ALAS2 deficiency

Normally, about 90% of the iron obtained daily from the diet reaches the erythroblasts, where it is required for the final step of heme biosynthesis, namely the incorporation of iron into the tetrapyrrolic ring of protoporphyrin IX. The first and the last three of the eight steps of the heme biosynthetic pathway take place in the mitochondrion. The first and rate-limiting step consists of the condensation of glycine and succinyl-co-enzyme A to 5-aminolevulinate. This reaction is catalyzed by 5-aminolaevulinate synthase (ALAS) and it requires pyridox-al 5'-phosphate (PLP) as a cofactor. Two isoforms of ALAS are known; both have a homodimeric structure but they are encoded by different genes. ALAS1 is an ubiquitously expressed housekeeping gene, whereas ALAS2 is erythroid-specific.

Table 12.3 Classification of the sideroblastic anemias.

INHERITED

Mode of

Chromosomal

Clinical manifestations

inheritance

locus

Gene

Type of mutation

other than SA

X-linked

Xp11.21

ALAS2

Missense

None

X-linked

Xq1.3-q13.3

hABC7 (Fe-Su cluster

Missense

Cerebellar ataxia

transporter protein)

Autosomal recessive

1q23.2-23.3

SLC19A2 (thiamine

Missense, nonsense,

Thiamine-responsive megalo-

transporter protein)

frameshift

blastic anemia, diabetes mellitus,

sensorineural deafness

Autosomal dominant

Not known

Not known

None

Mitochondrial,

Usually from nt 8469 to

Deletions

Pancreatic exocrine dysfunction,

e.g. Pearson's MPS

nt 13447 (see Fig. 12.3)

cytopenia, metabolic acidosis

ACQUIRED

Refractory anemia with ring sideroblasts (RARS)

Drug-induced (e.g. isoniazid, chloramphenicol, ethanol)

Secondary to systemic, metabolic, malignant disorders

ALAS2, 8-aminolevulinate synthase 2; PGK1, phosphoglycerate kinase 1; SA, sideroblastic anemia; MPS, marrow-pancreas syndrome.

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