Cerebello–Brainstem Dominant Form of X-linked Adrenoleukodystrophy Without Apparent Brain MRI Abnormalities at Disease Onset

Cerebello-brainstem dominant form of X-linked adrenoleukodystrophy (X-ALD) is a rare adult-onset phenotype that typically presents with slowly progressive spasticity and cerebellar ataxia. This phenotype can exhibit no apparent parenchymal signal abnormalities on brain MRI, thereby mimicking spinocerebellar ataxia. We encountered a 48-year-old Japanese man who developed slowly progressive spasticity and cerebellar ataxia beginning at age 35. Brain MRI performed 4 years later revealed only subtle cerebellar atrophy. Repeat-expansion testing identified an intermediate-length ATXN3 allele with 49 CAG repeats, and he received a provisional diagnosis of spinocerebellar ataxia type 3. Thirteen years after onset, follow-up MRI revealed new bilateral T2 hyperintensities in frontopontine fibers and cerebellar white matter. Markedly elevated very-long-chain fatty acid levels in plasma and a pathogenic ABCD1 variant confirmed the diagnosis of cerebello-brainstem dominant form of X-ALD. Detailed assessment identified compensated adrenal insufficiency, and his mother displayed mild neurologic symptoms, suggesting symptomatic carriage. This case highlights the importance of careful evaluation for adrenal insufficiency and a detailed family history assessment to detect subtle X-linked features in recognizing cerebello-brainstem dominant form of X-ALD in patients with progressive ataxia. It also suggests that longitudinal brain MRI can provide important diagnostic clues in patients with undiagnosed progressive ataxia, as characteristic demyelinating lesions along the frontopontine tract might emerge over time. Furthermore, because intermediate alleles in polyglutamine diseases are low-penetrance variants present in the general population, clinicians should avoid premature diagnostic closure and maintain careful diagnostic follow-up when encountering this finding to avoid missing treatable alternatives.