MedGen

Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets. [from GeneReviews]

Acute intermittent porphyria (AIP), an autosomal dominant disorder, occurs in heterozygotes for an HMBS pathogenic variant that causes reduced activity of the enzyme porphobilinogen deaminase. AIP is considered "overt" in a heterozygote who was previously or is currently symptomatic; AIP is considered "latent" in a heterozygote who has never had symptoms, and typically has been identified during molecular genetic testing of at-risk family members. Note that GeneReviews does not use the term "carrier" for an individual who is heterozygous for an autosomal dominant pathogenic variant; GeneReviews reserves the term "carrier" for an individual who is heterozygous for an autosomal recessive disorder and thus is not expected to ever develop manifestations of the disorder. Overt AIP is characterized clinically by life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs, often accompanied by nausea, vomiting, tachycardia, and hypertension. Attacks may be complicated by neurologic findings (mental changes, convulsions, and peripheral neuropathy that may progress to respiratory paralysis), and hyponatremia. Acute attacks, which may be provoked by certain drugs, alcoholic beverages, endocrine factors, calorie restriction, stress, and infections, usually resolve within two weeks. Most individuals with AIP have one or a few attacks; about 3%-8% (mainly women) have recurrent attacks (defined as >3 attacks/year) that may persist for years. Other long-term complications are chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Attacks, which are very rare before puberty, are more common in women than men. Latent AIP. While all individuals heterozygous for an HMBS pathogenic variant that predisposes to AIP are at risk of developing overt AIP, most have latent AIP and never have symptoms. [from GeneReviews]

Variegate porphyria (VP) is both a cutaneous porphyria (with chronic blistering skin lesions) and an acute porphyria (with severe episodic neurovisceral symptoms). The most common manifestation of VP is adult-onset cutaneous blistering lesions (subepidermal vesicles, bullae, and erosions that crust over and heal slowly) of sun-exposed skin, especially the hands and face. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. Cutaneous manifestations may improve in winter and be less prevalent in northern regions and in dark-skinned individuals. Acute neurovisceral symptoms can occur any time after puberty, but less often in the elderly. Acute manifestations are highly variable, but may be similar from episode to episode in a person with recurrent attacks; not all manifestations are present in a single episode; and acute symptoms may become chronic. Symptoms are more common in women than men. The most common manifestations are abdominal pain; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a primarily motor neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis. Psychiatric disturbances and autonomic neuropathy can also be observed. Acute attacks may be severe and are potentially fatal. [from GeneReviews]

Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility. [from GeneReviews]

ALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (Jaffe and Stith, 2007). [from OMIM]

An increased concentration of 5-aminolevulinic acid (CHEBI:17549) in the urine. [from HPO]