Samd9l-Related Ataxia-Pancytopenia Syndrome

Clinical characteristics.

SAMD9L-related 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 ranged 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-related ATXPC syndrome is established in a proband by identification of a heterozygous germline 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; bone marrow transplantation and/or chemotherapy for myelodysplasia and leukemia; supportive management for ataxia to prevent falls and injury.

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 speech.

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.

Genetic Counseling.

SAMD9L-related ATXPC syndrome is inherited in an autosomal dominant manner. To date, no individuals diagnosed with SAMD9L-related ataxia-pancytopenia have the disorder as the result of a de novo SAMD9L pathogenic variant. Each child of an individual with SAMD9L-related 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-related ATXPC syndrome and preimplantation genetic testing are possible.

Suggestive Findings

SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome can be considered in an individual with any of the following clinical features, radiographic features, or family history, and suspected if more than one of these characteristics are present:

• Cerebellar ataxia
• Variable hematopoietic cytopenias affecting one or more lineages (e.g., anemia, neutropenia, thrombocytopenia)
• Myeloid leukemia or myelodysplasia with partial or complete monosomy 7
• Cerebellar atrophy and white matter changes on brain MRI examination
• Family history of any of the above clinical or radiographic features

Establishing the Diagnosis

No formal clinical criteria for SAMD9L-related ATXPC syndrome have been established. The diagnosis of SAMD9L-related ATXPC syndrome is established in a proband by identification of a heterozygous germline pathogenic variant in SAMD9L on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Perform sequence analysis of SAMD9L.
  Note: SAMD9L-related ATXPC syndrome is postulated to occur through a gain-of-function mechanism. Large intragenic deletion or duplication has not been reported; testing for intragenic deletion or duplication is not indicated.
• A multigene panel that includes SAMD9L and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome is a rare autosomal dominant condition characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure, myelodysplasia, and myeloid leukemia, sometimes associated with monosomy 7. Manifestations usually have onset in childhood and hematologic impairment can be severe, mimicking aplastic anemia or idiopathic thrombocytopenia purpura. There is marked inter- and intrafamilial variability in age of onset, severity of neurologic and hematologic abnormalities, and rate of progression. Only four families with molecularly confirmed SAMD9L-related ATXPC syndrome in a total of 25 individuals have been described [Li et al 1978, Li et al 1981, Chen et al 2016, Tesi et al 2017]; a fifth published family with a consistent phenotype is unavailable for molecular confirmation [Daghistani et al 1989].

Hematologic manifestations. Hematologic abnormalities are variable and can be intermittent. The onset of hematologic abnormalities has been reported as early as age three months.

The cytopenias in all cell lineages ranged from mild to very severe. Anemia and/or mild macrocytosis (maximum recorded mean corpuscular volume [MCV]: 108 fl) were documented in many affected individuals. Immunodeficiency was documented in one family [Tesi et al 2017]. Non-leukemic marrows were hypoplastic in three individuals examined. Partial or complete monosomy 7 was found in marrow cells from four affected individuals, one of whom eventually developed leukemia [Li et al 1981]; two had myelodysplasia [Tesi et al 2017]. The effect of the disease on the hematopoietic system accounts for the increased mortality. In the four molecularly confirmed families, five affected individuals died in childhood from marrow failure and/or acute myeloid leukemia [Li et al 1981, Chen et al 2016]. Two children with myelodysplasia received matched unrelated marrow transplants and were alive 1.5 and seven years later [Tesi et al 2017].

In the family suspected to have ATXPC syndrome, one of three affected people had pancytopenia at age five years with mild macrocytosis (MCV 109 fl), decreased marrow cellularity, and monosomy 7 identified in marrow cells. This child died from acute myeloid leukemia that developed one year following diagnosis [Daghistani et al 1989].

Neurologic manifestations. Neurologic involvement was observed in all individuals with SAMD9L pathogenic variants who were carefully examined. Two individuals withSAMD9L pathogenic variants were not assessed neurologically [Tesi et al 2017] and one individual who was not noted to have neurologic problems during life had cerebellar atrophy detected on autopsy [Chen et al 2016]. Onset of neurologic impairment ranged from infancy to 62 years. Horizontal and vertical nystagmus and dysmetria were evident in most individuals. Deep tendon reflexes were usually increased, ankle clonus was easily elicited, and some affected individuals had extensor plantar responses [Li et al 1978, Chen et al 2016, Tesi et al 2017]. Strength and sensation to touch and proprioception were preserved, but one individual had decreased vibration sense in the lower extremities [Li et al 1978]. Gait impairment and other neurologic abnormalities were slowly progressive. Some individuals eventually require a wheelchair [Chen et al 2016].

The severities of hematologic and neurologic abnormalities are not concordant. An individual who died at age 16 years from a retroperitoneal bleed secondary to thrombocytopenia had no clinically reported neurologic manifestations, despite the presence of cerebellar atrophy. Several individuals had moderate to severe neurologic involvement with only mild or undetected hematologic involvement [Li et al 1981, Chen et al 2016].

Neuroimaging and neuropathology. Eight individuals with a range of neurologic manifestations have been evaluated by brain imaging or autopsy. Marked cerebellar atrophy and loss of Purkinje cells were detected in four individuals, age seven to 16 years, in two families whose brains were examined postmortem. Moderate loss of neurons in the inferior olives and central nuclei was noted in two of these individuals [Li et al 1981, Chen et al 2016]. CT imaging of two of these children and their father revealed moderate to marked cerebellar atrophy at a time when their ataxia was described as mild to moderate [Li et al 1981]. At age 54 years, the surviving sib in this family had moderately severe ataxia and required a walker to ambulate. Brain MRI at age 52 years showed severe diffuse cerebellar atrophy as well as diffuse bilateral white matter signals throughout the cerebrum [Chen et al 2016].

In the second family reported by Chen et al [2016], brain MRIs revealed marked cerebellar degeneration, pronounced in the midline, in a man age 32 years with severe ataxia, and moderate midline cerebellar atrophy in his sister age 38 years, who had only mild clinical manifestations. Cerebellar atrophy and white matter abnormalities were also noted on MRI of two individuals reported by Tesi et al [2017].

Genotype-Phenotype Correlations

As only four families with identified pathogenic variants in SAMD9L have been reported, it is not possible to determine if there are genotype-phenotype correlations. Two of six affected individuals with pathogenic variant p.Cys1196Ser [Li et al 1978, Li et al 1981] and none of 17 with any of the other three known pathogenic variants [Chen et al 2016] have developed acute leukemia to date, but this tally does not include the two individuals who received marrow transplantation for myelodysplasia [Tesi et al 2017]. Somatic mosaicism for loss of the SAMD9L pathogenic variant has been documented in hematopoietic tissues of some individuals in three of the families [Chen et al 2016, Tesi et al 2017]. It is speculated that the presence of a clone that has uniparental disomy for the normal allele may ameliorate the severity of the hematologic manifestations [Tesi et al 2017].

Penetrance

To date, all 24 carefully assessed affected individuals in the four families with pathogenic variants in SAMD9L exhibited clinical manifestations. One individual without hematologic cytopenias was not neurologically examined. Expressivity of both hematologic and neurologic manifestations is extremely variable and shows no difference for males and females.

Nomenclature

The disorder was initially called myelocerebellar syndrome by Li et al [1978].

Prevalence

True prevalence is unknown, but the disorder is extremely rare. To the authors' knowledge, only four families with molecularly confirmed ataxia-pancytopenia syndrome have been described in the scientific literature [Li et al 1978, Chen et al 2016, Tesi et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SAMD9L-related ataxia-pancytopenia (ATXPC) syndrome, the following evaluations are recommended if they have not already been completed:

• Medical history and physical examination including neurologic examination
• Brain MRI examination and referral to a neurologist
• Complete blood count with differential
• Referral to a hematologist/oncologist; bone marrow examination including chromosome 7-targeted FISH if hematologic abnormalities are more than minimal
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Hematologic manifestations

• Management of hematologic impairment is based on the severity of cytopenias and consists of red cell or platelet transfusions as needed.
• Evaluate and treat for unrelated causes of anemia such as iron and vitamin deficiencies.
• Marrow transplantation for myelodysplasia was successful in two individuals to date.

Note: There are no data to support use of erythropoietin or granulocyte-stimulating factor in SAMD9L-related ATXPC syndrome; these growth factors may increase the risk for myelodysplasia and myeloid leukemia.

Neurologic manifestations. Management of ataxia is supportive, as there is no known therapy to delay or halt the progression of the disease.

• Individuals should continue to be active and use canes and walkers to prevent falls.
• Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
• Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.

Surveillance

The following are appropriate:

• Complete blood count annually. If cytopenias are identified, these should be monitored more frequently.
• Patient/family education to seek prompt clinical evaluation if any signs or symptoms suggestive of hematopoietic cytopenia develop (e.g., fatigue, pallor, unexpected bleeding, recurrent infections).
• Annual evaluation of gait, coordination, and speech.

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 consuming alcohol and medications that cause sedation, which can increase problems with gait and coordination.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the SAMD9L pathogenic variant in the family in order to identify as early as possible those who would benefit from hematologic surveillance and prompt initiation of treatment for severe cytopenias and myelodysplasia.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no information of the effect of pregnancy on manifestations of SAMD9L-related ATXPC syndrome. Anemia, thrombocytopenia, or neutropenia may increase the risk of pregnancy complications.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.