AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities ... AMACR deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (summary by Smith et al., 2010).
Ferdinandusse et al. (2000) reported 2 unrelated patients of European descent with a neurologic disorder associated with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and the C27 bile acid intermediates di- and trihydroxycholestanoic acid (DHCA ... Ferdinandusse et al. (2000) reported 2 unrelated patients of European descent with a neurologic disorder associated with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and the C27 bile acid intermediates di- and trihydroxycholestanoic acid (DHCA and THCA). A 44-year-old man had retinitis pigmentosa with restriction of his visual field and acuity. He also had primary hypogonadism and epileptic seizures. Nerve conduction studies showed a widespread axonal sensorimotor neuropathy affecting the legs more severely than the arms. He had shown mild developmental delay in childhood. Analysis of plasma VLCFAs, branched-chain fatty acids, and bile-acid intermediates ruled out Refsum disease (266500). The second patient was a woman who was well until the age of 48, when she began to tire easily and was found to be hypothyroid. She then developed heaviness of the legs on exercise, with dragging of both feet on walking. She had a spastic paraparesis, but the MRI scan of the cervical spine showed no abnormality. Nerve conduction studies showed a demyelinating polyneuropathy. Analysis of plasma very long chain fatty acids was undertaken to determine whether the patient had adrenomyeloneuropathy (300100) as a symptomatic heterozygote for this X-linked disorder. McLean et al. (2002) provided a detailed clinical description of the man reported by Ferdinandusse et al. (2000). He was a poor student and unable to keep jobs. At age 18 years, he had an acute encephalitic illness, characterized by headache, nausea, photophobia, confusion, irritability, and coma, that left him temporarily blind. EEG showed generalized slowing and loss of alpha activity. Ophthalmologic examination showed extensive pigmentary retinopathy. He had several seizures over the following years, a decline in vision, and daily migraine headaches after a traffic accident. Physical examination showed primary hypogonadism, distal sensory impairment with an axonal neuropathy, and increased pristanic acid, DHCA, and THCA. Clarke et al. (2004) reported a 53-year-old woman with AMACR deficiency. She had a long history of tremor affecting the upper limbs, head, and voice, and developed severe depression at age 45 and visual difficulties at age 52. Physical examination showed early cataracts, retinitis pigmentosa, and optic atrophy. She had cerebellar dysarthria with marked postural and intention tremor of all limbs, but no gait ataxia. She also had mild pyramidal weakness. Brain MRI showed deep white matter changes in the pons, basal ganglia, thalami, and cerebral peduncles. Biochemical studies showed increased pristanic acid and increased bile acid intermediates, suggesting AMACR deficiency. The diagnosis was confirmed by enzymatic assay and genetic analysis. She later developed an acute encephalopathic episode with headache, nausea, vomiting, confusion, agitation, and left hemiparesis. EEG showed bihemispheric epileptiform discharges. Plasma exchange decreased the levels of pristanic acid, but there was no clinical improvement. Thompson et al. (2008) reported a 57-year-old woman who presented with a decline in cognition, apathy, and unsteady gait. She had a complex neurologic history, with onset of seizures in her early teens and episodes of neurologic decline throughout her life. These episodes were characterized by confusion, hemiparesis, headache, and depression. On physical examination, she showed poor attention, poor naming, and apraxic gait. Brain MRI showed diffuse involutional changes and high signals in the cortex and subcortical white matter. Nerve conduction studies showed a mild sensory neuropathy. Laboratory studies showed increased serum pristanic acid, normal phytanic acid, and increased C27 bile acid intermediates, suggesting a peroxisomal disorder. Smith et al. (2010) reported a 45-year-old man who developed seizures in early adulthood. He had a lifelong difficulty in reading and mathematics. At age 43, he developed status epilepticus resulting in global encephalopathy and left hemiparesis. After some recovery, he had a second episode and was aphasic for a time. He also had primary hypogonadism, retinal pigmentary epithelial changes in the left macula, and a mild peripheral neuropathy with prolonged distal latencies on nerve conduction velocity studies. Biochemical studies showed increased pristanic acid and an increased pristanic:phytanic acid ratio. Dietary restriction of pristanic acid led to some clinical improvement, although there was no change in serum abnormalities. There was no apparent liver disease. Dick et al. (2011) reported a 58-year-old man who presented with an 8-year history of gait unsteadiness, cerebellar dysarthria, a few tonic/clonic seizures, and decline in short-term memory. Nerve conduction studies showed a mild sensorimotor polyneuropathy, and brain MRI showed high signal on T2-weighted images in the white matter of the cerebral hemispheres, thalami, midbrain, and pons, with brainstem atrophy. There was also some frontal atrophy. Laboratory studies showed increased phytanic and pristanic acids, indicating a peroxisomal disorder. Genetic analysis identified a homozygous mutation in the AMACR gene (S52P; 604489.0001), consistent with AMACR deficiency. Dick et al. (2011) noted the unusual phenotypic presentation in this patient, with minimal cognitive decline and prominent cerebellar ataxia.
In 2 unrelated patients with adult-onset sensorimotor neuropathy and alpha-methylacyl-CoA racemase (AMACR) deficiency, Ferdinandusse et al. (2000) identified the same homozygous mutation in the AMACR gene (S52P; 604489.0001). The mutation resulted in a complete loss of enzyme activity. ... In 2 unrelated patients with adult-onset sensorimotor neuropathy and alpha-methylacyl-CoA racemase (AMACR) deficiency, Ferdinandusse et al. (2000) identified the same homozygous mutation in the AMACR gene (S52P; 604489.0001). The mutation resulted in a complete loss of enzyme activity. The patients with AMACR deficiency reported by Clarke et al. (2004) and Thompson et al. (2008) were each homozygous for the S52P mutation. Smith et al. (2010) identified a homozygous S52P mutation in a 45-year-old man with adult-onset neurologic deterioration due to AMACR deficiency.