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Genetics

The porphyrias are inherited genetic conditions, which means that people with a porphyria have changes to certain genes that affect their body’s ability to regulate itself.  When genes are copied, either to make new cells or to make a child, sometimes the body makes an imperfect copy.  There can be little changes in the genes, called mutations, which can occur randomly.  Sometimes these changes do not make any difference in how well the gene works, but other times they can keep the gene from working properly (referred to as mutations) and are disease causing.

In the porphyrias, these mutations are in the genes involved in a certain chemical pathway, called the heme biosynthetic pathway. Heme is a compound that the body needs to make hemoglobin and there are several steps to make this compound in the body. Each type of porphyria is caused by a defect in a specific enzyme in the heme biosynthetic pathway. Without these enzymes working properly, the body is not able to finish making heme and it causes a buildup of other compounds, called porphyrins. It is the buildup of different types of porphyrins that causes the types of porphyria.

INHERITANCE OF THE PORPHYRIAS

Each type of porphyria is caused by a mutation, or change, in the gene coding for a specific enzyme in the heme pathway. PCT is unique as it is the only porphyria where most patients do not have  mutations in a gene, but instead have acquired, or sporadic, PCT.

Type Inheritance Deficient Enzyme Gene
ALA-Dehydratase Porphyria (ADP) Autosomal recessive ALA-Dehydratase ALAD
Acute Intermittent Porphyria (AIP) Autosomal dominant Hydroxymethylbilane synthase (Porphobilinogen deaminase)  HMBS
Congenital Erythropoietic Porphyria (CEP) Autosomal recessive Uroporphyrinogen III synthase UROS
Porphyria Cutanea Tarda (PCT), familial form Autosomal dominant Uroporphyrinogen decarboxylase UROD
Hepatoerythropoietic Porphyria (HEP) Autosomal recessive Uroporphyrinogen decarboxylase UROD
Hereditary Coproporphyria (HCP)  Autosomal dominant Coproporphyrinogen oxidase CPOX
Variegate Porphyria (VP) Autosomal dominant  Protoporphyrinogen oxidase PPOX
Erythropoietic Protoporphyria (EPP)
X-linked Protoporphyria (XLP)
Autosomal recessive
X-linked
Ferrochelatase
δ-Aminolevulinate synthase 2
FECH
ALAS2

      
The inherited porphyrias are either autosomal dominant (inherited from one parent), autosomal recessive (inherited from both parents), or X-linked (the gene is located on the X-chromosome). "Autosomal" genes always occur in pairs, with one coming from each parent. Individuals with an autosomal dominant form of porphyria have one mutated gene paired with a normal gene, and there is a 50% chance with each pregnancy that the mutated gene will be passed to a child.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Individuals with an autosomal recessive type of porphyria have mutations on both copies of a specific gene, one passed to them from each of their parents. Each of their children will inherit one mutated gene for that porphyria, and the child will be a “carrier” but will not have symptoms.

In X-linked disorders, the gene is located on one of the sex chromosomes, called the X-chromosome. Females have two X-chromosomes, and males have one X-chromosome and one Y-chromosome. Both males and females will likely have symptoms from a mutated gene on the X-chromosome, but females, with a normal gene on the other X-chromosome, usually are less severely affected than males. The risk for children depends on the gender of the affected parent. A female with an X-linked gene mutation will have a 50% risk of passing that mutation to any of her children with each pregnancy. However, a male will pass the mutation to all of his daughters but none of his sons.

BASIC GENETICS

To find out more information on the basic genetics of Porphyria visit:

Basic genetics: http://learn.genetics.utah.edu/content/basics/

Mutations: http://learn.genetics.utah.edu/content/basics/mutation/

Dominance/recessive: http://learn.genetics.utah.edu/content/basics/patterns/