congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome is a multisystem condition that predominantly affects neurological development. It is linked to pathogenic variants in the ASNS gene, which plays a critical role in asparagine synthesis. This autosomal recessive disorder typically presents in infancy with signs evident at birth and is extremely rare, affecting fewer than 1 in a million individuals. The clinical picture reflects the involvement of multiple organ systems, with the central nervous system being prominently affected.

The clinical presentation is marked by profound neurological features, including microcephaly, severe global developmental delay, and a range of seizure types such as clonic seizures. Brain imaging typically reveals global brain atrophy, dilated ventricles, and reduced cerebral white matter volume, while structural abnormalities of the brainstem and cerebellum are also consistently observed. Other characteristic findings include cerebral visual impairment, blindness, and spastic tetraplegia. In addition to these neurologic manifestations, affected children often present with failure to thrive, feeding difficulties, and sleep apnea, and they may experience irritability. Not all individuals experience every feature, and severity varies considerably.

This condition is caused by pathogenic variants in the ASNS gene, which is essential for normal protein synthesis. It follows an autosomal recessive inheritance pattern, meaning that an affected child inherits two altered copies of the gene, one from each parent. This condition is more common when parents share a common ancestor, as the likelihood that both are carriers of the rare variant is increased. Genetic counseling is recommended for families to understand recurrence risks and to explore carrier testing options.

Currently, management focuses on supportive care and symptom management, as there are no specific foundational therapies or FDA-approved treatments for this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team to address the neurological, gastrointestinal, and respiratory challenges observed. Regular surveillance and monitoring by specialists are essential to detect emerging complications early, and families are encouraged to discuss treatment options and supportive interventions with their healthcare team. Genetic counseling is also recommended to help families navigate care and future planning.

The outlook for individuals with congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome is variable, with outcomes influenced by the degree of neurological involvement and access to specialized care. With current standards of care, many individuals receive supportive interventions that help manage symptoms, although the condition remains lifelong. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists experienced in this condition and with genetic counselors for guidance on future planning.

Clinical trials are underway exploring new treatment approaches for this condition. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.