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 () 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.
Figure 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; (more ...)
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