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.

Suggestive Findings

SAMD9L-ATXPC syndrome should be suspected in individuals with one or more of the following clinical, imaging, and family history findings.

Clinical features

• 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

Imaging. Cerebellar atrophy and/or white matter changes are seen on brain MRI examination.

Family history is consistent with autosomal dominant inheritance (e.g., males and females with any of the above clinical or radiographic features in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SAMD9L-ATXPC syndrome is established in a proband by identification of a heterozygous germline pathogenic variant in SAMD9L on molecular genetic testing (see Table 1).

Note: Identification of a heterozygous SAMD9 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SAMD9L-ATXPC syndrome is broad, individuals with both cerebellar and hematologic findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with cerebellar ataxia and/or myelodysplasia are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, 85 individuals from 36 families have been identified with a pathogenic variant in SAMD9L [Chen et al 2016; Gorcenco et al 2017; Schwartz et al 2017; Tesi et al 2017; Bluteau et al 2018; Nagata et al 2018; Pastor et al 2018; Wong et al 2018; Ahmed et al 2019; Bowden et al 2019; Cheah et al 2019; Thunström & Axelsson 2019; Author, unpublished data]. In addition, approximately 15% of children with myelodysplastic syndrome are found to have a germline pathogenic variant in SAMD9L. The following description of the phenotypic features associated with this condition is based on these reports.

The manifestations of SAMD9L ataxia-pancytopenia (ATXPC) syndrome 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.

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].

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.

• Mild thrombocytopenia or anemia and/or mild macrocytosis (maximum recorded mean corpuscular volume: 108 fL) were documented in many affected individuals.
• Immunodeficiency was documented in two families [Tesi et al 2017, Bowden et al 2019].
• Non-leukemic marrows were hypoplastic in multiple individuals examined.
• Partial or complete monosomy 7 is frequent, with some having myelodysplasia; a few eventually developed leukemia [Li et al 1981, Bluteau et al 2018, Wong et al 2018].
• The effect of the disease on the hematopoietic system accounts for the increased mortality. Of eight published cases of hematopoietic stem cell transplant for myelodysplasia, six survived the procedure and have been followed for as long as 14 years post transplant [Tesi et al 2017, Ahmed et al 2019]; outcomes in additional unpublished cases are similar.

Neurologic manifestations. Neurologic involvement was observed in the majority of individuals with SAMD9L pathogenic variants who were carefully examined; one individual who was not noted to have neurologic problems during life had cerebellar atrophy detected on autopsy [Chen et al 2016], and another had white matter hyperintensities on MRI [Author, personal observation].

• Onset of neurologic impairment ranged from infancy to age 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 [Chen et al 2016, Gorcenco et al 2017].
• Strength and sensation were infrequently impaired [Wong et al 2018; Author, unpublished observations].
• Gait impairment and other neurologic abnormalities were slowly progressive. Some individuals eventually required a wheelchair [Chen et al 2016].

Ophthalmologic manifestations. In addition to nystagmus, some individuals reported difficulties with reading and visual focus.

Multifocal electroretinography has identified mostly intact central function with paracentral retinal dysfunction in at least two affected individuals [Gorcenco et al 2017].

Neuroimaging and neuropathology. Marked cerebellar atrophy and loss of Purkinje cells were detected post mortem in four individuals, age seven to 16 years, in two families. 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 was found in his sister, age 38 years, who had only mild clinical manifestations. Cerebellar atrophy and/or white matter abnormalities were also noted on MRI on multiple individuals, in some cases before obvious neurologic impairments were observed [Tesi et al 2017; Bluteau et al 2018; Bowden et al 2019; Cheah et al 2019; Author, unpublished reports]. A variety of other neuroimaging abnormalities have been reported, including dural ectasia [Wong et al 2018] and arachnoid and other cysts [Bluteau et al 2018, Wong et al 2018], but most individuals who presented with primarily hematologic disease were not imaged. Therefore, the frequency of these features overall is not known.

Genotype-Phenotype Correlations

With respect to validated pathogenic variants in SAMD9L, no genotype-phenotype correlations have been observed.

Penetrance

Given the variable expressivity of both hematologic and neurologic manifestations, the sometimes episodic asymptomatic cytopenias, the paucity of detailed neurologic/neuroimaging evaluations, and the effect of additional somatic genetic events on the hematologic manifestations (see Genotype-Phenotype Correlations), it is difficult to estimate the penetrance. However, the majority of persons with a pathogenic variant in SAMD9L will manifest some feature of the syndrome. There is no difference in range of manifestations for males and females.

The phenomena of hematopoietic clones with additional genetic alterations repopulating the bone marrow appear to explain striking reports of non-penetrance or spontaneous and long-term disease remission in some affected individuals and some unaffected carrier parents of affected children [Tesi et al 2017, Wong et al 2018].

Nomenclature

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

Prevalence

True prevalence is unknown, but the disorder is rare. With increasing testing of children with myelodysplasia and individuals with both mild hematologic cytopenias and ataxia, additional cases continue to be diagnosed. Approximately 12% of childhood myelodysplasia is attributable to germline pathogenic variants in SAMD9L [Bluteau et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and guide clinical care in an individual diagnosed with SAMD9L ataxia-pancytopenia (ATXPC) syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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 the proband's parents and 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 Molecular Pathogenesis, SAMD9L-specific laboratory technical considerations.)

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

Pregnancy Management

There is no information on the effect of pregnancy on manifestations of SAMD9L-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.

Mode of Inheritance

SAMD9L ataxia-pancytopenia (ATXPC) syndrome is an autosomal dominant disorder often caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with SAMD9L-ATXPC syndrome have the disorder as the result of a de novo SAMD9L pathogenic variant.
• Some individuals diagnosed with SAMD9L-ATXPC syndrome have the disorder as the result of a pathogenic variant inherited from a parent who may or may not have apparent features of the syndrome. Marked intrafamilial variation (i.e., in age of onset, neurologic manifestations, and hematologic abnormalities) has been observed in all multigenerational families reported to date. (Note: See Management, Evaluation of Relatives at Risk for information on evaluating risk in apparently asymptomatic parents.)
• Molecular genetic testing is recommended for the parents of the proband. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline mosaicism.
  • The proband inherited a SAMD9L-ATXPC-associated gain-of-function pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with a pathogenic SAMD9L variant. This scenario may cause a false negative molecular result when testing leukocyte DNA (see Molecular Pathogenesis, SAMD9L-specific laboratory technical considerations).
• The family history of an individual diagnosed with SAMD9L-ATXPC syndrome may appear to be negative for a variety of reasons: (1) failure to recognize the disorder in family members with subtle neurologic manifestations and/or episodic hematologic manifestations; (2) reduced penetrance (possibly resulting from a "protective" second genetic event); or (3) early death of the parent before the onset of symptoms or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing (including using the DNA derived from non-hematopoietic tissue) has confirmed that neither of the parents has the SAMD9L pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is heterozygous for the SAMD9L pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Marked intrafamilial clinical variability is observed; however, the majority of persons with a pathogenic variant in SAMD9L will manifest some feature of the syndrome (see Clinical Description).
• If the SAMD9L pathogenic variant found in the proband is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be slightly greater than that of the general population for one of two possible reasons:
  • Parental germline mosaicism for the SAMD9L pathogenic variant; or
  • A false negative result in a parent due to preferential loss of the chromosome with the SAMD9L pathogenic variant (see Molecular Pathogenesis, SAMD9L-specific laboratory technical considerations).
• If the parents have not been tested for the SAMD9L pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for SAMD9L-ATXPC syndrome for one of two possible reasons:
  • A parent has germline mosaicism; or
  • A parent is heterozygous but does not have apparent manifestations of SAMD9L-ATXPC syndrome because of reduced penetrance or phenotypic modification resulting from additional genetic events that confer a protective effect (see Penetrance).

Offspring of a proband. Each child of an individual with SAMD9L-ATXPC syndrome has a 50% chance of inheriting the SAMD9L pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SAMD9L pathogenic variant, his or her family members may be at risk of having a SAMD9L pathogenic variant and associated clinical manifestations including myelodysplasia (see Clinical Description).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the SAMD9L pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SAMD9L-ATXPC syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The role of SAMD9L in human bone marrow failure and malignancies is not known with certainty nor is the underlying cause of the varied neurologic manifestations. Many lines of evidence in primary tumors, cell cultures, and murine models show that SAMD9L has a role in cell proliferation, most likely as a tumor suppressor [Li et al 2007, Huang et al 2012, Wang et al 2014].

There are two prevailing hypotheses regarding the mechanism by which mutated SAMD9L impairs cell growth. One theory is that SAMD9L is involved in endosomal degradation of cytokine receptors [Nagamachi et al 2013]. Another theory is based on the observation that SAMD9L and its closely related contiguous gene SAMD9 both encode interferon-inducible host antiviral restriction factors targeted by virus-encoded virulence factors [Tanaka et al 2010, Li et al 2013, Liu & McFadden 2015, OhAinle et al 2018]. The suggestion is that these genes participate in host defense against viral infections by halting protein synthesis [Liu & McFadden 2015, Sivan et al 2018]. None of the pathogenic variants in SAMD9L reported to date are in the sterile alpha motif domain, arguing against its protein-protein interaction function being the driving mechanism in the pathogenesis of SAMD9L ataxia-pancytopenia (ATXPC) syndrome.

Studies in EBV-transformed leukocyte cell lines [Chen et al 2016] and transiently transfected HEK293 cells [Tesi et al 2017] provided evidence that cells diploid for wild type SAMD9L have a selective culture advantage over those heterozygous for mutated SAMD9L. It has been found that cells can spontaneously eliminate or abrogate mutated alleles in vivo by three different mechanisms:

• The loss of all or part of the chromosome 7 that bears the pathogenic allele. Unfortunately, monosomy for chromosome 7q also causes haploinsufficiency for EZH2, MLL3, and other genes located in this region that are evidently required for control of normal hematopoiesis, and markedly increases the risk for myelodysplasia [Inaba et al 2018]. It is speculated that transformation to acute myeloid leukemia requires additional mutations.
• SAMD9L can acquire cis nonsense, frameshift, or other somatic inactivating (suppressor) mutations that decrease the effect of the pathogenic variant [Tesi et al 2017, Bluteau et al 2018, Pastor et al 2018, Wong et al 2018].
• All or part of the chromosome 7 bearing the gain-of-function pathogenic variant can be replaced by the normal copy of chromosome 7 via copy-neutral loss of heterozygosity (cnLOH; uniparental disomy) [Chen et al 2016, Tesi et al 2017], resulting in cells that maintain two normal copies of chromosome 7.

The latter two phenomena, of somatic revertant clones repopulating the bone marrow, appear to explain striking reports of spontaneous long-term disease remission and of non-penetrance in some affected individuals and some unaffected carrier parents of affected children, respectively [Tesi et al 2017, Wong et al 2018]. To date such revertant effects have not been documented to affect the neurologic manifestations.

Mechanism of disease causation. It is postulated that SAMD9L-ATXPC syndrome is due to a toxic gain of function with suppression of precursor cell divisions.

SAMD9L-specific laboratory technical considerations. If a pathogenic SAMD9L variant is not detected but suspicion for SAMD9L-ATXPC syndrome remains high, consideration should be given to additional testing. Somatic genetic changes that eliminate the gain-of-function SAMD9L variant confer a selective culture advantage to hematopoietic cells (see Molecular Pathogenesis). This may result in a decreased fraction of cells with the pathogenic variant causing a false negative molecular result when testing leukocyte DNA. Therefore, evaluation of genomic abnormalities with SNP array and/or evaluation of low-abundance variants with deep sequencing (>1000x read depth) should be considered in individuals clinically suspected of having SAMD9L-ATXPC syndrome who have a negative genetic test result. If feasible, using the DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) should be considered.

Author Notes

The focus of research in the Raskind laboratory is to find and study genes responsible for inherited neurologic disorders. In a long-standing collaboration with Dr Thomas Bird, we identified ABCB7 for X-linked sideroblastic anemia with ataxia, PRKCG for SCA14, ATP6AP2 for X-linked parkinsonism with spasticity, and ADCY5 for ADCY5-related dyskinesia, in addition to SAMD9L for SAMD9L-ATXPC syndrome.
Website: https://www.gs.washington.edu/faculty/raskind.htm

Author History

Thomas D Bird, MD (2017-present)
Dong-Hui Chen, MD, PhD (2017-present)
Prasit Phowthongkum, MD; University of Washington (2017-2021)
Wendy H Raskind, MD, PhD (2017-present)

Revision History

• 4 February 2021 (ma) Comprehensive update posted live
• 1 June 2017 (sw) Review posted live
• 5 December 2016 (whr) Original submission

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