A 32-year-old woman presented with right arm numbness that persisted for 2 months, followed by an episode of optic neuritis; both resolved spontaneously. At 38 years of age, she presented with a left extensor plantar reflex, loss of dexterity in the right hand, appendicular ataxia that involved the right lower extremity, and mild gait ataxia. Brain magnetic resonance imaging (MRI) revealed mild diffuse atrophy and multiple foci of increased T2-weighted signal intensity in the periventricular white matter and cerebellum, consistent with a demyelinating disorder (). She was diagnosed as having relapsing-remitting MS. Lumbar puncture was not performed. Despite treatment, her condition deteriorated during the next 3 months, with reducing bilateral lower extremity sensation and motor function, worsening ataxia, and frequent urinary incontinence.
Figure 1 Magnetic resonance imaging (1.5 T) of the brain. A, Sagittal T2-weighted image shows thinning of the corpus callosum with poorly marginated regions of increased T2-weighted signal intensity. There is diffuse moderate cerebral volume loss for age and mild (more ...)
At 43 years of age, progression involved bilateral hand and lower extremity numbness, upper extremity intention tremor, gait ataxia, spastic paraparesis, short-term memory deficits, progressive dysarthria, disinhibition, and depression. During the next 9 years, additional medications, including weekly methotrexate, interferonbeta-1b, and mitoxantrone, were used. Her family history includes parkinsonism in her maternal grandfather and ovarian dysfunction (mid-30s) in her daughter, with workup revealing a premutation FMR1
allele (84 repeats). No other family history of fragile X syndrome was found. Given her daughter’s carrier status and her own neurologic problems, the patient was tested and found to have a premutation allele (75 repeats). The activation ratio (fraction of normal active FMR1
alleles) was 0.44. The FMR1
RNA level was elevated (mean [SD], 2.80 [0.12] times normal), consistent with premutation carrier status.2
She died at the age of 52 years after progressive memory impairment, loss of motor control, significant ataxia, and tremor.
Coronal sections of the brain (1133 g) showed moderate frontal gyral atrophy, with scattered, variably sized, discrete regions of gray discoloration in cerebral and cerebellar white matter, especially prominent in periventricular locations but also in the basal ganglia, brainstem, and left middle cerebellar peduncle. On microscopic examination, these abnormalities appeared as areas of demyelination in various stages of activity (). Microfoci of perivascular parenchymal pallor with lymphocytic infiltrates were present in early lesions. Midstage plaques showed infiltrates of foamy macrophages and lymphocytes, reactive astrocytosis, and microglial activity at their margins; scant perivascular mononuclear inflammatory infiltrates were also seen (). Inactive plaques showed parenchymal collapse with microcystic change. Correspondingly, Bielschowsky (axon) stain and Luxol fast blue/periodic acid–Schiff (myelin) stain showed varying degrees of axonal and myelin loss, respectively. Patchy areas of demyelination were seen in the molecular layers of both the cerebrum and cerebellum. Immunocytochemical staining for CD4+ lymphocytes (helper T cells) was negative in subacute lesions and revealed scant positive cells in aburned-out plaque (); CD8+ lymphocytes (killer T cells) were common in subacute plaques and scant in chronic plaques (). CD20 (B-cell) immunostaining was negative in both. Glial fibrillary acidic protein immunostaining showed reactive astrocytes in and around plaques and in nearby gray matter.
Figure 2 Microscopic examination of coronal sections of the brain. A, White matter with a sharply delineated plaque of demyelination on myelin stain (Luxol fast blue/periodic acid–Schiff, original magnification ×100). Arrowheads indicate the pallor (more ...)
Ubiquitin immunostaining identified few intranuclear inclusions in astrocytes throughout the brain and rare inclusions in cortical neurons, as described for FXTAS.4
Astrocytic inclusions were within regions of demyelinated white matter () and nondemyelinated white matter.