Juvenile or adult CACH syndrome

Juvenile or adult-onset CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination), also known as vanishing white matter disease (VWM) or leukoencephalopathy with vanishing white matter, is a rare inherited neurological disorder characterized by progressive deterioration of white matter in the brain. This form represents the later-onset variant of VWM disease, with symptoms appearing in late childhood, adolescence, or adulthood rather than in early childhood. The condition is caused by mutations in genes encoding subunits of the eukaryotic translation initiation factor 2B (EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5), which plays a critical role in protein synthesis regulation, particularly in glial cells of the central nervous system. The disease primarily affects the central nervous system, with progressive loss of white matter (leukoencephalopathy) visible on brain MRI, where affected white matter gradually becomes rarefied and eventually disappears, being replaced by fluid. Key clinical features in the juvenile and adult forms include progressive cerebellar ataxia (difficulty with coordination and balance), spasticity, cognitive decline, and sometimes seizures. A hallmark of VWM disease is episodic deterioration triggered by physiological stresses such as febrile infections, minor head trauma, acute fright, or surgery. In females, premature ovarian failure (ovarioleukodystrophy) may be an early or even isolated manifestation. The juvenile and adult forms generally have a milder and more slowly progressive course compared to the infantile form, though episodes of rapid neurological decline can occur. There is currently no cure or disease-modifying treatment for juvenile or adult CACH syndrome. Management is primarily supportive and includes physical therapy, occupational therapy, management of spasticity, seizure control with anticonvulsants when needed, and avoidance of known triggers of neurological deterioration. Stress management protocols, including aggressive treatment of fevers and infections, are important preventive measures. Hormonal replacement therapy may be indicated for females with ovarian failure. Genetic counseling is recommended for affected families.

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