Objective: Describe a rare genetic and clinical presentation of SPG7-related Hereditary Spastic Paraplegia.

Background: SPG7-related spastic paraplegia (SPG7) is a hereditary spastic paraplegia caused by an increasing number of identified genetic variants in the SPG7 gene and presents with significant clinical variability.[1]  Progressive bilateral lower extremity weakness and spasticity are typical of the SPG7 phenotype with variable presence of ataxia, ophthalmoplegia, intellectual disability, and seizures.[1–4] We present a patient with rare compound heterozygous mutations of SPG7, presenting with ataxia, periodic alternating nystagmus (PAN), and progressive lower extremity spasticity.

Method: Case report.

Results: A 42-year-old woman presented to our clinic for progressive balance disturbances and cerebellar atrophy on imaging. She had no family history of gait difficulties. She was diagnosed with a non-verbal intellectual disability at age 20. As a child she was clumsy and in her 20s physical activity became difficult. In her 30s, she developed left lower extremity weakness and bilateral lower extremity pain, and imaging revealed cerebellar atrophy.

Our initial clinical evaluation noted dysarthric speech, right eye exotropia, resting and gaze-evoked nystagmus, dysmetria with broad-based gait and irregular foot placement, lower extremity spasticity, brisk reflexes without clonus, and mild length-dependent sensory deficit. The patient was referred to neuro-ophthalmology and diagnosed with PAN. Whole exome sequencing identified two SPG7 variants. Parental testing revealed a likely pathogenic variant in the maternal allele introducing a frameshift mutation and early truncation (SPG7 NM_003119.4 c.1450-1 1457delGGAGAGGCG). A variant in the paternal allele with a single nucleotide mutation in the peptidase M41 domain was initially classified as having unknown significance but is concerning for likely pathogenic (Paternal: SPG7 NM_003119.4 c.1727C>G).[5]

     The patient was treated with baclofen with improved vision, stability, and less prominent PAN. Four years later the patient’s symptoms remain stable.

Conclusion: SPG7 should be considered in cases of undiagnosed ataxia. PAN, previously unassociated with SPG7, may be the result of the unique genetic mutations seen in our patient, or may be underdiagnosed in this population, and referral to neuro-ophthalmology is advisable, especially given PAN is responsive to treatment.

References: 1. Casari G, Marconi R. Spastic Paraplegia 7. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2023 Jan 6]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1107/
2. van Gassen KLI, van der Heijden CDCC, de Bot ST, den Dunnen WFA, van den Berg LH, Verschuuren-Bemelmans CC, et al. Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort. Brain. 2012;135:2994–3004.
3. Eriksen KO, Wigers AR, Wedding IM, Erichsen AK, Barøy T, Søberg K, et al. A novel homozygous variant in the SPG7 gene presenting with childhood optic nerve atrophy. American Journal of Ophthalmology Case Reports [Internet]. 2022 [cited 2023 Mar 11];26:101400. Available from: https://www.sciencedirect.com/science/article/pii/S2451993622001463
4. Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, et al. SPG7 mutations are a common cause of undiagnosed ataxia. Neurology [Internet]. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology; 2015 [cited 2023 Jan 6];84:1174–6. Available from: https://n.neurology.org/content/84/11/1174
5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med [Internet]. Nature Publishing Group; 2015 [cited 2022 Nov 4];17:405–23. Available from: https://www.nature.com/articles/gim201530

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