SAMD9L Ataxia-Pancytopenia Syndrome

Clinical characteristics: SAMD9L ataxia-pancytopenia (ATXPC) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure, myelodysplasia, and myeloid leukemia, sometimes associated with monosomy 7. The onset of hematologic abnormalities has been reported as early as age three months. The cytopenias in all cell lineages range from mild to very severe. Onset of neurologic impairment is variable. Nystagmus, dysmetria, increased deep tendon reflexes, and clonus are common. Gait impairment and other neurologic abnormalities are slowly progressive.

Diagnosis/testing: The diagnosis of SAMD9L-ATXPC syndrome is established in a proband by identification of a heterozygous germline gain-of-function pathogenic variant in SAMD9L on molecular genetic testing.

Management: Treatment of manifestations: Red cell or platelet transfusions as needed for cytopenias; evaluation and treatment for additional unrelated causes of anemia; standard treatment for neutropenia; bone marrow transplantation and/or chemotherapy for myelodysplasia and leukemia; consideration of riluzole to improve ataxia symptoms; supportive management for ataxia to prevent falls and injury; speech and language therapy with consideration of alternative communication methods, as needed for dysarthria; modify food consistency to reduce aspiration risk for those with dysphagia; nutrition assessment with consideration of nutritional and vitamin supplementation to meet dietary needs in those with poor weight gain or weight loss.

Surveillance: Annual complete blood count with more frequent monitoring for any identified cytopenia; prompt evaluation for clinical signs or symptoms of cytopenia; annual evaluation of gait, coordination, and progression of ataxia; assessment for alternative communication method, speech therapy, and signs and symptoms of aspiration risk as per symptom progression.

Agents/circumstances to avoid: Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic agents are contraindicated if thrombocytopenia is present and should be used with caution given the fluctuating nature of the cytopenias; avoid alcohol and medications that cause sedation, which can increase problems with gait and coordination.

Pregnancy management: Anemia, thrombocytopenia, or neutropenia may increase the risk of pregnancy complications.

Genetic counseling: SAMD9L-ATXPC syndrome is inherited in an autosomal dominant manner. Each child of an individual with SAMD9L-ATXPC syndrome has a 50% chance of inheriting the SAMD9L pathogenic variant; intrafamilial clinical variability has been observed. Once the SAMD9L pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for SAMD9L-ATXPC syndrome and preimplantation genetic testing are possible.