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Betegségjelentés · Metabolic

Acute Intermittent Porphyria

Whole genome sequencing identifies HMBS variants that determine acute intermittent porphyria susceptibility, enabling carrier screening and personalized trigger avoidance.

A betegségjelentés olyan ritka variánsokat keres, amelyekről ismert, hogy okozzák az általa lefedett betegségeket.

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A(z) condition ismertetése

A group of rare genetic disorders resulting from defects in heme synthesis, causing the accumulation of porphyrins and precursors, and manifesting in neurological, psychiatric, or skin symptoms.

Acute intermittent porphyria (AIP) is a rare autosomal dominant disorder of heme biosynthesis characterized by acute neurovisceral attacks triggered by specific drugs, hormonal changes, fasting, stress, or illness. Prevalence is approximately 1 in 75,000, though exact prevalence is uncertain due to underdiagnosis. Acute attacks feature severe abdominal pain (often colicky), nausea, vomiting, constipation, tachycardia, hypertension, and neuropsychiatric symptoms including confusion, anxiety, depression, and psychosis. Attacks can progress to dangerous complications including respiratory failure from neuromuscular involvement. Penetrance is remarkably low: only approximately 0.5-1% of germline HMBS variant carriers develop clinical attacks; approximately 20% penetrance is observed in known families with previous cases. Attacks are recurrent once initiated, with stress, menses, fasting, or medication triggering recurrence for decades. Many carriers never develop an attack and remain asymptomatic. The disease has been described as 'the little imitator' because acute presentation can mimic acute abdomen, psychiatric crisis, seizure, or other medical emergencies.

HMBS encodes hydroxymethylbilane synthase (porphobilinogen deaminase), the third enzyme in the heme biosynthesis pathway. It catalyzes the condensation of four molecules of porphobilinogen (PBG) into hydroxymethylbilane (HMB), a critical step in heme synthesis. Loss-of-function HMBS variants cause reduced enzyme activity, permitting accumulation of upstream pathway intermediates (δ-aminolevulinic acid, ALA, and porphobilinogen, PBG), which are neurotoxic. Elevated urine ALA and PBG are diagnostic for acute porphyria. More than 400 HMBS variants have been identified, including nonsense, missense, and splice-site mutations causing variable degrees of enzyme deficiency. In asymptomatic carriers (the majority), enzyme levels are sufficient to prevent attack unless triggered by factors that increase heme demand (e.g., drugs that induce cytochrome P450 enzymes, leading to increased demand for heme cofactor).

An HMBS pathogenic variant identification has major implications for lifestyle and medication safety. Confirmed AIP carriers must avoid 'porphyrinogenic' drugs including barbiturates (phenobarbitone, pentobarbital), sulfonamides, oral contraceptives (though hormone-specific subsets may be safer), NSAIDs, and many others; comprehensive drug lists are maintained at porphyria.org and debrisoquine.org. Carriers must maintain adequate calorie intake (fasting is a trigger), manage stress, and receive education about attack recognition. Acute attacks are treated with IV dextrose or IV hemin (hematin), the latter being highly effective at downregulating ALA synthase and terminating attacks. Givosiran (Givlaari), an RNA interference therapeutic targeting ALAS1 (the rate-limiting heme synthesis enzyme), was approved in 2019 and reduces annualized attack frequency from 12.5 to 3.2 attacks per year in phase 3 trials, a major therapeutic advance. For women, hormonal management during pregnancy and menopause requires careful planning.

A vizsgált betegség

Porphyria is a group of diseases in which substances called porphyrins build up, negatively affecting the skin or nervous system. Most types are inherited, but porphyria cutanea tarda may also be due to increased iron in the liver, hepatitis C, alcohol, or HIV/AIDS.

Mit változtat a diagnózis

Attack prevention through trigger avoidance, IV dextrose or hemin during acute attacks, RNA interference therapy (givosiran), genetic counseling

Vizsgált gének

29 kapcsolódó altípust tartalmaz ↓
  • acquired porphyria
  • acute intermittent porphyria
  • autosomal erythropoietic protoporphyria
  • chester porphyria
  • CPOX-related hereditary coproporphyria
  • cutaneous porphyria
  • encephalopathy, porphyria-related
  • erythropoietic protoporphyria
  • erythropoietic uroporphyria associated with myeloid malignancy
  • familial porphyria cutanea tarda
  • harderoporphyria
  • hepatic cutaneous porphyria
  • hepatic porphyria
  • hepatoerythropoietic porphyria
  • hereditary coproporphyria
  • HMBS-related hepatic porphyria
  • inherited porphyria
  • leukoencephalopathy, porphyria-related
  • porphyria cutanea tarda
  • porphyria due to ALA dehydratase deficiency
  • porphyria, acute intermittent, nonerythroid variant
  • PPOX-related hepatic porphyria
  • protoporphyria, erythropoietic, 1
  • protoporphyria, erythropoietic, 2
  • sporadic porphyria cutanea tarda
  • UROD-related inherited porphyria
  • variegate porphyria
  • variegate porphyria, childhood-onset
  • X-linked erythropoietic protoporphyria
MONDO:0037939MedGen 1844832

Miért a teljes genom szekvenálás

Porphyria diagnosis is challenging because acute attacks are rare and unpredictable. Most HMBS carriers are asymptomatic and never diagnosed.

Most HMBS variant carriers remain asymptomatic and undiagnosed

Only approximately 0.5-1% of germline HMBS variant carriers develop clinical attacks; approximately 20% penetrance is observed in families with known cases. Many porphyria panels focus on the most common variants and may miss rare HMBS mutations. Diagnosis is typically made by measuring urine PBG and ALA during or immediately after an acute attack (levels normalize between attacks, making retrospective diagnosis difficult). Carrier testing is useful for presymptomatic family members but not routine. Whole genome sequencing captures all HMBS variants, enabling comprehensive carrier screening in families with known AIP or in individuals with unexplained acute neurovisceral attacks.

HMBS genotype enables lifelong trigger avoidance and attack prevention

Confirmed AIP carriers must permanently avoid porphyrinogenic drugs (barbiturates, sulfonamides, NSAIDs, many others), maintain adequate calorie intake, manage stress, and receive education about attack recognition. A genetic diagnosis enables cascade screening of first-degree relatives, identifying carriers who can be counseled on triggers and medication avoidance before an attack occurs. Documented in the medical record and communicated to the patient, HMBS genotype prevents life-threatening drug reactions and guides personalized attack prevention strategies. Givosiran (Givlaari), approved for AIP, reduces annualized attack frequency from 12.5 to 3.2 attacks per year and offers new hope for frequent attackers. Early identification through genetic screening enables prevention rather than crisis management.

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