J Neurol Neurosurg Psychiatry 79:448-450 doi:10.1136/jnnp.2007.129478
  • Short report

Relapsing encephalopathy in a patient with α-methylacyl-CoA racemase deficiency

  1. S A Thompson1,
  2. J Calvin2,
  3. S Hogg2,
  4. S Ferdinandusse3,
  5. R J A Wanders3,
  6. R A Barker1
  1. 1
    Department of Neurology, Addenbrooke’s Hospital, Cambridge, UK
  2. 2
    Biochemical Genetics Unit, Addenbrooke’s Hospital, Cambridge, UK
  3. 3
    Laboratory Genetic Metabolic Diseases, Academic Medical Centre, Amsterdam, The Netherlands
  1. Dr R A Barker, Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK; rab46{at}
  • Received 10 July 2007
  • Revised 14 October 2007
  • Accepted 29 October 2007
  • Published Online First 21 November 2007


α-Methylacyl-CoA racemase (AMACR) deficiency is a rare disorder of fatty acid metabolism which has recently been described in three adult cases. We have identified a further patient with clinical features of a relapsing encephalopathy, seizures and cognitive decline over a 40 year period. Biochemical studies revealed grossly elevated plasma pristanic acid levels, and a deficiency of AMACR in skin fibroblasts. Sequence analysis of AMACR cDNA identified a homozygous point mutation (c154T>C). This case adds to the phenotypic variation seen in this peroxisomal disorder and highlights the importance of screening for plasma pristanic acid levels in patients with unexplained relapsing encephalopathies.

α-Methylacyl-CoA racemase (AMACR) deficiency is an autosomal recessive peroxisomal disorder which leads to the accumulation of pristanic acid, a branched chain fatty acid, C27-bile acid intermediates and, to a lesser extent, phytanic acid. AMACR is not directly involved in the β oxidation of pristanic acid, but catalyses the conversion of the (R)- to the (S)-stereoisomer of pristanoyl-CoA, the latter being the substrate of the first enzyme in the oxidation pathway of pristanic acid.1 Thus a defect at this level causes the accumulation of the branched chain fatty acid (2R)-pristanic acid. Three adult and two childhood cases have thus far been described.25 The adult onset disorder bears some resemblance phenotypically to Refsum disease, which is caused by defective α-oxidation of phytanic acid, the precursor of pristanic acid. Patients with Refsum disease accumulate phytanic acid in blood and tissues, producing a characteristic clinical triad of demyelinating neuropathy, pigmentary retinopathy and progressive ataxia.6 Both retinopathy and peripheral neuropathy have been described in some, but not all, patients with AMACR deficiency. The phenotype of these patients appears to encompass a number of additional features, including epilepsy, encephalopathy, pyramidal tract signs, depression and headache. In this report, we describe a further case of AMACR deficiency in an adult with a long history of seizures, relapsing encephalopathy and cognitive decline.


The patient, a 57-year-old woman, presented with a decline in cognition, apathy and unsteadiness of gait, progressing over a 3-week period. She had a complex past neurological history, dating back to the age of 13 years, when she developed generalised tonic–clonic seizures, treated with phenobarbitone. At the age of 14 years she was admitted to hospital with a prolonged period of post-ictal confusion, lasting several days, from which she made a spontaneous recovery. Five years later, during the third trimester of her first pregnancy, she was again admitted to hospital following a generalised tonic–clonic seizure, with confusion, fever, headache and photophobia. Examination revealed meningism, pyrexia and a left hemiparesis. Cerebral angiography was normal, but CSF examination showed a pleocytosis, and an EEG suggested widespread right hemisphere dysfunction. She made a spontaneous recovery over several weeks, and was left with no residual deficit. She remained well for several years, apart from occasional tonic–clonic seizures.

At the age of 31 years she developed a depressive illness with significant anorexia and weight loss. Four months into this illness she suffered a further seizure followed by confusion progressing to coma, requiring invasive ventilation for a period of 10 days. Examination again revealed meningism, fever and a left hemiparesis. Investigations were non-diagnostic. She recovered over several weeks, but was left with a residual mild anomia.

Eighteen years later, at the age of 49 years, she suffered a further similar episode, characterised by a prolonged period of depressed consciousness following a seizure. Recovery was incomplete, and she was left with significant ongoing cognitive problems with anterograde memory impairment, poor attention and dysphasia. She was readmitted at the age of 57 years with a history of further deterioration in her memory, concentration and word finding abilities, with two brief periods of more pronounced confusion and disorientation. She denied headache and did not report any systemic symptoms apart from anorexia.

There was no family history of neurological illness in her parents, two female siblings, son or daughter, with the exception of an ischaemic stroke in old age in her mother.

On admission on this occasion she was found to be mildly disorientated, with poor attention and anterograde memory. She was severely anomic, but was able to follow simple two stage instructions. Her corrected acuity was 6/12 on the right and 6/18 on the left. She had a right homonymous visual field defect, but no signs of retinitis pigmentosa. Examination of the limbs revealed a left extensor plantar response and absent ankle reflexes. Her gait was apraxic. There was no focal weakness, ataxia or sensory abnormality. General physical examination was unremarkable.

MRI revealed diffuse involutional changes and high signal involving the cortex and subcortical white matter, pons and thalami (fig 1). EEG showed excess slow activity with intermittent episodes of delta waves in the frontotemporal regions, independently over both hemispheres. Nerve conduction studies showed evidence of a mild sensory neuropathy. Muscle biopsy showed mild myopathic changes only. Mitochondrial genetic studies for the common MELAS mutations were negative. A routine blood screen was unremarkable apart from a raised alanine aminotransaminase. CSF examination revealed slightly low glucose (2.9 mmol/l CSF; 6.9 mmol/l serum), but no other abnormalities.

Figure 1 Axial MR images of the brain, demonstrating diffuse involutional change and high signal involving the cortex and subcortical white matter of the left occipital lobe, cortex of the frontal and parietal regions on the right side, the pons and thalami bilaterally.

Plasma very long chain fatty acids, phytanic acid and pristanic acid were analysed by gas chromatography–mass spectrometry of their methylesters. Pristanic acid concentration was grossly elevated (347.7 μmol/l, reference range 0–2 μmol/l) although very long chain fatty acids and phytanic acid were normal, as was pipecholic acid. Analysis of bile acids revealed the presence of a significant amount of the C27-bile acid intermediates tauro-trihydroxycholestanoic acid and tauro-tetrahydroxycholestanoic acid in both plasma and urine. These results were consistent with a peroxisomal disorder affecting branched chain fatty acid metabolism and bile acid biosynthesis. Studies in cultured skin fibroblasts showed the normal presence of peroxisomes, plasmalogen biosynthesis, β-oxidation of very long chain fatty acids and pristanic acid, and α-oxidation of phytanic acid. There was, however, no detectable AMACR activity (controls, mean 101 (SD 29) pmol/min/mg). AMACR deficiency was confirmed by sequence analysis of AMACR cDNA, which identified a homozygous point mutation (c154T>C) leading to the amino acid substitution (pS52P). This amino acid substitution has been identified in other patients with AMACR deficiency and has been shown in previous expression studies to result in inactivity of AMACR.3


A number of similar features have been identified among the adult cases of AMACR deficiency (table 1) and these parallel those seen in Refsum disease.

Table 1 Clinical features of adult patients with α-methylacyl-CoA racemase deficiency

The cardinal features of Refsum disease are a demyelinating neuropathy, progressive cerebellar ataxia and retinitis pigmentosa. The clinical syndrome may present from late childhood, but may also have onset as late as the fifth decade. In three of the four adult patients with AMACR deficiency described, neurophysiological evidence of peripheral neuropathy was demonstrated, although the neuropathy was demyelinating in only one and entirely asymptomatic in our patient. Two patients developed visual failure with pigmentary retinopathy, and one patient had signs consistent with cerebellar disease. Seizures, however, have not been described in Refsum disease, but have been documented in three of the four patients with AMACR deficiency. Furthermore, encephalitic or encephalopathic episodes were described in two of the previously reported patients. Such episodes were recurrent in our patient and associated with the accumulation of neurological deficits. Acute and subacute presentations may occur in Refsum disease, and these have been associated with precipitants, including rapid weight loss, pregnancy or fever. Similarly, the “crises” previously described in an 18-year-old patient with AMACR deficiency, and 53-year-old patient, may have been attributable to similar triggers, leading to a rise in pristanic acid levels. Prolonged encephalopathic episodes occurred in our patient during pregnancy and following a period of significant weight loss, although on other occasions no particular factors were identified.

The mechanism of phytanic acid and pristanic acid toxicity remains uncertain. Recent studies suggest that phytanic acid directly impairs mitochondrial function causing disruption in the supply of ATP. Several mechanisms may be involved, including inhibition of the electron flow along the respiratory chain and of adenine nucleotide exchange across the inner mitochondrial membrane.7 In addition, a number of other possible processes have been postulated, such as stimulation of tumour necrosis factor α activation and secretion, and the induction of inducible nitric oxide synthase.8 AMACR deficiency may be treatable with dietary exclusion of phytanic and pristanic acid, as described successfully in Refsum disease. Dietary manipulation was attempted in two patients, but it is unclear as yet whether this has resulted in any significant clinical benefit. Lowering plasma phytanic acid by plasma exchange has been performed in Refsum disease, producing a rapid improvement in cases with an acute or subacute presentation.9 A clinical response was not, however, observed as a result of lowering plasma pristanic acid levels by plasma exchange in a single encephalopathic patient with AMACR deficiency.2 In our case, the patient is on a diet that excludes phytanic and pristanic acid and to date she has had no further episodes.

In conclusion, this case extends the phenotypic presentation of AMACR deficiency, which can easily be looked for by measuring serum phytanic and pristanic acid levels. Adult patients presenting with recurrent encephalopathic episodes should have appropriate biochemical screening, including branched chain fatty acid analysis. Dietary exclusion of phytanic and pristanic acid offers a potential long term treatment for this condition.


This work was supported by the Netherlands Organisation for Scientific Research (NWO, grant 916.46.109).


  • Competing interests: None.


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