Adult-onset vanishing white matter disease

Vanishing white matter disease is a rare autosomal recessive leukodystrophy characterized by increasing areas of abnormal white matter that show signal intensities close to those of CSF on all pulse sequences on MRI. The onset is usually in early childhood but juvenile- and adult-onset cases have also been reported. Clinically the disease leads to progressive cerebellar ataxia, spasticity and cognitive decline. The disease is chronic-progressive with additional episodes of rapid deterioration following minor head trauma or febrile infections in most patients. Five genes, EIF2B1–5, have been identified recently for vanishing white matter diases, which encode the five subunits of translation initiation factor eIF2B.

We report on a 36 year old male who experienced a rapidly-progressive movement disorder and paresis of all extremities at the age of 35 years. He suffered from epilepsy with grand mal seizures since 14 years of age and was evaluated for right sided spastic hemiparesis at age 16 years but no cause could be established. Initially, there was no intellectual impairment with an IQ of 118 and he worked as a toolmaker till the onset of rapid deterioration after a cycle accident at age 35 years. Neurological evaluation at age 36 years revealed dementia (MMSE: 22/30), cerebellar oculomotor disturbances, spastic tetraparesis and choreoathetoid hyperkinesia pronounced on the right side as well as severe ataxia of trunc and extremitites resulting in a complex movement disorder causing severe disability. Hyperkinesia was improved by sulpiride (150mg/d) and seizures were well controlled with valproic acid (1200mg/d) and levetiracetame (1000mg/d) but the patient was no longer able to walk or stand or to move along in a wheelchair. MRI revealed massive leukodystrophy with multiple cystic lesions predominantly in the frontal lobe. The affected white matter adjacent to the anterior horn had a signal intensity identical to that of CSF.

Mutation screening of the five eIF2B genes revealed a homozygous missense mutation 338G>A in exon 3 of the EIF2B5 gene leading to the substitution of arginine for histidine at position 113 of the eIF2B epsilon (Arg113His). In accordance with few other reports this mutation is likely to cause a particularly mild course of vanishing white matter disease and should be considered in the differential diagnosis of adult-onset leukodystrophies.