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.
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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Diagnosis
Suspected Diagnosis
ATXPC is suspected in persons who exhibit more than one of the following 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:
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
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.