Disorders of Heme Synthesis & Porphyrias: Lecture Notes

Disorders of Heme Synthesis & Porphyrias 

X-Linked Sideroblastic Anemia 

- is an inherited disorder caused by the lack of an enzyme in ALA synthase 2
- results in decreased hemoglobin synthesis in erythroid tissues
- manifest as microcytic and hypochromic anemia

Prevalence 
Rare genetic disorder

Inheritance Pattern
X-linked disorder

Pathological Manifestation 
- Mutation of the ALAS2 gene impairs the activity of ALA synthase 2 in erythroid tissue
- Decreases heme and hemoglobin synthesis 
- An increased build-up of the excess iron in the erythroblast forming a ring sideroblast (visualized by Prussian blue staining)

Diagnosis 
- Complete blood count and reticulocyte count
- Decreased hemoglobin & Microcytic and Hypochromic RBC
- Iron overload
- Bone Marrow aspirate shows sideroblasts ring

Confirmatory Diagnosis
- Mutation analysis of ALA2 gene 

Treatment 
- Treatments are available to relieve the symptoms
- Surveillance and maintenance of iron in the body (iron chelation)
- Administration of Pyridoxine in the responsive subjects
- Occasional Blood transfusion if necessary

ALA dehydratase Deficiency Porphyria 

- characterized by an almost complete deficiency of the enzyme ALA dehydratase. 
- manifest as an acute form of porphyria 

Prevalence 
Rare; 1<100,000

Inheritance Pattern 
- Autosomal Recessive Disorder

Pathological Manifestation 
- deficiency of the enzyme ALA dehydratase lead to the accumulation of substrate ALA 
- accumulated ALA leads to neurovisceral or acute attacks that include abdominal pain, vomiting. 
- peripheral neurological symptoms include numbness, tingling, sensitivity to touch, and lack of coordination
- In severe cases, psychosis has been reported

Diagnosis 
Measurement of urinary ALA, porphobilinogen & total porphyrins
- Increased accumulation  ALA 
Confirmatory Diagnosis
Mutation analysis of the ALAD gene 

Treatment 
- Hemin (Panhematin) is the FDA approved for the treatment of acute Porphyria
- Givosiran (Givalaari) for treatment of acute porphyria

Acute Intermittent Porphyria (Porphobilinogen Deaminase Deficiency)

- characterized by the reduced activity of the enzyme porphobilinogen deaminase  (hydroxymethylbilane synthase)
- manifest as an acute form of porphyria

Prevalence 
-Rare, 1 in 20,000

Inheritance Patten
-Autosomal Dominant

Pathological Manifestation 
- Heterozygote pathogenic mutation of gene HMBS 
- Resulting in the reduced activity of PBG deaminase
- Accumulation of porphobilinogen
- Manifest neurovisceral symptoms including acute abdominal pain, cramps, vomiting, etc.
- muscle weakness, convulsion, mental changes, and hyponatremia
- urine may be reddish-brown, reflecting the increased urinary concentration of porphyrins and porphobilinogen

Diagnosis 
- Increase urinary porphobilinogen in a fresh random sample
- Normal fecal porphyrin concentration or coproporphyrin isomer
- Normal porphyrin fluorescence emission at 620 nm
- Molecular Testing for the confirmatory diagnosis

Treatment 
- Reduce the symptoms 
-Givlaari (givosiran), Penhematic,

Congenital Erythropoietic Porphyria (Uroporphyrinogen III Synthase )

- Characterized by the deficiency of uroporphyrinogen III synthase deficiency-
- Manifest as severe cutaneous photosensitivity with blistering and increased friability of the light-exposed skin 

Prevalence 
- Rare Disease

Inheritance Pattern: Autosomal Recessive

Pathological Manifestation 
- Congenital erythropoietic porphyria results from markedly decrease uroporphyrinogen synthase deficiency
- Uroporphyrinogen synthase catalyzes the conversion of hydroxymethylbilane to uroporphyrinogen III
- deficiency of the enzyme caused the accumulation of hydroxymethylbilane and non-enzymatically converted into uroporphyrinogen I isomer.
- decarboxylation of uroporphyrinogen I lead to the formation of porphyrinogen I and coproporphyrinogen I. 
- Porphyrinogen I isomer are accumulated in bone marrow erythroid tissues and erythrocytes undergo  autooxidation and hemolysis of RBC
-Cutaneous photosensitivity with blistering and increased friability occurs because the porphyrins deposited in the skin are photocatalytic and cytotoxic compounds 
- Porphyrin deposition may lead to corneal ulcers and scarring, reddish-brown discoloration of the teeth (erythrodontia), and mild bone loss and/or expansion of the bone marrow. 

Diagnosis 
- Visibly dark discoloration of urine and characterized by the increase of uroporphyrinogen I and coproporphyrinogen isomers. 
- Marked Decreased Uroporphyrinogen synthase activity in erythrocytes
Molecular Diagnosis
- Identification of biallelic pathogenic mutation of UROS gene
- Rare form - mutation in X-linked GATA1 gene 

Treatment 
- No approved treatment available 

Porphyria Cutanea Tarda (Uroporphyrinogen Oxidase)

- Familial Porphyria Cutanea Tarda is characterized by skin blisters on the sun-exposed area,  facial hypertrichosis, and hyperpigmentation
- Severe thickening of the affected skin area (psuedocleroderma)

Inheritance Pattern

 Pathological Manifestation
- Hepatic uroporphyrinogen oxidase deficiency (also known as uroporphyrinogen decarboxylase) 
- Lead to oxidized porphyrins accumulated in the liver
- Excess porphyrinogen are deposited in the skin causing photosensitivity

Diagnosis
- Deficiency of uroporphyrinogen oxidase with reduced enzyme activity (< 20% of normal) 
- Increased plasma uroporphyrin & heptacarboxylporphyrin
- Increased urine uroporphyrin & heptacaboxylporphyrin 
- Increased stool heptacarboxylporphyrin
Molecular Diagnosis
- Sequence analysis for the detection of pathogenic mutations and deletions

Treatment 
- No curative therapy is available, treatment is available for treating symptoms such as iron chelators etc. 

Hereditary Coproporphyria (Coproporphyrinogen Oxidase)

- Hereditary Coproporphyria is an acute hepatic porphyria characterized by neurovisceral symptoms
- Caused by a deficiency of coproporphyrinogen oxidase enzyme that catalyzes the conversion of coproporphyrinogen to protoporphyrinogen
- Photosensitivity is caused by the accumulation of coproporphyrin

Prevalence 
-Rare form of porphyria

Inheritance Pattern

Pathological Manifestation 
- Mutation in the gene coproporphyrinogen oxidase and accumulation of the precursor including coproporphyrinogen & porphobilinogen
- Oxidation of coproporphyrinogen to coproporphyrin causes photosensitivity 
-  Accumulation of porphobilinogen causes neurovisceral symptoms

Diagnosis
- Defective of coproporphyrinogen oxidase with reduced enzyme activity 
- Increased urine porphobilinogen and coproporphyrin III
- Increased stool coproporphyrin III
Molecular Diagnosis
- Sequence analysis for the detection of pathogenic mutations and deletions of gene CPOX

Treatment 
- No therapy is available to treat disease, treatment is available for treating symptoms such as iron chelators, etc. Givorisin is an approved treatment to treat adults with acute porphyria.

Variegate Porphyria (Protoporphyrinogen Oxidase) 

- Variegate Porphyria is often presented with cutaneous porphyria and acute neurovisceral symptoms
- Caused by the deficiency of an enzyme protoporphyrinogen oxidase that catalyzes the conversion of protoporphyrinogen to protoporphyrin

Prevalence 
Rare, 3 in 1,000,000

Inheritance Pattern- Autosomal Dominant

Pathological Manifestation 
- The deficiency of enzyme protoporphyrinogen oxidase leads to the accumulation of its precursor protoporphyrinogen and porphobilinogen
- The typical photosensitivity symptoms are observed similar to porphyria cutanea tarda, hereditary porphyria etc.
- The neurovisceral symptoms are observed, with acute abdominal pain, nausea, vomiting etc.  
Diagnosis 
- Elevated urinary porphobilinogen, 
- Elevated urinary porphyrin ( ~626 ng fluorescence)
Molecular Diagnosis
- Mutation analysis of gene PPOX for pathogenic variants

Treatment 
- No therapy available to treat the disease.
- Givosiran (Givalaari) for treatment of acute porphyria

Erythropoietic Protoporphyria  (Ferrochelatase)

- Erythropoietic Protoporphyria is characterized by cutaneous photosensitivity after exposure to the sun
- Caused by a homozygous mutation of gene FECH that encodes for Ferrochelatase

Prevalence 
- Rare disorder with 2 to 5 in 1,000,000

Inheritance Pattern: Autosomal Recessive

Pathological Manifestation 
- Mutation in the gene FECH leads to defective synthesis of ferrochelatase enzyme and accumulation of the precursor protoporphyrin
-  Photosensitivity
- Hepatic dysfunction is observed in some subject

Diagnosis
- Decreased Ferrochelatase activity  (<10-30% of normal)
- Elevated erythrocytes free protoporphyrin
- Elevated plasma Protoporphyrin
- Normal urinary Protoporphyrin
- Normal or Increased Protoporphyrin

Molecular Diagnosis
- Mutation analysis of gene FECH for pathogenic variants

Treatment 
- No therapy available to treat the disease.

 
 

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