Late infantile CACH syndrome

Late infantile CACH syndrome (Childhood Ataxia with Central Nervous System Hypomyelination), also known as late infantile Vanishing White Matter disease (VWM), is a rare inherited leukoencephalopathy caused by mutations in genes encoding subunits of the eukaryotic translation initiation factor 2B (EIF2B1-EIF2B5). The late infantile form represents one of the more severe phenotypic variants of VWM disease, with onset typically occurring between ages 1 and 2 years. The disease primarily affects the central nervous system, specifically the white matter of the brain, which progressively deteriorates and is replaced by fluid-filled cavities — hence the name 'vanishing white matter.' Key clinical features of the late infantile form include progressive cerebellar ataxia (loss of coordination), spasticity, cognitive decline, and eventual loss of motor and intellectual abilities. A hallmark of VWM disease is that neurological deterioration can be triggered or dramatically worsened by episodes of physiological stress such as febrile infections, minor head trauma, or acute fright. Seizures may also occur. Brain MRI characteristically shows diffuse white matter abnormalities with progressive rarefaction and cystic degeneration. Ovarian failure (ovarioleukodystrophy) can be an associated feature in females, though this is more commonly noted in later-onset forms. There is currently no cure or disease-modifying treatment for late infantile CACH syndrome. Management is supportive and symptomatic, focusing on physical therapy, prevention and careful management of febrile episodes and infections, seizure control when needed, and nutritional support. Avoidance of physiological stressors that can precipitate neurological crises is a critical aspect of care. The prognosis for the late infantile form is generally poor, with progressive neurological decline leading to severe disability. Research into potential therapies, including gene therapy approaches, is ongoing.

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