Xeroderma pigmentosum complementation group F: A rare cause of cerebellar ataxia with chorea

Accepted Manuscript Xeroderma pigmentosum complementation group F: A rare cause of cerebellar ataxia with chorea

G Carré, C Marelli, M Anheim, C Geny, M Renaud, HR Rezvani, M Koenig, C Guissart, C Tranchant PII: DOI: Reference:

S0022-510X(17)30189-2 doi: 10.1016/j.jns.2017.03.021 JNS 15221

To appear in:

Journal of the Neurological Sciences

Received date: Revised date: Accepted date:

7 February 2017 13 March 2017 14 March 2017

Please cite this article as: G Carré, C Marelli, M Anheim, C Geny, M Renaud, HR Rezvani, M Koenig, C Guissart, C Tranchant , Xeroderma pigmentosum complementation group F: A rare cause of cerebellar ataxia with chorea. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi: 10.1016/j.jns.2017.03.021

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ACCEPTED MANUSCRIPT Xeroderma Pigmentosum complementati on group F: a rare cause of cerebellar ataxia with chorea Carré G, MD1 ; Marelli C, MD, PhD2 ; Anheim M, MD, PhD1,3 ; Geny C, MD2 ; Renaud M, MD2 ; Rezvani HR, PhD4 ; Koenig M, MD, PhD5 ; Guissart C, PharmD, PhD5 ; Tranchant C, MD1,3

Affiliations Department of Neurology, Strasbourg University Hospital, Strasbourg, France

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Department of Neurology, University Hospital Gui de Chauliac, Montpellier, France

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FMTS, Medecine Faculty, Strasbourg, France

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INSERM U1035- Bordeaux University, Bordeaux, France

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EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, University

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Hospital, Montpellier, France

Corresponding author:

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G Carré

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Department of Neurology, Hopital de Hautepierre, 1 Avenue Molière, 67000 Strasbourg, France

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[email protected]

Key words: Xeroderma pigmentosum group F; ataxia; chorea; mini-exome; Caucasian’s patient.

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ACCEPTED MANUSCRIPT SUMMARY The complementation group F of Xeroderma Pigmentosum (XP-F) is rare in the Caucasian population, and usually devoid of neurological symptoms. We report two cases, both caucasian, who exhibited progressive cerebellar ataxia, chorea, a mild subcortical frontal cognitive impairment, and in one case severe polyneuropathy. Brain MRI demonstrated cerebellar (2/2) and cortical (1/2) atrophy. Both patients had only mild sunburn sensitivity and no skin cancer. Mini-exome sequencing approach revealed in ERCC4, two heterozygous

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mutations, one of which was never described (c.580-584+1delCCAAGG, exon 3), in the first case, and an

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already reported homozygous mutation, in the second case. These cases emphasize that XP-F is a rare cause of recessive cerebellar ataxia and can in some cases clinically mimic Huntington’s disease due to chorea and

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executive impairment. The association of ataxia, chorea, and sun hypersensitivity are major guidance for the

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diagnosis, which should not be missed, in order to prevent skin neoplastic complications.

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1. INTRODUCTION Autosomal recessive (AR) cerebellar ataxia is a genetically and clinically heterogeneous group of inherited progressive neurodegenerative disorders where the associated neurological and extra -neurological signs may be very important to guide the molecular diagnosis 1. Recently, the development of mini-exomes allowed the identification of causes that would not have been suspected, due to unusual presentations or mild phenotypes 2.

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Xeroderma pigmentosum (XP) is a rare AR disease with prominent dermatological and ocular involvement 3,4. Extreme sensitivity to sunlight and predisposition to skin cancers usually defines the disease. Ocular signs are

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variable, from keratopathy to premalignant dysplasia. Neurological signs are found in only 20 to 30 % of the

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cases 3. Eight forms of the disease have been described (XP-A to G and XP-V), respectively due to mutations either in any one of seven genes whose products are involved in nucleotide excision repair (NER) of ultravio let-

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induced DNA lesions (XP-A to XP-G), or in one gene involved in replicating DNA containing ultraviolet induced damage (XP-V). The complementation group F of XP (XP-F), is due to mutations in the ERCC4 gene.

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XP-F is rare in the Caucasian population 5, most cases being described in Japan, and usually devoid of neurological symptoms 6,7. In order to contribute to a better description of this rare disease, we report on two

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Caucasian patients with XP-F revealed by late-onset recessive ataxia and chorea, identified by mini-exome

2. METHODS

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sequencing approach.

Genetic analysis was performed after signature of a written informed consent approved by the Local Ethics

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Committee. DNA was extracted by standard procedures , than analyzed by “mini-exome” sequencing with the Trusight One sequencing panel kit (www.illumina.com/trusightone) on an Illumina MiSeq sequencer (Montpellier CHRU NGS platform). Variants were analyzed for pathogenicity with in -house pipelines, which combine splice site prediction (HSF, MaxEnt, and SplicePort software), scoring of protein coding changes (SIFT and PolyPhen2 software) and coupling to read-depth based CNV analysis as described earlier 2. Briefly, the analysis, initially restricted to a panel of 117 known ataxia-causing genes, was extended, for negative cases, to the 4813 disease-causing genes derived from the mini-exome. Only variants with a frequency ≤1% (based on Exome Variant Server database from the NHLBI exome sequencing project) were further analyzed. The pathogenic variants were confirmed by Sanger sequencing.

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ACCEPTED MANUSCRIPT 3. RESULTS Case 1: In this 31 year-old Caucasian woman, ambulance driver, a brain CT-scan performed at age 23 because of headache, had revealed an asymptomatic cerebellar atrophy. At age 30, after one fall, neurological examination revealed cerebellar ataxia (SARA score: 8.5/40), hypometric saccades, increased lower limbs reflexes, right extensor plantar reflexe, pes cavus, and mild diffuse chorea (video). Brain MRI confirmed isolated cerebellar atrophy (Figure 1). Fundoscopic examination was normal, as well as electromyography that revealed no

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polyneuropathy. Neuropsychological testing showed a mild subcortical frontal profile with executive dysfunction and reduction of speed of mental processing. Vitamin E, alpha foetoprotein (AFP), cholestanol,

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phytanic and pristanic acids, lactate, pyruvate, and very long chain fatty acids levels was normal. Genetic testing

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for Huntington’s disease and Friedreich ataxia were negative, as well as search for acanthocytes. Two different mutations were found in ERCC4 (NM_005236): c.2395C>T (exon 11) causing a previously

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reported missense change p.Arg799Trp 8 and the novel mutation c.580_584+1delCCAAGG (exon3) causing the re-creation of the exon 3 donor splice site 6 nucleotides up -stream of the initial position. The Spliceport

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software (http://spliceport.cbcb.umd.edu) predicts that the novel up-stream donor splice site has a score reduced from 1.23 (wild-type) to -0.10 (mutant). Assuming usage of the weaker up-stream splice site (there is no

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alternative predicted cryptic splice site in exon 3 or intron 3), the mut ation is predicted to cause the in-frame deletion of two amino acids highly conserved among all eukaryotes, p.Pro194_Arg195del. Assuming skipping of

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exon 3 predicts a frame-shift after glycine130. Therefore, in any circumstances, the mutation is predicted pathogenic. We confirmed the presence of the two heterozygous ERCC4 mutations by Sanger sequencing. The parents were each heterozygous for one mutation, confirming compound heterozygosity in the patient. After XP -

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F diagnosis, the patient acknowledged having noticeable sunburn sensitivity and multiple freckles on exposed skin were noticed by the referring dermatologist. Case 2: This 67 year-old Caucasian man, born as a result of a consanguineous marriage, had developed since age 40 a progressive unsteady gait. He was previously briefly reported 2. The neurological examination showed gait and limb cerebellar ataxia, dysarthria (SARA score: 15/40), saccadic pursuit, bilateral Babinski sign s, mild spasticity, decreased lower limb vibration sensation, and absent ankle tendon reflexes. Generalized non -disabling chorea was noticed and according to the patient, was present since childhood. Neuropsychological evaluation demonstrated dysexecutive troubles, and episodic and working memory dysfunction. The MMSE was slightly altered and scored at 25/30. Brain MRI showed cortical and cerebellar atrophy (Figure 1). Electromyography

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ACCEPTED MANUSCRIPT confirmed a severe lower limb sensory axonal polyneurop athy. Fundoscopic examination was normal. Vitamin E, AFP, cholestanol, phytanic and pristanic acids, lactate, pyruvate levels were normal, and biological data excluded usual causes of late onset acquired polyneuropathy (diabetes, alcohol, vitamin deficiencies, monoclonal gammathy…). Genetic testing for Huntington’s disease, SCA17, Dentatorubral-pallidoluysian atrophy, benign hereditary chorea, FXTAS, and Friedreich ataxia was negative. Mini-exome sequencing revealed homozygosity for the previously reported 8 p.Arg799Trp missense mutation in ERCC4. However, the repair kinetics of

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cyclobutane pyrimidine dimers (CPD) performed in fibroblasts was similar to that from normal patients, and analysis of unscheduled DNA synthesis (UDS) using fluorescent 5-ethynyl-2’-deoxyuridine (Edu) showed that

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these fibroblasts displayed UDS activities identical to the wild-type cells. Despite normality of the test, the

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p.Arg799Trp mutation is the real cause of the disease in this case because the same mutation was identified in case 1 and in two homozygous patients with mild XPF presentation 5, 8. Subsequent to the diagnosis, the

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patient acknowledged sunburn sensitivity and persistent erythema after minimal sun exposure; multiple freckles and area of both hypo and hyper pigmentation were noticed on exposed skin

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4. DISCUSSION

Although only few cases have been reported, XP-F is usually characterized by mild late onset cutaneous

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manifestations, occurrence of cutaneous carcinoma in less than 50% of cases [9], and the lack of neurological abnormalities 6, 7. Including the present two cases, only four cases of XP-F with neurological disorders have

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been reported (Table 1) 8,10. In contrast to other XP groups, in which neurological involvement is more frequent and often appearing before 10 years of age, in XP-F the neurological symptoms began later, i.e. after

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the age of 30 years in 3 out of 4 patients; however, CT scan performed at age 23 in case 1, seven years before diagnosis, already showed asymptomatic cerebellar atrophy. The four patients experienced cerebellar ataxia and chorea. Since chorea is also a feature of other XP groups, but is rare in ARCA, except ataxia telangiectasia (AT), AOA1 and AOA2 1, it should be considered as a strong red flag for XP in patients with AR ataxia. Moreover, due to the presence of chorea and executive cognitive impairment, XP should be included in the list of Huntington’s disease-like syndromes 11.

Mild cognitive impairment has been found in the three oldest

patients, but without progression to dementia even after 20 years of disease duration (case 2). Electromyography revealed mild axonal polyneuropathy in case 4 and severe axonal s ensory polyneuropathy in case 2. Thus XP-F should be classified among cerebellar ataxia with sensory polyneuropathy 1. MRI demonstrated marked cerebellar atrophy (3/3), and associated cortical atrophy (2/3). In all four cases, cutaneous signs were mild, as

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ACCEPTED MANUSCRIPT described in XP-F 6-8. Moreover, in cases 1 and 2 moderate hypersensitivity to sunlight was fou nd only retrospectively, suggesting that XP-F is possibly under diagnosed in absence of neurological symptoms. Neither of our 2 patients had, at time of examination, developed either skin cancer or other neoplasia. Since about 50% of XP-F patients develop tumors 9 (2/4 in our series with neurological symptoms), strict sun protection and clinical and dermatological follow-ups should be recommended.

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ERCC4 encodes the XPF protein that is a part of the ERCC1-XPF complex, a two-subunit nuclease, which participates in nucleotide excision repair (NER) of DNA and in chromosome stability maintenance 12,13.

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Besides genetic studies, functional analysis on living cells including cellular ultraviolet (UV) hypersensitivity, UDS, and host-cell reactivation are used to screen DNA repair abnormalities. However, cell survival curves and

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DNA repair efficiency are only moderately affected after UV exposure in XP-F patients, unlike for other XP

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forms 5,8. This may explain the rather moderate dermatological manifestation and the late development of skin cancer compared to other types of XP. Indeed, cellular tests performed in case 2 were normal suggesting

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incomplete sensitivity of these tests for the late onset, slowly progressive, XP-F cases. The pathophysiology of neurological damage is not yet understood, and may be different from the pathophysiology of skin damage. It may be related to transcriptional disturbances rather than to DNA repair

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defect, since the dual role of XP factors in both nucleo tide excision repair and initiation of transcription is well established 14,15; this mechanism has already been suggested for ataxias with elevated AFP, such as AT,

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AOA1 and AOA2 1. Interestingly, in these diseases, as like as in XP, ataxia may be associated with chorea and polyneuropathy, reinforcing the idea of a common disease mechanism and involved pathways.

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Genetic data were available for all 4 patients (Table 1), reporting a novel mutation c.580_584+1delCCAAGG (case 1) and the already known pathogenic missense mutation p.Arg799Trp (cases 1, 2 and 4) in the ERCC4 gene. Interestingly, the p.Arg799Trp mutation was found in another XP-F caucasian patient, who, at the time of the report (22 years) did not show any neurological abnormalities 5. This missense mutation affects the region of the XPF protein that is required for stable interaction with ERCC1 16. Since the p.Arg799Trp mutation was found in at least 4 families 5, 8 (and this study) it will be interesting to determine whether this is due to a mutational ‘hot spot’ or to a Caucasian founder event. Case 3, the only Japanese patient, is compound heterozygous for two different mutations 17 (Table 1), one of which is a missense mutation, p.Arg454Trp, affecting the helicase-like domain of the XPF protein.

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ACCEPTED MANUSCRIPT To our knowledge, no homozygous truncating mutation has been reported in ERCC4. Only a few truncating mutations were described in compound heterozygosity with a missense mutation 18,19 suggesting that complete gene inactivation is not compatible with life. The fact that homozygous ERCC4 mutant mice die at approximately 3 weeks of age 20 supports this hypothesis. 5. CONCLUS ION

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XP-F is a rare cause of recessive cerebellar ataxia, often associated with chorea. The presence of a history of sunlight hypersensitivity is a pointer for the diagnosis, which should not be missed, in order to prevent skin

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neoplastic complications.

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Conflict of Interest: HRR acknowledges support from the patients’ support group “Les Enfants de La Lune”.

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GC, CM, MA, CGE, MR, CGU, CT declare that they have no conflict of interest . Fundi ng sources: ANR/ E-rare Jo int-Transnational-Call 2011 (2011-RA RE-004-01 “Euro-SCA R”) to M K.

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Acknowledgment: We wish to thank JP Villemin for bioinformatics analyses. References:

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[1] Anheim M, Tranchant C, Koenig M. The Autosomal Recessive Cerebellar Ataxias. N Engl J Med 2012; 366:636-646

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[2] Marelli C, Guissart C, Hubsch C, Renaud M, Villemin JP, Larrieu L, Charles P, et al. Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias. Hum Mutat. 2016;

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37(12):1340-1353.

[3] Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis. 2011; 6:70. [4] Anttinen A, Koulu L, Nikoskelainen E, Portin R, Kurki T, Erkinjuntti M, Jaspers NG et al. Neurological symptoms and natural course of xeroderma pigmentosum. Brain, 2008; 131: 1979-89. [5] Norris PG, Hawk JL, Avery JA, Giannelli F. Xeroderma pigmentosum complementation group F in a non Japanese patient. J Am Acad Dermatol. 1988; 18:1185-8. [6] Yamamura K, Ichihashi M, Hiramoto T, Ogoshi M, Nishioka K, Fujiwara Y. Clinical and photobiological characteristics of xeroderma pigmentosum complementation group F: a review of cases from Japan. Br J Dermatol. 1989; 121(4):471-80. [7] Fujiwara Y, Ichihashi M, Uehara Y, Matsumoto A, Yamamoto Y, Kano Y, Tanakura Y. Xeroderma

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ACCEPTED MANUSCRIPT pigmentosum groups C and F: additional assignments and a review of the subjects in Japan. J Radiat Res. 1985; 26(4):443-9. [8] Sijbers AM, Van Voorst Vader PC, Snoek JW, Raams A, Jaspers NG, Kleijer WJ. Homozygous R788W point mutation in the XPF gene of a patient with xeroderma pigmentosum and late-onset neurologic disease. J Invest Dermatol.1998; 110(5):832-6. [9] Tofuku Y, Nobeyama Y, Kamide R, Moriwaki S, Nakagawa H. Xeroderma pigmentosum complementation

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group F: Report of a case and review of Japanes e patients. J Dermatol. 2015; 42(9):897-9.

[10] Moriwaki S, Nishigori C, Imamura S, Yagi T, Takahashi C, Fujimoto N, Takebe H. A case of xeroderma

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pigmentosum complementation group F with neurological abnormalities. Br J Dermatol. 1993; 128(1):91-4.

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[11] Martino D, Stamelou M, Bhatia KP. The differential diagnosis of Huntington's disease -like syndromes: 'red flags for the clinician. J Neurol Neurosurg Psychiatry. 2013 Jun; 84(6):650-6.

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[12] Manandhar M, Boulware KS, Wood RD. The ERCC1 and ERCC4 (XPF) genes and gene products. Gene, 2015; 569(2):153-61.

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[13] Sijbers AM, de Laat WL, Ariza RR, Biggerstaff M, Wei YF, Moggs JG, Carter KC et al. Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Cell. 1996; 86(5):811-22.

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[14] Egly JM, Coin F. A history of TFIIH: two decades of molecular biology on a pivotal transcription/repair factor. DNA Repair (Amst). 2011;10(7):714-21

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[15] Egly JM. The 14th Datta Lecture. TFIIH: from transcription to clinic. FEBS Lett. 2001;498(2-3):124-8. [16] De Laat WL, Sijbers AM, Odijk H, Jaspers NG, Hoeijmakers JH. Mapping of interaction domains between

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human repair proteins ERCC1 and XPF. Nucleic Acids Res. 1998; 26(18):4146-52. [17] Matsumura Y, Nishigori C, Yagi T, Imamura S, Takebe H. Characterization of molec ular defects in xeroderma pigmentosum group F in relation to its clinically mild symptoms. Hum Mol Genet. 1998; 7(6):96974.

[18] Bogliolo M, Schuster B, Stoepker C, Derkunt B, Su Y, Raams A, Trujillo JP et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum Genet. 2013; 92(5):800-6. [19] Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, Fawcett H et al. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am J Hum Genet. 2013; 1992(5):807 -19 [20] Tian M, Shinkura R, Shinkura N, Alt FW. Growth retardation, early death, and DNA repair defects in mice

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ACCEPTED MANUSCRIPT deficient for the nucleotide excision repair enzyme XPF. Mol Cell Biol. 2004;24(3):1200-5

Legends Video. Case 1: unsteady Romberg test, gait and tandem walking; Nose-finger test and

Finger chase test

showing mild action tremor and dysmetria; irregular fast alternating hand movements; saccadic pursuit eyes

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movement; chorea in upper limbs, trunk, neck and face. Figure 1: Brain magnetic resonance imaging, 3T. Case 1: A: sagital T1, B: axial T2 FLAIR mild cerebellar and

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cortical atrophy; Case 2: C: axial T2 FLAIR, D: sagital T2: severe cerebellar atrophy, global atrophy and diffuse

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white matter abnormalities

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Table 1: characteristics of the 4 patients with XP-F and neurological complications BCC basal cell carcinoma; BDC: bile duct cancer; KA: keratoacanthoma; ND not done; SCC: squamous cell

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carcinoma;

* No deficiency in the repair of UV-induced DNA damage was detected with both repair kinetics of cyclobutane pyrimidine dimers (CPD) and unscheduled DNA synthesis (UDS); ** Overall 22% reduction of UV-induced

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incorporation of tritiated thimidine measured by autoradiography (UDS).

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Fig. 1

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ACCEPTED MANUSCRIPT Table 1: characteristics of the 4 patients with XP-F and neurological complications *

No deficiency in the repair of UV-induced DNA damage was detected with both repair kinetics of cyclobutane pyrimidine dimers (CPD) and unscheduled DNA synthesis (UDS); ** Overall 22% reduction of UV-induced incorporation of tritiated thimidine measured by autoradiography (UDS); BCC basal cell carcinoma; BDC: bile duct cancer; KA: keratoacanthoma ND not done; SCC: sqamous cell carcinoma;

Phot Pigm Frec oented kles sensit macu ivity le

Neurological characteristics

Ax Cere Pyra ona bellar midal l ataxi signs PN a P

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Case 3 Japanese M 10,17

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Case 4 Caucasian M 8

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Patient origin/sex

Repai r effici ency of Neur UVoERCC4 gene Ch Cogn Tumours induc itive imagi mutation ore ed altera ng a DNA tion dama ge in skin fibro blasts Cereb c.580_584+1d ellar + + elCCAAGG atrop ND /p.Arg799Trp hy Globa l cortic 93% al, ± 7* subco p.Arg799Trp + + rtical /p.Arg799Trp and cereb ellar atrop hy Corti cal ND and c.1608_1617d 1 digestive + + subco el10 tumour BDC rtical /p.Arg454Trp atrop hy Corti cal 8BCC, and 78%* p.Arg799Trp + + 9SCC, cereb * /p.Arg799Trp 1KA ellar atrop hy

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Skin characteristics

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ACCEPTED MANUSCRIPT Highlight:

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Xeroderma pigmentosum type F (XP-F) is a rare cause of recessive cerebellar ataxia. XP-F is often associated with chorea. A novel mutation was described in ERCC4, c.580_584+1delCCAA GG (exon3), causing XP-F.

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