X-linked sideroblastic anemia (ORPHA:75563)
X-linked sideroblastic anemia is a constitutional microcytic, hypochromic anemia of varying severity that is clinically characterized by manifestations of anemia and iron overload and that may respond to treatment with pyridoxine and folic acid.
Epidemiology
Prevalence is unknown. Around 200 cases and fewer than 100 unrelated probands are described in the literature.
Clinical description
The anemia can present at any age from birth to the 9th decade. Some patients are asymptomatic and are detected incidentally by hematological screening or through a family study. Clinical features are those of anemia and/or iron overload such as pallor, fatigue, weakness. Breathlessness, mild splenomegaly, cardiac problems, abnormal liver function, hyperglycemia, glucose intolerance and skin hyperpigmentation are seen more rarely.
Etiology
SA is due to inherited or de novo mutations in the ALAS2 gene (Xp11.21) encoding the erythroid form of delta amino levulinic acid synthase (ALAS2), which altered function leads to impaired heme synthesis. The increased ineffective and expanded erythropoiesis leads to increased absorption of dietary iron and a risk of iron overload. Female carriers are usually unaffected, however, one quarter of probands are female who have X-chromosome inactivation skewed against the unaffected allele and almost half of the female probands have macrocytic rather than microcytic red blood cells due to the heterozygous inheritance of a severe/null allele.
Diagnostic methods
Diagnosis requires a full blood and reticulocyte count, measurement of iron stores, exclusion of thalassemia as a cause, bone marrow aspirate showing ringed sideroblasts, and mutation analysis of the ALAS2 gene.
Differential diagnosis
The differential diagnosis should include other types of inherited sideroblastic anemia and in case of macrocytic red cells in females also acquired myelodysplasia (refractory anemia with ringed sideroblasts or RARS (see these terms). Most female carriers show some evidence of microcytic, hypochromic red blood cells but hematological parameters cannot be relied upon for genetic counseling purposes and DNA analysis is required
Antenatal diagnosis
Prenatal diagnosis is rarely indicated or requested, but should be offered in case of family history.
Genetic counseling
Genetic counseling for the family of affected individuals is recommended, as early diagnosis in a child may be of great benefit for treatment of anemia and prevention of iron overload, the main cause of early death in the past.
Management and treatment
Treatment is supportive and involves hematological monitoring, the surveillance of iron levels, lifetime pyridoxine supplementation in those who respond and folic acid supplementation. Pyridoxine response varies in degree and is rarely complete. Prophylactic occasional phlebotomy can be performed to prevent iron overload, if anemia is very mild or corrected by pyridoxine. If iron overload has already developed, phlebotomy, iron chelation or a combination of both can be used to normalize iron levels. In some cases iron depletion may simultaneously increase the hemoglobin level. Blood transfusions may be needed on occasion but are only required on a regular basis for those most severely affected.
Prognosis
Prognosis is variable but for patients with pyridoxine-responsive anemia whose iron stores are kept low, normal life expectancy should be achievable

                            Last update: 
                            July 2013


                            - Expert reviewer(s): 
                            Pr Clara CAMASCHELLA