Leukoencephalopathy with vanishing white matter (VWM), also called Childhood ataxia with central hypomyelination (CACH) syndrome. Early childhood onset form.
Incidence
CACH/VWM is inherited in an autosomal recessive manner. The prevalence is not known, but CACH/VWM is considered one of the most common leukodystrophies. In some countries, its incidence is close to that of metachromatic leukodystrophy.
Clinical Characteristics
Early-childhood-onset form. Most patients develop normally; however, some have mild motor or speech delay. New-onset ataxia is the most common initial symptom between ages one and five years [Hanefeld et al 1993]. Some patients develop coma or dysmetric tremor, spontaneously or acutely following mild head trauma or febrile illness [Hanefeld et al 1993, Schiffmann et al 1994, van der Knaap et al 1997]. Subsequently, generally progressive deterioration results in increasing difficulty walking, tremor, spasticity with hyperreflexia, dysarthria, and seizures. Once a patient becomes nonambulatory, the clinical course may remain stable for several years. Head circumference is usually normal. Swallowing difficulties and optic atrophy develop late in the disease. The peripheral nervous system is usually normal. Mental abilities are relatively preserved. The time course of disease progression is variable from patient to patient even within the same family, ranging from rapid progression with death occurring one to five years after onset to very slow progression with death occurring many years after onset. Neuropathologic examination. The findings in general are a "cavitating orthochromatic leukodystrophy with rarity of myelin breakdown and relative sparing of axons". Cerebral and cerebellar myelin is markedly diminished, whereas the spinal cord is relatively spared. Vacuolation and cavitation of the white matter are diffuse giving a spongiform appearance. Oligodendrocytes are increased in number. The hallmark is the presence of oligodendrocytes with "foamy" cytoplasm and markedly hypotrophic and sometimes atypical astrocytes.
Precipitants
Some patients develop coma or dysmetric tremor, acutely following mild head trauma or febrile illness.
Provocation Tests
no
Diagnostic Procedures
The diagnosis of childhood ataxia with central nervous system hypomyelination/leukoencephalopathy with vanishing white matter (CACH/VWM) can be made with confidence in patients with typical clinical findings, characteristic abnormalities on cranial MRI, and identifiable mutations in one of the five causative genes. Routine laboratory tests, including spinal fluid analysis, are normal.The diagnosis of CACH/VWM can be made with confidence in patients with typical clinical findings, characteristic abnormalities on cranial MRI, and identifiable mutations in one of five causative genes ( EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the five subunits of the eucaryotic translation initiation factor, eIF2B. Mutations have been found in more than 95% of patients, using sequence analysis or mutation scanning.