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X-linked sideroblastic anemia and spinocerebellar ataxia
A rare syndromic, inherited form of sideroblastic anemia characterized by mild to moderate anemia (with hypochromia and microcytosis) and early-onset, non- or slowly progressive spinocerebellar ataxia.
ORPHA:2802Classification level: Disorder
X-linked sideroblastic anemia and ataxia (XLSA-A) prevalence is unknown. Less than 20 genetically confirmed patients have been reported to date.
.XLSA-A usually presents before the age of 3 years. Anemia is usually asymptomatic. In males, spinocerebellar symptoms are apparent in childhood and can include delayed walking, predominantly truncal ataxia, dysmetria and dysdiadochokinesis. Dysarthria and intention tremor are sometimes present. Ataxia may improve over time, but in the fifth to sixth decade of life a slow deterioration of walking is noted. Upper motor neuron signs in the legs such as equivocal or extensor plantar responses, brisk deep tendon reflexes and unsustained ankle clonus are sometimes present. Strabismus, as well as mild learning disability and depression, have also been reported in some, but intellectual abilities are generally within the normal range. Hepatic and systemic iron overload does not occur. Females are clinically asymptomatic.
XLSA-A is caused by mutations in the ABCB7 gene (Xq13.3), encoding a mitochondrial ATP-binding cassette (ABC) transporter protein, which plays a role in heme production and iron homeostasis. A pathogenic variant in this gene alters the availability of reduced iron and therefore disrupts heme biosynthesis. The ABCB7 gene is highly expressed in both the bone marrow and the cerebellum, which may explain ataxia.
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 variation, confirming the 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.
Prenatal testing is possible in families with a known ABCB7 mutation.
The pattern of inheritance is X-linked recessive and gentic counselling should be offerend to affected families. Where the female is a carrier, the risk to male offspring inheriting the disease is 50%, female offspring have a 50% risk of being carriers. Where a male is affected, female offspring are obligate carriers, and male offspring do not inherit the pathogenic mutation.
Management and 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.
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.
A summary on this disease is available in Italiano (2004) Español (2020) Français (2020) Nederlands (2020)
Disease review articles
- Clinical genetics review
- English (2014) - GeneReviews
- Guidance for genetic testing
- Français (2019, pdf) - ANPGM
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