Congenital or early infantile CACH syndrome

Congenital or early infantile CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) is the most severe form of vanishing white matter disease (VWM), also known as leukoencephalopathy with vanishing white matter. This form presents at birth or within the first year of life and follows a rapidly progressive course. It is caused by biallelic pathogenic variants in one of the five genes encoding subunits of the eukaryotic translation initiation factor 2B (EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5). These genes are essential for protein synthesis in all cells, but the brain's white matter is particularly vulnerable, leading to progressive destruction and cystic degeneration of cerebral white matter. The congenital and early infantile forms represent the most severe end of the VWM disease spectrum. Affected infants may present with severe neurological decline from birth, including progressive spasticity, cerebellar ataxia, seizures, feeding difficulties, and failure to thrive. Congenital cases may show additional features such as cataracts, hepatosplenomegaly, renal abnormalities, and ovarian dysgenesis (in females). Brain MRI characteristically shows diffuse white matter abnormalities with areas of cystic degeneration and rarefaction, giving the appearance of 'vanishing' white matter. Neurological deterioration is often rapid and can be triggered or worsened by febrile infections, minor head trauma, or other physiological stressors. There is currently no cure or disease-modifying treatment for congenital or early infantile CACH syndrome. Management is supportive and symptomatic, focusing on seizure control, nutritional support, physical therapy, and prevention of known triggers of neurological deterioration such as fever and infections. The prognosis for this severe form is poor, with most affected children experiencing rapid neurological decline and significantly shortened life expectancy, often dying within the first few years of life. Genetic counseling is recommended for affected families.

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