This clinical case involves two siblings, a 6 year old girl and a 13 year old boy, children of consanguineous parents, diagnosed with acute porphyria due to ALA-dehydratase deficiency. They have been followed at our center since the summer of 2022. Diagnosis was confirmed through exome sequencing, which revealed a homozygous variant in the ALAD gene in both siblings, resulting in reduced enzyme activity and elevated urinary ALA and coproporphyrin III, along with increased blood levels of protoporphyrin-Zn. The male presents with axonal polyneuropathy, difficult-to-control arterial hypertension, mild cognitive deficit, sensorineural hearing loss requiring a prosthesis and mood swings. The female exhibits axonal polyneuropathy, tetraparesis with tendon contractures, resistant arterial hypertension, psychomotor retardation, prosthetic sensorineural deafness, and requires PEG for nutritional support. Since age 8 for the boy and age 5 for the girl, both have experienced monthly acute crises characterized by headache, nausea, abdominal and limb pain, and hypertensive episodes necessitating hospitalization and sometimes intensive care to manage pain and high blood pressure. On one occasion, the girl required intubation and ventilatory support due to severe respiratory failure. Following their diagnosis, the treatment regimen included hemin (4 mg/kg/day iv) during exacerbations and subsequently as prophylaxis, givosiran (2.5 mg/kg sc) during exacerbations and periods of well-being, continuous hydroxyurea (10–20 mg/kg/day orally), plasmaexchange/erythroexchange during acute phases and as prophylaxis, and continuous opioid therapy. In the boy, painful crises subsided for about a year, allowing near-complete neuromotor recovery, but recurred following psychophysical stress, resulting in severe motor deficits and dysphonia, making him wheelchair-dependent. The girl’s monthly neurovisceral crises, more severe and frequent than her brother’s, were consistently accompanied by resistant hypertensive crises. Over the past 20 months, both siblings have endured severe monthly neurovisceral crises involving significant peripheral, central, and autonomic neurological impairment. Triggers for these crises remain unidentified, and ALA levels have persistently remained high, even during periods of well-being. Hemin, administered during acute phases and subsequently as bi-weekly prophylaxis, effectively resolved acute crises (latency of 48–72 hrs) and reduced urinary ALA levels but did not ensure prolonged well-being. Givosiran had no effect on clinical symptoms or urinary ALA reduction. Hydroxyurea significantly reduced erythrocyte protoporphyrins but did not impact clinical symptoms or urinary ALA levels. Plasmaexchange/erythroexchange were ineffective in reducing or preventing acute crises, providing only temporary reductions in urinary ALA. Frequent changes in opioid medications (morphine, methadone, fentanyl) were necessary to manage chronic pain and flare-ups.