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Ataxia Pancytopenia Syndrome - Causes, Symptoms, and Treatment

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Ataxia pancytopenia is a rare genetic condition that affects part of the brain and bone marrow. Read the article below to know more.

Written byDr. Geetha Bhavani Gaddam

Medically reviewed byDr. Abhishek Juneja

Published At March 9, 2023
Reviewed AtMarch 9, 2023

What Is Ataxia Pancytopenia (AP) Syndrome?

Ataxia pancytopenia is also called myelocerebellar disorder. It is a congenital condition that causes neurological and hematological (blood-related) problems and predisposes the body to certain cancerous conditions like myeloid leukemia and myelodysplastic syndrome.

To date, 85 individuals from 36 families have been diagnosed with this syndrome, and symptoms have an early onset, worsening as the condition progresses. The neurological and hematological symptoms are not always concordant, the former always being more severe than the latter.

What Causes Ataxia Pancytopenia (AP) Syndrome?

It is caused due to inherited mutations (alteration) in the SAMD9L gene. The SAMD9L gene produces tumor suppressor protein that regulates cell growth, production, and division, especially in the bone marrow and the cerebellum (part of the brain).

The mutation responsible for causing AP syndrome is postulated to be a gain-in-function type, meaning the mutated SAMD9L gene will produce more of the regulating protein, which will suppress not only the excess production of the cells but also the normal production of the cells in the bone marrow and the cerebellum.

In the bone marrow, the resulting reduction will create a shortage of red blood cells, white blood cells, and platelets leading to pancytopenia (reduced platelets and red and white blood cells). In the brain, this will cause cerebellar atrophy (deterioration of the cerebellum), leading to ataxia (loss of voluntary muscle control).

The mutation can also predispose the affected individual to cancers; this is a contradictory feature of the alteration because the same mutation, which enhances the tumor suppressor function of the SAMD9L gene, also increases the risk of developing cancerous conditions.

This contradiction is likely due to the development of additional genetic changes in the bone marrow as a response to the SAMD9L mutation. These additional genetic changes disable the gain-in-function of the mutation and allow cells to grow and divide uncontrollably, leading to cancer.

What Are the Symptoms of Ataxia Pancytopenia (AP) Syndrome?

A syndrome, by definition, is a group of symptoms that correlate with each other, and AP syndrome is no exception. Depending on the extent of the mutation and the mode of inheritance, there can be several manifestations of the syndrome, some of which are mentioned below:

a) Hematological Manifestations: These have been known to develop as early as three months and can range from mild to severe. Some of the commonly seen hematological manifestations are:

  • Thrombocytopenia: It is a condition that occurs when the blood platelet count is too low.

  • Anemia: Refers to lower levels of healthy red blood cells leading to shortness of breath, dizziness, and fatigue.

  • Macrocytosis: It is a term used to describe when the red blood cells are larger than normal.

  • Immunodeficiency: It is a condition that develops due to the absence of body-protecting immune cells like phagocytes, lymphocytes, and complement system leading to the inability of the body’s immune system to fight against infections and cancer.

b) Neurological Manifestations:

  • Nystagmus: It is defined as the involuntary back-and-forth movement of the eye; patients with AP syndrome have been known to have both horizontal and vertical nystagmus.

  • Dysmetria: It is defined as the misjudging of the distance or scale.

  • Ataxia: Refers to poor coordination, movement, and balance.

  • Clonus: A term used to describe uncontrollable muscle movements.

c) Ophthalmic Manifestations: This includes difficulty in reading in focus.

Some less common manifestations are hypoplastic bone marrow, deep tendon reflexes, extensor plantar responses, impaired strength and sensation, gait impairment, etc.

How Is Ataxia Pancytopenia (AP) Syndrome Diagnosed?

A thorough family history, symptoms, and imaging are useful in developing an initial diagnosis; however, these alone cannot be used to establish a definitive diagnosis because the symptoms of AP syndrome often mimic other genetic abnormalities like dyskeratosis congenita (inherited bone marrow failure), ataxia-telangiectasia (a genetic condition characterized by uncoordinated and enlarged blood vessels), x-linked sideroblastic anemia (an inherited disorder characterized by small and pale red blood cells), and ataxia.

To establish a definitive diagnosis for AP syndrome is genetic testing, and based on the laboratory and phenotypic findings, the genetic testing can be done in two ways -

  1. Option 1: This includes the use of single-gene testing and a multigene panel and is done only when the phenotypic and laboratory findings are indicative of AP syndrome.

  2. Option 2: This involves comprehensive genomic testing and is done when the phenotype is indistinguishable from other genetic disorders.

How Is Ataxia Pancytopenia (AP) Syndrome Treated?

The following steps are undertaken to manage AP syndrome -

a) Evaluations: These are done to establish the extent of the condition and are done based on the area of concern; some of which are -

  • Hematologic and Oncologic: This includes a complete blood count (to evaluate for anemia, thrombocytopenia, etc.) and a bone marrow exam if hematological abnormalities are severe.

  • Neurologic: This includes electrophysiologic studies like EMG (electromyography) and NCS (nerve conduction velocity) to detect neurogenic changes and signs of neuropathy and a brain MRI (magnetic resonance imaging) to evaluate cerebellar atrophy.

  • Ophthalmologic: This includes assessment by an ophthalmologist to assess retinal function and possible visual impairment.

  • Speech: Comprises speech and language evaluation.

b) Treatment of Manifestations: Patients with AP syndrome will need the following treatments:

  • Anemia: Can be managed with red blood cell transfusions.

  • Thrombocytopenia: Platelet transfusions will be needed depending on the severity.

  • Neutropenia: Treatment is done based on the suggestions of a hematologist.

  • Myelodysplasia: Bone marrow transplant should be considered.

  • Ataxia: Treatment should be done under the care of a physiatrist. This includes adaptive devices to maintain and improve mobility, physical training (like balance exercises and muscle strengthening) to maintain mobility and function, home adaptations to prevent falls, etc.

  • Dysarthria: Can be treated with the help of speech and language therapy.

  • Dysphagia: Modifying the consistency of the food can help with dysphagia.

  • Poor Weight Gain: Nutritional and vitamin supplements should be considered after assessment by a nutritionist.

c) Surveillance: This includes the same tests done for evaluation to monitor the disease progression. For example, annual complete blood count, neurological assessment, etc.

d) Agents to Avoid: This is done to prevent exacerbation of the existing cytopenias. Some triggering agents to avoid are nonsteroidal anti-inflammatory drugs, anticoagulants, thrombolytic agents, and alcohol.

Along with the above-mentioned management strategies, genetic counseling also plays an important role in preventing and identifying symptoms of AP syndrome.

Conclusion

AP syndrome is a progressive genetic condition caused due to mutation in the SAMD9L gene. Affected individuals show neurological, hematological, and ophthalmological symptoms to various extents. Diagnosis involves thorough family history, laboratory, imaging, and genetic testing. Current treatment is concentrated on managing the symptoms and preventing progression through a thorough evaluation and genetic counseling.

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Frequently Asked Questions

"Ataxia-Pancytopenia Syndrome with SAMD9L Mutations" refers to a rare genetic disorder characterized by a mutation in the SAMD9L gene. This syndrome is marked by neurological symptoms like ataxia (loss of coordination) and hematological abnormalities, including pancytopenia (low red blood cells, white blood cells, and platelets). SAMD9L mutations can lead to various clinical features and medical complications, requiring specialized care and management.
Ataxia-Pancytopenia Syndrome is not typically triggered by B12 deficiency. Mutations in the SAMD9L gene primarily cause it. B12 deficiency can lead to a different condition called megaloblastic anemia, which affects red blood cell production and can result in symptoms like fatigue and weakness.
Several medications are associated with causing pancytopenia, a condition characterized by low levels of red blood cells, white blood cells, and platelets. Some of these medications include certain chemotherapy drugs, antiepileptic medications like phenytoin and carbamazepine, and certain antibiotics like chloramphenicol. However, the occurrence of pancytopenia due to medication use is relatively rare and usually requires close monitoring by healthcare professionals.
The three main categories of ataxia are:
 
- Hereditary Ataxia: This includes various inherited forms of ataxia caused by genetic mutations. Examples include Friedreich's ataxia and Spinocerebellar ataxias.
- Acquired Ataxia: This is typically caused by factors such as brain injury, stroke, multiple sclerosis, or alcohol abuse.
- Idiopathic Late-Onset Cerebellar Ataxia (ILOCA): This refers to cases of ataxia where the cause is unknown, and symptoms usually appear later in life.
The antibiotic “chloramphenicol” has been linked to the development of pancytopenia. Chloramphenicol can suppress bone marrow function, leading to decreased production of red blood cells, white blood cells, and platelets, which characterize pancytopenia. Due to its potential to cause serious adverse effects, chloramphenicol is reserved for specific cases where other antibiotics are ineffective or inappropriate.
Inherited ataxia syndrome refers to a group of neurological disorders characterized by a lack of muscle control or coordination due to genetic mutations. These mutations can affect various parts of the nervous system, particularly the cerebellum, leading to symptoms like unsteady gait, tremors, and difficulties with fine motor skills. Examples of inherited ataxia syndromes include Friedreich's ataxia and Spinocerebellar ataxias.
Multiple myeloma is a form of cancer that begins in plasma cells, a subset of white blood cells. It can lead to pancytopenia by crowding the bone marrow and interfering with the normal production of blood cells. The excessive growth of abnormal plasma cells can replace healthy bone marrow cells, resulting in lower levels of red blood cells, white blood cells, and platelets.
Pancytopenia is not typically caused by a deficiency in iron alone. Pancytopenia is a condition where there's a decrease in all three major types of blood cells. While iron deficiency can lead to anemia (low red blood cells), it doesn't usually directly cause decreased white blood cells and platelets, which are also characteristic of pancytopenia. Pancytopenia is more commonly associated with issues such as bone marrow disorders, infections, medications, and certain medical conditions that affect the bone marrow's ability to produce cells.
Yes, a lack of folic acid (folate deficiency) can contribute to pancytopenia. Folic acid is essential for producing and maturing red blood cells, white blood cells, and platelets. A deficiency can lead to ineffective blood cell formation and result in pancytopenia.
Leukemia can cause pancytopenia by overcrowding the bone marrow with abnormal white blood cells. This crowds out the space for producing other blood cells like red blood cells and platelets, leading to pancytopenia. Leukemia cells also often infiltrate the bone marrow and disrupt its normal functioning.
The life expectancy for individuals with Ataxia-Pancytopenia Syndrome can vary significantly based on the specific genetic mutation, the severity of symptoms, and the availability of supportive care. Some individuals have a relatively normal life expectancy with appropriate management, while others face more significant challenges that can impact their lifespan.
Strategies to minimize ataxia symptoms include physical therapy to improve coordination and balance, occupational therapy to enhance daily functioning, and assistive devices to aid mobility. Medications can be prescribed to manage symptoms such as tremors or muscle stiffness. Engaging in lifestyle changes, like adhering to a nutritious diet and remaining physically active, can enhance the overall health of those with ataxia.
The severity of ataxia can vary in terms of progression. Some forms of ataxia are progressive, meaning that the symptoms tend to worsen over time. In other cases, the progression might be relatively stable or slow. The rate of progression depends on the underlying cause of ataxia, its specific genetic basis, and other individual factors.
Parvovirus B19 is a virus that can give rise to pancytopenia. This virus can infect bone marrow cells and suppress their production of red blood cells, white blood cells, and platelets, leading to a temporary decrease in their levels.
Ataxia itself is not necessarily a fatal condition. The outlook is determined by the root cause of ataxia, its severity, and associated complications. Certain varieties of ataxia are relatively mild and can be effectively managed, whereas others can be considerably more severe and impact daily functioning. In some cases, particularly when ataxia is associated with other serious medical conditions, there can be increased health risks. Individuals with ataxia need to work closely with healthcare professionals to manage their condition and address any potential complications.
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