Recovery of chronic motor neuropathy due to acute intermittent porphyria after givosiran treatment in a young boy: a case report.

BACKGROUND: We describe the first case of a pediatric patient with acute intermittent porphyria and severe chronic porphyric neuropathy treated with givosiran, a small-interfering RNA that drastically decreases delta-aminolevulinic acid production and reduces porphyric attacks' recurrence. CASE REPORT: A 12-year-old male patient with refractory acute intermittent porphyria and severe porphyric neuropathy was followed prospectively for 12 months after givosiran initiation (subcutaneous, 2.5 mg/kg monthly). Serial neurological, structural, and resting-state functional magnetic resonance imaging (MRI) evaluations were performed, including clinical scales and neurophysiological tests. Delta-aminolevulinic acid urinary levels dropped drastically during treatment. In parallel, all the administered neurological rating scales and neurophysiological assessments showed improvement in all domains. Moreover, an improvement in central motor conduction parameters and resting-state functional connectivity in the sensory-motor network was noticed. At the end of the follow-up, the patient could walk unaided after using a wheelchair for 5 years. CONCLUSIONS: A clear beneficial effect of givosiran was demonstrated in our patient with both clinical and peripheral nerve neurophysiologic outcome measures. Moreover, we first reported a potential role of givosiran in recovering central motor network impairment in acute intermittent porphyria (AIP), which was previously unknown. This study provides Class IV evidence that givosiran improves chronic porphyric neuropathy.

Neurological manifestations of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inherited metabolic disease due to a deficiency of the hydroxymethylbilane synthase in the haem biosynthesis. It manifests with occasional neurovisceral crises due to overproduction of porphyrin precursors such as aminolaevulinic acid (ALA) which is released from the liver to the circulation. The majority of the acute attacks manifest as a combination of abdominal pain, mild mental symptoms and autonomic dysfunction mainly due to vagal insufficiency. However, both acute peripheral neuropathy and encephalopathy may develop if an acute attack proceeds especially due to administration of porphyrinogenic drugs. Acute porphyric neuropathy is predominantly motor and associates with a history of abdominal pain and dysautonomia, CNS involvement and mild hepatopathy. Other features include preservation of achilles reflexes while global hyporeflexia and neuropathic or myalgic pain. The pathogenesis of porphyric neuropathy is complex but overproduction of ALA via direct neurotoxicity, oxidative damage, and modification of glutamatergic release may initiate the neuronal damage. Acute encephalopathy manifests as a combination of mental symptoms, seizures, SIADH, but rarely focal CNS deficits. Posterior reversible encephalopathy syndrome (PRES), which has been found in patients' MRI during an acute attack with severe encephalopathy, could explain the pathogenesis of encephalopathy and seizures in AIP. Neurological manifestations are unspecific and careful interpretation of abnormal excretion of porphyrin precursors should be done before the symptoms can be related to inherited acute porphyrias and not to secondary porphyrinuria. Currently the prognosis of neuropathy and encephalopathy in AIP is good even in severe attacks, but physicians should be aware of a potentially fatal outcome of the disease.