Anemia sideroblastic and spinocerebellar ataxia

Other Names: ASAT; Sideroblastic anemia with spinocerebellar ataxia; Pagon Bird Detter syndrome; X-linked sideroblastic anemia with ataxia; X-linked sideroblastic anemia and ataxia; XLSA-A; Pagon-Bird-Detter syndrome; X-linked sideroblastic anemia and spinocerebellar ataxia

X-linked sideroblastic anemia and ataxia is a rare condition characterized by a blood disorder called sideroblastic anemia and movement problems known as ataxia. This condition occurs only in males.

Epidemiology

X-linked sideroblastic anemia and ataxia is a rare disorder; only a few affected families have been reported.

Cause

Mutations in the ABCB7 gene cause X-linked sideroblastic anemia and ataxia. The ABCB7 gene provides instructions for making a protein that is critical for heme production. Heme is a component of the hemoglobin protein, which is vital for supplying oxygen to the entire body. The ABCB7 protein also plays a role in the formation of certain proteins containing clusters of iron and sulfur atoms. Overall, researchers believe that the ABCB7 protein helps maintain an appropriate balance of iron (iron homeostasis) in developing red blood cells.

ABCB7 mutations slightly alter the structure of the ABCB7 protein, disrupting its usual role in heme production and iron homeostasis. Anemia results when heme cannot be produced normally, and therefore not enough hemoglobin is made. It is unclear how changes in the ABCB7 gene lead to ataxia and other problems with movement.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. Carriers of an ABCB7 mutation can pass on the mutated gene but do not develop ataxia or other health problems associated with X-linked sideroblastic anemia and ataxia. However, carriers may have abnormally small, pale red blood cells and related changes that can be detected with a blood test.

Signs and symptoms

• Sideroblastic anemia results when developing red blood cells called erythroblasts do not make enough hemoglobin, which is the protein that carries oxygen in the blood.
• People with X-linked sideroblastic anemia and ataxia have mature red blood cells that are smaller than normal (microcytic) and appear pale (hypochromic) because of the shortage of hemoglobin. This disorder also leads to an abnormal accumulation of iron in red blood cells. The iron-loaded erythroblasts, which are present in bone marrow, are called ring sideroblasts. These abnormal cells give the condition its name. Unlike other forms of sideroblastic anemia, X-linked sideroblastic anemia and ataxia does not cause a potentially dangerous buildup of iron in the body. The anemia is typically mild and usually does not cause any symptoms.
• X-linked sideroblastic anemia and ataxia causes problems with balance and coordination that appear early in life. The ataxia primarily affects the trunk, making it difficult to sit, stand, and walk unassisted. In addition to ataxia, people with this condition often have trouble coordinating movements that involve judging distance or scale (dysmetria) and find it difficult to make rapid, alternating movements (dysdiadochokinesis). Mild speech difficulties (dysarthria), tremor, and abnormal eye movements have also been reported in some affected individuals.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Anemia(Low number of red blood cells or hemoglobin)
• Ataxia
• Neurological speech impairment(Speech disorder)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)

30%-79% of people have these symptoms

• Global developmental delay
• Hyperreflexia(Increased reflexes)

5%-29% of people have these symptoms

• Intrauterine growth retardation(Prenatal growth deficiency)
• Muscular hypotonia(Low or weak muscle tone)
• Scoliosis
• Strabismus(Cross-eyed)

Diagnosis

Diagnosis is based on the presence of characteristic neurological and blood test findings. Mild to moderate hypochromic, microcytic anemia is noted in all males and both whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) are elevated. Bone marrow examination demonstrates the presence of increased iron stores with ring sideroblasts and peripheral blood smear reveals Pappenheimer bodies. In the majority of cases magnetic resonance imaging (MRI) shows cerebellar atrophy/hypoplasia. Female carriers display hematological abnormalities. Molecular genetic testing identifies a ABCB7 gene mutation, confirming the diagnosis.

Differential diagnosis

The main differential diagnosis includes other forms/causes of ataxia that typically present before the age of 3 years such as ataxia-telangiectasia, infantile-onset spinocerebellar ataxia, congenital disorder of glycosylation, and cerebellar malformations (e.g. Dandy-Walker malformation) . Ataxia with vitamin E deficiency, Friedreich ataxia, ataxia - oculomotor apraxia type 1 and 2, and X linked sideroblastic anemia , the most common form of congenital sideroblastic anemia (without ataxia), should also be excluded.

Antenatal diagnosis

Prenatal testing is possible in families with a known ABCB7 mutation.

Treatment

There is no cure for XLSA-A and treatment is symptomatic. Anemia does not require treatment. Early physical therapy may aid in the acquisition of gross motor skills. Ankle fixation orthoses and walkers may be required to aid with mobility. Weighted eating utensils promote independent skills in children. Speech therapy is recommended for those with dysarthria. Crutches or a wheelchair may be needed by some patients.

Prognosis

While prognosis information is limited due to very few existing reports, XLSA-A does not appear to have a significant impact on life expectancy. Quality of life, however, can be significantly affected.

NIH genetic and rare disease info

• NIH info on Anemia sideroblastic and spinocerebellar ataxia

Anemia sideroblastic and spinocerebellar ataxia is a rare disease.

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