Alkaline ceramidase 3 deficiency

Alkaline ceramidase 3 deficiency (also referred to as ACER3 deficiency) is an ultra-rare autosomal recessive disorder caused by biallelic pathogenic variants in the ACER3 gene, which encodes alkaline ceramidase 3, an enzyme involved in the metabolism of ceramides and sphingolipids. This enzyme catalyzes the hydrolysis of ceramides and dihydroceramides, and its deficiency leads to the accumulation of specific ceramide species, placing this condition within the broader category of sphingolipidoses (ICD-10: E75.2). The disease primarily affects the central nervous system. Affected individuals present in early childhood with progressive leukodystrophy, characterized by psychomotor regression, progressive spasticity, and intellectual disability. Brain MRI typically reveals white matter abnormalities consistent with leukodystrophy. Additional neurological features may include seizures and peripheral neuropathy. The condition follows a progressive neurodegenerative course. Alkaline ceramidase 3 deficiency was first described in a small number of families, and the molecular basis was elucidated through whole-exome sequencing approaches. Currently, there is no specific or curative treatment available for this condition. Management is supportive and symptomatic, focusing on seizure control, physical therapy for spasticity, and multidisciplinary care to optimize quality of life. Research into sphingolipid metabolism disorders continues, but no targeted therapies have been developed for ACER3 deficiency at this time.

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