Objective: To characterize the phenotypic variability of spastic paraplegia type 7 in a single family.

Background: Spastic paraplegia type 7 (SPG7) is an autosomal recessive condition due to mutations in the SPG7 gene which encodes paraplegin with onset from young to late adulthood. It is characterized by progressive bilateral leg weakness, spasticity, and neuropathy. Additional features include ataxia, nystagmus, dysarthria, urinary dysfunction, optic neuropathy, supranuclear gaze palsy, hearing loss, and amyotrophy [1,2]. Neuroimaging may show cerebellar atrophy and white matter changes.

Method: We reviewed the clinical presentation of a patient with late-onset SPG7 and positive family history.

Results: A 60-year-old right-handed woman with cervical and lumbar radiculopathy developed worsening right leg dragging and gait imbalance 9 years ago. She reported frequent falls, limb stiffness, writing difficulties, toe numbness, and vision changes. Family history was notable for a brother who in his mid-20s developed progressive walking difficulties, dysarthria, leg numbness, vertical gaze difficulties but did not undergo genetic testing. There was no history of consanguinity. Pertinent examination findings were diplopia on leftward gaze, sustained horizontal nystagmus on rightward gaze, end target nystagmus on saccade testing, saccadic smooth pursuits, mild rigidity in the neck and arms and mild spasticity in bilateral legs, normal strength, reduced vibratory sensation in bilateral toes, symmetrically brisk reflexes throughout, flexor plantar responses, dysmetria and mild dysdiadochokinesia with left arm, spastic wide-based gait with irregular steps and reduced step height, and postural instability. Serologic evaluation revealed normal creatine kinase, vitamin E, GAD-65 antibody, and thyroid studies including antithyroid antibodies. MRI brain showed few subcortical white matter abnormalities. Both comprehensive ataxia and spastic paraplegia panels detected a heterozygous pathogenic nonsense variant and a heterozygous missense variant of uncertain significance, previously reported to be pathogenic, in the SPG7 gene [3,4].

Conclusion: SPG7 is known to have clinical heterogeneity between families. This case demonstrates intrafamilial phenotypic variability in time of onset and severity of disease. The cause of this variable expressivity within families warrants further research; genetic and non-genetic risk factors likely play a role.

References: 1. Hedera P. Hereditary Spastic Paraplegia Overview. 2000 Aug 15 [Updated 2021 Feb 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1509/

2. Casari G, Marconi R. Spastic Paraplegia 7. 2006 Aug 24 [Updated 2018 Oct 25]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1107/

3. Fogel, B. L., Lee, H., Deignan, J. L., Strom, S. P., Kantarci, S., Wang, X., Quintero-Rivera, F., Vilain, E., Grody, W. W., Perlman, S., Geschwind, D. H., & Nelson, S. F. (2014). Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA neurology, 71(10), 1237–1246. https://doi.org/10.1001/jamaneurol.2014.1944

4. Wilkinson, P. A., Crosby, A. H., Turner, C., Bradley, L. J., Ginsberg, L., Wood, N. W., Schapira, A. H., & Warner, T. T. (2004). A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia. Brain : a journal of neurology, 127(Pt 5), 973–980. https://doi.org/10.1093/brain/awh125

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intrafamilial-phenotypic-variability-of-spastic-paraplegia-type-7-a-case-report/