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Alexander disease, a rare leukodystrophy disorder, is caused by autosomal dominant GFAP mutations, typically presenting in infancy or juvenile years. However, adult-onset cases are increasingly recognized. Similarly, Pontocerebellar Hypoplasia (PCH) is a group of rare, heterogeneous, and progressive disorders with prenatal onset, resulting from a deficiency of selenoprotein due to autosomal recessive SEPSECS gene mutations. There is no literature on the concurrent expression of pathogenic variants in adult-onset ataxia. We report the first case of concurrent GFAP and SEPSECS heterozygous mutations identified in a patient with Adult-Onset Alexander Disease (AOAD).

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A 35-year-old previously healthy man presented with a 7-year history of dysarthria and a 1-year history of progressive left-sided weakness, ataxia, jaw and leg myoclonus, and dysphagia. His family history was negative. On examination, he exhibited spastic dysarthria, gaze-evoked nystagmus, optic ataxia, palatal myoclonus, left-sided weakness with spasticity, diminished muscle bulk, hyperreflexia, sustained clonus, and positive Hoffman and Babinski signs. He had dysmetria, dysdiadochokinesia, and was wheelchair-bound due to severe ataxia. MRI neuroaxis revealed moderate cerebellar atrophy of the inferior cerebellum, medulla, and cervicomedullary junction, periventricular hyperintensities, corticobulbar and corticospinal tract atrophy involving cerebral white matter tracts, and diffuse cervical and upper thoracic spinal cord volume loss. Work-up, including vitamin deficiencies, TSH, RPR, heavy metals, spinocerebellar ataxia panel, and serum paraneoplastic antibodies, were unremarkable. However, the leukodystrophy panel identified a likely pathogenic variant in the GFAP gene (c.219G>A) and a pathogenic variant in the SEPSECS gene (c.766G>T). PCH was excluded due to the absence of clinical characteristics. Alexander Disease was diagnosed based on clinical, imaging, and genetic findings.

Early genetic work-up should be considered in patients with adult-onset ataxia to guide supportive treatment and genetic counseling for their families. Novel mutations continue to be identified, thereby expanding the phenotypic spectrum of the disease.