Porphyria, Variegate

Protoporphyrinogen IX oxidase (PPO) is the last common enzyme in chlorophyll and heme biosynthesis pathways. In humans, point mutations on PPO are responsible for the dominantly inherited disorder disease variegate porphyria (VP). It is found that several VP-causing mutation sites are located on an α-helix cluster (consisting of α-5, α-6, and α-7 helix, named the G169 helix cluster) of human PPO, although these mutation sites are outside the active site of the human PPO. In this work, we investigated the role of the G169 helix cluster via site-directed mutagenesis, enzymatic kinetics, and computational studies. Kinetic studies showed that mutations on the G169 helix cluster affect the activity of PPO. The MD simulation showed that mutations on the G169 helix cluster reduced the activity of PPO by affecting the proper orientation of substrate protoporphyrinogen within the active site of PPO and possibly the dipole moment of the G169 helix cluster. Moreover, the mutation abolished the interaction between the mutated site and other residues, thus affecting the secondary structure and hydrogen bond interactions within the G169 helix cluster. These results indicated that the integrity of the G169 helix cluster is important for the stabilization of protoporphyrinogen within the active site of PPO to facilitate the interaction between protoporphyrinogen and cofactor FAD and provide a proper electrostatic environment for the activity of PPO. Our result provides new insight into understanding the relationship between the structure and function of PPO.

Vascular Parkinsonism (VP) is clinical term represents a progressive ischemic changes and subcortical lacunar infarct leading to Parkinsonism mainly in the lower limbs so called lower body Parkinsonism. The VP neuropathology is differed from that of PD neuropathology which rarely associated with basal ganglion lesions. Dopamine transporters are normal in VP but are highly reduced in PD, and dopaminergic agonists had no effective role on VP. The neuropathological mechanisms of VP are related to vascular injury which induces the interruption of the neural connection between basal ganglion and cerebral cortex. Hyperlipidemia and other cardiometabolic risk factors augment VP risk and the related neuropathology. Targeting of these cardiometabolic disorders by lipid-lowering statins may be effective in the management of VP. Therefore, this mini-review aims to clarify the possible role of statins in the management of VP. Statins have neuroprotective effects against different neurodegenerative diseases by anti-inflammatory, antioxidant and antithrombotic effects with enhancement of endothelial function. In conclusion, statins can prevent and treat VP by inhibiting inflammatory and oxidative stress disorders, mitigating of white matter hyperintensities and improving of neuronal signaling pathways. Additional preclinical, clinical trials and prospective studies are warranted in this regard.

The tracheoesophageal puncture for the voice prosthesis (VP) placement is the recognized gold standard in post-laryngectomy voice rehabilitation. Despite the development of specific intraoperative techniques, a subset of patients will suffer from poor functional outcomes due to pharyngoesophageal spasms (PES). This paper evaluates the functional outcomes after transcutaneous botulinum toxin type A (BTX-A) infiltration for PES with a videofluoroscopy-guided technique.

Since 2022, eight consecutive patients with VP and affected by PES were treated with BTX-A injection by a standard videofluoroscopic guided technique at the European Institute of Oncology, IRCCS (IEO) in Milan. A lidocaine test was performed pre-operatively to evaluate the potential effect of chemical neurectomy. All patients with positive lidocaine tests were injected with 50 IU of BTX-A (Allergan, Irvine, CA) according to the sites marked during the videofluoroscopy. Reported symptoms (VHI, SECEL), perceptual (INFVo), aerodynamic (MPT) and manometric parameters were collected before and after treatment.

In all cases, BTX-A was performed as an outpatient procedure without complications. For seven patients, only one BTX-A injection was needed, while one patient required a re-injection. Subjective and perceptive improvement after BTX-A was significant for VHI, SECEL and INFVo. MPT showed significant improvement after a chemical neurectomy. After a mean follow-up of 6 months, all patients maintained a good TES quality.

The videofluoroscopic guided BTX-A injection of the pharyngoesophageal tract showed to be a feasible and reproducible technique in all cases. The pharyngoesophageal videofluoroscopy allows defining of patients' anatomical landmarks that help the surgeon to perform a homogeneous injection, empowered by post-injection massage.