Ophthalmological changes in hereditary spastic paraplegia and other genetic diseases with spastic paraplegia

Journal Pre-proof Ophthalmological changes in hereditary spastic paraplegia and other genetic diseases with spastic paraplegia

Júlian Letícia de Freitas, Flávio Moura Rezende Filho, Juliana M.F. Sallum, Marcondes Cavalcante França, José Luiz Pedroso, Orlando G.P. Barsottini PII:

S0022-510X(19)32385-8

DOI:

https://doi.org/10.1016/j.jns.2019.116620

Reference:

JNS 116620

To appear in:

Journal of the Neurological Sciences

Received date:

19 August 2019

Revised date:

16 November 2019

Accepted date:

5 December 2019

Please cite this article as: J.L. de Freitas, F.M.R. Filho, J.M.F. Sallum, et al., Ophthalmological changes in hereditary spastic paraplegia and other genetic diseases with spastic paraplegia, Journal of the Neurological Sciences (2019), https://doi.org/10.1016/ j.jns.2019.116620

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© 2019 Published by Elsevier.

Journal Pre-proof Ophthalmological changes in hereditary spastic paraplegia and other genetic diseases with spastic paraplegia

Júlian Letícia de Freitas1 , MD, Flávio Moura Rezende Filho1 , PhD, MSc; Juliana M. F. Sallum 2 , MD, PhD, Marcondes Cavalcante França Jr 3 , MD, PhD; José Luiz Pedroso1* , MD, PhD, Orlando G. P. Barsottini1 , MD, PhD

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1 – Ataxia Unit, Department of Neurology, Universidade Federal de São Paulo, SP,

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Brazil;

2 – Retina Sector, Ophthalmology Department, Universidade Federal de São Paulo, SP,

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Brazil;

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3 – Department of Neurology, Universidade de Campinas, SP, Brazil.

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Correspondence to: José Luiz Pedroso, MD, PhD. Department of Neurology, São

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Paulo Hospital, Universidade Federal de São Paulo (UNIFESP). E-mail: [email protected]

Journal Pre-proof

Page 2.

Financial disclosures: nothing to disclosure. Conflict of interest: The authors declare that there is no conflict of interest.

Text word count: 4.355

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Characters count of the title: 108 Number of references: 116

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Number of tables: 2

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Number of figures: 3

Journal Pre-proof Abstract: Ophthalmological abnormalities may occur in specific subtypes of hereditary spastic paraplegia (HSP) and in genetic diseases that present with spastic paraplegia mimicking HSP. These ophthalmological changes may precede the motor symptoms and include pigmentary retinal degeneration, ophthalmoplegia, optic atrophy, cataracts and nystagmus. Some ophthalmological abnormalities are more prevalent in specific forms of HSP. Considering that the diagnosis of HSP is usually difficult and complex,

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specific ophthalmological changes may guide the genetic testing. There are other genetic diseases such as autosomal recessive spastic ataxia of Charlevoix-Saguenay

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(ARSACS), X-linked adrenoleukodystrophy and spastic paraplegia, optic atrophy and

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neuropathy (SPOAN) that may mimic HSP and also may present with specific

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ophthalmological changes. In this article, we review the main ophthalmological changes

Keywords:

hereditary

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observed in patients with HSP and HSP-like disorders. spastic

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ophthalmological changes.

paraplegia;

spastic

paraplegia;

optic

atrophy;

Journal Pre-proof Introduction

Hereditary spastic paraplegia (HSP), first described in 1880 by Strumpell[1], are a clinically and genetically heterogeneous group of neurological diseases that affects individuals of all age groups causing a degenerative process in corticospinal tracts and posterior columns[2,3]. The prevalence of HSP ranges from 0.0 to 5.3 per 100,000 for autosomal recessive (AR) HSP and 0.5 to 5.3 per 100,000 people for autosomal

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dominant (AD) HSP[4]. More than 70 genetic subtypes and several patterns of inheritance have been described in HSP: autosomal dominant, autosomal recessive, and

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X-linked recessive[5]. Up to now, 80 HSP subtypes have been described so far[6]. HSP

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is classified in two major phenotypes: a pure phenotype characterized by progressive

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spasticity and weakness of the lower limbs, and occasionally sensory disturbances or bladder dysfunction, and a complex phenotype which may be combined with additional or

non-neurological

such

cognitive

impairment

and

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cerebellar symptoms[5,7].

manifestations

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neurological

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To determine the specific diagnosis in an individual with HSP may be a challenging task, due to the great number of genetic loci combined with the heterogeneity of the phenotypes. Furthermore, there is significant overlap of the phenotypic features of HSP and other groups of hereditary disorders, including hereditary ataxias, leukodystrophies, metabolic and mitochondrial diseases[7,8]. In order to overcome such challenges, the clinician may obtain diagnostic clues from careful examination of the visual system. Ophthalmological abnormalities have been reported in a considerable number of patients with HSP (Table 1). Retinal pigment changes, cataract, optic atrophy, ophthalmoplegia, ptosis and nystagmus may occur and are more prevalent in specific subtypes of HSP. Conversely, ophthalmological signs

Journal Pre-proof could also be found in hereditary ataxias, leukodystrophies and other groups of genetic disorders. Those which exhibit spasticity and pyramidal signs constitute HSP mimics that need to be ruled out during investigation[8]. Autosomal recessive ataxia of Charlevoix-Saguenay, X-linked adrenoleukodystrophy and Spastic paraplegia, optic atrophy and neuropathy (SPOAN) are examples of such conditions. Characterizing the ophthalmological phenotype is therefore an important step in the search for the diagnosis. In this review, we discuss the main subtypes of HSP and HSP mimics in

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which prominent ophthalmological signs/symptoms occur. The review focuses in the ophthalmological phenotypes that are either relatively common in the neurogenetics

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clinic or specific in the diagnosis of spasticity of presumed genetic origin.

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For this article we performed a comprehensive search in MEDLINE and

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LILACS databases for articles published from 1950 to 2018. We used combinations of the following search terms: hereditary spastic paraplegia, spastic paraplegia, optic

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atrophy, ophthalmological changes, optical coherence tomography, retinitis pigmentosa

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and spastic ataxia. We also reviewed and incorporated relevant papers from the

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reference lists of the pre-selected articles.

Spastic paraplegia type 15 (SPG15) and spastic paraplegia type 11 (SPG11)

Spastic paraplegia type 15 (MIM 270700) and spastic paraplegia type 11 (MIM 604360) are HSP with a complex phenotype caused by homozygous or compound heterozygous

mutations

in

the

genes

ZFYVE26/Spastizin

(MIM

612012)

on

chromosome 14q24.1 and SPG11/Spatacsin (MIM 610844) on chromosome 15q21[9], respectively. Kjellin syndrome, a distinct phenotype of SPG11 and SPG15, was first described in 1959[10], as an autosomal recessive disorder clinically defined by spastic paraplegia, retinal degeneration, distal amyotrophy and mental retardation[10,11].

Journal Pre-proof Neuroimaging abnormalities, including thin corpus callosum and cerebellar atrophy, were later reported [11]. The most important ophthalmological change is retinal degeneration (Kjellin syndrome), classically associated with SPG15, but also described in SPG11[12]. Fundoscopic evaluation shows yellow retinal flecks, located at the level of the retinal pigment epithelium (RPE), and distributed bilaterally throughout the macula[13]. Blockade of choroidal fluorescence by the central aspect of the flecks and

angiography[13,14].

Fundus

autofluorescence

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hyperfluorescence of the fleck periphery are characteristics typically seen in fluorescein studies

identified

halos

of

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hypoautofluorescence with hyperautofluorescence in the center of the visible flecks[13];

Tarantola

et

al described

accumulation of hyperreflective material

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disease[15].

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such pattern differs from that found either in fundus flavimaculatus or Stargardt

accounting flecks located at the inner layer of the RPE visible at spectral domain-optical

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coherence tomography[13] (Figure 1).

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Puech et al followed patients with Kjellin syndrome and SPG11 mutations for

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ten years. They observed that ocular signs first appeared after the age of 20 years, when the neurologic manifestations are already advanced[16]. It is likely that the central retinal degeneration develops at late disease stages. Low visual acuity complaints are rare early in the disease course, despite the abnormal ophthalmologic evaluation that already shows these typical findings. This suggests that funduscopic signs may precede visual deterioration by several years. Kjellin syndrome is complete in only a minority of patients with genetic pathogenic variants. Retinal degeneration and MRI features can be absent in some patients, even in patients with long time of disease. Both spastizin and spatacsin are related to lysosomal and autophagic dysfunction [17] and axonal transport. It has been shown that dysfunctional autophagy contributes to

Journal Pre-proof neurodegeneration in cultured neurons of SPG11 knock-out mice by increasing intracellular gangliosides[18]. More recently, Branchu et al have further investigated the pathogenesis of SPG11 and demonstrated that the loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration[19]. Despite the advances in the understanding of the motor phenotype of SPG11, the pathogenesis of retinal degeneration in Kjellin syndrome remains unclear. However, strong expression of spatacsin and spastizin has been reported in the retina and

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photoreceptor cells of an animal model[20]. Thus, it may be speculated that abnormal autophagy affects retinal pigment epithelium function, leading defective degradation of

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external segments of photoreceptors and accumulation of lipofuscin and related

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Spastic Paraplegia type 7 (SPG7)

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molecules in the retina of individuals with Kjellin syndrome.

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SPG7 (MIM 607259) results from mutations in PGN (MIM 602783) gene,

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which encodes the protein paraplegin [21]. This gene may be responsible for a significant proportion of SPG cases [22], and the p.Ala510Val variant has been highlighted as the most common mutation causing adult onset neurogenetic disease in patients of British origin [23]. A substantial proportion of patients with undetermined ataxia might have SPG7 [24]. Clinical presentation is heterogeneous and varies from a pure SPG to a complicated phenotype consisting of cerebellar ataxia [21,22], peripheral neuropathy

[25],

ptosis and

progressive external ophthalmoplegia (PEO)

[26],

supranuclear gaze palsy [27] and optic neuropathy [21,28]. Remarkably, the mode of inheritance of SPG7 can be either autosomal dominant or autosomal recessive [29].

Journal Pre-proof Optic atrophy was reported in several families with SPG7, but not all patients displaying this feature had reduced visual acuity. Optic atrophy occurred in 3/49 cases of SPG7 in a Dutch cohort. Two sibs with optic atrophy had a homozygous missense mutation in PGN gene. They manifested vision loss as the presenting symptom and developed full blindness in the course of their illnesses.

Post-mortem examination of

one of these sibs disclosed severe atrophy affecting the optic nerves, optic chiasm and optic tracts with loss of axons, demyelination and astrogliosis[30]. In accordance with

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these data, an investigation employing OCT (Spectralis®) disclosed global RNFL thinning in the eyes of two out of three individuals with SPG7. Retinal fibers loss was

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more prominent in the temporal quadrant (Figure 2). Those with RNFL thinning had a

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complex phenotype comprising cerebellar involvement, cognitive impairment and optic

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atrophy, while the third patient had pure lower limb spasticity [31]. OCT use likely increases the detection of optic nerve abnormalities in individuals with SPG7 in

SPG7

underwent

ophthalmological

evaluation

and

peripapillary OCT

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confirmed

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comparison to fundoscopy. In the study of Klebe et al, ten patients with molecularly

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(Stratus®). Visual acuity was decreased in four individuals, ranging from 6/10 to 9/10, and optic disc pallor on fundoscopy occurred in 60%. All eyes were reported to have a reduction in retinal nerve fiber layer (RNFL) thickness in OCT, although the criteria to consider this measurement abnormal were not clearly stated. The authors performed a genome-wide linkage analysis and detected the mutation p.Asp411Ala in seven individuals with isolated optic neuropathy, demonstrating that this is a possible SPG7 phenotype. However, after negative screening for paraplegin gene variants in 152 other cases of hereditary optic neuropathies, they concluded that SPG7 is a rare cause of isolated optic neuropathy [28]. Future studies could correlate disease severity and

Journal Pre-proof duration with peripapillary RNFL thickness in OCT in larger cohorts of SPG7, to determine its role as a biomarker. It has been demonstrated that a subset of patients with chronic PEO have pathogenic variants in the PGN gene, suggesting PEO is part of the phenotypic spectrum of SPG7. In this study, nine out of 68 cases of PEO had paraplegin mutations. The researchers concluded that SPG7 should be considered in patients with a suspected disorder of mitochondrial function and prominent spastic ataxia [26].

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Paraplegin is a metalloprotease known to cleave optic atrophy protein 1 (OPA1) into two active subunits, which locate in the inner mitochondrial membrane and regulate

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multiple mitochondrial functions, including fusion [32]. Abnormal paraplegin function

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may therefore result in ocular signs commonly found in mitochondrial disorders,

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including optic atrophy, ptosis and PEO, which represent clues for the diagnosis of

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SPG7 in a patient with spastic paraparesis with suspected genetic origin.

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Spastic paraplegia, optic atrophy and neuropathy (SPOAN)

SPOAN (MIM 609541) is an autosomal recessive disorder, first described in 2005 in a large consanguineous Brazilian family[33], characterized by early-onset progressive spastic paraplegia, congenital optic atrophy and progressive motor and sensory axonal neuropathy[33,34]. This syndrome results from homozygous deletions located in the noncoding upstream region of the KLC2 gene (MIM 611729) on chromosome 11q13.2, which result in gene overexpression. KLC2 gene codes kinesin light chain-2, a protein involved in a macromolecules cargoes and anterograde axoplasmatic transport of organelles. Patients also present dysarthria, spine deformity, joint retractions, acoustic startle response and no cognitive impairment. Symptoms

Journal Pre-proof related to optic atrophy such as subnormal vision and fixation nystagmus manifest early in life and are typically not progressive[35]. Macedo-Souza et al evaluated 22 individuals diagnosed with SPOAN and found subnormal vision in 21 and fixation nystagmus was observed in 18 probands [30]. Optic coherence tomography could be employed to further characterize the ophthalmologic phenotype of SPOAN and possibly reveal biomarkers of the disorder.

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Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)

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ARSACS (MIM 270550) is an autosomal recessive condition initially described

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in a French-Canadian families living in the regions of Charlevoix and Saguenay,

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Quebec. The 42 patients of the original series exhibited a remarkably homogeneous phenotype comprising unsteadiness and falls at gait initiation, followed by slowly The

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progressive spastic ataxia and axonal-demyelinating peripheral neuropathy [36].

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identification of SACS (MIM 604490) as the causative gene occurred in 2000 [37]. This

mitochondrial

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gene encodes sacsin, a large 520 kDa multiple domain protein which appears to regulate fusion

and

fission

and

intermediate

neurofilament

assembly

and

dynamics [38–40]. After the discovery of SACS, several cases of ARSACS were molecularly confirmed in different regions of the world, including Japan [41], Italy [42], Spain [43], North Africa [44,45], The Netherlands [46], Belgium [47], Brazil [48], Germany [49] and UK [50].

More diverse phenotypes were encountered outside

Quebec, and it became clear that the ataxia, spasticity, and peripheral neuropathy of the classic ARSACS presentation might each be missing in individuals affected by SACS mutations [49,51]. Therefore, a SACS-related disorder could be considered in the

Journal Pre-proof differential

diagnosis

of

complicated

SPG,

particularly

if

spastic

paraparesis

predominates over other neurological signs. Brain MRI findings associated with SACS mutations include upper cerebellar vermis atrophy, thickening of middle cerebellar peduncles, posterior fossa arachnoid cyst, parietal atrophy, lateral pontine T2 hyperintensities and linear pontine T2 hypointensities, the latter being likely the most specific and not described in SPGs [49,52,53]. SACS-related disease and complicated SPGs may both present corpus

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callosum thinning [49,54].

French-Canadian patients affected by SACS mutations have a very distinctive

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fundus appearance characterized by an increased visibility of the retinal nerve fibers

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hiding parts of the retinal vessels, which occurs less consistently in other populations

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(Figure 3). Other ocular signs include saccadic pursuit and gaze evoked nystagmus [36]. Recently optical coherence tomography (OCT) expanded the range of SACS-

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related retinal abnormalities by showing a thickened peripapillary retinal nerve fiber

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layer, an increase in macular thickness with loss of foveal depression, a dentate

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appearance of the inner retina, a papillomacular fold and macular microcysts [55–57]. Desserre et al observed increased average macular thickness and foveolar thickness in OCT scans of two patients with ARSACS and stated the “filling in” of foveal depression resulted from thickening of ganglion cell and inner plexiforme layers, which are normally absent in the foveola [56]. Nethisinghe et al pointed that RNFL extended across the macula and covered the foveal pit in the OCT scan of an individual with pathogenic SACS mutations and commented on the absence of nerve fibers in the fovea of normal subjects [58]. However, in a case report of a teenager with ARSACS, Shah et al have found thickened RNFL did not extend across the foveal center in a macular OCT scan. They identified an apparent failure of extrusion of the inner retinal layers

Journal Pre-proof leading to the loss of foveal pit, consistent with foveal hypoplasia and possibly resulting from an interruption in the foveal development. The authors stated foveal appearance in ARSACS was similar to the one encountered in foveal hypoplasia of other causes and underlined that previously published images of OCT macular scans in ARSACS were also compatible with foveal hypoplasia [59]. One study of retinal segmentation in ARSACS suggested the abnormal macular thickness results from thickening of the inner glial limiting membrane, the RNFL and

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the ganglion cell layer, but the authors have presented unitless and unrealistic quantitative data of individual retinal layer thicknesses [60].

Others have proposed that

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the papillomacular fold and the dentate appearance of the ARSACS retina result from

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an excess of neural tissue in inner layers, which wrinkles and folds to accommodate to a

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limited retinal surface [55].

Evidence indicates OCT is more accurate than fundoscopy in identifying retinal

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signs of SACS mutations and constitutes an important diagnostic tool in the context of

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recessive ataxia. In a recent study, researchers performed peripapillary OCT in 79

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recessive ataxia and tested those with RNFL thickness above the 95th percentile for SACS variants. Seventeen individuals with SACS-related ataxia were diagnosed, indicating that a peripapillary RNFL thickness greater than 119 micrometers

had a

sensitivity of 100% and a specificity of 99.4% [61]. OCT is also sufficiently sensitive as to detect RNFL thickening in asymptomatic carriers of a single pathogenic SACS variant [62]. Since RNFL thickening has not been reported in any form of SPG, OCT would likely be useful as a guide for genetic testing in undetermined SPGs, especially if ataxia and peripheral neuropathy are also present. Although retinal degeneration was documented in an individual with biallelic SACS mutations [63], most of those with ARSACS and related phenotypes have normal visual acuity [61]. Authors have

Journal Pre-proof proposed different theories to explain RNFL thickening in ARSACS. While some believe it results from hyperplasia of the retinal tissue [64], others suggest axonal edema as the underlying mechanism [65]. RNFL thickening could be a consequence of an excess number of retinal nerve fibers axons or greater axonal diameter. Taking into consideration the absence of abnormalities in the retrobulbar optic nerves in the MRI in ARSACS, Nethisinghe et al speculated retinal abnormalities result from defects in axoplasmic transport in the non-myelinated (intraocular) retinal nerve fibers, which lead

The occurrence of macular microcysts visible in OCT [55] and

electroretinogram

signs

of

ganglion

cells

dysfunction

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RNFL[58].

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to axonal edema, increased visibility of these fibers in fundoscopy and thickened

[66]

may

suggest

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neurodegeneration and favor the axonal edema hypothesis. However, the identification

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of foveal hypoplasia in OCT[59] and the excessive number of pontocerebellar fibers in brain tractography of ARSACS patients[60] indicate a neurodevelopmental disorder,

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thus supporting hyperplasia of RNFL or a combined pathophysiology. Pathologic

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changes.

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studies of retinal sections are necessary to clarify the true nature of SACS-related retinal

X-linked adrenoleukodystrophy

Adrenoleukodystrophy (MIM 300100) results from mutations in ABCD1 (MIM 300371) gene, which is located in chromosome Xq28 [67], and therefore inherited in a recessive X-linked mode [68]. Loss of function of ABCD1 disrupts the metabolism of very long chain fatty acids, which accumulate throughout the body, particularly in the central nervous system, peripheral nerves, testes and adrenal cortex [69]. The prevalence of the disorder is 1-5/100.000, and remarkable phenotypic heterogeneity

Journal Pre-proof occurs [70]. The two most frequent forms are childhood cerebral adrenoleukodystrophy and adrenomyeloneuropathy, but five other presentations were described: adult cerebral, adolescent, pure adrenal insufficiency, heterozygotes and asymptomatic [71]. Childhood

cerebral adrenoleukodystrophy typically occurs within the first

decade of life and leads to complete disability after 3 years of disease onset, while adrenomyeloneuropathy affects individuals in the third decade of life and progresses more slowly [70]. Men with adrenomyeloneuropathy present sensory ataxia with

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impaired vibration sense, sphincter dysfunction, pain in the legs and impotence [72]. Up to 50% of women with a ABCD1 pathogenic variant, the heterozygotes, exhibit

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progressive spastic paraparesis and sphincter disturbances [73].

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Ocular signs of adrenoleukodystrophy comprise impaired visual function, optic

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disc pallor and demyelination of optic nerves in MRI [74]. Studies of the afferent visual system in adrenoleukodystrophy are scarce in the childhood cerebral subtype, likely due

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to early onset and rapid progression. In a cohort of 15 children, visual acuity ranged

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from normal to light perception, and optic nerve pallor was present in seven individuals.

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Loss of visual acuity occurred in all five patients in which follow-up was possible, after 20 months on average [75]. All 17 boys in a clinical and pathological series eventually developed some degree of visual loss and optic atrophy. The authors performed postmortem examination in 16 of these patients and detected severe involvement of the central portion of the optic nerves in every case [68]. It has been demonstrated that OCT measurements

do

not

differ

significantly

in

pre-symptomatic

boys

with

adrenoleukodystrophy and normal controls [76], but the thicknesses of ganglion cell layer and inner plexiform layer were reduced in a symptomatic 10 year-old patient [77]. Patients with adrenoleukodystrophy that manifests in the neonatal period have a collection of ocular findings, including epicanthal folds, esotropia, nystagmus, cataracts,

Journal Pre-proof optic atrophy and a retinal pigment abnormality described as leopard spot fundus [78,79]. OCT in one individual with neonatal adrenoleukodystrophy revealed outer retina atrophy, hyperreflective opacities in the vitreous, thickened RNFL layer and subretinal hyperreflective nodules corresponding to the location of leopard spots in the fundus. The authors suggested that the vitreous and subretinal hyperreflective lesions represent the inclusion-laden macrophages found in pathology specimens. In this case, the electrorretinogram was consistent with photoreceptor loss and dysfunction of inner

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retina or synaptic transmission [80].

The adrenomyeloneuropathy phenotype also exhibits visual system dysfunction.

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In a study involving 59 adult patients, 25% had abnormal visual evoked potentials, and

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63% had MRI alterations of the visual pathway, the most common being T2In line with these

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hyperintensity of lateral geniculate body or optic radiations [74].

data, the Farnsworth-Munsell 100 Hue Test detected color vision defects in 12 out of 27

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men [81]. More recently, OCT revealed bilateral peripapillary RNFL thinning and

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reduced macular volume in a single case of adrenomyeloneuropathy, which had reduced

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visual acuity and hemianoptic visual field defect. The researchers stated OCT provided evidence of active demyelination as the underlying mechanism of optic neuropathy in adrenomyeloneuropathy [82]. Future studies could address the potential of OCT measurements, particularly RNFL and ganglion cell layer thickness, as biomarkers of disease progression in childhood adrenoleukodystrophy, adrenomyeloneuropathy and heterozygotes. OCT may also prove helpful in distinguishing adrenomyeloneuropathy and heterozygotes from other hereditary causes of spasticity in which demyelination of the optic nerve is not part of the phenotype.

Other genetic diseases with spastic paraplegia and ophthalmological changes

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Many inherited disorders present with prominent spastic paraplegia but are not formally

classified

as

HSP.

Some

of

these

conditions

may

present

major

ophthalmological involvement (Table 2). Optic atrophy 1 (MIM 605290) is the most common dominant optic atrophy. The disease is characterized by slowly progressive, painless bilateral visual loss, temporal pallor of the optic disk with decreased thickness of RNFL, central or

described

scotomas

and

dyschromatopsia[83].

Additional features

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cecocentral

have

been

such as deafness, myopathy, ataxia, neuropathy, progressive external

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pr

ophthalmoplegia and spastic paraparesis[84,85].

Friedreich ataxia (MIM 229300) is an autosomal recessive ataxia caused by

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homozygous GAA expansions situated in intron 1 in the FXN gene (MIM 606829) with

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an estimated prevalence of 1 in 50,000[86,87]. Classical phenotype is characterized by onset around puberty, cerebellar ataxia, absent tendon reflexes, Babinski sign, scoliosis

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and pes cavus[88,89]. Non-neurological features such cardiac involvement and diabetes

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mellitus are common in the early-onset disease form[87]. Other phenotypes include late onset of Friedreich ataxia (LOFA) and very late onset Friedreich ataxia (VLOFA) and they are defined as FRDA with onset after 25 years and after 40 years respectively[90]. Those forms may present with spasticity, preserved or even increased tendon reflexes. Ophthalmic manifestations include optic neuropathy. Patients usually have a subclinical optic atrophy,

although some individuals progress to

poor visual acuity with

predilection for patients compound heterozygotes[86,91,92]. Fortuna et al described diffuse and progressive pattern of RNFL loss in optical coherence tomography and showed a significant correlation between disease duration, neurological involvement and RNFL thickness[92].

Journal Pre-proof Cerebrotendineous xanthomatosis (MIM 213700) is lipid storage autosomal recessive disorder caused by mutations in CYP27A1 (MIM 606530)[93]. Clinical features include chronic diarrhea, tendon xanthomas, juvenile cataracts, cerebellar ataxia, spastic paraparesis and cognitive impairment[93,94]. Childhood-onset bilateral cataracts are a frequent phenotypic finding in cerebrotendinous xanthomatosis occurring in 76-88% of patients[95,96]. The cataracts found in this disorder characteristically display diffuse flecks best seen by retroillumination, combined with posterior capsular

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opacities[97]. In the Cerebrotendinous Xanthomatosis Prevalence Study, researchers measured colestanol levels in 170 patients with juvenile-onset idiopathic bilateral identified

cerebrotendinous

3

cases

xanthomatosis.

of biochemically

The

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and

authors

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cataracts

and

estimated

molecularly the

confirmed

prevalence

of

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cerebrotendinous xanthomatosis in the study was 500-fold the prevalence in general population, and suggested juvenile-onset bilateral cataracts as a screening marker[98].

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Dotti et al performed a comprehensive investigation of ophthalmological findings in

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cerebrotendinous Xanthomatosis and identified optic disc pallor as the second most

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frequent abnormality, affecting 6 out of 13 patients. Additionally, the authors reported premature retinal senescence comprising sclerosis of retinal vessels e retinal pigment epithelium changes and underlined premature atherosclerosis and oxidative unbalance as possible underlying mechanisms. symmetric

T2

hyperintensities

in

The brain MRI shows cerebellar atrophy, dentate

nuclei,

substantia

nigra

and

white

matter[93,99]. OCT could be used to further characterize optic neuropathy in cerebrotendinous xanthomatosis and expand our understanding of this rare condition. Early diagnosis is important in order to prevent clinical deterioration in this disorder, which is potentially treatable with bile acids.

Journal Pre-proof The acronym neurodegeneration with brain iron accumulation (MIM 300894) represents a heterogeneous group of inherited neurodegenerative diseases characterized by parkinsonism, dystonia, cognitive dysfunction, optic atrophy, retinal abnormalities and pyramidal signs[100]. Pantothenate kinase-associated neurodegeneration (PKAN), also known as NBIA type 1 (MIM 234200), is a very rare disease with a prevalence of 1/1,000,000[100,101]. PKAN is an autosomal recessive disease caused by mutation of PANK2 gene (MIM 606157). This gene encodes mitochondrial pantothenate kinase

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which is a regulatory enzyme in the biosynthesis of coenzyme A. Classic PKAN has early-onset and rapid progressive course[101]. The affected patients present progressive which involves mostly cranial region and

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dystonia

the limbs. Pyramidal tract

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involvement is common and manifest as brisk reflexes and spasticity. Cognition is

Ophthalmic changes encountered

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frequently impaired and tends to be more severe in those with earlier onset[100,101]. in PKAN

are retinitis pigmentosa and optic

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atrophy[8,102,103]. Retinitis pigmentosa leading to visual field constriction and night

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blindness, clinical course usually dramatic in this condition[103]. Optic atrophy is a

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very rare unusual sign encountered in patients with latter onset and slower progression of the disease compatible with atypical PKAN[102]. MR imaging shows the ‘eye-ofthe-tiger’ sign, defined as T2-weighted hypointense globus pallidus with a central anteromedial region of T2

hyperintensity[101]. Mitochondrial membrane protein-

associated neurodegeneration (MPAN, MIM 614298) results from C19orf12 (MIM 614297) mutation and is inherited in autosomal recessive trait[100,104]. The most common features are prominent pyramidal and extrapyramidal signs, motor axonal neuropathy,

optic

atrophy,

intellectual

impairment

and

neuropsychiatric

abnormalities[8,100]. Optic atrophy is more severe in young onset cases[105]. Brain MRI shows hypointensity in substantia nigra and globus pallidus on T2* and GRE

Journal Pre-proof sequences

with

generalized

atrophy[104].

Fatty

acid

2-hydroxylase-associates

neurodegeneration, also known as SPG35 (MIM 612318), is inherited in autosomal recessive trait and caused by FA2H mutations (MIM 611026). The clinical phenotype is characterized by early-onset spastic paraplegia, dystonia, ataxia and cognitive impairment. Optic atrophy may occur or not in the progression of the disease. Changes on brain MRI include bilateral globus pallidus T2 hypointense signal, periventricular T2 white matter hyperintense signal, cerebellar atrophy and cortical atrophy[100,106].

Gordon-Holmes syndrome (MIM 212840),

oo f

PNPLA6-related disorders are a group of autosomal recessive diseases that include Boucher-Neuhäuser syndrome (MIM

pr

215470), Laurence-Moon syndrome (MIM 245800), Oliver-McFarlane syndrome (MIM

e-

275400) and Spastic paraplegia type 39 (MIM 612020)[107,108]. The PNPLA6 gene

Pr

(MIM 603197) encodes an enzyme that catalyzes the deesterification of membrane phosphatidylcholine into fatty acids and glycerophosphocholine. Therefore this is an

al

important gene for membrane integrity[108,109]. The main clinical features of

spastic ataxia.

are

hypogonadism,

Jo u

hypogonadotropic

disease

rn

PNPLA6-associated

variable

combinations

chorioretinal dystrophy,

of

cerebellar

spastic

ataxia,

paraplegia

and

Axonal peripheral neuropathy is a frequent concomitant feature

[108,110]. Patients present subnormal vision or even blindness and fundoscopy evaluation

discloses

chorioretinal

dystrophy[108,110].

Rainier

et

al considered

complicated hereditary spastic paraplegia a prominent phenotype of PNPLA6[111]. In a cohort of 12 individual, 6 had spastic paraplegia[108] and in the first description of Gordon-Holmes syndrome and Boucher-Neuhäuser syndrome the authors describe three patients with clinical signs of upper motor neuron disease like spasticity, brisk reflexes and positive extensor plantar reflex[112–114].

Journal Pre-proof Sjogren-Larsson syndrome (MIM 270200) results from mutations in ALDH3A2 (MIM 609523) inherited three

cardinal

symptoms:

paraplegia[116]. photophobia

as an autosomal recessive trait[115] and is characterized by

are

congenital

ichtyosis,

macular

dystrophy,

Crystalline the

most

common

periventricular signal changes on T2-

mental

decreased

ophthalmological weighted

retardation visual

and

spastic

acuity

and

abnormalities[115].Severe

imaging are described in this

oo f

syndrome[3,115].

Conclusions

pr

HSP and several genetic diseases that present with spastic paraplegia may

e-

present with ophthalmological manifestations. The ocular involvement may precede

Pr

the motor symptoms. Considering that the diagnostic work-up of HSP and HSP-like disorders is usually difficult and complex, specific ophthalmological changes may guide interpretation of genetic testing. Therefore, a detailed

al

the proper choice and

HSP.

Bibliography [1]

Jo u

rn

ophthalmological examination should be part of the clinical evaluation in patients with

A. Strumpell, XXXVI, Beitrage zur Pathologie des Ruckenmarks., Arch. Psychiatr. Nervenkr. 10 (1880) 676–717.

[2]

S. Salinas, C. Proukakis, A. Crosby, T.T. Warner, Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms, Lancet Neurol. 7 (2008) 1127– 1138. doi:10.1016/S1474-4422(08)70258-8.

[3]

A.E. Harding, Classification of the Hereditary Ataxias and Paraplegias, Lancet. 321 (1983) 1151–1155. doi:10.1016/S0140-6736(83)92879-9.

Journal Pre-proof [4]

L. Ruano, C. Melo, M.C. Silva, P. Coutinho, The global epidemiology of hereditary ataxia and spastic paraplegia: A systematic review of prevalence studies, Neuroepidemiology. 42 (2014) 174–183. doi:10.1159/000358801.

[5]

J.K. Fink, Chapter 77 – Hereditary Spastic Paraplegia, Elsevier Ltd, 2015. doi:10.1016/B978-0-12-410529-4.00077-2.

[6]

M.A. Farazi Fard, A.P. Rebelo, E. Buglo, H. Nemati, H. Dastsooz, I. Gehweiler, S. Reich, J. Reichbauer, B. Quintáns, A. Ordóñez-Ugalde, A. Cortese, S. Courel,

oo f

L. Abreu, E. Powell, M. Danzi, N.B. Martuscelli, D.M. Bis-Brewer, F. Tao, F. Zarei, P. Habibzadeh, M. Yavarian, F. Modarresi, M. Silawi, Z. Tabatabaei, M.

pr

Yousefi, H.R. Farpour, C. Kessler, E. Mangold, X. Kobeleva, A.J. Mueller, T.B.

e-

Haack, M. Tarnopolsky, Z. Gan-Or, G.A. Rouleau, M. Synofzik, M.J. Sobrido,

Pr

A. Jordanova, R. Schüle, S. Zuchner, M.A. Faghihi, Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia, Am. J. Hum. Genet. 104 (2019)

J. Finsterer, W. Löscher, S. Quasthoff, J. Wanschitz, M. Auer-Grumbach, G.

rn

[7]

al

767–773. doi:10.1016/j.ajhg.2019.03.001.

Jo u

Stevanin, Hereditary spastic paraplegias with autosomal dominant, recessive, Xlinked, or maternal trait of inheritance, J. Neurol. Sci. 318 (2012) 1–18. doi:10.1016/j.jns.2012.03.025. [8]

K. H.M., R. R.H., D.-M. H.V., Ophthalmic manifestations of inherited neurodegenerative disorders, Nat. Rev. Neurol. 10 (2014) 349–362. http://www.nature.com/nrneurol/archive/index.html%5Cnhttp://ovidsp.ovid.com/ ovidweb.cgi?T=JS&PAGE=reference&D=emed11&NEWS=N&AN=201439240 3.

[9]

C.A. Hughes, P.C. Byrne, S. Webb, P. McMonagle, V. Patterson, M. Hutchinson, N.A. Parfrey, SPG15, a new locus for autosomal recessive complicated HSP on

Journal Pre-proof chromosome 14q, Neurology. 56 (2001) 1230–1233. doi:10.1212/WNL.56.9.1230. [10]

K. Kjellin, Familial Spastic Paraplegia with Amyotrophy, Oligophrenia, and Central Retinal Degeneration, AMA. Arch. Neurol. 1 (1959) 133–140. doi:10.1001/archneur.1959.03840020007002.

[11]

S. Webb, V. Patterson, M. Hutchinson, Two families with autosomal recessive spastic paraplegia, pigmented maculopathy, and dementia, J. Neurol. Neurosurg.

[12]

oo f

Psychiatry. 63 (1997) 628–632. doi:10.1136/jnnp.63.5.628.

S. Hanein, E. Martin, A. Boukhris, P. Byrne, C. Goizet, A. Hamri, A. Benomar,

pr

A. Lossos, P. Denora, J. Fernandez, N. Elleuch, S. Forlani, A. Durr, I. Feki, M.

e-

Hutchinson, F.M. Santorelli, C. Mhiri, A. Brice, G. Stevanin, Identification of the

Pr

SPG15 Gene, Encoding Spastizin, as a Frequent Cause of Complicated Autosomal-Recessive Spastic Paraplegia, Including Kjellin Syndrome, Am. J.

R.M. Tarantola, V. Nguyen, A. Agarwal, Characterization of kjellin syndrome

rn

[13]

al

Hum. Genet. 82 (2008) 992–1002. doi:10.1016/j.ajhg.2008.03.004.

Jo u

using spectral-domain optical coherence tomography and fundus autofluorescence, Retin. Cases Br. Reports. 5 (2011) 49–55. doi:10.1097/ICB.0b013e3181d5e942. [14]

F. Autofluorescence, I.B. Frisch, P. Haag, H. Steffen, B.H.F. Weber, F.G. Holz, Kjellin ’ s Syndrome, (2002) 1484–1491.

[15]

V.M. de Castro, A. Meirelles, R.S. Arcieri, K. Messias, A. Messias, Macular dystrophy associated with Kjellin’s syndrome: A case report, Arq. Bras. Oftalmol. 78 (2015) 120–122.

[16]

B. Puech, A. Lacour, G. Stevanin, B.G. Sautiere, D. Devos, C. Depienne, E. Denis, E. Mundwiller, D. Ferriby, P. Vermersch, S. Defoort-Dhellemmes, Kjellin

Journal Pre-proof syndrome: Long-term neuro-ophthalmologic follow-up and novel mutations in the SPG11 gene, Ophthalmology. 118 (2011) 564–573. doi:10.1016/j.ophtha.2010.07.024. [17]

B. Renvoisé, J. Chang, R. Singh, S. Yonekawa, E.J. FitzGibbon, A. Mankodi, A. Vanderver, A.B. Schindler, C. Toro, W.A. Gahl, D.J. Mahuran, C. Blackstone, T.M. Pierson, Lysosomal abnormalities in hereditary spastic paraplegia types SPG15 and SPG11, Ann. Clin. Transl. Neurol. 1 (2014) 379–389.

[18]

oo f

doi:10.1002/acn3.64.

M. Boutry, J. Branchu, C. Lustremant, C. Pujol, J. Pernelle, R. Matusiak, A.

pr

Seyer, M. Poirel, E. Chu-Van, A. Pierga, K. Dobrenis, J.P. Puech, C. Caillaud, A.

e-

Durr, A. Brice, B. Colsch, F. Mochel, K.H. El Hachimi, G. Stevanin, F. Darios,

Pr

Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration, Cell Rep. 23 (2018) 3813–

J. Branchu, M. Boutry, L. Sourd, M. Depp, C. Leone, A. Corriger, M. Vallucci,

rn

[19]

al

3826. doi:10.1016/j.celrep.2018.05.098.

Jo u

T. Esteves, R. Matusiak, M. Dumont, M.P. Muriel, F.M. Santorelli, A. Brice, K.H. El Hachimi, G. Stevanin, F. Darios, Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration, Neurobiol. Dis. 102 (2017) 21–37. doi:10.1016/j.nbd.2017.02.007. [20]

R.P. Murmu, E. Martin, A. Rastetter, T. Esteves, M.P. Muriel, K.H. El Hachimi, P.S. Denora, A. Dauphin, J.C. Fernandez, C. Duyckaerts, A. Brice, F. Darios, G. Stevanin, Cellular distribution and subcellular localization of spatacsin and spastizin, two proteins involved in hereditary spastic paraplegia, Mol. Cell. Neurosci. 47 (2011) 191–202. doi:10.1016/j.mcn.2011.04.004.

[21]

G. Casari, M. De Fusco, S. Ciarmatori, M. Zeviani, M. Mora, P. Fernandez, G.

Journal Pre-proof De Michele, A. Filla, S. Cocozza, R. Marconi, A. Dürr, B. Fontaine, A. Ballabio, Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease, Cell. 93 (1998) 973–983. doi:10.1016/S0092-8674(00)81203-9. [22]

F. Brugman, H. Scheffer, J.H.J. Wokke, W.M. Nillesen, M. De Visser, E. Aronica, J.H. Veldink, L.H. Van Den Berg, Paraplegin mutations in sporadic

doi:10.1212/01.wnl.0000319700.11606.21. [23]

oo f

adult-onset upper motor neuron syndromes, Neurology. 71 (2008) 1500–1505.

R.H. Roxburgh, R. Marquis-Nicholson, F. Ashton, A.M. George, R.A. Lea, D.

pr

Eccles, S. Mossman, T. Bird, K.L. Van Gassen, E.J. Kamsteeg, D.R. Love, The

e-

p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common

Pr

mutation causing adult onset neurogenetic disease in patients of British ancestry, J. Neurol. 260 (2013) 1286–1294. doi:10.1007/s00415-012-6792-z. G. Pfeffer, A. Pyle, H. Griffin, J. Miller, V. Wilson, L. Turnbull, K. Fawcett, D.

al

[24]

rn

Sims, G. Eglon, M. Hadjivassiliou, R. Horvath, A. Németh, P.F. Chinnery, SPG7

Jo u

mutations are a common cause of undiagnosed ataxia, Neurology. 84 (2015) 1174–1176. doi:10.1212/WNL.0000000000001369. [25]

C.J. McDermott, R.K. Dayaratne, J. Tomkins, M.E. Lusher, J.C. Lindsey, M.A. Johnson, G. Casari, D.M. Turnbull, K. Bushby, P.J. Shaw, Paraplegin gene analysis in hereditary spastic paraparesis (HSP) pedigrees in northeast England, Neurology. 56 (2001) 467–471. doi:10.1212/WNL.56.4.467.

[26]

G. Pfeffer, G.S. Gorman, H. Griffin, M. Kurzawa-Akanbi, E.L. Blakely, I. Wilson, K. Sitarz, D. Moore, J.L. Murphy, C.L. Alston, A. Pyle, J. Coxhead, B. Payne, G.H. Gorrie, C. Longman, M. Hadjivassiliou, J. McConville, D. Dick, I. Imam, D. Hilton, F. Norwood, M.R. Baker, S.R. Jaiser, P. Yu-Wai-Man, M.

Journal Pre-proof Farrell, M. McCarthy, T. Lynch, R. McFarland, A.M. Schaefer, D.M. Turnbull, R. Horvath, R.W. Taylor, P.F. Chinnery, Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance, Brain. 137 (2014) 1323–1336. doi:10.1093/brain/awu060. [27]

T. Warnecke, T. Duning, A. Schwan, H. Lohmann, J.T. Epplen, P. Young, A novel form of autosomal recessive hereditary spastic paraplegia caused by a new

doi:10.1212/01.wnl.0000266667.91074.fe. [28]

oo f

SPG7 mutation, Neurology. 69 (2007) 368–375.

S. Klebe, C. Depienne, S. Gerber, G. Challe, M. Anheim, P. Charles, E. Fedirko,

pr

E. Lejeune, J. Cottineau, A. Brusco, H. Dollfus, P.F. Chinnery, C. Mancini, X.

e-

Ferrer, G. Sole, A. Destée, J.M. Mayer, B. Fontaine, J. De Seze, M. Clanet, E.

Pr

Ollagnon, P. Busson, C. Cazeneuve, G. Stevanin, J. Kaplan, J.M. Rozet, A. Brice, A. Durr, Spastic paraplegia gene 7 in patients with spasticity and/or optic

E. Sánchez-Ferrero, E. Coto, C. Beetz, J. Gámez, A. Corao, M. Díaz, J. Esteban,

rn

[29]

al

neuropathy, Brain. 135 (2012) 2980–2993. doi:10.1093/brain/aws240.

Jo u

E. del Castillo, G. Moris, J. Infante, M. Menéndez, S. Pascual-Pascual, A. López de Munaín, M. Garcia-Barcina, V. Alvarez, SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V, Clin. Genet. 83 (2013) 257–262. doi:10.1111/j.1399-0004.2012.01896.x. [30]

K.L.I. Van Gassen, C.D.C.C. Van Der Heijden, S.T. De Bot, W.F.A. Den Dunnen, L.H. Van Den Berg, C.C. Verschuuren-bemelmans, H.P.H. Kremer, J.H. Veldink, E. Kamsteeg, H. Scheffer, B.P. Van De Warrenburg, Genotype – phenotype correlations in spastic paraplegia type 7 : a study in a large Dutch cohort, (2012) 2994–3004. doi:10.1093/brain/aws224.

Journal Pre-proof [31]

S. Wiethoff, A. Zhour, L. Schöls, M.D. Fischer, Retinal nerve fibre layer loss in hereditary spastic paraplegias is restricted to complex phenotypes, BMC Neurol. 12 (2012). doi:doi: 10.1186/1471-2377-12-143.

[32]

P. Martinelli, E.I. Rugarli, Emerging roles of mitochondrial proteases in neurodegeneration, Biochim. Biophys. Acta - Bioenerg. 1797 (2010) 1–10. doi:10.1016/j.bbabio.2009.07.013.

[33]

L.I. Macedo-souza, F. Kok, S. Santos, S.C. Amorim, A. Starling, A. Nishimura,

oo f

K. Lezirovitz, A.M.M. Lino, Spastic Paraplegia , Optic Atrophy , and Neuropathy Is Linked to Chromosome 11q13, (2005) 730–737.

L.I. Macedo-Souza, F. Kok, S. Santos, L. Licinio, K. Lezirovitz, N. Cavaçana, C.

e-

[34]

pr

doi:10.1002/ana.20478.

Pr

Bueno, S. Amorim, A. Pessoa, Z. Graciani, Á. Ferreira, A. Prazeres, Á.N. de Melo, P.A. Otto, M. Zatz, Spastic paraplegia, optic atrophy, and neuropathy:

al

New observations, locus refinement, and exclusion of candidate genes, Ann.

L.I. Macedo-souza, T. Figueiredo, A.R. Muotri, G. Joseph, G. Coux, P. Armas,

Jo u

[35]

rn

Hum. Genet. 73 (2009) 382–387. doi:10.1111/j.1469-1809.2009.00507.x.

N.B. Calcaterra, S. Amorim, K. Griesi-oliveira, G.C. Coatti, C.R.R. Rocha, C.F.M. Menck, M.S. Zaki, F. Kok, M. Zatz, S. Santos, H. Genome, S. Cell, E. Biology, S. Paulo, J. Pessoa, C. Grande, C.N. De Investigaciones, M.G. Analysis, © The Author 2015 . Published by Oxford University Press . All rights reserved . For Permissions , please email : [email protected], (2015) 1–27. [36]

J.P. Bouchard, A. Barbeau, R. Bouchard, R.W. Bouchard, Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay ( ARSACS ), Can. J. Neurol. Sci. 5 (1978) 61–69.

[37]

J.C. Engert, P. Bérubé, J. Mercier, C. Doré, P. Lepage, B. Ge, J.P. Bouchard, J.

Journal Pre-proof Mathieu, S.B. Melançon, M. Schalling, E.S. Lander, K. Morgan, T.J. Hudson, A. Richter, ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF, Nat. Genet. 24 (2000) 120– 125. doi:10.1038/72769. [38]

B.J. Gentil, G.T. Lai, M. Menade, R. Larivière, S. Minotti, K. Gehring, J.P. Chapple, B. Brais, H.D. Durham, Sacsin, mutated in the ataxia ARSACS,

2982–2994. doi:10.1096/fj.201801556R. [39]

oo f

regulates intermediate filament assembly and dynamics, FASEB J. 33 (2019)

M. Girard, R. Lariviere, D.A. Parfitt, E.C. Deane, R. Gaudet, N. Nossova, F.

pr

Blondeau, G. Prenosil, E.G.M. Vermeulen, M.R. Duchen, A. Richter, E.A.

e-

Shoubridge, K. Gehring, R.A. McKinney, B. Brais, J.P. Chapple, P.S.

Pr

McPherson, Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), Proc. Natl. Acad.

R. Larivière, R. Gaudet, B.J. Gentil, M. Girard, T.C. Conte, S. Minotti, K.

rn

[40]

al

Sci. 109 (2012) 1661–1666. doi:10.1073/pnas.1113166109.

Jo u

Leclerc-Desaulniers, K. Gehring, R.A. Mckinney, E.A. Shoubridge, P.S. Mcpherson, H.D. Durham, B. Brais, Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of charlevoix-saguenay, Hum. Mol. Genet. 24 (2015) 727–739. doi:10.1093/hmg/ddu491. [41]

T. Ogawa, Y. Takiyama, K. Sakoe, K. Mori, M. Namekawa, H. Shimazaki, I. Nakano, M. Nishizawa, Identification of a SACS gene missense mutation in ARSACS, Neurology. 62 (2004) 107–109. doi:10.1212/01.WNL.0000099371.14478.73.

[42]

C. Criscuolo, S. Banfi, M. Orio, P. Gasparini, A. Monticelli, V. Scarano, F.M.

Journal Pre-proof Santorelli, A. Perretti, L. Santoro, G. De Michele, A. Filla, A novel mutation in SACS gene in a family from southern Italy, Neurology. 62 (2004) 100–102. doi:10.1212/WNL.62.1.100. [43]

C. Criscuolo, F. Saccà, G. De Michele, P. Mancini, O. Combarros, J. Infante, A. Garcia, S. Banfi, A. Filla, J. Berciano, Novel mutation of SACS gene in a spanish family with autosomal recessive spastic ataxia, Mov. Disord. 20 (2005) 1358– 1361. doi:10.1002/mds.20579. A.M. Richter, R.K. Ozgul, V.C. Poisson, H. Topaloglu, Private SACS mutations

oo f

[44]

in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)

pr

families from Turkey, Neurogenetics. 5 (2004) 165–170. doi:10.1007/s10048-

G. El Euch-Fayache, I. Lalani, R. Amouri, I. Turki, K. Ouahchi, W.-Y. Hung, S.

Pr

[45]

e-

004-0179-y.

Belal, T. Siddique, F. Hentati, Phenotypic features and genetic findings in sacsin-

al

related autosomal recessive ataxia in Tunisia, Arch. Neurol. 60 (2003) 982–988.

S. Vermeer, R.P.P. Meijer, B.J. Pijl, J. Timmermans, J.R.M. Cruysberg, M.M.

Jo u

[46]

rn

doi:10.1001/archneur.60.7.982.

Bos, H.J. Schelhaas, B.P.C. Van De Warrenburg, N.V.A.M. Knoers, H. Scheffer, B. Kremer, ARSACS in the Dutch population: A frequent cause of early-onset cerebellar ataxia, Neurogenetics. 9 (2008) 207–214. doi:10.1007/s10048-0080131-7. [47]

J. Baets, T. Deconinck, K. Smets, D. Goossens, P. Van Den Bergh, K. Dahan, E. Schmedding, P. Santens, V.M. Rasic, P. Van Damme, W. Robberecht, L. De Meirleir, B. Michielsens, J. Del-Favero, A. Jordanova, P. De Jonghe, Mutations in SACS cause atypical and late-onset forms of ARSACS, Neurology. 75 (2010) 1181–1188. doi:10.1212/WNL.0b013e3181f4d86c.

Journal Pre-proof [48]

J.L. Pedroso, P. Braga-Neto, A. Abrahão, R.L.M. Rivero, C. Abdalla, N. Abdala, O.G.P. Barsottini, Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS): typical clinical and neuroimaging features in a Brazilian family, Arq. Neuropsiquiatr. 69 (2011) 288–291. doi:10.1590/S0004-282X2011000300004.

[49]

M. Synofzik, A.S. Soehn, J. Gburek-Augustat, J. Schicks, K.N. Karle, R. Schüle, T.B. Haack, M. Schöning, S. Biskup, S. Rudnik-Schöneborn, J. Senderek, K.T. Hoffmann, P. Macleod, J. Schwarz, B. Bender, S. Krüger, F. Kreuz, P. Bauer, L.

oo f

Schöls, Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS):

(2013). doi:10.1186/1750-1172-8-41.

J.C. Stevens, S.M. Murphy, I. Davagnanam, R. Phadke, G. Anderson, S.

e-

[50]

pr

Expanding the genetic, clinical and imaging spectrum, Orphanet J. Rare Dis. 8

Pr

Nethisinghe, F. Bremner, P. Giunti, M.M. Reilly, The ARSACS phenotype can include supranuclear gaze palsy and skin lipofuscin deposits, J. Neurol.

E. Gregianin, G. Vazza, E. Scaramel, F. Boaretto, A. Vettori, E. Leonardi, S.C.E.

rn

[51]

al

Neurosurg. Psychiatry. 84 (2013) 114–116. doi:10.1136/jnnp-2012-303634.

Jo u

Tosatto, R. Manara, E. Pegoraro, M.L. Mostacciuolo, A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy, Eur. J. Neurol. 20 (2013) 1486–1491. doi:10.1111/ene.12220. [52]

M.H. Martin, J.P. Bouchard, M. Sylvain, O. St-Onge, S. Truchon, Autosomal recessive spastic ataxia of Charlevoix-Saguenay: A report of MR imaging in 5 patients, Am. J. Neuroradiol. 28 (2007) 1606–1608. doi:10.3174/ajnr.A0603.

[53]

E. Prodi, M. Grisoli, M. Panzeri, L. Minati, F. Fattori, A. Erbetta, G. Uziel, S. D’Arrigo, A. Tessa, C. Ciano, F.M. Santorelli, M. Savoiardo, C. Mariotti, Supratentorial and pontine MRI abnormalities characterize recessive spastic ataxia of Charlevoix-Saguenay. A comprehensive study of an Italian series, Eur.

Journal Pre-proof J. Neurol. 20 (2013) 138–146. doi:10.1111/j.1468-1331.2012.03815.x. [54]

R. Schüle, N. Schlipf, M. Synofzik, S. Klebe, S. Klimpe, U. Hehr, B. Winner, T. Lindig, A. Dotzer, O. Rieß, J. Winkler, L. Schöls, P. Bauer, Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia, J. Neurol. Neurosurg. Psychiatry. (2009). doi:10.1136/jnnp.2008.167528.

[55]

F.M. Rezende Filho, M.H. Parkinson, J.L. Pedroso, R. Poh, I. Faber, C.M. Lourenço, W.M. Júnior, M.C. França Junior, F. Kok, J.M.F. Sallum, P. Giunti,

oo f

O.G.P. Barsottini, Clinical, ophthalmological, imaging and genetic features in

doi:10.1016/j.parkreldis.2018.12.024.

J. Desserre, D. Devos, B.G. Sautière, P. Debruyne, F.M. Santorelli, I. Vuillaume,

e-

[56]

pr

Brazilian patients with ARSACS, Park. Relat. Disord. (2019) 0–1.

Pr

S. Defoort-Dhellemmes, Thickening of peripapillar retinal fibers for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay,

E.M. Vingolo, R. di Fabio, S. Salvatore, G. Grieco, E. Bertini, V. Leuzzi, C.

rn

[57]

al

Cerebellum. 10 (2011) 758–762. doi:10.1007/s12311-011-0286-x.

Jo u

Nesti, A. Filla, A. Tessa, F. Pierelli, F.M. Santorelli, C. Casali, Myelinated retinal fibers in autosomal recessive spastic ataxia of Charlevoix-Saguenay, Eur. J. Neurol. 18 (2011) 1187–1190. doi:10.1111/j.1468-1331.2010.03335.x. [58]

S. Nethisinghe, L. Clayton, S. Vermeer, J.P. Chapple, M. Reilly, F. Bremner, P. Giunti, Retinal imaging in autosomal recessive spastic ataxia of charlevoixsaguenay, Neuro-Ophthalmology. 35 (2011) 197–201. doi:10.3109/01658107.2011.595043.

[59]

C.T. Shah, T.S. Ward, J.A. Matsumoto, Y. Shildkrot, Foveal hypoplasia in autosomal recessive spastic ataxia of Charlevoix-Saguenay, J. AAPOS. 20 (2016) 81–83. doi:10.1016/j.jaapos.2015.10.007.

Journal Pre-proof [60]

E. Garcia-Martin, L.E. Pablo, J. Gazulla, A. Vela, J.M. anue. Larrosa, V. Polo, M.L. Marques, J. Alfaro, Retinal segmentation as noninvasive technique to demonstrate hyperplasia in ataxia of Charlevoix-Saguenay, Invest. Ophthalmol. Vis. Sci. 54 (2013) 7137–7142. doi:10.1167/iovs.13-12726.

[61]

M.H. Parkinson, A.P. Bartmann, L.M.S. Clayton, S. Nethisinghe, R. Pfundt, J.P. Chapple, M.M. Reilly, H. Manji, N.J. Wood, F. Bremner, P. Giunti, Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-

[62]

oo f

Saguenay, Brain. 141 (2018) 989–999. doi:10.1093/brain/awy028. M. van Lint, K. Hoornaert, M.P.M. ten Tusscher, Retinal nerve fiber layer

L. Blumkin, T. Bradshaw, M. Michelson, T. Kopler, D. Dahari, T. Lerman-Sagie,

Pr

[63]

e-

doi:10.1016/j.jns.2016.09.023.

pr

thickening in ARSACS carriers, J. Neurol. Sci. 370 (2016) 119–122.

D. Lev, J.P. Chapple, E. Leshinsky-Silver, Molecular and functional studies of

al

retinal degeneration as a clinical presentation of SACS-related disorder, Eur. J.

E. Garcia-Martin, L.E. Pablo, J. Gazulla, V. Polo, A. Ferreras, J.M. Larrosa,

Jo u

[64]

rn

Paediatr. Neurol. 19 (2015) 472–476. doi:10.1016/j.ejpn.2015.02.005.

Retinal nerve fibre layer thickness in ARSACS: myelination or hypertrophy?, Br. J. Ophthalmol. 97 (2013) 238–241. doi:10.1136/bjophthalmol-2012-302309. [65]

P. Yu-Wai-Man, A. Pyle, H. Griffin, M. Santibanez-Korev, R. Rita Horvath, P.F. Chinnery, Abnormal retinal thickening is a common feature among patients with ARSACS-related phenotypes, Br. J. Ophthalmol. 98 (2014) 711–713. doi:10.1136/bjophthalmol-2013-304534.

[66]

F. Borruat, G.E. Holder, F. Bremner, Inner Retinal Dysfunction in the autosomal Recessive spastic ataxia of Charlevoix-saguenay, Front. Neurol. 8 (2017) 12–15. doi:10.3389/fneur.2017.00523.

Journal Pre-proof [67]

J. Mosser, A.M. Douar, C.O. Sarde, P. Kioschis, R. Feil, H. Moser, A.M. Poustka, J.L. Mandel, P. Aubourg, Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters, Nature. 361 (1993) 726– 730. doi:10.1038/361726a0.

[68]

H.H. Schaumburg, J.M. Powers, C.S. Raine, K. Suzuki, E.P. Richardson, Adrenoleukodystrophy: A Clinical and Pathological Study of 17 Cases, Arch. Neurol. 32 (1975) 577–591. doi:10.1001/archneur.1975.00490510033001. A. Semmler, W. Köhler, H.H. Jung, M. Weller, M. Linnebank, Therapy of X-

oo f

[69]

linked adrenoleukodystrophy, Expert Rev. Neurother. 8 (2008) 1367–1379.

H.W. Moser, Adrenoleukodystrophy: Phenotype, genetics, pathogenesis and

e-

[70]

pr

doi:10.1586/14737175.8.9.1367.

[71]

Pr

therapy, Brain. 120 (1997) 1485–1508. doi:10.1093/brain/120.8.1485. H.W. Moser, D.J. Loes, E.R. Melhem, G. V. Raymond, L. Bezman, C.S. Cox,

al

S.E. Lu, X-linked adrenoleukodystrophy: Overview and prognosis as a function

rn

of age and brain magnetic resonance imaging abnormality. A study involving 372

[72]

Jo u

patients, Neuropediatrics. 31 (2000) 227–239. doi:10.1055/s-2000-9236. H.W. Moser, A. Mahmood, G. V Raymond, X-linked adrenoleukodystrophy, Nat. Clin. Pract. Neurol. 3 (2007) 140–151. doi:10.1038/ncpneuro0421. [73]

B.P. O’Neill, H.W. Moser, K.M. Saxena, L.C. Marmion, Adrenoleukodystrophy: Clinical and biochemical manifestations in carriers, Neurology. 34 (1984) 798– 801. doi:10.1212/wnl.34.6.798.

[74]

P.W. Kaplan, B. Kruse, R.J. Tusa, J. Shankroff, J. Rignani, H.W. Moser, Visual system abnormalities in adrenomyeloneuropathy, Ann. Neurol. 37 (1995) 550– 552. doi:10.1002/ana.410370419.

[75]

E.I. Traboulsi, I.H. Maumenee, Ophthalmologic Manifestations of X-linked

Journal Pre-proof Childhood Adrenoleulcodystrophy, Ophthalmology. 94 (1987) 47–52. doi:10.1016/S0161-6420(87)33504-3. [76]

J.J. Aquino, E.S. Sotirchos, S. Saidha, G. V Raymond, P.A. Calabresi, Pediatric Neurology Optical Coherence Tomography in X-Linked Adrenoleukodystrophy, Pediatr. Neurol. 49 (2013) 182–184. doi:10.1016/j.pediatrneurol.2013.04.012.

[77]

Y. Ohkuma, T. Hayashi, S. Yoshimine, H. Tsuneoka, N. Ebihara, A. Murakami, N. Shimozawa, Retinal Ganglion Cell Loss in X-linked Adrenoleukodystrophy

335. doi:10.3109/01658107.2014.950430.

B.J. Glasgow, H.H. Brown, J.B. Hannah, R.Y. Foos, Ocular Pathologic Findings

pr

[78]

oo f

with an ABCD1 Mutation ( Gly266Arg ), Neuro-Ophthalmology. 38 (2014) 331–

e-

in Neonatal Adrenoleukodystrophy, Ophthalmology. 94 (1987) 1054–1060.

[79]

Pr

doi:10.1016/S0161-6420(87)33345-7.

C.J. Lyons, G. Castano, A.Q. McCormick, D. Applegarth, Leopard spot retinal

al

pigmentation in infancy indicating a peroxisomal disorder, Br. J. Ophthalmol. 88

R.J. Courtney, M.E. Pennesi, Interval Spectral-Domain Optical Coherence

Jo u

[80]

rn

(2004) 191–192. doi:10.1136/bjo.2003.023010.

Tomography and Electrophysiology Findings in Neonatal Adrenoleukodystrophy, JAMA Ophthalmol. 131 (2013) 807. doi:10.1001/jamaophthalmol.2013.2089. [81]

G.H. Sack Jr., M.B. Raven, H.W. Moser, Color vision defects in adrenomyeloneuropathy, Am. J. Hum. Genet. 44 (1989) 794–798.

[82]

B.T. Grainger, T.L. Papchenko, H. V. Danesh-Meyer, Optic nerve atrophy in adrenoleukodystrophy detectable by optic coherence tomography, J. Clin. Neurosci. 17 (2010) 122–124. doi:10.1016/j.jocn.2009.08.019.

[83]

B.Y. Chun, J.F. Rizzo, Dominant optic atrophy: Updates on the pathophysiology

Journal Pre-proof and clinical manifestations of the optic atrophy 1 mutation, Curr. Opin. Ophthalmol. 27 (2016) 475–480. doi:10.1097/ICU.0000000000000314. [84]

P. Yu-Wai-Man, P.G. Griffiths, G.S. Gorman, C.M. Lourenco, A.F. Wright, M. Auer-Grumbach, A. Toscano, O. Musumeci, M.L. Valentino, L. Caporali, C. Lamperti, C.M. Tallaksen, P. Duffey, J. Miller, R.G. Whittaker, M.R. Baker, M.J. Jackson, M.P. Clarke, B. Dhillon, B. Czermin, J.D. Stewart, G. Hudson, P. Reynier, D. Bonneau, W. Marques, G. Lenaers, R. McFarland, R.W. Taylor,

oo f

D.M. Turnbull, M. Votruba, M. Zeviani, V. Carelli, L.A. Bindoff, R. Horvath, P. Amati-Bonneau, P.F. Chinnery, Multi-system neurological disease is common in

M. Ranieri, R. Del Bo, A. Bordoni, D. Ronchi, I. Colombo, G. Riboldi, A. Cosi,

Pr

[85]

e-

doi:10.1093/brain/awq007.

pr

patients with OPA1 mutations, Brain. 133 (2010) 771–786.

M. Servida, F. Magri, M. Moggio, N. Bresolin, G.P. Comi, S. Corti, Optic

al

atrophy plus phenotype due to mutations in the OPA1 gene: Two more Italian

E. Daǧ, N. Örnek, K. Örnek, I.E. Erbahçeci-Timur, Optical coherence

Jo u

[86]

rn

families, J. Neurol. Sci. 315 (2012) 146–149. doi:10.1016/j.jns.2011.12.002.

tomography and visual field findings in patients with friedreich Ataxia, J. NeuroOphthalmology. 34 (2014) 118–121. doi:10.1097/WNO.0000000000000068. [87]

A.R.M. Martinez, A. Moro, A. Abrahao, I. Faber, C.R. Borges, T.J.R. Rezende, C.R. Martins, M. Moscovich, R.P. Munhoz, S.L. Segal, W.O. Arruda, M.L. Saraiva-Pereira, S. Karuta, J.L. Pedroso, A. D’Abreu, L.B. Jardim, Í. LopesCendes, O.G. Barsottini, H.A.G. Teive, M.C. França, Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes, Cerebellum. 16 (2017) 253–256. doi:10.1007/s12311-015-0755-8.

[88]

L. Montermini, A. Richter, K. Morgan, C.M. Justice, D. Julien, B. Castellotti, J.

Journal Pre-proof Mercier, J. Poirier, F. Capozzoli, J.P. Bouchard, B. Lemieux, J. Mathieu, M. Vanasse, M.H. Seni, G. Graham, F. Andermann, E. Andermann, S.B. Melançon, B.J.B. Keats, S. Di Donato, M. Pandolfo, Phenotypic variability in friedreich ataxia: Role of the associated GAA triplet repeat expansion, Ann. Neurol. 41 (1997) 675–682. doi:10.1002/ana.410410518. [89]

E.A. Harvey, K.S. Jones, Child Neurology: Friedreich ataxia with upper motor neuron findings, Neurology. 91 (2018) 426–428.

[90]

oo f

doi:10.1212/WNL.0000000000006086.

M.H. Parkinson, S. Boesch, W. Nachbauer, C. Mariotti, P. Giunti, Clinical

pr

features of Friedreich’s ataxia: Classical and atypical phenotypes, J. Neurochem.

S. Noval, I. Contreras, I. Sanz-Gallego, R.K. Manrique, J. Arpa, Ophthalmic

Pr

[91]

e-

126 (2013) 103–117. doi:10.1111/jnc.12317.

features of Friedreich ataxia, Eye. 26 (2012) 315–320. doi:10.1038/eye.2011.291. F. Fortuna, P. Barboni, R. Liguori, M.L. Valentino, G. Savini, C. Gellera, C.

al

[92]

rn

Mariotti, G. Rizzo, C. Tonon, D. Manners, R. Lodi, A.A. Sadun, V. Carelli,

Jo u

Visual system involvement in patients with Friedreich’s ataxia, Brain. 132 (2009) 116–123. doi:10.1093/brain/awn269. [93]

S. Nie, G. Chen, X. Cao, Y. Zhang, Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management, Orphanet J. Rare Dis. 9 (2014) 179. doi:10.1186/s13023-014-01794.

[94]

S. Jayadev, T.D. Bird, Hereditary ataxias: Overview, Genet. Med. 15 (2013) 673–683. doi:10.1038/gim.2013.28.

[95]

J.C. Wong, K. Walsh, D. Hayden, F.S. Eichler, Natural history of neurological abnormalities in cerebrotendinous xanthomatosis, (2018).

Journal Pre-proof [96]

A. Mignarri, G.N. Gallus, M.T. Dotti, A. Federico, A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis, (2014). doi:10.1007/s10545-013-9674-3.

[97]

S. Tibrewal, P.B. Duell, A.E. Debarber, A.R. Loh, Cerebrotendinous xanthomatosis: early diagnosis on the basis of juvenile cataracts, J. AAPOS. (2017). doi:10.1016/j.jaapos.2017.07.211.

[98]

S.F. Freedman, C. Brennand, J. Chiang, A. Debarber, M.A. Del Monte, P.B.

oo f

Duell, J. Fiorito, R. Marshall, Prevalence of Cerebrotendinous Xanthomatosis Among Patients Diagnosed With Acquired Juvenile-Onset Idiopathic Bilateral

A. Pudhiavan, A. Agrawal, S. Chaudhari, A. Shukla, Cerebrotendinous

e-

[99]

pr

Cataracts, 27710 (2019) 1–5. doi:10.1001/jamaophthalmol.2019.3639.

Pr

xanthomatosis - The spectrum of imaging findings, J. Radiol. Case Rep. 7 (2013) 1–9. doi:10.3941/jrcr.v7i4.1338.

al

[100] R.P.A. Salomão, J.L. Pedroso, M.T.D. Gama, L.A. Dutra, R.H. Maciel, C.

rn

Godeiro-Junior, H.F. Chien, H.A.G. Teive, F. Cardoso, O.G.P. Barsottini, A

Jo u

diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging, Arq. Neuropsiquiatr. 74 (2016) 587–596. doi:10.1590/0004-282x20160080. [101] M.C. Kruer, Pantothenate Kinase-Associated Neurodegeneration, Rosenberg’s Mol. Genet. Basis Neurol. Psychiatr. Dis. Fifth Ed. (2014) 473–481. doi:10.1016/B978-0-12-410529-4.00043-7. [102] J. Han, D.W. Kim, C.H. Lee, S.H. Han, Optic atrophy in a patient with atypical pantothenate kinase-associated neurodegeneration, J. Neuro-Ophthalmology. 36 (2016) 182–186. doi:10.1097/WNO.0000000000000335. [103] J. Jesus-Ribeiro, C. Farinha, M. Amorim, A. Matos, A. Reis, J. Lemos, M.

Journal Pre-proof Castelo-Branco, C. Januário, Visual and ocular motor function in the atypical form of neurodegeneration with brain iron accumulation type I, Br. J. Ophthalmol. (2017) 1–7. doi:10.1136/bjophthalmol-2017-310181. [104] M. Hartig, H. Prokisch, T. Meitinger, T. Klopstock, Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN), 1st ed., Elsevier Inc., 2013. doi:10.1016/B978-0-12-410502-7.00004-1. [105] E. Gore, B.S. Appleby, M.L. Cohen, S.D. DeBrosse, J.B. Leverenz, B.L. Miller,

oo f

S.L. Siedlak, X. Zhu, A.J. Lerner, Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN),

pr

Neurocase. 22 (2016) 476–483. doi:10.1080/13554794.2016.1247458.

e-

[106] S.A. Schneider, H. Houlden, K.P. Bhatia, A. Gregory, J.C. Anderson, W.D.

Pr

Rooney, P. Hogarth, Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation, Am. J. Neuroradiol. 33 (2012) 407–414.

al

[107] K. Koh, F. Kobayashi, M. Miwa, K. Shindo, E. Isozaki, H. Ishiura, S. Tsuji, Y.

rn

Takiyama, Novel mutations in the PNPLA6 gene in Boucher-Neuhaüser

Jo u

syndrome, J. Hum. Genet. 60 (2015) 217–220. doi:10.1038/jhg.2015.3. [108] M. Synofzik, M.A. Gonzalez, C.M. Lourenco, M. Coutelier, T.B. Haack, A. Rebelo, D. Hannequin, T.M. Strom, H. Prokisch, C. Kernstock, A. Durr, L. Schöls, M.M. Lima-Martínez, A. Farooq, R. Schüle, G. Stevanin, W. Marques, S. Züchner, PNPLA6 mutations cause Boucher-Neuhäuser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum, Brain. 137 (2014) 69– 77. doi:10.1093/brain/awt326. [109] O. Patsi, C. De Beaufort, P. Kerschen, S. Cardillo, A. Soehn, M. Rautenberg, N.J. Diederich, A new PNPLA6 mutation presenting as Oliver McFarlane syndrome, J. Neurol. Sci. 392 (2018) 1–2. doi:10.1016/j.jns.2018.06.016.

Journal Pre-proof [110] M. Synofzik, C. Kernstock, T.B. Haack, L. Schöls, Ataxia meets chorioretinal dystrophy and hypogonadism:Boucher-Neuhäuser syndrome due to PNPLA6 mutations, J. Neurol. Neurosurg. Psychiatry. 86 (2015) 580–581. doi:10.1136/jnnp-2014-307793. [111] S. Rainier, M. Bui, E. Mark, D. Thomas, D. Tokarz, L. Ming, C. Delaney, R.J. Richardson, J.W. Albers, N. Matsunami, J. Stevens, H. Coon, M. Leppert, J.K. Fink, Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease,

oo f

Am. J. Hum. Genet. 82 (2008) 780–785. doi:10.1016/j.ajhg.2007.12.018. [112] G.A. Holmes, A form of familial degeneration of the cerebellum., Brain. (1907)

pr

466–489.

e-

[113] G.F. Boucher BJ, Familial ataxia, hypogonadism and retinal degeneration. Acta

Pr

Neurol Scand 1969; 45: 507–10., Acta Neurol Scand. (1969) 507–510. [114] O.J. Neuhauser G, Autosomal recessive syndrome of cerebellar ataxia and

al

hypogonadotropic hypogonadism., Clin Genet. (1975) 426–434.

rn

[115] J. Fuijkschot, T. Theelen, M.M.B. Seyger, M. Van Der Graaf, I.J.M. De Groot,

Jo u

R.A. Wevers, R.J.A. Wanders, H.R. Waterham, M.A.A.P. Willemsen, SjögrenLarsson syndrome in clinical practice, J. Inherit. Metab. Dis. 35 (2012) 955–962. doi:10.1007/s10545-012-9518-6. [116] S. Jagell, K.H. Gustavson, G. Holmgren, Sjogren-Larsson syndrome in Sweden. A clinical, genetic and epidemiological study, Clin Genet. 19 (1981) 233–256. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&do pt=Citation&list_uids=7273467.

Legend of the figure 1: Patient with typical findings observed in SPG15. A. Retinography of the right eye discloses multiple round, yellowish lesions (arrow on

Journal Pre-proof display), known as flecks and consistent with fundus flavimacullatus. B. Fundus autofluorescence of the same eye depicting hyper-autofluorescence in the flecks, which are surrounded by areas of hypo-autofluorescence (arrow on display). C. Macular OCT scan of the same patient; the green line marks the horizontal section shown in D, which includes a fleck (arrowhead). D. Horizontal B-scan depicting the OCT appearance of a fleck: an elevated hyperreflective nodule in the retinal pigmented epitelium/Bruch’s membrane complex protruding into the outer nuclear layer with no loss of continuity of

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the external limiting membrane (arrowhead).

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Legend of the figure 2: Patient with SPG7. A. Left eye retinography depicting an

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atrophic optic disc. Pallor is more prominent in the temporal region of the disc and there

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is temporal peripapillary atrophy (arrowhead). B. RNFL thickness map and graph confirm loss of retinal nerve fibers, predominantly in the temporal sector. C. OCT

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horizontal B-scan centered at the fovea, which displays a normal macular architecture.

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An asterisks marks the foveal pit.

Legend of the figure 3: Patient with ARSACS. A. Retinography from left eye depicting increased visibility of retinal nerve fibers, which hide the contours of retinal vessels (arrows). B. Red-free fundus image discloses augmented demarcation of retinal nerve fibers (arrows) and a papilomacullar fold (arrowheads). C. Horizontal section thru the macula of the right eye reveals absence of foveal pit in the fovea (asterisk), consistent with foveal hypoplasia, and macular microcysts of inner nuclear and ganglion cell layers (arrow). D. Dentate appearance of inner retinal layers (arrowheads). E. Peripapillary RNFL thickness map (left) and graph (right) from the patient’s right eye showing increased thickness, particularly in superior and inferior sectors.

Journal Pre-proof Table 1. Ophthalmologic manifestations in SPG

SPG2, SPG7, SPG16, SPG35, SPG45, SPG54,

Optic atrophy

SPG55, SPG57, SPG68 SPG11, SPG15

Cataract

SPG9, SPG25, SPG46

Ophthalmoplegia

SPG7

Strabismus

SPG7, SPG45

Congenital glaucoma

SPG25

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Yellow retinal flecks

Journal Pre-proof Table 2. Ophthalmologic manifestations in which spastic paraplegia occur

Gene

X-Linked adrenoleukodystrophy

Protein function

Ophthalmol ogic manifestation

Metabolism of very long chain fatty acids

Optic atrophy, cataract, retinal pigment changes, RNFL thinning and reduction of total macular volume in OCT

Protein

ABCD1

ABCD1

KLC2

Kinesin light chain-2

ARSACS

SACS

Sacsin

Pr

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SPOAN

Anterograde axoplasmatic transport of organelles and macromolecular cargoes Regulate mitochondrial fusion and fission and intermediate neurofilament assembly and dynamics

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Disease

OPA1

Cerebrotendineus Xanthomatosis

CYP27A1

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FAHN

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OPA1

Human homolog of the S. pombe dynaminrelated protein Msp1 Mitochondrial enzyme sterol 27hydroxylase

FA2H

Fatty acid 2-hydroxylase

MPAN

C19orf12

Unknown

PKAN

PANK2

Pantothenate kinase

Multiple mitochondrial functions including mitochondrial function

Bile acid synthesis.

Synthesis of galactosylceramides and sulfatides, essential lipid components of normal myelin Valine, leucine, and isoleucine degradation and fatty acid metabolism CoA biosynthesis, catalyzing the cytosolic phosphorylation of pantothenate (vitamin B5), Npantothenoylcysteine, and pantetheine

Optic atrophy, subnormal vision, fixation nystagmus

Hypertrophy of RNFL, foveal hypoplasia

Optic atrophy with severe loss of visual acuity, temporal optic pallor, color vision deficits, centrocecal scotoma Cataract, optic disk paleness, retinal vessel sclerosis, cholesterol-like deposits

Optic atrophy, progressive visual loss

Optic Atrophy

Pigmentary retinopathy, optic atrophy, disturbed vertical saccades

Journal Pre-proof

Sjögren-Larsson syndrome

ALDH3A2

Fatty aldehyde dehydrogenase

Oxidation of fatty alcohol to fatty aldedy and then to a fatty acid

Crystalline macular dystrophy, decreased visual acuity, photophobia

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Abbreviations: ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay, FAHN, fatty acid 2-hydroxylase-associates neurodegeneration; MPAN, mitochondrial membrane protein -associated neurodegeneration; OCT, optical coherence tomography, OPA1, optic atrophy 1; PKAN, Pantothenase kinase-associated neurodegeneration; RNFL, retinal nerve fiber layer; SPOAN, spastic paraplegia, optic atrophy and neuropathy.

Journal Pre-proof Highlights  Hereditary spastic paraplegia may present with ophthalmological manifestations 

Important ophthalmological degeneration



Ptosis and progressive external ophthalmoplegia are clues for the diagnosis of SPG7

associated

with

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change

SPG15

is

retinal

Figure 1

Figure 2

Figure 3