Adult‐onset cerebello‐brainstem dominant form of X‐linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review

Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello-brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy confirmed cases exceedingly rare. We report a 69-year-old white man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X-ALD or Addison’s disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities, and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss, and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of multiple system atrophy. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS-positive, CD68-positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft-like trilamellar cytoplasmic inclusions in macrophages typical of X-ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello-brainstem dominant form of X-ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult-onset cerebello-brainstem dominant form of X-ALD. Although rare, X-ALD should be considered in the differential diagnosis of MSA.

Cerebellar ataxia in progressive supranuclear palsy: An autopsy study of PSP‐C

“…The differences in frequency might be related to ethnic and genetic factors as is the case with cerebellar ataxia in MSA—MSA‐C is more common in Japan than European countries or the United States . Other disorders that have cerebellar variants, such as adrenoleukodystrophy, also appear to be more frequent in Japan . Indeed, ethnic differences in frequency of the MAPT haplotype are well known .…”

The neuropathology of the adult cerebellum

“…Heritable leukodystrophies with adult onset may present with ataxia, and neuropathologic examination may disclose characteristic lesions of the cerebellar white matter in adrenoleukodystrophy (OMIM 300100) (Ogaki et al, 2016), Alexander disease (OMIM 203450) (Spalke and Mennel, 1982; Stumpf et al, 2003), metachromatic leukodystrophy (OMIM 250100) (Guseo et al, 1975), Krabbe globoid cell leukodystrophy (245200) (Shao et al, 2016), and adult-onset dominant leukodystrophy (OMIM 169500) (Coffeen et al, 2000; Alturkustani et al, 2013). …”

Adult‐onset adrenoleukodystrophy of the olivopontocerebellar form and lacking cerebral involvement

“…Among several phenotypes, it is reported that the olivopontocerebellar (OPC) form comprised 8.4% of all patients with ALD in Japan . The characteristic finding of the OPC form might be classified into the following: (i) Olivopontocerebellar atrophy (OPCA) type atrophy; (ii) dentate–rubral pathway involvement; and (iii) pontocerebellar pathway involvement . Here, we report an adult‐onset ALD patient with the OPC form.…”