neurol Neurosurg Psychiatry 2002;72:396–399 [PMC free article] [PubMed]
4. Ronicke S, Kruska N, Kahlert S, Reiser G. The influence of the branched-chain fatty acids pristanic acid and Refsum disease-associated phytanic acid on mitochondrial functions and calcium regulation of hippocampal neurons, astrocytes, and oligodendrocytes. Neurobiol Dis 2009;36:401–410 [PubMed]
5. Assoum M, Salih MA, Drouot N, et al. Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain 2010;133:2439–2447 [PubMed]
6. Wierzbicki AS. Peroxisomal disorders affecting phytanic acid alpha-oxidation: a review. Biochem Soc Trans 2007;35:881–886 [PubMed]

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