Spastic Paraplegia Type 8: A First Report from India : Annals of Indian Academy of Neurology

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Spastic Paraplegia Type 8: A First Report from India

Mahale, Rohan; Arunachal, Gautam1; Davuluri, Anudeep; Padmanabha, Hansashree; Mailankody, Pooja

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Annals of Indian Academy of Neurology 26(2):p 189-190, Mar–Apr 2023. | DOI: 10.4103/aian.aian_901_22
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Dear Sir,

Spastic paraplegia type 8 (SPG8) is a rare autosomal-dominant hereditary spastic paraplegia (AD-HSP) caused by the mutation in the WASHC5 (KIAA0196) gene on chromosome 8. Patients with SPG8 commonly present with progressive lower limb spasticity and become wheelchair bound by the fifth decade of life. Patients may develop upper limb spasticity, impaired vibration sense in the distal lower limbs, urinary urgency or incontinence, spastic dysarthria, and dysphagia.[1] Rare presentation of paroxysmal, exercise-induced diurnally fluctuating dystonia and levodopa-responsiveness has been described in SPG8. Hereby, we report a 45-year-old male with progressive lower limb spasticity and overactive bladder who had missense mutation in the WASHC5 gene suggestive of SPG8. SPG8 has not been reported in India.

A 45-year-old man born out of non-consanguineous parentage presented with progressive difficulty in walking of 3-year duration. The walking difficulty was due to stiffness in both lower limbs. He had urinary urgency with incontinence for 1 year. There was no diurnal variation, stiffness in upper limbs, craniobulbar symptoms, sensory symptoms, incoordination, seizures, and cognitive decline. His father had walking difficulty at the seventh decade and was diagnosed as spastic paraparesis. There were no similar complaints in his siblings [Figure 1]. Neurological examination showed normal cognition, speech, and cranial nerves. Motor examination showed lower limbs power of 4/5 (assessment hindered by spasticity) and upper limbs power of 5/5, spasticity in both lower limbs (grade 2 according to modified Ashworth scale), grade 4+ deep tendon reflexes in lower limbs and grade 2+ in upper limbs, and absent jaw jerk. Sensory examination showed impaired proprioception in distal lower limbs. There were no signs of incoordination, and Romberg’s test was negative. Plantar responses were extensor. A clinical diagnosis of hereditary spastic paraplegia of possible AD inheritance was considered. Complete hemogram, renal, hepatic, and thyroid functions were normal. Serological tests for human immunodeficiency virus and syphilis were negative. Whole spine and brain magnetic resonance imaging showed mild cord atrophy with no corpus callosal abnormalities or “ear of the lynx” sign. Cerebrospinal fluid analysis was normal. Somatosensory evoked potentials of median nerve, and tibial nerves showed normal cortical potentials. Nerve conduction studies were normal. Whole exome sequencing showed missense variant NM_014846.4 (WASHC5):c.1876G>T (p.Val626Phe) at exon 16 in WASHC5 gene. The p.Val626Phe missense variant was predicted to be damaging by both SIFT and PolyPhen2. This missense variant caused the same amino acid change as a previously established pathogenic variant in ClinVar [Accession ID: VCV000001161.6] database. The clinical phenotype of the proband matches with that of the disorder caused by pathogenic variants in WASHC5 gene. For these reasons, this variant was classified as pathogenic. A final diagnosis of SPG8 (pure AD-HSP) was made. Patient was started on oral baclofen for spasticity and darifenacin for spastic bladder symptoms.

Figure 1:
Proband pedigree chart

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous group of inherited neurodegenerative disorders characterized by length-dependent retrograde corticospinal tract degeneration. They can be classified as “pure” and “complicated” HSPs. Pure HSP has lower limb spasticity without prominent additional clinical findings other than mild urinary symptoms and impaired distal vibratory sensation. Complicated HSPs are associated with neuropathy, seizures, cognitive decline, parkinsonism, dystonia, deafness, and amyotrophy. Over 80 genes causing HSP have been already identified. The HSPs can be of autosomal dominant and recessive, X-linked recessive, and mitochondrial inheritance.[2] Around 50% of individuals with AD-HSP have mutations in SPG4, SPG3A, and SPG31 genes, whereas SPG8 accounts for less than 1%. The WASHC5 (KIAA0196) gene mutated in SPG8 encodes strumpellin which is a member of the multiprotein Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complex involved in the endosome sorting. The strumpellin has N- and C-terminal with intervening spectrin repeat domain. Mutation in the spectrin repeat domain hampers the interaction of strumpellin with other proteins. A decrease in CAV1 protein abundance and endosomal fission defects results from the pathogenic SPG8 mutations.[3] Around 13-point mutations and a single large deletion mutation in WASHC5 (KIAA0196) gene have been reported. The mutation in WASHC5 (KIAA0196) gene was first reported by Valdmanis et al.[1] (2007) in six families of SPG8. A seventh family of SPG8 was reported by de Bot et al.[4] in 2013 from Netherlands. A study from Canada by Chrestian et al.[2] (2016) on 150 patients with HSP reported a SPG8 frequency of 5% (eight patients). However, Japan Spastic Paraplegia Research Consortium (JASPAC) reported a 1% frequency of SPG8 analyzing 206 Japanese AD-HSP families, and a study from China on 52 patients with clinically suspected HSPs reported one patient with SPG8 (c.1725T>A p.N575K).[5,6] Ginanneschi et al.[7] (2020) from Italy reported four new mutations in the KIAA0196 gene. We report a patient diagnosed as SPG8 with missense variant (NM_014846.4 (WASHC5):c.1876G>T (p.Val626Phe)) in the WASHC5 gene. He presented with spastic paraparesis with onset at the fifth decade and similar symptoms in his father suggesting AD inheritance and pure HSP. There has been no report of SPG8 from India so far.

AD-HSP constitutes about 75–80% of cases of HSP, and SPG4 is the most common AD-HSP. Clinically, it is difficult to differentiate SPG8 from the most common AD-HSP form. However, SPG8 is one of the causes for pure AD-HSP and should be in differential diagnosis in pure AD-HSP.

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2. Chrestian N, Dupré N, Gan-Or Z, Szuto A, Chen S, Venkitachalam A, et al. Clinical and genetic study of hereditary spastic paraplegia in Canada. Neurol Genet 2016;3:e122.
3. Lee S, Park H, Zhu PP, Jung SY, Blackstone C, Chang J. Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion. Sci Signal 2020;13:eaau7500 doi:10.1126/scisignal.aau7500.
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7. Ginanneschi F, D'Amore A, Barghigiani M, Tessa A, Rossi A, Santorelli FM. SPG8 mutations in Italian families:Clinical data and literature review. Neurol Sci 2020;41:699–703.
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