Late onset vanishing white matter disease

Abstract

Sirs: Vanishing white matter disease (VWM; MIM# 603896) or childhood ataxia with diffuse central nervous system hypomyelination (CACH) is a progressive leukodystrophy beginning usually in early childhood [7]. Common clinical findings include cerebellar ataxia, spasticity, epileptic seizures, severe cognitive decline and a progressive course with rapid deterioration following stress conditions such as minor head trauma, febrile infections or fright [13]. Neuropathological abnormalities indicate a selective disruption of oligodendrocytes and astrocytes with sparing of neurons [1, 14]. VWM is an autosomal recessive disease caused by mutations in each of the five genes (EIF2B1 – EIF2B5) encoding the eukaryotic translation initiation factor 2B (eIF2B) [5]. So far 77 different mutations have been identified, two-thirds affecting the epsilon subunit (eIF2B5) [2]. EIF2B mutations are speculated to lead to increased susceptibility to various physiological stress conditions [4, 6]. The identification of the genetic defect led to the recognition of a wider phenotypical spectrum of VWM. Here we report the case of a 36 year old man who was admitted because of rapid progressive cognitive decline and a complex movement disorder. The patient had a history of infrequent generalized tonic-clonic seizures since the age of 14 years. Two years later mild right sided hemiparesis of unknown cause was recognised by a neurologist but no imaging was performed. However, the patient recognised no handicap and development was otherwise normal. After finishing junior high school he worked as a tool maker until the age of 35 years. Then, rapid deterioration occurred shortly after a bicycle accident. Eighteen months later the patient became bedridden. Clinical examination revealed encephalopathy with frontal lobe symptoms including slowness, apathy and positive grasp reflex. Mini Mental Status Examination revealed dementia with 22 of 30 points. Motor signs included severe ataxia, spasticity more pronounced in lower limbs and dystonia as well as choreoathetotic movements of arms and hands. He was no longer able to stand or walk unassisted and needed help for almost all activities of daily living. He died in a vegetative state 24 months after onset of deterioration. Magnetic resonance imaging (MRI) of the brain at the age of 36 years showed severe symmetric leukencephalopathy suggestive of VWM: Cystic breakdown of cerebral white matter and replacement by CSF was present predominantly in the deep frontal white matter but also involving the subcortical U-fibres. There was no gadolinium enhancement of the lesions (Figure 1A and B). MR spectroscopy revealed an almost complete loss of all main white matter metabolites (Figure 1C). Screening of the genes encoding eIF2B demonstrated the homozygous missense mutation p.His113Arg in the e-subunit (eIF2B5). As in a few other reports this mutation is associated with milder forms of VWM [11, 12]. In contrast, different mutations like the Cree mutation (Arg195His in eIF2B5) are associated with most severe courses of the disease [2]. Our observation provides further evidence that VWM also may manifest as adult-onset leukodystrophy and should be considered in complex movement disorders with cognitive decline even if obvious disease starts as late as 35 years of age. In addition to our MR spectroscopy findings two papers report on lactate and glucose in VWM spectra [3, 8]. However, this seems to be not specific, but rather due to partial volume effects and these findings most likely represent CSF rather than pathological brain tissue contribution. Since similar MR spectra as in our case are found in childhood onset cases of VWM [9, 10] it is likely that extensive loss of white matter metabolites represents a hallmark in neuroimaging of the disease independent of onset age.