SAMD9L Deficiency – Definition
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.
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
Pattern of inheritance:
Autosomal dominant
Prevalence:
Unknown
Genotype-phenotype correlation:
Unknown
Penetrance:
Incomplete
The overall phenotypic pattern of hematological and neurological manifestations is very variable.
SAMD9L Deficiency – Diagnosis
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 detecting a heterozygous germline mutation in the SAMD9L gene through single-gene (sequence) analysis or using 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 essential leukemogenic step in these patients.
Clinical Diagnostics
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
- Severe aplastic anemia
- Idiopathic thrombocytopenic purpura
- X-chromosomal sideroblastic anemia and ataxia
- Ataxia telangiectasia
- Fanconi anemia
- Dyskeratosis congenita
- MIRAGE syndrome (SAMD9 deficiency)
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.
Special Features of Treatment
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.
Diagnosis of SAMD9L Deficiency- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of SAMD9L Deficiency- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
The following examinations should be carried out:
- Complete blood count once a year and more frequently if the blood count is unstable
- A bone marrow puncture once a year (together with a punch biopsy, aspirate, and cytogenetic analysis) should be considered
- Educate the patient and family about symptoms that indicate cytopenia (e.g., fatigue, paleness, bleeding, recurring infections)
- Annual clinical examination, especially about gait, coordination, and speech
- Additional Information
