ポルフィリン症

BACKGROUND: The neurological manifestations of acute attacks and chronic symptoms were evaluated both prospectively and retrospectively in 90 patients with acute porphyria and integrated with data from previously published series. RESULTS: Most acute attacks presented with a combination of abdominal pain, mild cognitive and behavioral symptoms, and autonomic dysfunction, predominantly attributed to vagal insufficiency. Acute peripheral neuropathy and encephalopathy developed if an acute attack proceeded. Acute peripheral neuropathy emerged 1-3 weeks after the onset of an attack and was predominantly motor in nature. It was consistently associated with preceding abdominal pain (100%) and dysautonomia (100%), and frequently accompanied by central nervous system involvement (50%) and mild hepatopathy (75%). Acute encephalopathy (AE), which was transient resolving within a few days, manifested 3-19 days after attack onset. AE was characterized by a triad of seizures, confusion, and/or blurred vision. PRES was identified on MRI in 42% of patients with AE during acute attacks; among these, 88% were hyponatremic and 94% had mild hepatopathy. Of the patients with recurrent attacks, ∼40% experienced chronic symptoms. The most common clinical pattern consisted of chronic mild-to-moderate neuropathic pain, fatigue, and nausea, typically developing within the first year of cyclical attacks. All patients in this subgroup exhibited persistently elevated urinary porphobilinogen (PBG) excretion. Most patients without recurrent attacks reported no chronic symptoms. Seven patients experienced chronic neuropathic pain, fatigue, and nausea despite the absence of recurrent attacks. Only three of them exhibited persistently elevated urinary PBG excretion. They had previously demonstrated cyclical attacks that had spontaneously subsided but subsequently evolved into chronic mild pain and fatigue, often exacerbated by stress or infections, without further overt attacks. The remaining four patients had a mild increase in urinary PBG levels, and their chronic symptoms developed 3-23 years after their last documented acute attack. CONCLUSION: The pathogenesis of autonomic and peripheral neuropathy in acute porphyria is complex; delta-aminolevulinic acid is considered a potential initiator of neuronal injury. The mechanisms underlying AE remain incompletely understood, but current evidence suggests a multifactorial process involving abrupt hypertensive episodes, SIADH, and acute metabolic or inflammatory factors of hepatic origin. Chronic symptoms are common among patients with recurrent attacks. The most effective treatment should focus on preventing recurrent attacks.

BACKGROUND: Acute intermittent porphyria (AIP) is the most common form of acute porphyria, a group of rare inherited disorders of heme biosynthesis. Severe attacks may be associated with life-threatening complications, including peripheral motor neuropathy, encephalopathy and seizures. Very rarely, an acute AIP attack can be complicated by rhabdomyolysis as illustrated in this case report. CASE SUMMARY: A 28-year-old female presented with severe abdominal pain and muscle weakness, which progressed to severe rhabdomyolysis and acute kidney injury requiring dialysis. The disease course was further complicated by an acute severe axonal peripheral motor neuropathy with quadriparesis and respiratory muscle weakness requiring prolonged invasive mechanical ventilation. An important clue for diagnosis was red urine without hematuria. The diagnosis was established by the finding of elevated δ-aminolevulinic acid and porphobilinogen in a random urine sample and later confirmed by genetic testing. The patient was initially treated with hemin and parenteral glucose. However, since she needed prolonged treatment, givosiran was commenced and continued after discharge. When the period between givosiran administrations was extended to two months, this led to a new (milder) attack. After 40 months of givosiran treatment and continued physical rehabilitation, the patient is ambulatory and without acute attacks. CONCLUSION: Our case illustrates that treatment with hemin and givosiran for longer than two years may be needed for neurological recovery after an AIP attack with severe motor polyneuropathy and multisystem involvement.

X-linked erythropoietic protoporphyria (XLEPP) is a rare non-acute porphyria associated with severe photosensitivity and, in some patients progressive hepatobiliary disease. We describe the perioperative management of a middle-childhood-aged female with XLEPP, end-stage liver disease, portal hypertension-related thrombocytopenia and coagulopathy who required urgent dental extractions to facilitate transplant preparation. Key anaesthetic considerations included avoidance of phototoxic light exposure, safe drug selection, altered pharmacology in liver disease and bleeding risk. Surgery was performed under propofol-remifentanil total intravenous anaesthesia using the hospital's iLED 7 (Baxter Medical Systems GmbH + Co. KG, Saalfeld, Germany) light-emitting diode (LED) theatre lighting system, without additional optical filters or intraoperative light dosimetry. Additional precautions included avoidance of sunlight and fluorescent lighting, theatre-blind closure, occlusive coverings during transfer and recovery, coagulation optimisation, tranexamic acid and meticulous local haemostasis. The patient had no perioperative phototoxic injury, haemodynamic instability or red cell transfusion requirement and was discharged home the following day. This case highlights multidisciplinary planning in rare paediatric photosensitive liver disease.

INTRODUCTION: Porphyrias are rare inherited disorders of heme synthesis caused by reduced activity of one of the eight enzymes in the pathway. When early precursors accumulate, acute hepatic porphyrias occur, which present as severe neurovisceral attacks. When later, light-sensitive porphyrins accumulate, they cause cutaneous forms with chronic photosensitivity, blistering and skin fragility. Although these patterns are usually distinct, acute, and cutaneous features may appear together. This may reflect two separate genetic defects, but more often occurs when oxidative stress, such as from iron overload, chronic infection, or drugs, secondarily inhibits the fifth enzyme, uroporphyrinogen decarboxylase. This creates a mixed porphyrin pattern in which the usual distinctions between acute and cutaneous porphyrias are blurred, making diagnosis challenging. CASE PRESENTATION: A 22-year-old woman living with human immunodeficiency virus (HIV) infection presented with recurrent abdominal pain during the luteal phase of menstruation, autonomic instability, and limb weakness that improved following heme arginate therapy. Urine porphobilinogen was markedly elevated, and hydroxymethylbilane synthase (HMBS) gene sequencing confirmed acute intermittent porphyria (AIP). However, her porphyrin studies also demonstrated pronounced urinary uroporphyrin elevation together with faecal isocoproporphyrins, a pattern characteristic of porphyria cutanea tarda (PCT). DISCUSSION: The findings are consistent with AIP complicated by secondary hepatic inhibition of uroporphyrinogen decarboxylase. In this patient, secondary uroporphyrinogen decarboxylase (UROD) inhibition was likely driven by persistent HIV viraemia, antiretroviral-associated hepatic oxidative stress, and chronic inflammatory activation which are well-recognised risk factors for acquired PCT-like biochemical patterns. CONCLUSION: This case demonstrates how co-morbidities can modify classical porphyria biochemical patterns and reinforces the need for integrated urine, plasma, and faecal interpretation, especially when biochemical profiles appear mixed. Clinically, patients living with HIV who have porphyria may benefit from closer monitoring for factors that increase liver stress, especially ongoing viraemia, hepatotoxic or porphyrinogenic drugs, alcohol use and iron overload. When virological control is poor, the risk of secondary UROD inhibition and mixed biochemical findings may increase. Regular review of HIV virological control, liver function, medication safety and porphyrin profiles may therefore help prevent recurrent attacks and reduce diagnostic confusion.

BACKGROUND: Heme synthesis is critical for several biological processes, including mitochondrial energy production and oxygen delivery via hemoglobin. The initial and rate-limiting step in heme synthesis is the conjugation of glycine with succinyl-CoA to form 5-aminolevulinic acid (ALA), which is catalyzed by two closely related enzymes that are coded by highly homologous genes, known as ALAS1 and ALAS2. Loss-of-function variants in ALAS2 result in sideroblastic anemia, whereas gain-of-function variants result in porphyria. We present a case of a woman who died with severe metabolic acidosis and was found to have a rare variant in ALAS2. We propose the hypothesis that the ALAS2 variant, in conjunction with other factors, was responsible for her demise. CASE REPORT: A previously healthy 34-year-old woman presented to the emergency department of her local hospital complaining of severe fatigue. Her arterial pH was 6.95. No cause for her acidosis could be identified, and she expired from unremitting acidosis. The autopsy was notable for an enlarged liver. Whole exome sequencing identified a rare, paternally inherited variant in ALAS2. This prompted a re-evaluation of the autopsy and the development of a novel hypothesis to explain her acidosis. We propose that the ALAS2 variant identified in this family, NM_000032.5(ALAS2)c.1273C>T(p.Pro425Ser), is a conditional allele that can contribute to mitochondrial dysfunction under unusual conditions. DISCUSSION: We hypothesize that the P425S variant identified in ALAS2 leads to dysfunction of the homeostatic down-regulation of ALAS2 in times of cofactor deficiency. This case illustrates that DNA sequencing as a part of the autopsy procedure will, as it becomes more routine, lead to the identification of sequence variants that may or may not be clinically relevant. The pursuit of hypotheses, prompted by genetic data, has the potential to identify novel pathogenic mechanisms.