Thread by @AaronGoodman33

Sideroblastic anemias!
[Tweetorial]

Pathological iron deposition in mitochondria of erythroid precursors

Pathologic finding
🚫a specific diagnosis!

Broad classification of sideroblastic anemias.

1. Congenital
-Syndromic
-Non-syndromic

2. Acquired
-Clonal
-Metabolic
-Drugs

WHO defined types of sideroblasts

Type 1: <5 siderotic granules in cytoplasm.
Type 2: ≥5 granules but no perinuclear distribution.
Type 3 = ringed sideroblast: ≥ 5 granules in a perinuclear position, surrounding nucleus or encompassing one third of nuclear circumference.

Mitochondria Anatomy
Sideroblasts = Mitochondria problems

Outer membrane
-Porins for proteins

Intermembrane space

Inner membrane
-Oxidative phosphorylation
-ATP synthase

Cristae
-Expand membrane space

Matrix
-Mitochondrial DNA
-TCA cycle
-Heme synthesis
-Oxidaiton of lipids

Mitochondrial Genetics

Maternally inherited

5-10 copies of 16569 BP circular DNA per mitochondria
13 mRNAs (respiratory complexes)
22 mt-tRNAs
2 mt-rRNAs

Mitochondria Trafficking

Lots of proteins used in mito not coded by mito DNA
(> 1000 proteins) trafficked:
Through outer membrane (TOMs)
Through intermembrane space (TIMs)

Proteins trafficked through:
All of Krebs cycle
4 heme synthesis enzymes
All mitochondrial transporters

Congenital Sideroblastic Anemias

Heme synthesis defects
-XLSA

Mitochondrial transporter defects
-SLC25A38
-Thiamine responsive megaloblastic anemia

Fe-S biogenesis defects
-X-linked sideroblastic anemia with ataxia

Mitochondrial protein synthesis defects
-Pearson’s syndrome

X-linked Sideroblastic Anemia (XLSA)

Mutations in ALAS2
-First step in heme synthesis!
-Occurs in mitochondria
-Over 80 mutations
-Catalytic domain
-Reduced enzymatic activity

X-linked Sideroblastic Anemia (XLSA)

Males (age 40)
Rare female 2/2 skewed X inactivation
Transfusion dependence rare

Smear:
Microcytic
Hypochromic
Dimorphic (⬆️RDW)
Pappenheimer bodies

Treatment:
Pyridoxine(B6) > 50 mg day
Mutations altering pyridoxine binding are responsive

Sideroblastic anemia 2/2 mutations in SLC25A38

Severe hypochromic anemia resembles XLSA but lacked ALAS2 mutation.
Anemia first weeks of life
Unresponsive to B6
Chronic transfusion support

SLC25A38 mutations
Inner mito membrane
Transports ALA out of mito
Glycine import to mito

Thiamine (B1) Responsive Megaloblastic Anemia
Sideroblastic+Megaloblastic!

Mutation mitochondria B1 transp SLC19A2

B1 cofactor mitochondria enzymes:
Transketolase = ribose for nucleotide
PDH = SucCoA for heme synthesis

⬇️B1->
⬇️Nucleotide = megaloblastic
⬇️Heme = sideroblastic

X-linked sideroblastic anemia with ataxia (XLSA/A)

Early onset motor delay, spinocerebellar hypoplasia
Ataxia with severe cerebellar hypoplasia
Mild sideroblastic anemia
Mutation ABC7 transporters:
Transports components involved in construction of Fe-S clusters.

Board Review Question!

What is your differential for an infant with anemia and pancreatic insufficiency?
1. Shwachman-Diamond syndrome
2. Pearson’s syndrome

Pearl: Pearson’s syndrome has ringed sideroblasts while Shwachman-Diamond syndrome does not.

Pearson's syndrome = Mitochondrial DNA

Presents in infants
-Lactic acidosis
-Pancreatic insufficiency
-Myopathy

Spectrum of Kearns-Sayre syndrome
Pancytopenia, ringed sideroblasts
Vacuolization hematopoietic precursors
Maternally inherited
4977 bp deletion mitochondrial genome

Acquired Sideroblastic Anemia

Clonal
-RARS
-RARS-T
-RCMD-RS

Metabolic
-Copper deficiency
-Zinc toxicity

Drugs
-Chloramphenicol
-INH
-Linezolid

Alcoholism

Hypothermia

Clonal

RARS: dysplasia confined to the erythroid cell lineage.
-All have SF3B1 mutation

RARS-T: Anemia+thrombocytosis
-SF3B1+JAK2 V617F which frequently has the

RCMD-RS: MDS with additional dysplastic features involving granulopoiesis and/or megakaryopoiesis.
-SF3B1

Copper deficiency

⬇️Cu disrupts iron metabolism
⬇️Intestinal Fe absorption 2/2 lack of ceruloplasmin and ferroxidase function in haphaestin
⬇️ferrous iron in mitochondria 2/2 ⬇️cytochrome c oxidase (necessary for heme synthesis)

⬆️Zinc excess causes ⬇️copper
-⬇️ Cu absorption

Drugs

INH: Interferes with B6 metabolism
Depletes ALAS2 of pyridoxal phosphate

Chloramphenicol/Linezolid: Inhibits bacterial ribosomes:
⬇️Mitochondrial rRNA

My clinical approach to sideroblastic anemias

Pearls

Anemia usually mild 9-12 for all except:
SLC25A38 (severe and young age)

WBC and plt count usually normal except:
Pearson’s syndrome (pancytopenia)
Copper deficiency (neutropenia)
RARS-T (thrombocytosis)

XLSA in female mimics RARS!
High MCV
Dimorphic RBCs

Treatment

General principles
Avoid unnecessary transfusion
Iron overload
Iron chelation therapy
Phlebotomy

XLSA = high dose B6

EtoH = Stop the booze

Copper deficiency = Parental or high dose PO copper

RARS = EPO, luspatercept

INH = Supplement with B6