SAMD9L deficiency, also called ataxia pancytopenia syndrome (ATXPC, OMIM #159550) is a genetic disease caused by mutations in the SAMD9L gene. It is characterized by cerebellar ataxia, varying degrees of hematological cytopenia, and a predisposition to bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia.

Key Data

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Synonym Ataxia pancytopenia syndrome
Gene SAMD9L (sterile alpha motif domain containing 9-like gene)
Gene product SAMD9L
Function Plays a role in cell proliferation, mostly as a tumor suppressor
Heredity Autosomal dominant
Prevalence Unknown
Genotype-phenotype correlation Unknown
Penetrance Incomplete
The overall phenotypic pattern of hematological and neurological manifestations is very variable.
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Suspected Diagnosis

ATXPC is suspected in persons who exhibit more than one of the following findings:

  • Cerebellar ataxia

  • Variable hematological cytopenia in at least one cell line (e.g. anemia, neutropenia, thrombocytopenia)

  • Myeloid leukemia or myelodysplastic syndrome with partial or complete, in part transient monosomy 7

  • Cerebellar atrophy and changes in the white substance in the MRI

  • A positive family history for one of the above findings

Genetic Diagnostics

The diagnosis of “SAMD9L deficiency” is confirmed by detection of a heterozygous germline mutation in the SAMD9L gene through single-gene (sequence) analysis or the use of panel studies consisting of multiple genes.

The SAMD9L mutation is “toxic” to hematopoietic cells of mutation carriers. The frequently observed loss of genetic material of chromosome 7 (e.g. monosomy 7) in hematopoietic cells in those affected results in a loss of the mutated allele (adaptation through the aneuploidy mechanism). For this reason, it may be helpful to analyze non-hematopoietic tissue for diagnostic purposes. Commonly observed monosomy 7 appears to be an important leukemogenic step in these patients.

Klinische Diagnostik

To determine the extent of the disease, the following clinical diagnostics should be carried out after the genetic diagnosis has been established:

  • Evaluation of the medical history

  • Clinical examination, including a neurological examination

  • Cranial MRI

  • Complete blood count

  • Bone marrow puncture

Differential Diagnoses

Clinical Presentation

Clinical manifestations usually occur for the first time during childhood, although the age of manifestation and the severity of the neurological or hematological diseases varies greatly within a particular family and between families. Hematological and neurological diseases are not concordant in their severity.

Hematological Manifestations

The occurrence and age of manifestation varies greatly with hematological manifestations. The earliest occurrence described was at the age of 3 months. Cytopenias of all cell lines may range from mild to very severe. Anemia occurs in many cases, while immunodeficiency is only described in one family. In addition, cases of myelodysplastic syndrome or acute myeloid leukemia (AML) are described that are frequently associated with partial or complete monosomy 7.

Neurological Manifestations

A neurological manifestation has so far been diagnosed in all patients with an SAMD9L mutation. The age of manifestation varies greatly, with ages ranging from infancy to 62 years. Ataxia usually presents itself clinically as horizontal and vertical nystagmus, dysmetria, tendon reflexes, and easily triggered clonus of the foot. A positive Babinski reflex was able to be observed in a few patients. Impaired gait and other neurological abnormalities generally exhibit a slow progression. X-rays show cerebellar atrophy and changes in the white substance.

Therapeutic Considerations

Patients with SAMD9L deficiency should be treated by an interdisciplinary team, and it is helpful to discuss this with the EWOG MDS principal investigator.

Hematological Manifestations

  • With thrombocytopenia, NSAID, anticoagulants, and thrombolytically active substances should be avoided.

  • Administer erythrocyte or thrombocyte concentrates depending on the severity of the cytopenia.

  • Treatment of other causes of anemia, such as with iron or vitamin substitution

  • Treatment of myeloid neoplasia in patients with an SAMD9L mutation should be discussed thoroughly with the corresponding study center.

  • A bone marrow transplant may be an option, especially for patients with myeloid neoplasia.

Neurological Manifestations

The treatment of ataxia is purely supportive, since no therapy is yet available that can slow down or stop the progression of the disease.

  • Alcohol and sedating medications should be avoided, since they impair gait and coordination even more.

  • Patients should remain mobile as long as possible. Walking aids can help to prevent falls.

  • Keep weight under control, since obesity will limit mobility even more.

Surveillance Recommendations

Surveillance Recommendations

The following examinations should be conducted:

  • Complete blood count once a year, and more frequently if the blood count is unstable

  • A bone marrow puncture once a year should be considered (together with a punch biopsy, aspirate and cytogenetic analysis).

  • Educate the patient/family concerning symptoms that indicate cytopenia (e.g. fatigue, paleness, bleeding, recurring infections).

  • Annual clinical examination, especially with regard to gait, coordination, and speech

Additional Information

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