The Neuropathology of MIRAGE Syndrome

Area of Science:

• Genetics and Neurology
• Rare Genetic Disorders
• Molecular Medicine

Background:

• MIRAGE syndrome is a rare multisystem disorder caused by mutations in the sterile alpha motif domain containing 9 (SAMD9) gene.
• Clinical features include myelodysplasia, infections, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy.
• Previous reports suggest potential neurological involvement like hydrocephalus and cerebellar hypoplasia, but neuropathologic details were lacking.

Purpose of the Study:

• To describe the detailed postmortem neuropathologic findings in two patients with MIRAGE syndrome and confirmed SAMD9 mutations.
• To elucidate the spectrum of neurological abnormalities associated with SAMD9 mutations in MIRAGE syndrome.
• To compare neuropathologic findings with known SAMD9L-related disorders.

Main Methods:

• Postmortem neuropathologic examination of the brain tissue from two patients diagnosed with MIRAGE syndrome.
• Confirmation of SAMD9 gene mutations in both patients.
• Detailed histological analysis and macroscopic assessment of brain structures.

Main Results:

• Consistent neuropathologic features included microcephaly, hydrocephalus, white matter abnormalities, and perivascular calcifications.
• One patient exhibited severe cerebellar hypoplasia, neuronal loss (Purkinje and granule cells), multifocal polymicrogyria, and significant white matter volume loss.
• The second patient showed less severe neuropathologic findings, indicating variability in presentation.

Conclusions:

• This study provides the first detailed neuropathologic description of MIRAGE syndrome, revealing significant CNS abnormalities.
• The findings demonstrate considerable variation in neuropathologic manifestations, even within the same genetic disorder.
• Observed neuropathologic similarities to ataxia-pancytopenia syndrome (caused by SAMD9L mutations) suggest potential shared pathomechanisms.