Vladimir Agrigoroaei

The First Psalters in Old French and their 12 th Century Context

There are two ways in which one may write the introduction to the history of medieval French literature. The first one -more common -starts with the Song of Roland. The second one -just as acceptable -starts with the St Albans Psalter (nowadays preserved in Hildesheim, Cathedral Library of Saint Mary, without a designated number). It was there, in this Psalter, that one of the most seminal texts of the Middle Ages was written -the Song of St Alexis -, but it was also from this Latin Psalter that the first translations of the sacred texts into French were ever made.

The Oxford Psalter, the very first French medieval translation of the Psalter and the most extensively copied, 1 is arguably one of the best wordby-word translations of the Psalms and Old Testament Canticles ever made, and it stems from that particular text. The autograph of this translation 2 is preserved in the Douce 320 manuscript of the Bodleian Library in Oxford. Completely different from the mise-en-page of the other French Psalters of the time, its avatars, the Oxford Psalter's layout presents us with a monolingual codex. It dates back to the first half of the 12 th century and it was written in England, in the Anglo-Norman dialect of the time. Nothing is known about the original context in which it was produced. The only thing known for certain is that the Oxford Psalter was part of the library of the Benedictine abbey of Montebourg, in Normandy, at the beginning of the 14 th century, where it was bound with a copy of a French translation of the Rule of Saint Benedict -dating back to the beginning of the 13 th century -in what is nowadays known as the composite manuscript Douce 320. This is why it was also called the Montebourg Psalter for quite some time. Its new name, the Oxford Psalter, refers only to the place where it is nowadays preserved.

Unlike the first manuscript of the Song of Roland (Oxford, Bodleian Library, Digby 23 -a pocketbook for a troubadour), the Douce 320 manuscript is a normal size codex, of 29 x 20 cm. Its text is written in a single block of text, on an average of forty lines per page, with little space left for the margins. The red and green initials and lettrines were used in an

1 For the 12 th and 13 th century manuscripts presenting the Oxford Psalter version, see Dean, MacCann Boulton 1999, no. 445, 239-240. 2 For this notion, see Short, Careri, Ruby 2010.

Notes

Vernacular Psalters and the Early Rise of Linguistic Identities: The Romanian Case, 2019, p. 29-37 | 29 Center for Advanced Studies in Medieval Civilization, Poitiers (céscm, umr 7302) -cnrs alternate manner. It contains the translation of the 150 Psalms of a mixed version of the Gallicanum, followed by the canticles of Isaiah, Ezekiel, Anna, Moses, Habakkuk, Moses again, and the children of Israel. It was written in prose, contrary to the general Anglo-Norman preference for verse translations, and its text was edited twice: first in the middle of the 19 th century, and recently, in 2015. 3 It has been often implied that the Oxford Psalter could be a copy of a bilingual codex, but newer hypotheses have recently showed that the Oxford Psalter is an original, that certain translation choices link it to the peculiar Latin version preserved in the St Albans Psalter, and that its scribe may have been one of the copyists working on the latter manuscript. But what is truly interesting is that the Oxford Psalter was copied in a countless number of manuscripts.

Most of these manuscripts are double-columned. It is the case of the Winchester Psalter, also known as the Psalter of Henry of Blois, a manuscript dating back to ca. 1160 (London, British Library, Cotton Nero c iv). It contains the Oxford Psalter French translation of the Psalms and the Latin text of the Gallicanum, copied on separate parallel columns, folio by folio. This manuscript also has a calendar and a famous Christological image cycle with legends in French. The picture cycle is inserted between the calendar and the French-Latin text of the Psalms. 4 It was probably painted at the Saint Swithun priory, close to Winchester, and it was intended for Henry of Blois, the bishop of Winchester (1096Winchester ( -1171Winchester ( , bishop 1126Winchester ( -1171)), whence its second name. The fact that such a richly illustrated Psalter contains a French version of the Psalms testifies perhaps to the usefulness of translation. It must have been copied at the request of the bishop, although the bishop knew Latin very well and did not really need a translation. The French text had both a pedagogical and an esthetical value.

These double psalters, also referred to as 'parallel' or 'bilingual' Psalters, 5 contain the two main texts (Latin and French) written on two separate columns: the Latin text often occupies the more prestigious place, on the left, and the French text occupies the right column, but this is not always so. Changes may take place according to a logic that nowadays eludes us. All the double Psalters are avatars of the translation transcribed in the Oxford Douce manuscript and one of the best examples is the manuscript from Paris, Bibliothèque Nationale de France n. acq. lat. 1670. It is not necessarily the most ancient of them all, for it dates back only to the end of the 12 th century, but its layout is somehow 'classical'. We may find the same layout in many other manuscripts, with minor changes. The symmetry of the two columns structures the manuscript in a perfect manner: each Latin verse is followed, in the right column, by a French verse which occupies the same number of lines. Identical ornate initial letters introduce the various segments of the two text; they were written by the same copyist. It has been said that the "text editing comes before the text itself. " 6 Text editing became a general rule for the double Psalters. However, another manuscript, dating from the last quarter of the 12 th century, introduced a slightly compositional variation. It is a Paris codex preserved in the Bibliothèque Nationale de France (lat. 768), once called the Corbie Psalter, although it probably originated in Canterbury. When reading it, one is again face to face with a version derived from that of the Oxford Psalter. The French was erased on the first pages of the psalms, until Ps 68 (f. 10 r -58 v ), and it occupies the second place, on the right column. Some-

Notes

Fig. 2. Oxford Psalter (Oxford, Bodleian Library, Douce 320), f. 37 v . Detail. The high number of erasures and emendations in this manuscript, some of whom are visible in the photo, is proof of its autograph nature. Photo of the author, courtesy of The Bodleian Libraries, The University of Oxford.

times there is a balance problem between the two columns. 7 The copyist therefore had problems with the disparities created by the different sizes (and number of words) in the two texts.

The same layout, with the French text on the second column, opposite the Latin text, is to be found in the Copenhagen Psalter (Universitetsbiblioteket Arnamagnasanske Samling 618 4o). It dates back to the last third of the 12 th century and it was written somewhere in England. The French text, transcribed by the same copyist who copied the first column, that of the Latin Gallicanum, is irretrievably lost. It was erased so that the second column encloses an Icelandic translation of the Psalms, dated 1586. 8 Another Psalter is preserved in a fragmentary manner, in the parchment leaves included in the binding of a book of 1593: Oxford, Saint John's College, hb4 / 4.a.4.21 (I.subt.1.47). 9 There is the Additional 35283 manuscript in the British Library. It dates back to the last quarter of the 12 th century, or -more likely -from the first part of the next century. 10 And there are many more manuscripts like these. But there is also proof of a certain evolution in this long line of Latin-French double Psalters.

The three folios of a bilingual Psalter, preserved today at Maidstone, in the Kent County Archives, in the file Fa Z 1, contain only the verses Ps 55: 7-Ps 59: 10, and Ps 68: 15-70, but these fragments are enough to identify the French text with an avatar of the Oxford Psalter. 11 With regard to their layout, it gives the impression of being similar to that of the double Psalters. The text has been transcribed on two columns, except that it no longer presents two autonomous texts. Latin and French verses alternate within each column. There is only one text, of a composite nature, and the hierarchy of languages dictates only that the Gallicanum should be copied first. This witness marks the passage to another group or category of bilingual (and even trilingual) Psalters, where the French language occupies the place reserved for glosses. This transformation would seem natural after the strict symmetry of the two-column Psalters. It is "of the greatest convenience in reading, in order to establish the linguistic correspondences. " 12 This other tradition starts with the Orne Psalter (Paris, Archives nationales, ab xix 1734, Orne dossier), a mid-12 th century manuscript fragment preserving an intercalary translation. 13 This bifolio leaf was also part of a book binding. It contains two fragments of an interlinear translation of Ps 77:40-62 and Ps 87:10-Ps 87:14, similar in aspect to a Medieval Latin gloss. This layout dictated that the translation choices be very close to the structure Latin text, so much so that it is difficult to say whether it is a different translation or a very free adaptation of the Oxford version.

The Arundel Psalter, sometimes called the London Psalter (British Library, Arundel 230), is the second best example in the category of interlinear translations of Psalms. 14 It dates back to the end of the 12 th century. 15 Nonetheless, it has nothing in common with the Orne Psalter, except for the use of an intermediate gloss. The Arundel Psalter better integrates the series of double Psalters. In most cases, its interlinear gloss is servile to the Oxford Psalter's translation choices. That is why it used to be considered a redesign of the latter, 16 but the question is much too complicated and it may well also be that the Arundel translator had to make the same translation choices because of his idiolect or sociolect.

The usage of these French Psalters is debated, and it should perhaps still remain mysterious. No one can really argue that they have been used in liturgy, for it was forbidden to hold mass in another language than Latin. 7 "Un souci d'équilibre entre les deux colonnes" ; Careri, Ruby, Short 2011, p. 170 (for the quotation and for the description). Cf. Ruby 2010, p. 174, 176;Avril, Stirnemann 1987, no. 75;Brayer, Bouly de Lesdain 1968, p. 74. 8 For the French version, see Skårup 1977, p. 90-94. For the modern Icelandic translation of the Psalms, see Kirby 1986, p. 127 et seqq. Cf. Ruby 2010, p. 178;Careri, Ruby, Short 2011, p. 40. 9 For the two fragments, see [START_REF] Kerr | [END_REF]. Cf. Ruby 2010, p. 178, 180;Careri, Ruby, Short 2011, p. 67

Notes

Several other interpretations have been proposed, most of them speaking of the private reading of these manuscripts, but these hypotheses are conjectural and resemble other hypotheses proposed for the early Psalters in Czech, Hungarian, English, or even in Romanian for that matter. The private use of these Psalm translations can be ascertained only for a third category of manuscripts: the Psalm commentaries in French, among which many are accompanied by a French interlinear translation of the Latin text. I do not intend to present here the three versions (nor the five or six rewritings) of these commentaries on the Psalms. On the merits of the case, however, some general notes are essential to be made.

Only the first Commentary to the Psalms, continental in its origin (and not British), will be mentioned here, because some of its copies are the only ones preserving an interlinear translation of the Gallicanum. This first French Commentary, written for Laurette of Alsace in the second half of the 12 th century, was copied with the Gallicanum in three of its manuscript witnesses. 17 The Latin text, transcribed in large letters, is accompanied by a French interlinear translation which doesn't seem to be clearly related to the Oxford Psalter version, to the Arundel, to the Orne, nor to the Eadwine Psalter (which will be immediately discussed). The most important manuscript of this Commentary, preserved in New York (Pierpont Morgan Library, codex 338), has the Latin text copied on the interior side of the folio, on a tight column, with a small vernacular gloss following it word by word. The bulk of the French commentary -itself translated from an avatar of the Media Glossatura -is arranged in a much wider lateral margin and continues on the following lines, covering the whole width of the page. The Latin text is therefore interrupted by the French commentary, the Gallicanum verses are isolated from each other, they do not form an autonomous text, but it is just as obvious that this layout follows in fact the cum textu disposition of the Medieval Latin commentaries.

A slightly different, word-by-word, translation was copied in another manuscript of the same Commentary, nowadays in Hereford (Cathedral Library, o iii 15). It dates back to the end of the 12 th century, the Latin Gallicanum is written on the entire width of the folio, as in the Orne Psalter, but the disposition of the interlinear gloss and the commentary copied after it remains more or less the same. It is thought that this codex, clearly produced in England, must have adapted its continental model -such as one may see in the Morgan 338 manuscript -to a slightly different insular practice where intercalary glosses had reached a certain stability. Finally, a book in Durham (Cathedral Library, a ii 11), the first of a series of three codices containing a complete copy of the Commentary, lacks this interlinear translation, The editor of the first version of the Commentary (Ps 1-50), argued that other similar aspects to those of the Oxford Psalter may be found in the Morgan manuscript, at least in the parts written by a certain scribe, whom he names "h3". It is therefore possible to imagine that a local interlinear translation, made in England, might have influenced the one transcribed in the continental Commentary on the Psalms, that the interlinear gloss in Morgan 338 may simply perpetuate a local fashion. Nevertheless, the same editor argued that the links with the Oxford Psalter cannot be proven, and that the translation copied in the three manuscripts of the first French Commentary to the Psalms must have been independent, done directly on the basis of the Latin text copied in these manuscripts. 18 Another separate interlinear French translation is found in the Eadwine 18 For all these date, and for other notions mentioned below, see Gregory 1990, vol. 1, p. 6-10. For the presentation of the manuscripts, see also Careri, Ruby, Short 2011 (who do not deal with the manuscript from Durham).

Notes

The first Psalters in Old French and their 12 th century context | Psalter, the most famous codex of our corpus, but this other Psalter contains a translation that has nothing to do with all the previous translations. The Eadwine represents a completely different tradition. This other translation is preserved in two manuscripts only. The first is one is now preserved in Cambridge (Trinity College r.17.1) and was written in ca. 1155-1160 at the priory of Christ Church, in other words in the cultural context of Canterbury Cathedral. 19 The main scribe's portrait (Eadwinus) at the end of the codex gave its modern name. The second codex, a copy of the first, 20 is nowadays preserved in Paris (Bibliothèque Nationale de France, lat. 8846), but is of a later date and it contains only the translation of Ps 1-97. Both of these manuscripts are rich in miniatures and they belong to the tradition of the Utrecht Psalter, a Carolingian manuscript, from an iconographic point of view. 21 The Eadwine Psalter contains the complete text of the French interlinear translation. 22 Its layout is simply stunning. The manuscript contains, on three columns, the three Latin versions of the Psalter. The Gallicanum gets the lion's share: its column occupies about half of the written space on the folios. The other two versions (Romanum and Hebraicum), transcribed on smaller columns, occupy the rest of the space. One should also pay attention to the miniatures in this manuscript, covering the entire width of the folios, and located at the beginning of each psalm. And that is not all; the manuscript has a critical apparatus. The copyists have transcribed a modified version of the Parva Glossatura, with additions, on 19 Gibson 1992b, p. 209-210. Cf. De Poerck, Van Deyck 1970, p. 27

Notes

The first Psalters in Old French and their 12 th century context | the margins of the Gallicanum. 23 Finally, two vernacular translations gloss over each Latin word, in between the lines of the non-liturgical versions. The interline of the Romanum version has Old English glosses. The one of the Hebraicum has an Anglo-Norman translation copied in small letters above the Latin words. This French translation is a fairly faithful translation of the Latin text and does not have any clear link with the Oxford Psalter either, simply because it was grafted on another Hieronymian text, the Hebraicum. 24 This other group of Psalters is even more puzzling from the point of view of their use. Nobody can really tell what these manuscripts were really used for. The only clue that may point towards their probable usage is the lavish nature of their images and the encyclopaedically structured layout. If they were used, they were supposed to impress their readers with their beauty as well as with their multi-layered contexts. Perhaps the same may be said about the last category of this short presentation: the verse translations of the Psalms.

Of course a verse translation had no practical purpose. Long before the Reformation, these verse translations could not be sung during the church service. But still, such French Psalters did indeed exist. 25 One of them, the very first one in verse, was copied in two manuscripts and it was written in stanzas of six verses, rhymed aab ccb. This translation dates from the end of the 12 th century of from the beginning of the next and each Latin verse of the Psalter is paraphrased in three up to six verses in French. The long poem is still unedited 26 and it was copied in two 13 th century manuscripts preserved nowadays in the British Library.

The Additional 50000 manuscript (Oscott Psalter, richly illuminated) gives the impression of the most important manuscript because of its size and layout. However, the other manuscript (Harley 4070) appears to be much closer from a textual point of view to the lost autograph source. Its text favours the French version, carefully copied as the principal text, with Latin lemmas on the margins for references, most of them abbreviated; while the version copied in the Additional manuscript sacrifices sometimes entire verses of the French text, because the vernacular text Fig. 8. Oscott Psalter (Additional 50000 ms of the British Library), f. 25 r . End of Ps 8:8-10 and beginning of Ps 9:2-5. Drawing after the online facsimile available at bl.uk. 23 Gibson 1992a, p. 108-110. 24 Margarete Förster considers that the various similar translation choices between the Oxford and Eadwine Psalter translations may be explained by the derivation of the latter from the first (a hypothesis that does not hold), but also because certain biblical words could have already been present in Old French (an idea that deserves to be highlighted). was supposed to accompany the Latin text on its margins, in red and blue ink, meaning that the French text had to adapt to the Latin one. 27 The Harley manuscript also contains a short prologue of seven stanzas which was copied as an introduction to the Arundel Psalter prose translation at a later date. On the contrary, the Additional seems to be a normal Latin psalter (with a calendar, with an image cycle, with canticles) on whose margins the French poem plays a marginal if not ornamental role. 28 Nevertheless, even in the early verse translations, at a time when the notion of 'translation' was not at all definite, when it meant what best suited its author, from adaptation and paraphrase to literary translation or to a word by word translation, these verse translations were not very different from the prose translations like the Oxford Psalter. It may have been that the authors were sharing a common language, maybe even a common sociolect, and that most of them had to appeal to the same words in their translations. This happened because the French language was not ready, from a cultural linguistic point of view, to adapt and interpret such complicated grammatical and lexical structures such as those from Latin. And it was not ready even after two more centuries, because the translator of the Lorraine Psalter, also known as the Metz Psalter (1370) confessed these problems in the prologue of his work: 29

Quar pour tant que laingue romance et especiaulment de Lorenne est imperfaite, et plus asseiz que nulle aultre entre les langaiges perfaiz, il n'est nulz, tant soit boin clerc ne bien parlans romans, qui lou latin puisse translateir n romans quant a plusour mos dou latin; mais couvient que, per corruption et per diseite des mos françois, que en disse lou romans selonc lou latin, si com : iniquitas 'iniquiteit', redemptio 'redemption', misericordia 'misericorde' ; et ainsi de mains et plusours aultres telz mos, que il couvient ainsi dire en romans comme on dit en latin. Aucune fois li latins ait plusours mos que en romans nous ne poions exprimeir ne dire proprement, tant est imperfaite nostre laingue, si com on dit on latin : erue, eripe, libera me, pour les quelz .iii. mos en latin nous disons un soul mot en romans : 'delivre moi' ; et ainsi de maint et plusours aultres telz mos, des quelz je me coise quant a present pour cause de briesteit. Aucune fois li latin warde ses rigles de gramaire et ses congruiteiz et ordenances en figures, en qualiteiz, en comparison, en persones, en nombres, en temps, en declinesons, en causes, en muef, et en perfection : que en romans ne en françoiz on ne puet proprement wardeit, pour les varieteiz et diversiteiz des lainguaiges et lou deffault d'entendement de maint et plusour, qui plus souvent forment lour mos et lour parleir a lour volenteit et a lour guise que a veriteit et au commun entendement. Et pour ceu que nulz ne tient en son parlier ne rigle certenne, mesure ne raison, est laingue romance si corrumpue qu'a poinne li uns entent l'aultre, et a poinne puet on trouveir a jour d'ieu persone qui saiche escrire, anteir ne prononclieir en une meismes semblant meniere; mais escript, ante et prononce il uns en une guise et li aultre en une aultre.

27 See for this De Fonblanque 1994, who deals with this subject from the point of view of an art historian.

28 The manuscript was mainly studied by art historians. See for this Neiswander 1979, who studied the image cycle; but also Morgan 1988, p. 139;Brown, Meredith-Owens, Turner 1961;and Turner 1969. From the point of view of the style and execution of the paintings, the Oscott Psalter has been compared to the Salvin Horae (ms Additional 48985 of the British Library). See e. g. Brown 1957.

29 Bonnardot 1884, p. 1-2.

Notes

Boyle 1985

Édith Brayer, Anne-Marie Bouly de Lesdain, "Les prières usuelles annexées aux anciennes traductions du Psautier", Bulletin de l'Institut de recherche et d'histoire des textes, 15, 1967-1968, p. 69-120.

Brayer, Bouly de Lesdain 1968

The Holy Bible, Containing the Old and New Testaments, with the Apocryphal Books, in the Earliest English Versions, Made from the Latin Vulgate by John Wycliffe and His Followers, eds. Josiah Forshall, Frederic Madden, Oxford, 1850.

Forshall, Madden 1850

Margarete Förster, Die französischen Psalmenübersetzungen vom xii. bis zum Ende des xviii. Jahrhunderts: ein Beitrag zur Geschichte der französischen Übersetzungskunst, PhD thesis of the Friedrich-Wilhelms University in Berlin, 1914. Förster 1914Helius Eobanus Hessus: Psalterium universum, ed. Mechthild Fuchs, Berlin, 2009.

Fuchs 2009

Gaertner, "Latin Verse Translations of the Psalms. 1500-1620", The Harvard Theological Review, 49, 1956, p. 271-305. Gaertner 1956 László Gáldi, Introducere în istoria versului românesc, Bucharest, 1971. Gáldi 1971 W. Leonard Grant, "Neo-Latin Verse-Translations of the Bible", The Harvard Theological Review, 52, 3, 1959, p. 205-211.

Gant 1959

Isabelle Garnier-Mathez, "

Garnier-Mathez 2006

Alin-Mihai Gherman, "O psaltire calvino-română necunoscută", în Lucrări și comunicări științifice, 1, 1973, p. 179-191.

Gherman 1973

Alin-Mihai Gherman, "Versificaţia în psaltirile calvino-române", Revista de istorie şi teorie literară, 31, 2, 1982, p. 176-182.

Gherman 1982

Alin-Mihai Gherman, "Păreri despre limbă la Teodor Corbea", Cercetări de lingvistică, 35, 1, 1990, p. 13-20.

Gherman 1990

Alin-Mihai Gherman, "Un experiment poetic în secolul al xvii-lea: Teodor Corbea", Steaua, 44, 2, 1993, p. 48-49.

Gherman 1993

Teodor Corbea: Dictiones latinae cum Valachica interpretatione, ed. Alin-Mihai Gherman, Cluj-Napoca, 2001.

Gherman 2001

Alin-Mihai Gherman, "Despre cronologia şi tipologia textelor lui Dosoftei", Annales Universitatis Apulensis. Series Historica, 12, 2, 2008, p. 161-175.

Gherman 2008

Teodor Corbea: Psaltirea în versuri, ed. Alin-Mihai Gherman, Bucharest, 2010.

Gherman 2010a

Alin-Mihai Gherman, Un umanist român: Teodor Corbea, Cluj-Napoca, 2010.

Gherman 2010b

Ion Gheţie, "Textele rotacizante şi originile scrisului literar românesc. Chestiuni de metodă", Studii de limbă literară şi filologie, 1, 1969, p. 189-241.

Gheţie 1969

Ion Gheţie, "Simbolul atanasian din Psaltirea Scheiană", Limba română, 22, 3, 1973, p. 241-248.

Gheţie 1973

Ion Gheţie, "A existat un izvor latin al psaltirilor românești din secolul al xvi-lea?", Limba română, 31, 2, 1982, p. 181-185.

Gheţie 1982a

Fragmentul Todorescu, ed. Ion Gheție, in Texte românești din secolul al xvi-lea, ed. Ion Gheție, Bucharest, 1982.

Gheţie 1982b

Ion Gheție, Alexandru Mareș, Originile scrisului în limba română, Bucharest, 1985.

Gheție, Mareș 1985

Ion Gheție, Alexandru Mareș, Diaconul Coresi și izbânda scrisului în limba română, Bucharest, 1994.

Gheție, Mareș 1994

Kantik Ghosh, The Wycliffite Heresy: Authority and the Interpretation of Texts, Cambridge, 2002.

Ghosh 2002

Fig. 1 .

 1 Fig. 1. Oxford Psalter, f. 43 v . End of Ps 32:7-22, Ps. 33 and beginning of Ps 34:1-2. Drawing after a photo of the author.

Fig. 3 .

 3 Fig. 3. Psalter of Henry of Blois, f. 46 v . End of Ps 2:3-13 and beginning of Ps 3:2-9. Drawing after the online facsimile available at bl.uk.

Fig. 4 .

 4 Fig. 4. Arundel Psalter, f. 16r. End of Ps 12:4-6 and beginning of Ps 13:1-3. Drawing after a microfilm facsimile.

17

  For an edition of the first version of this text (Ps 1-50), see Gregory 1990.

Fig. 5 .

 5 Fig. 5. Durham manuscript A ii 11 of the Psalm Commentary for Laurette of Alsace, f. 7 v (without interlinear translation). From the end of Ps 3:2 to the beginning of Ps 3:5. Drawing after the online facsimile available at https://iiif.durham.ac.uk.

Fig. 6 - 7 .

 67 Fig. 6-7. Entire folio and detail of the French and English gloss of the Eadwine Psalter (ms. Cambridge, Trinity College r.17.1), f. 36 v . Ps 21:2-4. © Courtesy of the Master and Fellows of Trinity College Cambridge.

26

  Three passages (two stanzas of the prologue, the translation of Ps 41, and two stanzas of the Ps 44) have been published by Bonnard 1884, p. 130-132. The poem has been briefly analysed by Goedicke 1910, who quoted other short passages; and Meyer 1866 edited the prologue from the Arundel 230 manuscript version.

Notes

Fig. 9 .

 9 Fig. 9. Harley 4070 ms of the British Library, f. 28 v -29r. End of Ps 8:8-10 and beginning of Ps 9:2-5. Drawing after the online facsimile available at bl.uk.

Fig. 10 .

 10 Fig. 10. Arundel Psalter, f. 6r. The verse prologue added at a later date. Drawing after a microfilm facsimile.

3

  Short 2015. For the very first edition of this text, see Michel 1876.

	4 For this image cycle, see Witzling
	1984.
	5 Ruby 2010, who speaks of "bilin-
	gual parallel Psalters" (p. 173); and
	Careri, Ruby, Short 2011, who
	consider them as "parallel Psalters".

6 « La mise en texte […] semble primer sur le texte ». Careri, Ruby, Short 2011, p. 200 (for the quotation).

  , who also edit the French fragments.10 Talbot 1952, p. 272. 11 Careri, Ruby, Short 2011, p. 108.

	12 Ch. Ruby 2010, p. 180 (for the
	quotation).
	13 For an edition of this fragmentary
	text, see Samaran 1929.
	14 Cf. Beyer 1887; Beyer 1888. A.
	Beyer also edited the Latin text.
	15 Careri, Ruby, Short 2011, p. 68. Cf.
	Short, Careri, Ruby 2010, p. 39.
	16 For a different opinion, see Rector
	2009, p. 201, who considers it an inde-
	pendent version, without providing
	further arguments. For the study of
	the language of the manuscript, see
	Pignatelli 2015.

  , who date it back to 1120.20 Stirnemann 1992. Cf. Avril, Stirnemann 1987, no. 76 ;Dodwell 1990.

	21 The Utrecht Psalter arrived in
	Canterbury in ca. 1000.
	22 For an edition of this text, see the
	PhD thesis of Markey 1989, who also
	edited the Latin text of the Hebraicum
	version from this manuscript. For
	the very first edition of this text, see
	Michel 1876.

  Bibliographical AbbreviationsCzech-kódex: 1513, ed. Csilla N. Abaffy, intr. Csilla N. Abaffy, Csaba Csapodi,Budapest, 1990. Clément Marots Psalmenübersetzung, Marburg, 1921 Becker 1920 Marie Benešová, Kamil Boldan, "Metody vizualizace filigránů a využití filigranologie pro datování nejstarších českých tisků na příkladu tzv. Nového zákona se signetem", in Výzkum a vývoj nových postupů v ochraně a konzervaci písemných památek(2005-2011), eds. Marie Benešová et al., Prague, 2011, p. 117-131. Cărți sfinte, sfinții cărților, cărțile sfinților, Sibiu, 2016.Bogdan 2016 Florin Bogdan, Tipăritu-s-au în Ardeal, în cetatea Belgradului. 450 de ani de la tipărirea primei cărți la Alba Iulia, Sibiu / Cluj-Napoca, 2017. Innocent iii and the Vernacular Versions of Scripture", in The Bible in the Medieval World: Essays in memory of BerylSmalley, eds. Katherine Walsch, Diana Wood, New York, 1985, p. 97-107.

	Philipp August Becker, Benešová, Boldan 2011
	A. Beyer, "Die Londoner Psalterhandschrift Arundel 230", Zeitschrift für	Beyer 1887
	romanische Philologie, 11, 1887, p. 513-534.
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Maxime Boutry

Sara Morais

Giovanni Stevanin
email: giovanni.stevanin@upmc.fr

Update on the genetics of spastic paraplegias

Keywords: Hereditary spastic paraplegia, motor neuron, pyramidal syndrome, neurodegenerative diseases, intracellular trafficking, neurological diseases Spastic Paraplegia Foundation [US]

come

Introduction

Hereditary spastic paraplegias (HSPs) are a large heterogeneous group of inherited neurodegenerative diseases. Patients present progressive spasticity and weakness, predominantly affecting the lower limbs [START_REF] Harding | Classification of the hereditary ataxias and paraplegias[END_REF].

The initial symptoms are subtle. Patients generally complain of frequent falls, with stiff legs, cramps and an abnormal or unstable gait. Disease progression is usually slow, but often leads to patients requiring assistance in the form of canes, walkers or wheelchairs as their gait becomes increasingly spastic and additional signs appear. Most patients display similar clinical features, including bilateral spasticity of the legs that is particularly marked on walking, a weakness of the muscles, leg hypertonicity, hyperreflexia and positive Babinski sign. Other frequently reported symptoms include bladder dysfunction, pes cavus and a loss of vibratory sensation at the ankles. The disease is considered to be uncomplicated, or pure, if these signs and symptoms are the only clinical features observed. By contrast, additional symptoms are identified in complex or complicated forms. These symptoms may be neurological or extraneurological and include cognitive/mental impairment, cerebellar ataxia, peripheral neuropathy, epilepsy, optic atrophy, retinal alterations, cataracts, dystonia and parkinsonism [START_REF] Fink | Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms[END_REF].

One of the common hallmarks of these diseases, based on the description of small numbers of pathological cases however, is axonal degeneration, which is most marked in the longest tracts. Postmortem analyses of patient tissues have revealed axonal degeneration to be most severe at the distal ends of the corticospinal tracts, fasciculus gracilis fibers, and spinocerebellar tracts, corresponding to the longest motor and sensory axons of the central nervous system.

Observations suggesting that degeneration began at the distal end of the axons, progressing towards the cell body, led to the hypothesis that these diseases were dying-back axonopathies [START_REF] Deluca | The extent of axonal loss in the long tracts in hereditary spastic paraplegia[END_REF][START_REF] Schwarz | Hereditary (familial) spastic paraplegia; further clinical and pathologic observations[END_REF]. Long axons with a unique, highly polarized architecture are commonly affected, suggesting a possible role for abnormalities of cellular processes in HSP, such as axonal transport, intracellular trafficking and mitochondrial functions; this hypothesis was confirmed by the implication of genes involved in these functions in these diseases [START_REF] Blackstone | Hereditary spastic paraplegias: membrane traffic and the motor pathway[END_REF][START_REF] Salinas | Hereditary spastic paraplegia: clinical features and pathogenetic mechanisms[END_REF]. However, other brain structures, such as the cerebellum, cerebral cortex, basal ganglia and white matter (including the corpus callosum), may be affected in complicated forms, as shown by postmortem examinations [START_REF] Denora | Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions[END_REF] and brain imaging [START_REF] França | Prospective neuroimaging study in hereditary spastic paraplegia with thin corpus callosum[END_REF]. A simple dying back of the long axons is thus an inadequate unifying model. Other mechanisms must also be involved, to explain the degeneration of other brain structures.

Considerable genetic heterogeneity

HSP has an estimated global prevalence of 4.26/100,000, with reported values ranging from 0.9-9.6/100,000, depending on the mode of inheritance and the geographic area considered [9*].

The genetic basis of HSP is extremely diverse, with all possible classical modes of inheritance reported. Autosomal dominant (AD) forms of HSP (ADHSP) predominate in Western countries, whereas autosomal recessive (AR) forms (ARHSP) are common in inbred populations, while X-linked and maternally inherited forms are rare. However, isolated cases are often seen in clinical practice. Such cases may correspond to inherited forms that remain undiagnosed due to the de novo nature of the variants involved, the death of the transmitting parent before identification/clinical expression of the variant, variable expressivity and, particularly for the dominant forms, low or age-dependent penetrance of the mutation.

The observed clinical heterogeneity can be at least partly explained by the immense genetic heterogeneity. Mutations or rearrangements of at least 64 genes (the SPastic Gait/Gene or SPG genes) have been reported to date, and another 13 associated loci have been localized on chromosomal regions (Table 1) [10][11][12][13]. The study of Novarino et al. [14**] highlights this considerable heterogeneity: these authors identified 18 new genes responsible for recessive forms of HSP, through a combination of exome-sequencing, whole-genome linkage analysis, bioinformatics and the functional validation of several genes in zebrafish models. Mutations of more than 30 other genes have been shown to mimic HSP in diseases including spastic paraplegia as a clinical feature. Indeed, Novarino et al. described an "HSPome" network of 589 genes, all of which are good candidate genes for HSP, as shown by the identification of mutations of three of these genes on candidate gene screening [14**]. However, these additional genes lie beyond the scope of this review and will not be considered further here, except for few relevant cases [10]. Several genes have been found mutated in single families only, and must therefore be considered as HSP-related genes with caution until functional studies or secondary cases are published.

Autosomal dominant forms

Twenty-two HSP loci/genes have been associated with ADHSP. Age at onset varies considerably and most cases are relatively pure. The dominant forms are mostly caused by variants or rearrangements of the SPAST (SPG4) gene, which account for 17-79% of all ADHSP cases. These variants cause a relatively pure form of HSP [START_REF] Burguez | Clinical and molecular characterization of hereditary spastic paraplegias: A next-generation sequencing panel approach[END_REF][START_REF] Dong | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China[END_REF][START_REF] Chrestian | Clinical and genetic study of hereditary spastic paraplegia in Canada[END_REF][START_REF] Schüle | Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients[END_REF], sometimes with cognitive impairment [START_REF] Ribaï | Mental deficiency in three families with SPG4 spastic paraplegia[END_REF][START_REF] Chamard | Cognitive impairment involving social cognition in SPG4 hereditary spastic paraplegia[END_REF]. Causal variants of ATL1 (SPG3A), REEP1 (SPG31) and KIF5A (SPG10) are also common. Together with the SPAST variants, they are responsible for the disease in about 50-60% of families with dominant forms of HSP [START_REF] Burguez | Clinical and molecular characterization of hereditary spastic paraplegias: A next-generation sequencing panel approach[END_REF][START_REF] Dong | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China[END_REF][START_REF] Chrestian | Clinical and genetic study of hereditary spastic paraplegia in Canada[END_REF][START_REF] Schüle | Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients[END_REF]. ATL1 mutations are principally associated with early onset, before the age of 10 years. Variants of NIPA1/SPG6, WASHC5/SPG8, RTN2/SPG12, HSP60/SPG13, BSCL2/SPG17 and CPT1C/SPG73 are much less common.

Autosomal recessive forms

ARHSP has been shown to be associated with 50 loci (Table 1), in which 45 causal genes have been identified as mutated [10]. SPG11 is the gene most frequently mutated, accounting for about 21% of cases and causing a complex form of the disease [START_REF] Stevanin | Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration[END_REF]. Other frequent causes, accounting for about 20% of the ARHSP families in total, are variants of the CYP7B1 (SPG5), SPG7 and ZFYVE26 (SPG15) [START_REF] Burguez | Clinical and molecular characterization of hereditary spastic paraplegias: A next-generation sequencing panel approach[END_REF][START_REF] Dong | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China[END_REF][START_REF] Chrestian | Clinical and genetic study of hereditary spastic paraplegia in Canada[END_REF][START_REF] Schüle | Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients[END_REF] genes. In several countries, variants in the SACS gene responsible for the spastic ataxia of Charlevoix-Saguenay have also been implicated in ARHSP.

In addition, CAPN1 (SPG76) loss-of-function mutations have recently been identified in a number of families in multiple successive publications, suggesting that their frequency in ARHSP forms are probably higher than initially thought [START_REF] Gan-Or | Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia[END_REF][START_REF] Wang | Defects in the CAPN1 gene result in alterations in cerebellar development and cerebellar ataxia in mice and humans[END_REF][START_REF] Tadic | CAPN1 mutations are associated with a syndrome of combined spasticity and ataxia[END_REF][START_REF] Travaglini | Expanding the clinical phenotype of CAPN1-associated mutations: A new case with congenital-onset pure spastic paraplegia[END_REF][START_REF] Kocoglu | Homozygous CAPN1 mutations causing a spastic-ataxia phenotype in 2 families[END_REF].

X-linked and mitochondrial forms

Five X-linked loci have already been associated with HSP, and the causal gene has been identified for three of these loci: L1CAM (SPG1), PLP1 (SPG2) and SLC16A2 (SPG22). These X-linked forms remain rare in HSP cohorts, but SPG1 has been implicated in the MASA and CRASH syndromes in children, whereas SPG2 which is allelic to Pelizaeus-Merzbacher disease, can cause late-onset pure HSP in women.

MT-ATP6 is located on the mitochondrial DNA and is, therefore, maternally inherited. It has also been associated with an HSP-like phenotype in a single family [START_REF] Verny | Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation[END_REF]. It encodes one of the subunits of ATP synthase (Complex V), the final enzyme in oxidative phosphorylation (OXPHOS). As no SPG number was attributed to this gene and as the clinical description associated with variants of this gene is rare, it is not included in Table 1.

Mixed inheritance forms

One of the most intriguing findings in this field in recent years is the multiple modes of inheritance reported for variants of a number of these causal genes, including REEP2/SPG72, ALDH18A1/SPG9 and KIF1A/SPG30 [28*,29-31]. For SPG72, dominant mutations have a dominant-negative effect on the wild-type protein, preventing REEP2 binding to the endoplasmic reticulum (ER) membrane and resulting in a loss of function, as observed for recessive mutations in the same gene [28*]. For SPG30, dominant transmission of missense variants is based on a dominant-negative effect disrupting KIF1A binding to microtubules [32*]. In recessive HSP cases, the phenotype associated to KIF1A missense variants is less severe. The frequency of KIF1A mutations with an AD mode of inheritance remains unclear, but such mutations may be common in sporadic patients of ADHSP given the high frequency of de novo cases.

Other forms seem to display mostly one main mode of inheritance. For example, ATL1/SPG3A has been reported to display mainly autosomal dominant transmission, although at least one causal variant has been shown to be recessive [33]. Other causal genes are mostly recessive, but several reports have exposed possible dominance for some variants, as demonstrated for SPG7 [34,35*] and, more recently, for ERLIN2/SPG18/SPG37 [36].

Sporadic forms

Most cases of spastic paraplegia are sporadic. Once other differential diagnoses, such as structural abnormalities of the brain or spinal cord, infection by human T-lymphotrophic virus type 1 [HTLV1], multiple sclerosis, dopa-responsive dystonia, amyotrophic or primary lateral sclerosis, have been excluded by MRI and biochemical analyses, mutations should be sought in genes known to be associated with or related to HSP. Such analyses have revealed that a substantial proportion of apparently sporadic cases are actually genetic. SPAST, ATL1 and SPG11 variants are frequent, as are KIF1A variants, for which large numbers of de novo cases have already been reported. Gonadal mosaicism has also been reported for SPG4 [37].

Clinical variability and overlap with other neurological conditions, phenotype-genotype correlations

Age-at-onset is variable for HSP, with the first manifestations of the disease occurring anyway between early infancy and old age. There may also be considerable variability in age at HSP onset within a given family [38]. Mutations of several ADHSP genes, including SPAST [39*],

REEP1 [START_REF] Beetz | REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31[END_REF] and BSCL2 [START_REF] Musacchio | ALS and MMN mimics in patients with BSCL2 mutations: the expanding clinical spectrum of SPG17 hereditary spastic paraplegia[END_REF][START_REF] Windpassinger | Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome[END_REF], display incomplete penetrance, suggesting an effect of as yet unknown modifying factors. Two SPG4 polymorphisms (p.S44L, p.P45Q) have been suggested to modulate or attenuate disease severity through changes in the stability of spastin (SPAST/SPG4 gene product) isoforms; they may act as weak mutations in association with other SPAST alterations [START_REF] Schickel | Isoform-specific increase of spastin stability by N-terminal missense variants including intragenic modifiers of SPG4 hereditary spastic paraplegia[END_REF]. Penetrance and age-at-onset have also been shown to depend on gender for SPG4 [39*].

HSP progression is also highly variable. Some patients present disabilities that progress relatively little over many years, whereas the disease rapidly worsens in others. The rate of progression may also change over time in individual patients. For example, many patients display a rapid worsening during adolescence, with slower rates of progression thereafter. The disease often eventually seems to stabilize, probably due to a number of factors, including possible functional compensation through neuroplasticity [START_REF] Fink | Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms[END_REF]. Earlier disease onset has also been reported to be associated with a less severe presentation [START_REF] Schüle | Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients[END_REF]. Further variability is observed for clinical presentation, with most of the causal genes associated with both pure and complex forms of the disease. The "additional" neurological and extraneurological signs observed in complex forms are also highly variable, even within the same family. However, clinical signs of intellectual disability and ataxia are frequently reported. For example, variants of the SACS gene usually cause a spastic ataxia phenotype, but several patients have been identified with mutations of this gene and phenotypes at the extreme ends of the spastic ataxia spectrum: either isolated ataxia or spasticity [START_REF] Bouhlal | Autosomal recessive spastic ataxia of Charlevoix-Saguenay: an overview[END_REF][START_REF] Gregianin | A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy[END_REF]. It is often difficult to classify patients on this spectrum of spastic ataxia phenotypes. For example, GBA2 mutations may cause conditions that can be classified as ataxia or HSP [START_REF] Martin | Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia[END_REF][START_REF] Hammer | Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity[END_REF]. Many patients with HSP display peripheral neuropathy, highlighting the overlap with Charcot-Marie-Tooth disease. As the number of patients with each mutation increases, so does the phenotypic spectrum of each genetic entity and the overlap with other neurological conditions. There is an increasing number of genes primarily associated with other neurodegenerative disorders that are sometimes considered as differential diagnoses for HSP, such as leukodystrophies, that are now being shown to be responsible for pure forms of spastic paraplegia. HSP and leukodystrophies have at least three causal genes in common (PLP1, HSPD1, GJC2), and at least eight other genes have been reported to mimic HSP in some cases (ABCD1, ADAR, EIF2B5, GJA1, IFIH1, RNASEH2B, SAMHD1 and TUBB4A). This is the case, for example, for ATP13A2 (SPG78/PARK9) which has recently been shown to be associated with HSP, but was previously associated only with Parkinson's disease [START_REF] Kara | Genetic and phenotypic characterization of complex hereditary spastic paraplegia[END_REF]. Loss of function mutations in another gene possibly related to Parkinson's disease, UCHL1 (SPG79/PARK5), has also been found in spastic ataxia patients [START_REF] Rydning | Novel UCHL1 mutations reveal new insights into ubiquitin processing[END_REF]. Neurodegeneration with iron accumulation is also caused by defects of genes that have been implicated in HSP: C9orf72 and FA2H. Another recent example relates to ACO2 mutations, initially associated with infantile cerebellar-retinal degeneration combining optic atrophy, retinal degeneration, severe encephalopathy, epilepsy, and cerebellar ataxia, which have now been associated with mild to complex HSP variably associating intellectual disability, microcephaly and optic atrophy with no phenotype-genotype correlations [START_REF] Bouwkamp | ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia[END_REF][START_REF] Marelli | ACO2 mutations: A novel phenotype associating severe optic atrophy and spastic paraplegia[END_REF].

Conversely, mutations of some HSP genes have also been shown to cause other diseases. For example, SPG11 mutations are also associated with amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease [START_REF] Stevanin | Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum[END_REF][START_REF] Orlacchio | SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis[END_REF][START_REF] Montecchiani | ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease[END_REF], and KIF1A mutations have been linked to hereditary autonomic neuropathy or mental retardation [30][31][32][START_REF] Hamdan | Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability[END_REF][START_REF] Riviere | KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2[END_REF][START_REF] Klebe | KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations[END_REF].

These wide spectra for age-at-onset, progression and symptoms, together with their clinical overlap with other neurological diseases and the high degree of genetic heterogeneity, make it difficult to establish phenotype-genotype correlations. The various presentations of the disease are sometimes associated with different modes of inheritance. For example, heterozygous variants of HSPD1 are associated with HSP, whereas homozygous missense variants are responsible for hypomyelinating leukodystrophy type 4 [START_REF] Magen | Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy[END_REF]. Another illustration is provided by TFG, for which a heterozygous variant in the P/Q-rich domain causes autosomal dominant hereditary motor and sensory neuropathy [START_REF] Ishiura | The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement[END_REF], whereas homozygous variants of the coiled-coil and PB1 domains have been linked to HSP [START_REF] Beetz | Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure[END_REF][START_REF] Elsayed | Hereditary spastic paraplegias: Identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan[END_REF], suggesting that different pathogenic mechanisms may be involved. Similarly, the nature, location and zygosity of KIF1A mutations explain the phenotype: hereditary autonomic neuropathy results from a complete loss of function [START_REF] Riviere | KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2[END_REF], whereas homozygous missense mutations cause a relatively pure HSP phenotype [30,[START_REF] Klebe | KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations[END_REF], and heterozygous missense mutations in the motor domain result in dominant negative effects on the kinesin protein, accounting for early-onset complex HSP [32*]. For SPG7, the p.A510V mutation is more often associated with ataxia than with spastic paraplegia [62*]. By contrast, mutations of PNPLA6 and ALDH18A1 underlie multiple phenotypes and/or are transmitted by multiple modes of inheritance, sometimes without spasticity, and with no clustering according to the nature or location of the mutations [63*,29].

Pathogenic mechanisms

We still know little about the mechanisms underlying the degeneration of distal portions of the corticospinal tracts, and of other brain structures in complex forms. However, the identification of a number of causal genes and determination of the functions of their products have suggested that alterations to intracellular trafficking may be a common element. The affected functions include active axonal transport, the activities of the endolysosomal system, organelle shaping, and lipid metabolism. In some clinicogenetic forms, effects on myelination, mitochondrial functions and axon guidance have also been observed. Several HSP-related proteins are known to be involved in multiple of these pathways, which may well be interconnected. It is, therefore, often difficult to determine which dysfunction is the principal cause of the neurodegeneration for a given gene/protein.

Intracellular active transport

Three HSP proteins perfectly illustrate the requirement of intracellular trafficking for the maintenance of long axons. Mutations of KIF5A (SPG10) result in a lower affinity of the kinesin-1 motor protein encoded by this gene for microtubules and a decrease in the gliding velocity of microtubule-dependent anterograde axonal transport [START_REF] Ebbing | Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity[END_REF]. The SPG30 and SPG58 forms are caused by mutations of the genes encoding the KIF1A and KIF1C proteins, respectively. Both dominant and recessive mutations have been described for SPG30, with a dominant negative effect disrupting KIF1A binding to microtubules underlying dominant transmission [32*]. For SPG58, all the mutations identified to date affect the ATPase and the microtubule-binding domains of KIF1C and minor or subclinical signs can be observed in heterozygous parents of homozygous patients [START_REF] Caballero Oteyza | Motor protein mutations cause a new form of hereditary spastic paraplegia[END_REF]. A spontaneous mutation of KIF1C in Charolais cattle has been shown to cause a frequent spastic ataxia with severe demyelination in the brain [66*].

Many other HSP proteins may be involved in intracellular trafficking. Spastin (SPAST/SPG4), an adenosine triphosphatase (ATPase), has three domains with different cellular activities: a microtubule-interacting domain, a microtubule-interacting and endosomal trafficking domain (MIT) and an ATPase (AAA) domain with microtubule-severing activity [START_REF] White | Recognition of C-terminal amino acids in tubulin by pore loops in spastin is important for microtubule severing[END_REF]. Spastin exists in two main isoforms: M1, which is mostly associated with the ER, and M87, which is cytoplasmic [START_REF] Connell | Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion[END_REF][START_REF] Park | Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network[END_REF]. SPAST knockout mice have focal swellings of the spinal cord axons, with abnormal accumulations of organelles and cytoskeletal components, suggesting an impairment of axonal transport associated with mild late motor impairment with no detectable neuron loss [START_REF] Tarrade | A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition[END_REF]. These defects occur close to growth cones, in regions of transition between stable and dynamic microtubules. Spastin localizes to areas of the cytoplasm important for microtubule dynamics [START_REF] Errico | Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody and the distal axon[END_REF], and the overproduction of this protein results in microtubule depletion in cultures of mammalian cells [START_REF] Evans | Linking axonal degeneration to microtubule remodeling by spastin-mediated microtubule severing[END_REF] and disruption of the microtubule network in Drosophila melanogaster [START_REF] Trotta | The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function[END_REF][START_REF] Sherwood | Drosophila spastin regulates synaptic microtubule networks and is required for normal motor function[END_REF] and Caenorhabditis elegans [START_REF] Matsushita-Ishiodori | The C. elegans homologue of the spastic paraplegia protein, spastin, disassembles microtubules[END_REF]. These findings led to suggestions that the axon degeneration observed in spastic paraplegia was due to defective axonal microtubule organization. Spastin has several other functions (some of which will be discussed below). In particular, it interacts with CHMP1B [START_REF] Reid | The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B[END_REF], which is associated with the endosomal sorting complex of the ESCRT transport machinery. This complex is involved in several pathways, and plays a role in the completion of cell division. The M87 isoform is required for cytokinesis and the microtubule disruption that normally occurs during this process is impaired in its absence [START_REF] Connell | Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion[END_REF][START_REF] Yang | Structural basis for midbody targeting of spastin by the ESCRT-III protein CHMP1B[END_REF]. Truncating and missense mutations of Spastin are thought to result in a loss of function through haploinsufficiency or dominant negative effects.

Spastin interacts with Atlastin-1 (SPG3A) [START_REF] Evans | Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance[END_REF][START_REF] Sanderson | Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners[END_REF], a transmembrane dynamin/guanylatebinding protein. Its subcellular distribution (ER, cis-Golgi, vesicular structures in axonal growth cones, varicosities and axonal branch points) [START_REF] Zhu | Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin[END_REF][START_REF] Zhu | SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development[END_REF] suggests a functional role in both intracellular trafficking and axonal development, consistent with the early onset of disease in SPG3A patients. Some atlastin-1 mutations affect the GTPase activity of the protein [START_REF] Zhu | SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development[END_REF]. These mutations have been reported to affect the budding of vesicles from the ER, or their targeting to the Golgi apparatus, possibly due to impairment of the interaction of Atlastin-1 with p24, a protein of the p24/emp/gp25L protein family [START_REF] Namekawa | Mutations in the SPG3A gene encoding the GTPase atlastin interfere with vesicle trafficking in the ER/Golgi interface and Golgi morphogenesis[END_REF].

Another HSP protein, Spartin (SPG20), has been implicated in epidermal growth factor receptor [EGFR] endocytosis and transport [START_REF] Bakowska | Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking[END_REF]. It is found in synapse-like structures, neurites and the trans-Golgi network of differentiated neurons [START_REF] Robay | Endogenous spartin, mutated in hereditary spastic paraplegia, has a complex subcellular localization suggesting diverse roles in neurons[END_REF]. Maspardin (SPG21) is found in endosomes and trans-Golgi vesicles and is thought to be involved in membrane sorting [START_REF] Mc | Interaction of the SPG21 protein ACP33/maspardin with the aldehyde dehydrogenase ALDH16A1[END_REF].

The NIPA1 protein (SPG6) is a transmembrane protein specific to neurons, present in the early endosomal compartment and on the plasma membrane, where it is thought to transport magnesium [START_REF] Goytain | NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg 2+ transporter[END_REF]. Pathogenic missense mutations of the gene encoding this protein prevent its transfer from endosomes to the plasma membrane. This effect probably results from a dominant-negative gain of function, because large gene deletions do not cause HSP in humans.

NIPA1 ortholog in Drosophila (Spict) interacts with bone morphogenetic protein (BMP) receptors, promoting their internalization [START_REF] Wang | Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules[END_REF]. BMP signaling is required for normal assembly of the microtubule cytoskeleton, so NIPA1 mutations may also interfere with axonal transport.

Abnormal trafficking has also been implicated in several other disorders closely related to HSP, such as Charcot-Marie-Tooth disease, in which patients present neuropathies affecting the long axons of the peripheral nervous system, and ALS. For example, truncating mutations of ALS2, which encodes Alsin, have been implicated in various lower and upper motor neuron disorders with different clinical presentations [START_REF] Hadano | A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2[END_REF][START_REF] Yang | The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis[END_REF]. The knockout of Alsin in mouse leads to distal axonopathy [START_REF] Deng | Distal axonopathy in an alsin-deficient mouse model[END_REF] and abnormal trophic factor (IGF1, BDNF) receptor transport [START_REF] Devon | Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities[END_REF]. ALS2 missense variants are associated with Alsin delocalization from the endosomes and greater susceptibility to induced apoptotic stress in vitro [START_REF] Panzeri | The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function[END_REF].

Together, these observations suggest that alterations to intracellular trafficking are particularly deleterious for long axons.

Endoplasmic reticulum shaping

The ER is a membrane-bound organelle consisting of the nuclear envelope, sheets forming the rough ER and a tubular network connected to other organelles throughout the cell. It has many different functions (protein and lipid synthesis, calcium homeostasis regulation and exchange of molecules with other organelles), depending on its morphology. Long-axon neurons appear to be particularly dependent on the formation and maintenance of the ER, as several HSP proteins are involved in these processes. Indeed, the three most frequent autosomal dominant HSPs are caused by mutations of the SPG3A, SPAST/SPG4 and REEP1/SPG31 genes, encoding Atlastin-1, Spastin and REEP1, respectively. These proteins insert their hairpin loop domains into the membrane of the tubular ER, thereby contributing to the shaping of this structure.

Atlastin-1 mediates homotypic fusions of ER tubules, generating the three-way junctions between ER tubules that shape the characteristic morphology of the ER in the periphery of the cell. Atlastin-1 loss results in changes to the morphology of the ER [START_REF] Rismanchi | Atlastin GTPases are required for Golgi apparatus and ER morphogenesis[END_REF][START_REF] Orso | Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin[END_REF][START_REF] Hu | Membrane proteins of the endoplasmic reticulum induce high-curvature tubules[END_REF]. Spastin M1 interacts with Atlastin-1 and REEP1, and links the microtubule cytoskeleton to the ER tubule network [START_REF] Evans | Interaction of two hereditary spastic paraplegia gene products, spastin and atlastin, suggests a common pathway for axonal maintenance[END_REF]. The REEP1 and REEP 2-4 proteins also interact with microtubules [START_REF] Park | Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network[END_REF][START_REF] Schlaitz | REEP3/4 ensure endoplasmic reticulum clearance from metaphase chromatin and proper nuclear envelope architecture[END_REF], and these interactions are believed to underlie the formation and stabilization of the ER tubular network. REEP1 depletion decreases the number of ER three-way junctions [START_REF] Park | Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network[END_REF], and losses of and DDHD2 also lead to HSP, but the reasons for this are less well understood.

Overall, these findings suggest that the correct regulation of lipid metabolism is crucial for the neurons affected in HSP.

Endolysosomal trafficking pathway

Endolysosomal dysfunctions have been reported in various HSP models in recent years. Such dysfunctions may be associated with changes to lipid metabolism, as in lysosomal storage diseases (LSD), a group of diseases in which lipids and other materials accumulate in lysosomes due to a primary dysfunction of these organelles [113]. An accumulation of undigested materials reminiscent of that observed in LSD has been reported in some HSP models. This finding is of particular interest because patients with LSD sometimes display spasticity, which can lead to a misdiagnosis of HSP [114]. Electron microscopy analyses of the fibroblasts of SPG48 patients have revealed an accumulation of membrane material in the endolysosomes Thus, lysosomal functions appear to be crucial for neurons, and lysosomal dysfunction may impair a number of pathways in which these organelles are involved, including autophagy.

These changes would also contribute to alterations to lipid metabolism and the shaping of organelles, such as the ER, showing then the links between these cellular functions altered in

HSPs

Other functions

A few of the identified HSP genes encode proteins associated with mitochondrial functions. These genes include HSPD1 (HSP60), ACO2 and SPG7. Missense mutations of the gene encoding mitochondrial HSP60 cause SPG13, through the disruption of HSP60 activity and mitochondrial quality control [123]. The gene mutated in SPG7 encodes Paraplegin, a member of the mitochondrial AAA protease family. Paraplegin-deficient mice present an abnormal accumulation of mitochondria in axons, leading to motor deficits, followed by axon swelling and neurodegeneration [124]. ACO2 mutations impair the Krebs cycle through a reduction of the aconitase enzyme activity and a subsequent impaired mitochondrial respiration in lymphoblastoid cell lines of patients [START_REF] Bouwkamp | ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia[END_REF][START_REF] Marelli | ACO2 mutations: A novel phenotype associating severe optic atrophy and spastic paraplegia[END_REF].

The association of the microtubule-associated protein Spartin (SPG20) with mitochondria is also lost following mutation of the corresponding gene [125], which suggests that Troyer syndrome (SPG20) may result from a defect of microtubule-mediated mitochondrion transport.

Conclusions

The growing use of next-generation sequencing is improving diagnosis, but also leading to the continual identification of new causal genes for HSP. The increasing number of HSP genes identified up to now highlights the extreme genetic heterogeneity of these disorders and their clinical and functional overlap with other neurological conditions. The challenge facing us in the genetics of HSP is explaining the clinical variability between patients carrying identical mutations, some of whom may develop a complex HSP, whereas others develop another neurological condition in which spasticity is no more than a minor element, if present at all.

There is still no specific treatment for preventing or slowing neuronal degeneration or dysfunction. Only symptomatic treatments based on antispasticity drugs, botulinum toxin or physiotherapy can help to improve the patient's quality of life [START_REF] Fink | Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms[END_REF]. Several studies in animal models have identified compounds or strategies that may improve phenotypes [132-136], but their transfer into patient care will require further characterization of their effects and the identification of useful biomarkers for demonstrating their beneficial activity, a process currently underway for SPG5 [137**,138*]. Finally, several HSP models display a number of different cellular dysfunctions, complicating identification of the primary dysfunction, or the dysfunction of greatest relevance to the disease. However, several common pathways relating to intracellular membrane dynamics (Figure 1) are affected in multiple HSPs, suggesting that it may be possible to develop therapies targeting these common elements in the future. onset occurs significantly earlier in missense mutation carriers and that penetrance is lower in women despite a greater disease severity in female patients. ER: endoplasmic reticulum Table 1. Loci and genes implicated in spastic paraplegias, the proteins they encode and the associated clinical features in patients ARHSP-autosomal recessive hereditary spastic paraplegia; ATPase-adenosine triphosphatase; CMT 4D-Charcot-Marie-Tooth subtype 4D; ERendoplasmic reticulum; FR-frameshift; GTPase-guanosine triphosphatase; IFD-in-frame deletion or duplication; LL-lower limbs; MIM-Mendelian inheritance in man; MS-missense; NS-nonsense; RG-rearrangements; SPG-spastic gait gene; SPL-splice site mutations; TCC-thin corpus callosum; UL-upper limbs; UTR-untranslated region; WMH-white matter hyperintensities.

Locus (MIM) Chromosome

Gene

  REEP2 function cause ER sheet expansion[28*]. Other HSP-related proteins, such as ARL6IP1 (SPG61), RAB3GAP2 (SPG69) and Reticulon 2 (SPG12), are also involved in ER shaping.Depletion of the Drosophila ortholog of Reticulon 1, Rtnl1, leads to ER sheet expansion and a loss of tubular ER markers from distal motor axons[START_REF] O'sullivan | Reticulon-like-1, the Drosophila orthologue of the hereditary spastic paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of distal motor axons[END_REF]. Axonal continuity and the correct axonal transport of ER tubules were recently shown to require ER shaping genes, such as Rtnl1, in Drosophila [100*].These findings suggest that long axons are highly sensitive to changes in the morphology of the ER tubular network. However, the ER has many functions and it remains unclear which are the most relevant to the pathophysiology of HSP. Changes in the morphology of the ER have recently been shown to lead to a loss of contact between the ER and other organelles, consistent with the probable impairment of the functions of membranous contact sites in several HSPs [101*]. Changes in ER shaping may also underlie defects of lipid synthesis and metabolism, as the ER plays a crucial role in these functions.Lipid metabolismMany in vitro and in vivo models of HSP display alterations to lipid metabolism. Indeed, several HSP-related proteins have been implicated in regulating the number and size of lipid droplets (LDs). These organelles are the site of lipid storage within the cell. The changes to LDs dynamics in HSP may reflect the changes in ER shaping, as LDs are formed from the ER [102]. The modulation of Atlastin-1, Spastin or REEP1 expression has consistently been shown to lead to changes in the number or size of LDs [103-105]. Spastin M1 downregulation (or the expression of a dominant-negative variant) results in the presence of smaller numbers of LDs in nerves, skeletal muscles and fat bodies in a Drosophila model [105**]. Conversely, the cooverproduction of REEP1 and Atlastin-1 in mammalian cells results in the presence of very large LDs [104], and REEP1 has been shown to play a role in regulating LDs both in vitro and in vivo [103,106]. Furthermore, postmortem analyses of the brains of SPG54 patients with DDHD2 mutations have revealed the accumulation of large LDs in cells [107], and the absence of Spartin (SPG20) has been shown to be associated with the presence of larger numbers of LDs in the adipose tissue of female KO mice [108]. Finally, Seipin (SPG17) is an integral ER protein involved in LD biogenesis. Alterations to the LDs in axons may, therefore, contribute to the pathophysiology of HSP. Some cases of HSP are caused by mutations of genes encoding proteins directly involved in lipid metabolism. SPG26 is caused by mutations of B4GALNT1 [109], which encodes an enzyme involved in ganglioside synthesis. A loss of the function of this enzyme leads to GM3 ganglioside accumulation in cells [110]. Loss-of-function mutations affecting the GBA2 glucocerebrosidase enzyme (SPG46) [46,47] lead to glucosylceramide accumulation, resulting in changes to cytoskeletal dynamics in animal models [111]. SPG5 is caused by mutations of the gene encoding an enzyme involved in cholesterol metabolism, CYP7B1, and affected patients have high levels of oxysterol substrates in the plasma membrane and cerebrospinal fluid [112]. Finally, losses of function of the fatty acid hydroxylases PNPLA6, FA2H, DDHD1

  [115]. The gene mutated in SPG48 encodes AP5Z1, a subunit of the AP-5 complex involved in vesicular-mediated trafficking of cargoes. This protein interacts with Spatacsin (SPG11) and Spastizin (SPG15) [115]. The SPG11 and SPG15 HSP subforms are clinically indistinguishable. The loss of either of these proteins impairs the autophagic lysosome reformation (ALR) process [116]. Material has been shown to accumulate in the endolysosomal pathways of both SPG11 and SPG15 mice [117-119]. This material was recently identified as simple gangliosides in SPG11 mice, and its accumulation results from the impairment of lysosome reformation due to the loss of Spatacsin [120**]. The prevention of ganglioside accumulation prevented neuronal cell death in vitro and corrected the motor phenotype of a zebrafish model of the SPG11 disease, demonstrating the deleterious effects on neurons of ganglioside accumulation in lysosomes. Such an accumulation is also observed in various LSDs characterized by neurodegeneration and in more common neurodegenerative diseases, such as Alzheimer's disease [121,122]. It was recently suggested that defective endosome fission due to a loss of contact between the ER and endosomes might disturb the trafficking of lysosomal enzymes, accounting for the lysosomal dysfunctions observed in many forms of HSP [101*]. Lysosomal dysfunctions may be associated with a decrease in degradation capacity.

Finally,

  SPG77 is caused by mutations of FARS2, which encodes a mitochondrial phenylalanyl tRNA synthetase (mtPheRS)[126].Mitochondrial functions may also be altered indirectly in other HSPs. In patients with mutations affecting REEP1, the interactions between REEP1 and mitochondrial PGAM5 are abnormal, resulting in alterations to mitochondrial morphology [127*]. Abnormal development is clearly observed in two clinically different X-linked forms of HSP: SPG1 and SPG2. The cell surface glycoprotein L1-CAM, which is mutated in SPG1, plays a crucial role in the migration and differentiation of neurons. Alterations to this protein in patients and knockout mice are associated with developmental phenotypes (e.g., corpus callosum hypoplasia, adducted thumbs, psychomotor retardation, hydrocephalus, a small corticospinal tract and poor associations of non-myelinating Schwann cells) due to a lack of axonal guidance [128]. Mutations of PLP1, encoding an integral protein of myelin and involved in the maturation of oligodendrocytes, account for the occurrence of dysmyelination and axonal degeneration in the central nervous system of SPG2 patients and of cases with the allelic Pelizaeus-Merzbacher disease. PLP1 loss-of-function mutations in mice is associated with abnormal oligodendroglial dynamics, inflammation and degeneration of long axons at later stages [129]. Mutations of other HSP genes may result in developmental defects as well. This might be the case in HSP entities with early age at onset and/or clinical presentations combining spasticity with early cognitive deficiencies. Overt motor or brain developmental defects have been reported for knockdowns of SPAST (SPG4), SPG3A, SPG11, SPG15 and GBA2 (SPG46) in zebrafish, regardless of their known implication in neurodevelopment [130**,131,46].

patients from 16

 16 countries, to estimate the global prevalence of hereditary ataxias and spastic paraplegias. 10. Tesson C, Koht J, Stevanin G. Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum Genet. 2015;134, 511-538. 11. Hensiek A, Kirker S, Reid E. Diagnosis, investigation and management of hereditary spastic paraplegias in the era of next-generation sequencing. J Neurol. 2015;262, 1601-1612. 12. Parodi L, Fenu S, Stevanin G, Durr A. Hereditary spastic paraplegia: More than an upper motor neuron disease. Rev Neurol (Paris). 2017; 173:352-360 13. Parodi L, Coarelli G, Stevanin G, Brice A, Durr A. Hereditary ataxias and paraparesias: clinical and genetic update. Curr Opin Neurol. 2018;31(4):462-471. 14. **Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L, Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014;343(6170):506-511. The authors analyzed a cohort of 55 consanguineous families with HSP by exome sequencing, with gene validation in zebrafish experiments in a few cases. They identified the cause of the disease in three quarters of the families as a defect of a known or new (n=18) HSP gene. Bioinformatic analyses identified 589 interconnected genes, all 30. Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res. 2011;21:658-664. 31. Lee JR, Srour M, Kim D, Hamdan FF, Lim SH, Brunel-Guitton C, Décarie JC, Rossignol E, Mitchell GA, Schreiber A, Moran R, Van Haren K, Richardson R, Nicolai J, Oberndorff KMEJ, Wagner JD, Boycott KM, Rahikkala E, Junna N, Tyynismaa H, Cuppen I, Verbeek NE, Stumpel CTRM, Willemsen MA, de Munnik SA, Rouleau GA, Kim E, Kamsteeg EJ, Kleefstra T, Michaud JL. De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy. Hum Mutat. 2015;36:69-78. 32. *Cheon CK, Lim SH, Kim YM, Kim D, Lee NY, Yoon TS, Kim NS, Kim E, Lee JR. Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene. Sci Rep. 2017,7:12527. In silico and in vitro experiments showing that heterozygous missense mutations affecting the conserved motor domain of KIF1A act through a dominant-negative effect on the wild-type protein. 33. Khan TN, Klar J, Tariq M, Anjum Baig S, Malik NA, Yousaf R, Baig SM, Dahl N. Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation. Eur J Hum Genet. 2014;22:1180-1184. 34. Sánchez-Ferrero E, Coto E, Beetz C, Gámez J, Corao A, Díaz M, Esteban J, del Castillo E, Moris G, Infante J, Menéndez M, Pascual-Pascual S, López de Munaín A, Garcia-Barcina M, Alvarez V. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Clin Genet. 2013;83:257-262.

Figure 1 :

 1 Figure 1: Overview of the main altered/known functions of proteins involved in HSP.

Acknowledgments

We thank Drs F Mochel, F Darios, KH El-Hachimi and V Anquetil for fruitful discussions. The authors' work is funded by the European Union H2020 program (SOLVE-RD, to GS), the

(to GS), the Association Strümpell-Lorrain [FR] (to GS), the Agence Nationale de la Recherche [FR] (Spatax-Quest, to GS) and the E-Rare Program (Prepare, to GS). MB and SM held PhD fellowships from the ED3C Doctoral School (France) and the Fundação para a Ciência e a Tecnologia (Portugal), respectively.