Dear Sirs,

The hereditary spastic paraplegias (HSPs) are a genetically heterogeneous group of disorders characterised by progressive corticospinal tract degeneration and the development of lower limb spasticity [1, 2]. Autosomal-dominant HSP is the most commonly inherited form of the disease and in this group, SPG4 mutations account for ~40 % of cases [1]. The SPG4 gene codes for spastin, a critical neuronal protein that maintains organelle axonal transport by severing and rearranging the microtubule network [3, 4]. Dysfunctional mutant proteins or insufficient quantities of the wild-type protein inhibit this dynamic shuttling process resulting in axonal swelling and progressive retrograde degeneration that preferentially affects the long corticospinal axons [3, 4].

There is mounting evidence that the microtubule and mitochondrial networks are intrinsically linked at the cellular level [5]. This intriguing association has recently been highlighted by the clinical observation that autosomal-dominant optic atrophy (DOA)—a classical mitochondrial optic neuropathy caused by pathogenic OPA1 mutations—can result in complicated neurological phenotypes (DOA+) with features indistinguishable from HSP [6]. Furthermore, subclinical corticospinal tract dysfunction also seems to be a prevalent feature among OPA1 mutation carriers presenting with isolated visual failure, suggesting a wider disease spectrum than originally considered [7]. Interestingly, these overlapping genotype-phenotype manifestations have been reported previously in families with a rarer, autosomal-recessive form of HSP caused by pathogenic SPG7 mutations, in which bilateral optic atrophy was a prominent feature segregating with spastic paraplegia [8–10]. Given the emerging disease mechanisms linking corticospinal tract dysfunction with optic nerve degeneration, the aim of this study was to determine the neurological and ophthalmological manifestations of SPG4-related HSP, looking specifically for evidence of clinical or subclinical optic neuropathy among affected patients. The overall neurological disability, including cognitive function, was also evaluated to provide a comprehensive assessment of the burden of disease in this group of patients.

A comprehensive neurological (GP, RH, PFC) and ophthalmological (PYWM) assessment (Supplementary Method) was carried out on ten white patients from the North of England harbouring confirmed pathogenic SPG4 mutations (Table 1). A broad spectrum of neurological disability was observed among affected patients with scores ranging from one to nine on the modified EDSS scale (Table 2). Importantly, four patients had abnormal MOCA scores of less than 26 points. Seven patients performed poorly on the memory component of the MOCA test protocol and one patient had abnormal visuospatial/executive performance. The association between SPG4 mutations and progressive cognitive decline remains controversial [11–13] and our study of a well-characterised patient cohort provides further evidence favouring a true causal link. Two of the patients with abnormal MOCA scores were younger than the age of 30 years, clearly highlighting the need for clinical vigilance to detect early signs of cognitive impairment and to provide adequate level of support, especially to carers.

Table 1 Molecular genetic and ophthalmological features of the SPG4 patient cohort
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Table 2 Neurological and cognitive features of the SPG4 patient cohort
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Except for one patient who had bilateral nuclear sclerotic cataracts, all patients had best-corrected visual acuities of 20/20 bilaterally (Table 1). The ophthalmological examination was normal with full colour discrimination and no detectable optic disc or retinal abnormalities. Visual fields, RNFL thickness measurements and visual electrophysiology were within the normal range for the entire HSP patient cohort. Three patients had abnormal eye movements with horizontal square wave jerks and saccadic smooth pursuits. No significant ptosis or limitation of eye movements was noted on orthoptic assessment. Based on our comprehensive clinical and electrophysiological evaluation, visual loss secondary to optic nerve or retinal degeneration is unlikely to be a major phenotypic manifestation of SPG4-related disease. Affected patients and at-risk family members can therefore be reassured that unlike other genetically-determined forms of HSP [6–10], SPG4 mutations are not associated with the development of significant ophthalmological complications, in particular visual failure.