Late Adult-Onset Alexander Disease in Siblings with Prominent Autonomic and Cerebellar Dysfunction
Aditi Varma-Doyle1, Aidan Long2, Simon Cronin4, Otto Rapalino3, Nagagopal Venna2
1Brigham and Women's Hospital, Mass General Brigham, 2Massachusetts General Hospital, 3Radiology, Massachusetts General Hospital, 4Neurology, Cork University Hospital
Objective:
To highlight late-onset presentation of AOAD (55-60 years) with presentations of profound autonomic and cerebellar dysfunction, including novel finding of hemi-diaphragmatic palsy in siblings of Irish heritage with confirmed genetic mutation GFAP c.1154C>G (p. Ser385Cys) expanding the phenotypic spectrum in disease.
Background:
Adult-onset Alexander disease (AOAD) is a hereditary neurodegenerative disease, associated with mutations in Glial Fibrillary Acid Protein (GFAP) gene.
Design/Methods:
Sibling-1, a 67-year-old man presented with progressive gait imbalance, dyspnea on exertion, orthostatic intolerance, excessive lacrimation, and genitourinary dysfunction. Neurological exam was remarkable for large-fiber sensory deficits, 1+ ankle reflexes, positive Romberg, widened stance and tandem gait abnormalities. Chest X Ray (and chest fluoroscopy) demonstrated an elevated left hemidiaphragm with atelectasis, and paralysis, confirmed by a sniff testing. Sibling-2, a 61-year-old woman presented with gait imbalance, sleep apnea, bulbar symptoms including dysarthria, hypersalivation, and dysphonia. Neurological exam demonstrated dysarthria, extraocular movement abnormalities including square wave jerks, palatal myoclonus, upper limb incoordination, and broad-based gait with tandem abnormalities. Sibling-3, a 58-year-old man presented with gait imbalance, bulbar symptoms including dysphagia, and obstructive sleep apnea. Neurological examination demonstrated slow saccades, intention tremor of upper limb, and spastic ataxic gait.
Results:
Autonomic function testing demonstrated sympathetic adrenergic dysfunction with neurogenic orthostatic hypotension and parasympathetic abnormalities (heart rate variability to deep breathing and vagal maneuvers) in all three siblings. MRI brains demonstrated anterior and central medullary atrophy and hyperintensity, and upper cervical cord thinning in all three siblings. Comparable differences in loss of AP diameter of the medulla oblongata among the siblings, correlated with severity of symptom presentation.
Conclusions:
Clinical presentation of profound central autonomic dysfunction and cerebellar abnormalities in adults should raise suspicion for AOAD, in addition to differential diagnosis of non-heritable neurodegenerative disorders. Detailed radiological surveillance of lower brainstem and upper cervical spine is a valuable biomarker and correlates with symptom severity and progression.
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