Introduction:
Delta-aminolevulinic acid dehydratase deficiency porphyria (ADP) is a rare inherited disorder. Males are more commonly affected than females, and the disease can develop during infancy, childhood, or older age.M. Doss of Germany first described it, hence referred to as Doss porphyria.
What Is ALAD Deficiency Porphyria?
Heme is the iron component of hemoglobin, responsible for carrying oxygen-rich blood to the organs. There are various enzymes involved in heme synthesis in the liver and red blood cells. Delta-aminolevulinic acid dehydratase enzyme is also essential in heme production. It converts delta-aminolevulinic acid (ALA) to porphobilinogen (PBG). The deficiency of delta-aminolevulinic acid dehydratase leads to the build-up of ALA in the liver and red blood cells. It later gets released into the blood and causes various toxic effects.
What Causes ALAD Deficiency Porphyria?
Genetic changes or mutations in the ALAD gene located on chromosome 9q34 cause ALAD deficiency porphyria. The ALAD gene is responsible for creating the delta-aminolevulinic acid dehydratase enzyme required in heme synthesis. ALAD deficiency porphyria is an autosomal recessive disorder in which defective ALAD genes are obtained from both parents. Therefore, if the mother or father passes only one defective gene, the person remains the carrier (asymptomatic) of the disease.
What Are the Clinical Features of ALAD Deficiency Porphyria?
The symptoms of ADP depend on the degree ofdelta-aminolevulinic acid dehydratase deficiency. The symptoms are severe if there is excess loss of delta-aminolevulinic acid dehydratase enzyme.
It includes:
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Acute attacks occur in patients, and they consist of various severe symptoms and can last for weeks.
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Abdominal pain.
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Nausea, vomiting.
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Bloating.
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Constipation.
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Diarrhea can occur rarely.
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In infants: pain, hyponatremia (low sodium level in the blood), vomiting, and other respiratory disorders that interfere with average growth and development are observed.
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Neurological symptoms include hallucinations, fear, anxiety, restlessness, depression, confusion, and concentration difficulties.
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Peripheral neuropathy refers to the damage to the nerves outside the brain and spinal cord. It causes a tingling and burning sensation in the hands and feet and sensitivity to touch. When the nerves are severely affected, muscle weakness and impaired functioning of voluntary muscles occur.
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The other symptoms are seizures, increased blood pressure, and heart rate.
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What Are the Risk Factors of ALAD Deficiency Porphyria?
The factors that trigger the acute attacks in ALAD deficiency porphyria are as follows:
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Alcohol.
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Physical or mental stress.
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Infections.
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Anti-seizure medications and antibiotics that are known to induce the CYP enzyme (cytochromes P450) trigger the synthesis of delta-aminolevulinic acid, which aggravates the attacks.
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Dehydration.
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Low-calorie intake.
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Estrogen or progesterone use.
How Is ALAD Deficiency Porphyria Diagnosed?
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Physical Examination of the patient and a detailed medical history are essential to differentiate the symptoms from other porphyrias.
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Urine Screening involves testing urine samples collected during acute attacks to detect the amount of porphobilinogen and other porphyrins. The porphyrin levels are increased with decreased porphobilinogen in ADP patients.
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Genetic Testing evaluates the mutation in the ALAD gene that is responsible for heme synthesis.
What Is the Differential Diagnosis?
The disorders that possess symptoms similar to that of ALAD deficiency porphyria are as follows:
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Acute Intermittent Porphyria (AIP): It is a genetic disorder caused by an accumulation of porphyrin precursors. Certain drugs and hormonal and dietary changes trigger abdominal pain, seizures, peripheral neuropathy, high heart rate, and blood pressure.
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Lead Poisoning: It occurs due to the accumulation of lead over months to years. It suppresses the ALAD enzyme, and the blood levels of delta-aminolevulinic acid increase. It causes abdominal pain, vomiting, fever, and other neurological abnormalities.
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Variegate Porphyria: It is also a rare metabolic disorder characterized by the accumulation of porphyrin precursors in the blood. The symptoms such as increased sensitivity to sunlight, fluid-filled bumps (blisters) in areas exposed to the sun, muscle weakness, vomiting, and abdominal pain.
What Are the Complications of ALAD Deficiency Porphyria?
Further complications due to recurrent attacks are:
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Muscle weakness is usually along the legs.
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Dysarthria or slurred speech occurs due to the weakening of muscles involved in speech.
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Worsening of respiration that may require artificial ventilation.
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In infants, complications like impaired hearing and intellectual disability can occur.
How Is ALAD Deficiency Porphyria Treated?
The various supportive measures involved in the management of ALAD deficiency porphyria are listed below:
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Drinking more water and fluids to avoid dehydration.
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Antiemetic drugs are suggested to control nausea and vomiting.
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Intravenous fluid replacement therapy is provided to maintain the sodium and fluid levels in the body.
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Beta-adrenergic blocking agents are suggested to reduce the heart rate and blood pressure.
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Counseling the patient to avoid the triggering factors like alcohol, drugs (Phenytoin, Valproic acid, Rifampin, etc.), and reducing psychological stress.
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Intravenous administration of Hemin (Panhematin) to suppress the synthesis of ALA synthase enzyme, which reduces the build-up of porphyrin precursors in blood and urine. Hemin reduces the increased heart rate and blood pressure. However, it is suggested during severe nausea, vomiting, agitation, seizures, and hospitalization conditions. Hemin also prevents the recurrence of attacks.
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Infusion of glucose is also suggested for patients with ALAD deficiency porphyria to control mild symptoms as it has similar effects as Hemin.
Conclusion:
ALAD deficiency porphyria is a rare type of porphyria, and classical features like abdominal pain, peripheral neuropathy, and other neurological disorders are suspected of the diagnosis. Therefore, a multi-specialty approach is essential for patient counseling to avoid triggering factors, manage the ALAD deficiency porphyria, and improve the quality of life.
