Leukoencephalopathy with vanishing white matter (VWM), also called Childhood ataxia with central hypomyelination (CACH) syndrome. Infantile 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
Infantile form. A rapidly fatal severe form of CACH/VWM is characterized by onset in the first year of life and death a few months later. Two sisters described by Francalanci et al (2001) developed irritability, stupor, and rapid loss of motor abilities following an intercurrent infection at 10-11 months of age and died at 21 months of age. Another phenotype was described as "Cree leukoencephalopathy" because of its occurrence in the native North American Cree and Chippewayan indigenous population [Fogli, Wong et al 2002]. Infants typically have hypotonia followed by sudden onset of seizures (three to six months), spasticity, rapid breathing, vomiting (often with fever), developmental regression, blindness, lethargy, and cessation of head growth, with death by age two years. The infantile forms have never been observed within the same family. 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
no
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.