Eukaryotic Initiation Factor 2B4 Point Mutation Associated with Adult-onset Cerebellar Atrophy and Ataxia
David Fletcher1, Lea Colantonio1, Yongjia Deng1, Jessica Frey2
1School of Medicine, 2Department of Neurology, West Virginia University
Objective:
To describe a novel phenotype in eukaryotic initiation factor 2B (eIF2B)-related diseases.
Background:
eIF2B-related diseases are known to cause childhood ataxia with central nervous system hypomyelination and leukoencephalopathy with vanishing white matter (VWM). This case describes adult-onset cerebellar ataxia without VWM on imaging.
Design/Methods:
A 73-year-old male with a past medical history of Type II Diabetes Mellitus, hypertension, and gout presented with balance issues. Symptom onset was age 63 and progressed to where the patient required a rollator to walk. Examination was notable for a gravelly voice with scanning speech, impaired saccadic initiation requiring eye blink to initiate eye movements, ataxia with finger-to-nose, a wide-based gait with slow pace and short-stride length, inability to perform tandem gait, diminished arm swing, and stooped posture. Family history revealed that the patient’s mother, maternal uncle, and cousins all had significant balance problems later in life (after age 50) but had never been genetically tested.
Results:
Magnetic resonance imaging revealed severe cerebellar atrophy without white matter hyperintensities. Electromyography was normal without evidence of neuropathy. Genetic testing revealed a heterozygous point mutation in eIF2B4 [2p.23 (R208Q); exon 7]. A similar mutation has been described before as VWM4. eIF2B4 is a guanine nucleotide-exchange factor (GEF) that initiates protein translation. The degree to which GEF activity is impacted varies which may explain the spectrum of phenotypes.
Conclusions:
Childhood-onset eIF2B-related diseases are characterized by episodic deterioration triggered by stressors while adult-onset diseases are associated with dementia, psychiatric changes, seizures, and spasticity. A report has found adult-onset eIF2B-related diseases to manifest as late as age 62. In addition, ovarian failure is a common in females with adult-onset eIF2B-related diseases. Without this finding, these diseases may be underrecognized in males. This case demonstrates that in adult-onset ataxia without the characteristic VWM findings, genetic testing for eIF2B-related disease should still be considered.
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