ポルフィリン症

Worldwide, patients with porphyrias face critical delays in diagnosis. In Mexico this situation is no exception and, due to the characteristics of the local health system, population distribution and lack of access to health services and specialized porphyria centers, diagnosis and treatment are complex. Much work remains to be done, in collaboration with government authorities, physicians, advocacy groups and the pharmaceutical industry, to provide knowledge, diagnostic tools and targeted therapies to all porphyria patients in need.

Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.

δ-Aminolevulinic acid dehydratase deficient porphyria (ADP) is an exceedingly rare form of acute porphyria, with only fifteen published cases worldwide. This disorder has historically been considered an hepatic porphyria, as it was thought the overproduction of the toxic metabolite δ-Aminolevulinic acid (ALA) solely occurred in the liver. This case report demonstrates that treatments focused on reducing the hepatic ALA production had limited effect on this patient's symptoms. An earlier published hypothesis that patients with ADP also produce substantial levels of bone marrow derived ALA, was retested. We describe a Dutch patient in his early 60s, who has suffered from ADP since birth. His medical history mentions acute neurovisceral attacks, contractures of hand and feet, severe polyneuropathy, developmental delay, and renal insufficiency (eGFR 30-40 ml/min). For over a decade he was treated with weekly heme prophylaxis to reduce the frequency of neurovisceral attacks. Despite continuation, his chronic neurological symptoms aggravated and, in an attempt to suppress erythroid ALA production, weekly erythrocyte transfusions combined with hydroxyurea was started. The patient's symptoms improved and stabilized during this treatment. Oral chelation therapy was started to limit secondary iron overload caused by both heme and erythrocyte infusions. Years later we could trial givosiran, an ALAS1-siRNA to suppress the hepatic ALA production. After starting givosiran the heme infusions could be stopped without an increase in symptoms, but discontinuation of erythrocyte transfusions led to new onset neurovisceral attacks. His current schedule consists of continued givosiran and erythrocyte transfusions. This case report illustrates that ADP can be treated successfully with both hepatic and erythroid suppression. It also illustrates the challenges of treating a patient with a rare, complex and poorly understood disease, and the difficulty to balance the complications, side effects and the benefits of treatments.

Acute intermittent porphyria is a rare disorder causing neurotoxic precursor accumulation and severe neurological complications. We report a case progressing to tetraplegia and respiratory failure with delayed diagnosis. Treatment with hemin and givosiran resulted in prevention of attacks and functional recovery, highlighting the importance of early diagnosis and long-term therapy.

BACKGROUND AND PURPOSE: The CNS imaging manifestations of acute intermittent porphyria (AIP) are poorly systematized. We aimed to characterize the spectrum of MRI brain findings and evaluate the association between dysautonomia, CNS findings, and enteric manifestations. MATERIALS AND METHODS: We retrospectively identified patients with biochemically confirmed AIP who presented between 2008 and 2018 with acute neurovisceral episodes. This observational study did not include a control group. MRI brain studies performed during acute presentations were reviewed at the study level and categorized by predominant anatomical distribution into lobar-cortical, hippocampal, cortical-subcortical, deep gray matter, and normal patterns. Clinical and biochemical parameters were analyzed at the episode level with respect to dysautonomia status. RESULTS: Twenty-three patients with 27 acute neurovisceral episodes were identified; 17 underwent MRI, yielding 28 studies. The lobar-cortical pattern was most frequent (9/28; 32.1%), followed by hippocampal (6/28; 21.4%), cortical-subcortical (3/28; 10.7%), and deep gray matter (3/28; 10.7%); 7 of 28 studies (25.0%) were normal. Two patients showed evolving findings across serial MRI. Dysautonomia, documented in 12/27 (44.4%) episodes, was significantly associated with ileus (p < 0.001) and hyponatremia (p = 0.02). CONCLUSIONS: AIP is associated with a broader range of MRI brain appearances than classical PRES alone, with overlap from seizure-related, metabolic, and electrolyte-related processes; no single pattern is diagnostic on its own. The observed clustering of dysautonomia, ileus, and hyponatremia, together with the inverse correlation between aminolevulinic acid and serum sodium, supports a shared autonomic basis for these manifestations. Recognizing this combined imaging and clinical pattern may help raise AIP as a diagnostic consideration.