Leukoencephalopathy with vanishing white matter (VWM), also known as the CACH syndrome, is a rare autosomal recessive disease, characterized by an onset between 2 and 5 years of age, ataxia, spasticity, and variable optic atrophy. Although the prevalence of leukoencephalopathy with vanishing white matter is unknown, it is the most common inherited childhood leukoencephalopathy. There are five phenotypic forms of VWM, including a congenital form, a subacute infantile form, an early childhood onset form, a late childhood/juvenile onset form, and an adult onset form. The congenital form is the most severe one and it is characterized by encephalopathy, while patients with the adult-onset form have a milder clinical course characterized by behavioral changes, seizures, and dementia. Progression of the disease is typically slow with episodes of neurological deterioration triggered by stressful events such as infection, mild head trauma or other injury, fever, or extreme fright. Diagnosis of VWM is based on the clinical symptoms, MRI, and detection of eIF2B mutations. There is no cure or form of treatment for the VWM disease.
Mutations in the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) encoding the 5 subunits of the eukaryotic translation initiation factor 2B (eIF2B) protein are the cause of leukoencephalopathy with vanishing white matter. About 60% to 70% of all cases of VWM are caused by mutations in the EIF2B5 gene. The Arg113His is the most common mutation and is usually found in patients with the adult-onset form. The eIF2B protein is involved in regulating the rate of protein synthesis in the cell.
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Alsalem et al. (2012) described a three and a half year-old Saudi girl with leukodystrophy with vanishing white matter disease. Her birth weight was low (2.15 kg), and she had poor feeding. She presented at the age of 10 months with hypotonia and failure to thrive. She had recurrent episodes of hypoglycemia, and her ACTH and cortisol were low. Brain MRI revealed diffused white matter changes. She had some dysmorphic features including: saggy cheeks, deep set eyes, and microganthia. Performing homozygosity mapping and direct sequencing of the EIF2B2 gene, a homozygous novel missense mutation (c.803G>A) was identified in the affected girl. This mutation resulted in a substitution of a highly conserved amino acid residue (C268Y) that affects the protein secondary structure conformation.
Alamri et al. (2016) reported the first case of Diabetic Ketoacidosis (DKA) associated with Vanishing White Matter (VWM) disease. The proband was born at full term with a birth weight of 2.2 kg. At 8 months of age, he was admitted to the hospital due to vomiting and irritability. His blood glucose level was 25 mmol/L and HbA1c was 11.4%. He was also found to suffer from ketosis and metabolic acidosis. He had a history of hypotonia and had delayed milestones. He was diagnosed with DKA and treated with insulin injections of 0.30 IU/kg/day. He was admitted again at 1 year of age due to intractable seizures and generalized tonic-clonic convulsions. A brain CT and MRI found the patient to be suffering from diffuse white matter disease. He also had bilateral optic nerve atrophy. He died at two years of age due to severe hypotonia, gastroesophageal reflux and recurrent chest infections. Parents were first cousins and they had an unaffected daughter. They also had two other sons who died at 1 year of age with white matter disease, spastic quadriplegia and insulin dependent diabetes mellitus. Whole exome sequencing found a homozygous variant in the EIF2B1 gene (c.146T>G, p.Leu49Arg). The parents and unaffected sister were heterozygous for the mutation.
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