Spg7, also known as paraplegin, encodes a mitochondrial metalloprotease. Under normal physiological conditions, SPG7, along with AFG3L2, is tethered to prohibitin 1 (PHB1) to inhibit the opening of the mitochondrial permeability transition pore (mPTP), thus preventing mtDNA release and downstream inflammatory responses [1]. Mutations in SPG7 are associated with several neurodegenerative disorders. It is a causative gene for hereditary spastic paraplegia type 7 (SPG7), a neurodegenerative disorder characterized by progressive leg weakness and spasticity due to corticospinal axon degeneration [3].

In a study on a patient with cerebellar degeneration, compound heterozygous mutations in SPG7 were found, presenting with ataxia and impaired emotional communication, broadening the phenotypic boundary of SPG7 [2]. Additionally, SPG7 mutations have been identified in patients with isolated optic atrophy and infantile nystagmus, suggesting it should be considered as a cause for these conditions [3]. In a cohort of amyotrophic lateral sclerosis (ALS) patients, rare heterozygous SPG7 variants were detected, indicating SPG7 may act as a genetic risk factor for ALS, with patients showing overlapping features with HSP, especially cerebellar findings [4]. Also, in French Canadian patients with spastic ataxia, SPG7 mutations were identified, suggesting it is a common cause of recessive cerebellar ataxia in this population [5].

In conclusion, Spg7 is crucial in maintaining mitochondrial integrity by regulating mPTP opening. Its mutations are linked to various neurodegenerative diseases, including hereditary spastic paraplegia, ALS, and cerebellar ataxia. Studies on these mutations in different patient cohorts have expanded our understanding of the phenotypic spectrum associated with Spg7, highlighting its significance in neurodegenerative disease research.