Heme Synthesis Disorders

Heme is a metal containing protoporphyrin ring. There are 4 pyrrole rings with metal in the center. That metal is mainly iron in hemoglobin and myoglobin. Heme is synthesized partially in mitochondria and cytoplasm. There are a total of 8 steps of heme synthesis and these are equally divided in both locations. Porphyria disorders that result in the deposition of porphyrin pigment in tissues. It can be due to the deficiency of enzymes within the heme biosynthetic pathway and the enzyme deficiency determines the pattern of the accumulated porphyrin precursors.

Also Read: Phenylketonuria: Symptoms, Causes and Treatment

Heme Synthesis

1. X-linked Sideroblastic Anemia
   • It is due to the presence of defective ALA Synthase II and due to this protoporphyrin ring will not be synthesized.
   • Chelation of iron is prevented and that leads to its accumulation in mitochondria.
   • Iron accumulation in the mitochondria surrounds the nucleus of RBC precursors making it look like a ring which is why it is called sideroblastic anemia.
   • ALA Synthase II gene is present in the X chromosome that’s why it is called an X-linked sideroblastic anemia. 
2. Autosomal Recessive Sideroblastic Anemia
   • It is due to the impairment of transportation of glycine into the mitochondria.
   • This causes autosomal recessive sideroblastic anemia.
3. Acute Intermittent Porphyria
   • It is due to a deficiency of the enzyme porphobilinogen deaminase also called Uroporphyrinogen I synthase. This enzyme converts porphobilinogen to hydroxymethylbilane.
   • It is an autosomal dominant disorder.
   • There is an accumulation of porphobilinogen and Aminolevulinic acid.
   • The symptoms are:
     • Painful abdomen
     • Port wine-colored urine- that is the urine is red-tinged that oxidizes with air exposure.
     •  Polyneuropathy
     •  Psychological disturbances.
   • These symptoms are precipitated by factors that increase ALA synthesis enzymes like CYP-450 inducers.
   • The lab findings will show elevated serum and urinary porphyrins.
   • The neuropsychiatric manifestations are very important it is also called tic tac toe disease.
   • The management is done by infusing the patient with glucose and hemin. Hemin is a heme analogue.
4. Porphyria Cutanea Tarda
   • It is caused by the deficiency of an enzyme called Uroporphyrinogen decarboxylase.
   • There is an accumulation of products called Uroporphyrinogen III. There will be Tea colored urine.
   • The Clinical Features are:
     • There will be the presence of photosensitivity and hyperpigmentation. The patient will present with blister formation, atrophic scarring, and hypertrichosis.
     • It is the most common type of porphyria.
     • The causes are familial and Hepatitis C.
     • The treatment of Porphyria Cutanea Tarda is phlebotomy, sun avoidance, and hydroxychloroquine.
5. Lead Poisoning
   • The lead poisoning can alter the heme synthesis pathway and that can lead to acquired porphyria.
   • Lead inhibits 3 enzymes of Heme synthesis. The enzymes inhibited by lead are- Delta ALA dehydratase, Copro-porphyrinogen oxidase, and Ferro Chelatase.
   • Substrates like protoporphyrin and ALA are accumulated in the blood.
   • The clinical features are:
     • Microcytic anemia and Basophilic stippling in peripheral smear will be present. Ringed sideroblasts will be present in the bone marrow.
     • GI and Kidney Disease
     • On exposure, Children can suffer from mental deterioration.
     • In adults, environmental exposure to batteries and ammunition can occur and that can lead to headache, memory loss, and demyelination due to peripheral neuropathy.

Also Read: Lipids: Classification, Pufas, Lipoproteins, Ketone Body Synthesis & Utilization

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