What is SAMD9L deficiency?

SAMD9L deficiency, also called ataxia pancytopenia syndrome, is a genetic disease caused by mutations – or genetic changes – in the SAMD9L gene. Characteristic of this are cerebellar ataxia (a movement coordination disorder caused by damage to the cerebellum) and various forms of cytopenia (a reduction of cells in the blood – either red or white blood cells or blood platelets). In addition, those affected also have an increased risk of bone marrow failure, myelodysplastic syndrome (disease of the bone marrow), and acute myeloid leukemia (AML).

How is SAMD9L deficiency diagnosed?

Suspected Diagnosis

SAMD9L deficiency is suspected in persons who exhibit more than one of the following findings:

  • Cerebellar ataxia (a movement disorder due to dysfunction in the cerebellum)

  • Cytopenia of at least one cell line (e.g. anemia = a lack of red blood cells, neutropenia = a lack of white blood cells, thrombocytopenia = a lack of blood platelets)

  • Myeloid leukemia or myelodysplastic syndrome with monosomy 7 (a genetic change whereby chromosome 7 is present only as a single copy instead of the normal two copies)

  • Reduced cerebellar mass and changes in the white matter of the brain (visible in the MRI)

  • Occurrence of one of the above findings in the family

Genetic Diagnostics

The diagnosis of “SAMD9L deficiency” is conferred by detection of a mutation, i.e. a genetic change in the SAMD9L gene.

Clinical Diagnostics

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

  • Evaluation of the medical history

  • Clinical examination, including a neurological examination

  • MRI of the head

  • Complete blood count

  • Bone marrow puncture

What is the risk of cancer?

The known severe new signs of SAMD9L deficiency are myelodysplastic syndrome (MDS) and acute myeloid leukemia. It is still unknown how high the risk of developing these manifestations is. Moreover, it is also possible for cytopenia to develop as part of SAMD9L deficiency, with anemia – a lack of red blood cells – being the most common form. The severity of the cytopenia can range from mild to very severe. The earliest onset described for any disease of the blood-formation system is 3 months of age, although there is a high degree of variability with regard to the manifestation age as well.

Other forms of manifestation are neurological diseases. An anomaly of the nervous system has so far been diagnosed in all patients with a SAMD9L mutation. For example, cerebellar ataxia (a movement coordination disorder caused by damage in the cerebellum) has been identified. Signs of such ataxia include gait and balance difficulties, rhythmic eye twitching (nystagmus), exaggerated reflexes, and enunciation difficulties. Impaired gait and other neurological anomalies generally exhibit a slow progression. The age of onset has a very wide range – from infancy to 62 years. It is also possible for neurological symptoms to be absent.

What causes SAMD9L deficiency?

SAMD9L deficiency is caused by a mutation – or genetic change – in the SAMD9L gene. This gene encodes for the SAMD9L protein, which functions as a tumor suppressor; in other words, it controls cell proliferation in our body. Now if the SAMD9L gene is altered, the protein will no longer be able to function correctly as a tumor suppressor, resulting in the development of new alterations of the blood-formation system.

The SAMD9L deficiency can be passed on by parents to their children. In these cases, it is inherited as an autosomal dominant disease.

Is there a treatment?

Patients with SAMD9L deficiency should be treated by a coordinated team of doctors from different specialist disciplines such as pediatrics, hematology/oncology, neurology, and genetics. A discussion with the EWOG MDS principal investigator is advisable.

Manifestations of the Blood-Building System

  • In cases of thrombocytopenia (a lack of blood platelets), any medications that impair coagulation (e.g. ASA, ibuprofen, diclofenac) should be avoided.

  • Administer corresponding blood products depending on the severity of cytopenia.

  • Treat other causes of anemia, with iron or vitamin supplements.

  • 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 for as long as possible. Walking aids can help prevent falls.

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

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

The following examinations should be conducted:

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

  • Bone marrow puncture once a year should be considered.

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

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

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as you notice any increased or hard-to-stop bleeding (e.g. long-lasting or frequent nose bleeds), increased bruises, fatigue or a feeling of sickness, fever, night sweats, paleness, or frequent infections. Moreover, you should see a doctor right away if you suffer from gait or speech abnormalities, eye twitching, or other movement or coordination difficulties. If you develop new symptoms or complaints, they should likewise be evaluated as soon as possible.

Support Groups and Additional Information

Unfortunately, we are as yet unaware of any existing support groups for patients with SAMD9L deficiency. We will add new information as it becomes available.