alkaline ceramidase 3 deficiency

Alkaline ceramidase 3 deficiency is a multisystem condition that primarily affects neurological development and leads to progressive leukodystrophy. It is caused by pathogenic variants in the ACER3 gene, which plays a role in sphingolipid metabolism. The condition is inherited in an autosomal recessive pattern and is very rare, affecting fewer than one in a million people. Onset is in early childhood, and affected individuals experience significant developmental challenges and multiple neurological and systemic features.

The clinical presentation of alkaline ceramidase 3 deficiency includes a distinct constellation of features that affect multiple systems. Affected children exhibit a sloping forehead, coarse facial features, relative macrocephaly, and low-set ears. Neurologically, there is severe intellectual disability, dystonia, and a striking leukodystrophy, along with features such as cerebral atrophy, hypoplasia of the corpus callosum, and optic disc pallor. , after a period of apparently typical early development, affected children experience a phase of developmental regression marked by loss of previously acquired skills. Additional features such as joint contractures, axial hypotonia, appendicular spasticity, and neurogenic bladder are consistently observed. Not all individuals experience every feature, and severity varies considerably.

Alkaline ceramidase 3 deficiency results from mutations in the ACER3 gene. The protein produced by this gene is involved in the metabolism of sphingolipids, which are critical components of cell membranes and important for normal neurological function. This condition is inherited in an autosomal recessive pattern, meaning that an affected individual has received one mutated copy of the gene from each parent. It is more common when parents share a common ancestor because both are more likely to carry the same rare variant, and carrier testing may be particularly relevant for families with shared ancestry.

Currently, management of alkaline ceramidase 3 deficiency focuses on supportive care and symptom management, as there are no FDA-approved treatments. Treatment is tailored to the individual and typically involves a multidisciplinary team to address the range of neurological, developmental, and systemic issues. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Patients should discuss treatment options and supportive strategies, including physical and occupational therapies, with their healthcare team, and genetic counseling is recommended to support family planning.

Alkaline ceramidase 3 deficiency is a lifelong neurodevelopmental condition characterized by an initial regression, followed by a period of relative stabilization and, in some individuals, later motor decline. Outcomes vary depending on symptom severity, age at diagnosis, and access to specialized care, and the clinical spectrum ranges from milder to more severe presentations. With current standards of care, many individuals benefit from multidisciplinary management and regular monitoring, and outcomes described in medical literature continue to evolve as standards of care improve. Families are encouraged to connect with specialists and genetic counselors to discuss supportive strategies and long-term planning.