Hereditary spastic paraplegia: Novel insights into the pathogenesis and management.

Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs. Neurodegenerative disorders are conditions that result from cellular and metabolic abnormalities, many of which have strong genetic ties. While ageing is a known contributor to these changes, certain neurodegenerative disorders can manifest early in life, progressively affecting a person's quality of life. Hereditary spastic paraplegia is one such condition that can appear in individuals of any age. In hereditary spastic paraplegia, a distinctive feature is the degeneration of long nerve fibres in the corticospinal tract of the lower limbs. This degeneration is linked to various cellular and metabolic processes, including mitochondrial dysfunction, remodelling of the endoplasmic reticulum membrane, autophagy, abnormal myelination processes and alterations in lipid metabolism. Additionally, hereditary spastic paraplegia affects processes like endosome membrane trafficking, oxidative stress and mitochondrial DNA polymorphisms. Disease-causing genetic loci and associated genes influence the progression and severity of hereditary spastic paraplegia, potentially affecting various cellular and metabolic functions. Although hereditary spastic paraplegia does not reduce a person's lifespan, it significantly impairs their quality of life as they age, particularly with more severe symptoms. Regrettably, there are currently no treatments available to halt or reverse the pathological progression of hereditary spastic paraplegia. This review aims to explore the metabolic mechanisms underlying the pathophysiology of hereditary spastic paraplegia, emphasising the interactions of various genes identified in recent network studies. By comprehending these associations, targeted molecular therapies that address these biochemical processes can be developed to enhance treatment strategies for hereditary spastic paraplegia and guide clinical practice effectively.

Case Report: Response to ipilimumab and nivolumab in a patient with adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare malignancy with limited treatment options. The evidence for the use of immunotherapy in ACC has been conflicting, with overall response rates ranging from 6 - 33%. Case presentation: We describe the case of a 32 year old patient who was initially thought to have an inoperable clear cell renal cell carcinoma and was treated with immunotherapy with ipilimumab and nivolumab. The patient had an excellent partial response to treatment. Further work-up prior to consideration of surgery demonstrated that the tumour was an ACC, rather than a renal cancer. She had a right adrenalectomy and right hepatectomy, achieving an R0 resection and remains disease-free one year after surgery. Conclusion: This case illustrates the challenge of diagnosing ACC, and that doublet immunotherapy with ipilimumab and nivolumab can have significant clinical efficacy in ACC.