Objective: We report a case of late adult onset gradually progressive spastic paraplegia secondary to pathogenic variants in the POLG gene.

Background: Many pathogenic mutations in the POLG gene have been reported and no clear genotype-phenotype correlations exist. Hereditary spastic paraplegia (HSP) is a group of heterogeneous neurological disorders typified by corticospinal tract degeneration, clinically characterized by progressive spasticity and weakness of the lower limbs. A common downstream pathophysiological continuum of mitochondrial dysfunction unites POLG mitochondrial disease and HSP spectrum diseases in addition to mtDNA polymorphisms. Mitochondrial dysfunction can be most represented in those systems that require high energy such as the descending longest corticospinal tract axons and ascending spinocerebellar tracts. Spastic paraplegia in isolation is an unusual manifestation of POLG related disease not reported previously.

Method: Case report

Results: We present a 74-year old man with gradually progressive symptoms of lower limb stiffness and incoordination for 15 years. Initial exam was significant for lower limb minimal ataxia and moderate spasticity in the lower limbs with extensor plantars and exaggerated deep tendon reflexes in bilateral lower limbs. Other neurological examination was normal. MRI brain demonstrated mild cerebellar atrophy. Whole exome sequencing showed heterozygous biallelic pathogenic variants (c.752 C>T and C.1760 C>T) in the POLG gene.

Conclusion: Spastic predominant ataxia without the other ancillary features (ophthalmoplegia, neuropathy, myopathy and systemic features) has not been reported earlier in POLG disease. Furthermore, in addition to the clinical presentation, this insidious gradual onset and progression in our patient is reminiscent of HSP-like disease. Mitochondrial dysfunction might be the primary or secondary consequence of a genetic defect, with genetic defects in nuclear-encoded genes being more frequent than in mtDNA genes in both mitochondrial ataxias and HSPs. This case adds to a growing collection of case reports describing the various phenotypes of POLG-related disorders. Also, it points to a probable common pathophysiology of reactive oxidative stress and mtDNA polymorphisms in both diseases.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spastic-paraplegia-as-a-novel-phenotype-in-late-adulthood-onset-polg-disease-a-pathophysiological-continuum/