A number sign (#) is used with this entry because of evidence that ataxia-pancytopenia syndrome (ATXPC) is caused by heterozygous mutation in the SAMD9L gene (611170) on chromosome 7q21.

Heterozygous mutation in the SAMD9L gene can also cause monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1; 252270), which shows some overlapping features.

Ataxia-pancytopenia syndrome (ATXPC) is an autosomal dominant disorder characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to bone marrow failure and myeloid leukemia. The germline genetic defect is associated with somatic loss of chromosome 7 (monosomy 7) resulting in the deletion of several genes on chromosome 7 that may predispose to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) (summary by Chen et al., 2016 and Tesi et al., 2017).

Li et al. (1978, 1981) described a family with ataxia and pancytopenia. The propositus, the youngest of a sibship of 5, had cerebellar ataxia, developed hypoplastic anemia at age 3 years, and died of acute myelomonocytic leukemia at age 7. Serial cytogenetic studies of his hypoplastic bone marrow over a 25-month period showed progressive expansion of a clone of cells with monosomy 7 (252270). Cerebellar ataxia was found in the proband's father and all 4 sibs. Two brothers, including 1 with monosomy 7, died with hypoplastic anemia at ages 5 and 9 years, and a third brother died with acute myelocytic leukemia at age 10 years. The only surviving sib at the time of the report of Li et al. (1981) was a 19-year-old sister who had unexplained anemia, decreased mitotic activity in the bone marrow, and a slowly progressive cerebellar ataxia. In addition to progressive cerebellar ataxia, the father had marked progressive cerebellar ataxia, brisk deep tendon reflexes, bilateral Babinski reflexes, and diminished vibratory sensation in the legs. Unsteady gait first brought the father to medical attention at age 28 years and he was not able to work thereafter. Computed tomographic scans of the father, the sister, and 1 brother showed cerebellar atrophy. Autopsy in 1 brother showed marked cerebellar atrophy and loss of 90% of the Purkinje cells; the spinal column was normal. By 1989, the sister had given up her career in nursing because of increasingly severe cerebellar ataxia and the father was largely confined at home (Li, 1989).

In a family reported by Daghistani et al. (1989), the proband, a 5-year-old boy, presented with left facial abscess and pancytopenia, following a 2-year history of mild incoordination. He had nystagmus and dysmetria. Monosomy 7 was found. He died at the age of about 6 years from pancytopenia. The sister of the proband, 12 years old at the time of report, had the onset of mild progressive unsteadiness at the age of 7 years. She had nystagmus and dysarthria. Nerve conduction studies showed reduced velocities in both sibs. The mother of the 2 children had had onset of incoordination before age 5. She showed severe gait ataxia and pronounced dysarthria with upper extremity dysmetria and horizontal and vertical nystagmus. Nerve conduction studies showed reduced velocities. The father was normal neurologically and hematologically. None of the 3 patients had oculocutaneous telangiectasia, scoliosis, or cardiac dysfunction.

Chen et al. (2016) reported a large multigenerational family (UW-AP) of German, Irish, and Native American descent in which at least 9 individuals had ataxia-pancytopenia syndrome. The phenotype was highly variable, with onset of symptoms ranging from 6 to 62 years of age, although manifestations could be detected earlier by examination. Neurologic features included gait imbalance, horizontal and vertical nystagmus, dysmetria, hyperreflexia, ankle clonus, and sometimes extensor plantar responses. Brain imaging, performed in 2 patients, showed cerebellar atrophy or degeneration. Hematologic abnormalities, which were variable and sometimes intermittent, included anemia, leukopenia, and thrombocytopenia. Four adult sibs were described in detail. The first patient presented with pancytopenia at age 3 months. Bone marrow aspirate at age 11 years showed hypoplasia with normal maturation and some immature forms. He developed slowly progressive balance issues at age 30, and by age 47, he had nystagmus, dysarthria, dysmetria, hyperreflexia, and normal gait but difficulty with tandem walking. His brother presented at age 1 year with thrombocytopenia that later evolved to pancytopenia. He developed a retroperitoneal bleed and died at age 16 years. He had no neurologic manifestations or ataxia, but postmortem examination showed cerebellar atrophy with severe loss of Purkinje cells and gliosis in the hippocampus. The third patient developed unsteady gait at age 25 that progressed to severe ataxia requiring a walker by age 38. Other features included severe dysarthria, nystagmus, and hyperreflexia. Laboratory studies showed mild leukopenia and mild to moderate thrombocytopenia. The fourth patient first noted balance problems at age 36, but physical examination at age 25 had shown nystagmus and ankle clonus. She developed intermittent mild neutropenia and thrombocytopenia after age 45. Chen et al. (2016) noted that the severities of the hematologic and neurologic abnormalities were not concordant in this family. None of the patients had dysplastic marrow changes and none developed myelodysplasia or leukemia. Patient cells showed normal DNA repair responses, no increased sensitivity to ionizing radiation, and normal telomere lengths.

Gonzalez-del Angel et al. (2000) described a Mexican girl who developed cerebellar ataxia at age 3 years and pancytopenia at age 13 years. Cerebral computed tomography scan and magnetic resonance imaging showed evidence of severe cerebellar atrophy. Telangiectases were not present, and immunoglobulins and alpha-fetoprotein levels were normal, making ataxia-telangiectasia (208900) unlikely. Cytogenetic studies showed no abnormalities except for an increased frequency of chromosomal aberrations in response to bleomycin. The phenotype was considered consistent with the ataxia-pancytopenia syndrome, although monosomy of chromosome 7 was not found in bone marrow. The sensitivity to bleomycin suggested this may be a chromosomal instability disorder.

Tesi et al. (2017) reported 2 unrelated families of Swedish and Finnish origin, respectively, with a syndromic disorder characterized by hematologic and neurologic dysfunction. The proband in the first family was a 4-year-old boy with a history of CMV infection, trilineage cytopenia, hypogammaglobulinemia, and MDS associated with monosomy 7. He underwent successful hematopoietic stem cell transplantation and thereafter developed neurologic symptoms, including nystagmus, unsteady gait, and lower limb stiffness and weakness. Brain imaging showed white matter abnormalities and progressive cerebellar degeneration. His grandfather developed MDS at age 56 years and did not have monosomy 7. He had mildly impaired balance. None of the other affected family members had MDS, but several had transient thrombocytopenia or pancytopenia, often associated with uniparental disomy of chromosome 7q or a revertant SAMD9L variant. Most, but not all, patients had mild neurologic symptoms, mainly nystagmus and impaired balance. In the second family, a mother and her 2 affected children had recurrent infections suggesting mild immunodeficiency. They also had variable neurologic features, such as nystagmus, balance problems, and attention deficit-hyperactivity disorder. The 2 children had thrombocytopenia and pancytopenia, one with a hypoplastic bone marrow and the other with dysplastic megakaryocytes and MDS. Although both of these patients had uniparental disomy of 7q, only 1 had monosomy 7; the latter patient underwent hematopoietic stem cell transplantation.

The transmission pattern of ATXPC in the families reported by Li et al. (1978) and Chen et al. (2016) was consistent with autosomal dominant inheritance.

The transmission pattern of ATXPC in the families reported by Tesi et al. (2017) was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity.

In affected members of 2 unrelated families with ATXPC, including the family originally reported by Li et al. (1978), Chen et al. (2016) identified 2 different heterozygous missense mutations in the SAMD9L gene (H880Q, 611170.0001 and C1196S, 611170.0002). The mutation in the first family was found by a combination of linkage analysis and exome sequencing. Functional studies of the variants were not performed.

In affected members of 2 unrelated families with ATXPC, Tesi et al. (2017) identified germline heterozygous gain-of-function mutations in the SAMD9L gene (R986C, 611170.0003 and I891T, 611170.0004). The mutations, which were found by whole-exome or Sanger sequencing, segregated with the disorder in the family, although there was variable expressivity. In vitro functional expression studies in cells transfected with the mutations showed that they augmented the growth-suppressing activity of SAMD9L and halted cell proliferation compared to wildtype, consistent with a gain-of-function effect. Some patients developed MDS associated with monosomy 7; loss of chromosome 7 in these patients eliminated the SAMD9L mutations, suggesting that the SAMD9L mutations were not themselves conducive to tumor cell propagation, but that cytogenetic events eradicating the chromosome may explain the predisposition to MDS. This would be an example of 'adaptation by aneuploidy.' In contrast, other family members had less severe or limited manifestations associated with uniparental disomy of 7q or revertant SAMD9L mosaicism that likely mitigated the pathogenic effects of the familial mutations by acting as loss-of-function alleles. In in vitro studies, Tesi et al. (2017) found that stimulation of CD34+ hematopoietic stem cells with IFNA (147660) or IFNG (147570) induced SAMD9L expression. These findings provided a mechanism by which an immune response may indirectly lead to cytopenia, thus providing a basis for the selection of somatic SAMD9L revertant mutants.