Brain ventricular enlargement in human and murine acute intermittent porphyria

Abstract

The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyse brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.

Recent Insights into the Pathogenesis of Acute Porphyria Attacks and Increasing Hepatic PBGD as an Etiological Treatment

“…Among CNS-related abnormalities, structural changes and brain perfusion have been poorly characterized in patients with acute liver porphyria. Recently, neuroradiological studies have described an enlargement in the brain ventricles in eight patients with severe AIP and recurrent acute attacks without posterior reversible encephalopathy syndrome [74]. In addition, a decrease in brain perfusion during acute attacks was also reported in two of the patients in whom perfusion imaging data were acquired [74].…”

“…The effect of therapy to increase liver PBGD levels in response to these brain changes was studied in the AIP mouse model [74]. AIP mice developed chronic brain ventricle dilatation even in the presence of slightly increased porphyrin precursors.…”

“…AIP mice not exposed to phenobarbital challenge also exhibited reduced cerebral blood flow with normal systolic blood pressure [74]. Of interest, correction of liver PBGD deficiency reversed brain perfusion reduction and prevented progressive brain ventricle enlargement in AIP mice subjected to repeated acute porphyric attacks (Table 2) [74].…”

“…AIP mice not exposed to phenobarbital challenge also exhibited reduced cerebral blood flow with normal systolic blood pressure [74]. Of interest, correction of liver PBGD deficiency reversed brain perfusion reduction and prevented progressive brain ventricle enlargement in AIP mice subjected to repeated acute porphyric attacks (Table 2) [74]. The authors suggested that constitutive small vessel dysfunction associated with the systemic arterial hypertension that occurs during acute porphyria attacks could cause an imbalance in cerebrospinal fluid resulting in brain ventricle enlargement.…”

A joint ventricle and WMH segmentation from MRI for evaluation of healthy and pathological changes in the aging brain

“…Enlargement of the ventricles may occur due to atrophy or impaired cerebrospinal fluid (CSF) circulation [ 7 ]. Both WMHs and enlarged ventricles are also biomarkers for other conditions, e.g., genetic diseases [ 8 ] and autoimmune diseases, such as multiple sclerosis [ 9 ]. Hence, neurodegenerative diseases and normal aging can cause both WMHs and enlarged ventricles.…”