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Hereditary spastic paraplegia: membrane lipid synthesis in the brain as next causal “new entry”

Hereditary spastic paraplegias (HSP) is a general term for a group of hereditary degenerative neurological disorders that affect the upper spinal motor neurons, leading to weakness and stiffness in the leg muscles. In the brain and spinal cord, upper motor neurons send signals to lower motor neurons, which, in turn, send signals to the muscles. In HSP, these upper motor neurons gradually degenerate and muscles fail to receive the correct messages. This causes progressive spasticity and muscle weakness in the legs. Increasing stiffness in the legs means patients eventually have difficulty walking and, as the disease progresses, they often become wheelchair dependent. If HSP only affects the lower body, the disease is referred to as uncomplicated or pure, but if other systems in the body are affected, HSP is classified as complex or complicated. The involvement of these systems leads to additional symptoms including ataxia, epilepsy, hearing loss, impaired vision, impaired cognition, and peripheral neuropathy. Currently, there are no treatments available that can prevent, slow or reverse HSP. Symptoms are managed with drugs and physiotherapy. Several gene mutations have been linked to the development of HSP, but in a important percentage of cases, the cause is unknown.

Researchers at the University of Manchester have made an important discovery that could help scientists understand the cause of paraplegia and epilepsy in some sufferers. Their study pointed towards mutations in a gene that codes for an enzyme involved in the synthesis of a key membrane lipid that is particularly enriched in the brain. The finding could contribute towards the development of treatments for people with the mutations and people with related disorders. As reported in the journal Brain, Siddharth Banka and colleagues have now established a new genetic cause of complex HSP. Dr Banka is Clinical Senior and Consultant Clinical Geneticist at Saint Mary’s Hospital, Manchester University NHS Foundation Trust (MFT). The group he leads uses a combination of genomics, clinical and functional studies to investigate the potential causes of disease in patients with unsolved genetic conditions. The team performed a genetic analysis of five individuals with spastic paraparesis (partial paralysis of lower limbs) or tetraparesis (complete paralysis of the body from the neck down), epilepsy and progressive cerebral and cerebellar atrophy. Their analysis revealed that complex HSP is caused by mutations in a gene called PCYT2 that make it less active.

PCYT2 encodes an enzyme called phosphoethanolamine cytidylyl-transferase, which is used to synthesize a cell membrane lipid called phosphatidylethanolamine or PhE. This is one of the most abundant membrane lipids in the body and it is particularly enriched in the brain. The team studied the effects of HSP by comparing zebrafish with normal or reduced PCYT2 activity and cell samples taken from patients who had the disease. They found that survival rates among zebrafish with normal or reduced PCYT2 activity were significantly higher than among fish with a complete knockout of PCYT2. This led Banka and colleagues to conclude that complete loss of PCYT2 activity is likely to be incompatible with life in vertebrates. Collaborators in Amsterdam also identified abnormal biochemical signatures in the fibroblasts of patients who donated blood samples. Using patient fibroblasts, they demonstrated that these variants are hypomorphic, result in altered but residual protein levels and concomitant reduced enzyme activity. The researchers hope that these signatures could one day be used as biomarkers to help diagnose patients with the condition.

The researchers hope that studying the PCYT2 gene will also help researchers understand other types of HSP and other neurodegenerative conditions. Dr. Banka says that being able to combine his role as an academic researcher and his role as a clinician, has been key in making this discovery: “Saint Mary’s Hospital is one of the leading NHS and internationally recognized large-scale providers of genomic services. Being able to combine my clinical role at the hospital, with my academic research at The University of Manchester, has been crucial to this outcome. The link between academia and the NHS means the team can translate research from the bench to the bedside, for the benefit of patients. The identification of more patients in future will help in better understanding of the effects of hereditary paraplegia”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Vaz FM et al. Brain. 2019 Nov 1; 142(11):3382-3397.

Infante J et al. Matilla-Dueñas A. J Neurol. 2019 Oct 21. 

Wagner M et al. Nat Commun. 2019 Oct 21; 10(1):4790.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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