Variegate Porphyria Clinical Presentation
- Author: Maureen B Poh-Fitzpatrick, MD; Chief Editor: Dirk M Elston, MD more...
A family history of variegate porphyria may or may not be present. Studies of the clinical penetrance of the variegate porphyria trait found that ~60% of all individuals harboring a single protoporphyrinogen oxidase mutation remained silent carriers.[19, 20] Among the 40% who did manifest symptoms, photosensitivity alone was the presenting complaint far more often than neurological disturbances alone, while only a small minority (4-8%) experienced both types of symptoms. Skin lesions were the presenting sign in approximately 80% of 70 European patients recently identified.
A porphyric attack is typically described as abdominal discomfort that may have progressed over several hours to severe pain extending into the back, chest, arms, and legs. Nausea with vomiting, constipation, hypertension, tachycardia, anxiety, and agitation may be reported. Pain and weakness developing in extremities indicates an accelerating attack that may progress to flaccid quadriparesis. Central nerve paralysis, respiratory distress, confusion and bizarre behavior, seizures, or coma may have developed before the patient is assessed by medical personnel. Attack episodes of variegate porphyria can often be linked to history of a new medication. Factors historically associated with the onset of attacks in other acute porphyrias (eg, hormonal fluctuations due to menses, pregnancy or therapeutic hormones, infections, other stressors) appear to be less often responsible for attacks in variegate porphyria.
Photocutaneous lesions, the predominant presenting signs of variegate porphyria, include mechanical fragility, blistering, milia, furrowing, and scarring in sun-exposed skin. Hypertrichosis, dyspigmentation, sclerodermoid changes, and a weather-beaten or leathery texture may be present. Children with biallelic variegate porphyria experience photosensitivity of mutilating severity.[16, 21]
Neurovisceral dysfunctions occur less frequently and recur far less often in variegate porphyria than in acute intermittent porphyria (AIP). Pain in variegate porphyria may become excruciating; uncontrolled vomiting can lead to dehydration. Deteriorating neurological function produces multiple sequelae. Initial limb weakness may progress to areflexic quadriparesis. Respiratory failure may occur. Heart rate and blood pressure can rise to critical levels. During such crises, dark-orange or reddish urine is excreted; bowel and bladder function may be disturbed. Tonic-clonic seizures and coma may ensue.
Confusion, disorientation, agitation, mania, depression, and schizophrenialike behavior have all been reported. Psychiatric symptoms were noted in 80% of 18 Finnish patients during attacks, with 25% described as delirious and psychotic. In the larger South African experience, however, neuropsychiatric disturbances are infrequent in variegate porphyria, especially in the absence of other signs and symptoms of an attack. Metabolic encephalopathy may occur during variegate porphyria crises, contributing to some of these phenomena as well as to seizures and coma.
Hypervolemia and hyponatremia noted in more severe attacks may involve renal salt wasting, inappropriate antidiuretic hormone secretion, or infusion of inappropriate replacement fluids. Hypomagnesemia may also be present.
Because variegate porphyria may variably manifest with only neurovisceral symptoms, with only cutaneous photosensitivity, or with both, other diagnoses to be considered include porphyrias that share either type or both types of symptoms and nonporphyric bullous disorders that occur in sun-exposed skin. Acute ascending polyneuropathy (Landry-Guillian-Barre syndrome) may resemble aspects of porphyric neuropathies in causing progressive paralyses that may affect respiratory muscles, in altering sensation or producing pain, and in disordering autonomic nervous system functions.
Variegate porphyria arises from autosomal dominant inheritance of a gene mutation encoding a defective protoporphyrinogen oxidase enzyme protein. Individuals with one such mutation have total enzyme activity diminished to as much as 50% of normal. Most individuals with one mutation remain asymptomatic, but are at risk if exposed to environmental factors (most often drugs) that can induce overt phenotypical expression.
Inheritance of 2 mutant protoporphyrin oxidase genes causes a more profound reduction in residual enzyme activity to 25% or less, leading to more severe disease manifestations presenting in childhood.[17, 22]
The founder gene mutation common among South Africans encodes an enzyme with little or no residual activity that may be lethal in homozygotes. Four South African children manifesting variegate porphyria were compound heterozygotes with the founder mutation on one allele, but a different mutation apparently encoding an enzyme with enough residual activity to enable survival, on the other.
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