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Ehlers-Danlos syndromes and epilepsy: An updated review
Seizure 57 (2018) 1–4
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Review
Ehlers-Danlos syndromes and epilepsy: An updated review Francesca Cortinia,b , Chiara Villac,* a
Department of Clinical Sciences and Community Health, University of Milan, IRCCS Ca' Granda Foundation, Milan, Italy Genetics Laboratory, IRCCS Ca' Granda Foundation, Milan, Italy c School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy b
A R T I C L E I N F O
Article history: Received 1 February 2018 Received in revised form 17 February 2018 Accepted 23 February 2018 Available online xxx Keywords: Ehlers-Danlos syndromes Epilepsy Seizure Genetics
A B S T R A C T
The Ehlers-Danlos syndromes (EDS) comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs), characterised by joint hypermobility, hyperextensibility of the skin and tissue fragility that can induce symptoms from multiple organ systems. The latest EDS nosology distinguished thirteen subtypes with an overlap of phenotypic features, making the clinical diagnosis rather difficult and highlighting the importance of molecular diagnostic confirmation. Although the nervous system is not considered a primary target of the underlying molecular defect, recently, increasing attention has been focused on neurological manifestations of EDS. Among them, epilepsy represents a frequent cause of morbidity in these syndromes and can influence the long-term evolution of these patients, but the mechanisms are needed to be clarified. The aim of this review is to give a comprehensive overview and to analyze a possible association between EDS and epilepsy, focusing on the various brain anomalies and the types of epilepsy reported in patients affected by EDS. © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction The term Ehlers-Danlos syndromes (EDS) refers to a heterogeneous group of heritable connective tissue disorders (HCTDs), mainly affecting skin, ligaments, joints and blood vessels. EDS is characterised by genetic heterogeneity and phenotypic variability: while the past Villefranche classification delineated six subtypes, most of which caused by mutations in genes encoding the collagen structure or biosynthesis [1], recent advances in genetics led to a revised EDS classification in thirteen subtypes [2], including defects in both non-collagenous extracellular matrix (ECM) proteins and intracellular processes. Although the main features of EDS are generally recognised by specialists, emerging evidences define a wide spectrum of neurological manifestations that are unexpectedly common and potentially disabling: headache, fatigue, cerebrovascular disorders, chronic pain syndrome, peripheral neuropathy, plexopathy, spontaneous intracranial hypotension and epilepsy [3]. The severity of these manifestations ranges from very mild findings to severe debilitating illness [4]. Among the principal neurological features of EDS, epilepsy has been frequently described in
* Corresponding author. E-mail address: [email protected] (C. Villa).
literature, due mainly to structural anomalies often associated with periventricular heterotopia (PH) [5], a group of neuronal migration disorders characterised by abnormal neuronal positioning that also includes bilateral nodular heterotopia (PNH). Concerning this association, it is important to note a particular case of an EDS 12-year-old girl with PH, which reported sudden headache as first symptom of presentation [6]. Both generalized or focal seizures with various electroencephalography (EEG) features were found in these patients, associated with different kinds of epilepsy and specific brain malformations investigated by magnetic resonance imaging (MRI). In this review, we report and analyze all cases of patients affected by EDS and epilepsy from both a clinical and genetic point of view. 1.1. Classification The recent EDS nosology recognised thirteen subtypes based on clinical findings, inheritance pattern and molecular defects, as outlined in Table 1 [2]. All phenotypes show the basic clinical hallmarks of EDS, such as hypermobility, skin hyperextensibility and tissue fragility. The spectrum of joint hypermobility ranges from asymptomatic conditions to severe disabling symptoms. Given a great phenotypic and genetic EDS variability and the clinical overlap with the EDS subtypes or other HCTDs, a final
https://doi.org/10.1016/j.seizure.2018.02.013 1059-1311/© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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F. Cortini, C. Villa / Seizure 57 (2018) 1–4
Table 1 Clinical classification of Ehlers-Danlos Syndromes: inheritance pattern, genes and main functions of involved proteins. EDS subtypes (subtypes)
Inheritance pattern
Genes
Proteins
Main protein functions
Classical EDS (cEDS)
AD
COL5A1, COL5A2,
type V collagen
Classical-like EDS (clEDS)
AR
COL1A1 TNXB
type I collagen tenascin XB
Cardiac-valvular EDS (cvEDS) Vascular EDS (vEDS)
AR AD
COL1A2 COL3A1,
type I collagen type III collagen
Hypermobile EDS (hEDS) Arthrochalasia EDS (aEDS) Dermatosparaxis EDS (dEDS) Kyphoscoliotic EDS (kEDS)
AD AD AR AR
COL1A1 unknown COL1A1, COL1A2 ADAMTS2 PLOD1,
type I collagen unknown type I collagen ADAMTS-2 LH1
Brittle Cornea syndrome (BCS)
AR
FKBP14 ZNF469, PRDM5
FKBP22 ZNF469 PRDM5
Spondylodysplastic EDS (spEDS)
AR
B4GALT7, B3GALT6,
b4GalT7, b3GalT6,
SLC39A13
ZIP13
fibrillation of types I and III collagen and nucleation of collagen fibrillogenesis fibril-forming collagen in most connective tissues maintaining the integrity of the scaffold in which the collagen lays down and regulation the stability of the body’s elastic fibers fibril-forming collagen in most connective tissues fibril-forming collagen frequently in association with type I collagen fibril-forming collagen in most connective tissues unknown fibril-forming collagen in most connective tissues processing procollagen molecules into mature collagen hydroxylation of lysyl residues in collagen-like peptides into hydrolysine, essential to forming cross-links between individual of collagen chains acceleration the folding of proteins during protein synthesis regulating collagen fiber synthesis or organization regulating the expression of proteins involved in ECM development and maintenance synthesis of different glycosylated and saccharide structures transport of zinc into the cell, essential to the healthy function of connective tissues transfer of sulfate groups between different molecules production of a specific glycosaminoglycan, important in filling in connective tissue gaps, lending cohesion and stability. modifying the interactions between collagen I fibrils and the surrounding matrix if associated with type I collagen complement subcomponents, important for immune function
Musculocontractural EDS (mcEDS)
AR
CHST14, DSE
D4ST1 DSE
Myopathic EDS (mEDS)
AD or AR
COL12A1
collagen XII
Periodontal EDS (pEDS)
AD
C1R, C1S
C1r, C1s
AD: autosomal dominant; AR: autosomal recessive; ECM: extracellular matrix.
diagnosis requires molecular confirmation with the identification of causative genetic variant, except for the hypermobile (hEDS), based on only clinical findings. Both autosomal dominant and recessive inheritance patterns are found among different forms of EDS. These inheritance patterns are also common in other disorders that overlap clinical features with EDS. The genetic analysis can confirm or modify the clinical diagnosis and is thus essential for evaluating prognosis, making decisions on treatment and management strategies. Most of genes associated with EDS encode different types of collagen (COL1A1, COL1A2, COL1A3, COL5A1, COL5A2 and COL12A1) or proteins interacting with it or modifying enzymes (ADAMTS2, PLOD1, PRDM5, TNXB and ZNF469). Type-specific genetics, the involved proteins and their main functions are summarized in Table 1. The most common subtype of EDS is the hEDS, followed by the classical (cEDS) and the vascular (vEDS). The classification is very important for the management and counseling to the patients and their family. The subtypes are distinct from each other not only in their genetic causes, but also in their symptoms which can vary between individuals even in the same family. 1.2. EDS and epilepsy Epilepsy was reported in people affected by EDS, especially in cases with structural brain abnormalities, such as PH or polymicrogyria. However, the mechanisms linking seizures to a hereditary defect of the connective tissue remain likely heterogeneous and poorly studied. A possible explanation of this association may be related to the fact that collagen plays an important role in neurological growth, migration, metabolism and differentiation [7]. A further evidence supporting this hypothesis is that seizures also occurred in three reported cases of patients
affected by Stickler syndrome (STL), another connective tissue disorder [8]. Moreover, it has also been demonstrated the interaction between epidermal growth factor and the ECM is needed for the differentiation of cortical neurons [9]. So, a defect in collagen or in other ECM proteins in EDS patients may result in a structural failure of the cortical organization. The disruption in the link between the ECM and the cytoskeleton generates anomalies in cellular migration during development that can lead to malformations in vessels and brain parenchyma, contributing to seizures in EDS cases. In the literature, patients affected by EDS syndrome and epilepsy have been frequently reported, as summarized in Table 2. After the first case described by Herrero in 1972 [10], some years later, Cupo et al. reported a 30-year-old woman with EDS and grand mal seizures who died of an intractable ventricular fibrillation due to myocardial infarction (aneurysms of the sinuses of Valsalva) [11]. She also presented cerebral heterotopias that probably generated the seizure disorder. Other authors described a similar case of EDS and myocardial infarction in a 24-year-old woman with complex partial and right sensory motor seizures associated to PH [12]. Afterwards, in 1983 a 22-year-old female patient with EDS presented chronic focal seizures that began generalized, probably related to a congenital structural defect in the brain, as revealed by computed tomography (CT) [13]. Jacome reported seven cases affected by EDS and epilepsy with seizures onset in the childhood. Among them, two were affected by occipital horn syndrome, which is not included in EDS spectrum anymore, and focal seizures associated to frontal gliosis and Dandy-Walker malformation occurring in the cerebellum. The remaining five individuals with more stringent diagnosis of EDS showed different brain complications that probably caused seizures, such as basilar artery hypoplasia, left hemispheric
F. Cortini, C. Villa / Seizure 57 (2018) 1–4
3
Table 2 Reported cases of patients affected by EDS and epilepsy: clinical features and identified mutations. Authors
Cases Sex, age (yr)
Type of seizures
Gene mutations
MRI findings
Treatment
Herrero, 1972 Cupo, 1981 Pretorius, 1983 Thomas, 1996 Jacome, 1999
#1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12
n.a F, 30 F, 22 F, 24 M, 36 M, 29 F, 70 F, 28 M, 69 F, 35 F, 68 M, 29
n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.
n.a. PH n.a. PH frontal gliosis partial Dandy-Walker malformation basilar artery hypoplasia left hemispheric hypotrophy parietal venous angioma perisylvian encephalomalacia perisylvian encephalomalacia bilateral frontal polymicrogyria
#13
F, 22
n.a. grand mal focal and generalized focal focal focal focal focal focal and generalized focal generalized focal with secondary generalization generalized
n.a.
#14
F, 48
grand mal
#15
F, 24
generalized tonic-clonic
Sheen, 2005
#16 #17 #18 #19 #20 #21 #22
F,7 F, 24 F, 25 F, 53 M, 18 F, 29 F, 15
single seizure n.a. generalized n.a. focal generalized focal
Gòmez-Garre, 2006
#23
F, 68
#24
F, 19
focal with secondary generalization generalized
Ahmed, 2014 Kim, 2014
#25 #26
F, 4 F, 46
focal generalized tonic-clonic
p. Gly833Val COL3A1 p. Gly833Val COL3A1 n.a. n.a. n.a. n.a. n.a. n.a. p. Ala39Gly FLNA p. Ala128Val FLNA p. Ala128Val FLNA n.a. c. 1662 + 1 G>A COL3A1
bilateral congenital perisylvian syndrome with polymicrogyria n.a.
n.a. n.a. n.a. phenobarbital carbamazepine carbamazerpine and valproate carbamazepine and phenytoin AEDs valproate and phenytoin valproate phenobarbital phenobarbital, valproate, carbamazepine n.a.
Savasta, 2015 Horn, 2017
#27 #28
F,1 F, 5
afebrile generalized generalized
#29
M, 4
generalized
#30
M, 20
generalized tonic
Echaniz-Laguna, 2000
Palmeri, 2003
Sakka, 2017
COL5A1 p. Pro49Ala COL3A1 p. Pro49Ala COL3A1 COL3A1
n.a.
normal
n.a.
bilateral PNH PH PH PH PH PH bilateral PNH and megacisterna magna
n.a. n.a. n.a. n.a. n.a. n.a. n.a.
bilateral PNH
n.a.
bilateral PNH and megacisterna magna
n.a.
n.a. venous infarction at the right anterior insular cortex and right frontal lobe with micro-bleeds unilateral PH bilateral frontoparietal polymicrogyria
valproate and levetiracetam n.a.
bilateral frontoparietal polymicrogyria
n.a.
bilateral frontoparietal polymicrogyria
valproate and clobazam
valproate n.a.
MRI: magnetic resonance imaging; n.a: not available; PH: periventricular heterotopia; AEDs: antiepileptic drugs; PNH: bilateral nodular heterotopia.
atrophy, venous parietal angioma, intracranial bleed and a previous stoke [14]. In 2000, for the first time, some authors described two EDS cases, showing bilateral polymicrogyria as a cause of epilepsy. The first patient was a 29-year-old male with focal seizures that evolved then into generalized and well controlled only by the adding of carbamazepine to the phenobarbital and valproate treatment. The second, a 22-year-old female, presented intractable seizures that were drug resistant [15]. Among family studies, it is important to note an interesting case of a parental mosaicism: a point mutation p. Gly833Val in COL3A1 gene (coding the type III collagen) was detected not only in the family proband and in her mother, both affected by epileptic seizures, but unexpectedly also in the asymptomatic maternal grandmother, as a mosaic in somatic tissues [16]. Another family study was reported by Gòmez-Garre and collaborators in a Spanish family with three individuals affected by EDS, but only two of them had a history of seizures. The first, a 68-year-old woman, showed complex focal epilepsy followed by secondary tonic-clonic generalized seizures and the brain MRI revealed bilateral PNH. The second one, her 19-year-old grand-daughter, was affected by generalized epilepsy and had PNH associated with mega cisterna magna. Genetic analysis resulted in the identification of a novel missense mutation (p.Ala128Gly) in FLNA gene, encoding filamin A,
an actin binding protein involved in cytoskeletal organization [17]. These most common clinical manifestations among patients, carrying FLNA mutations and affected by EDS and PH, led some authors to suggest a separate syndrome, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH) [17–19]. Nevertheless, the latest EDS nosology excluded this rare variant from the spectrum disorder. Previously, Sheen et al. also reported a case with similar clinical features due to the p. Ala39Gly FLNA mutation in a study in which seven EDS patients with seizures and PH were described, further suggesting the strong association between epilepsy and this cerebral malformation [19]. Some authors described patients carrying mutations in genes encoding collagen, leading thus to an aberrant efficiency of protein secretion (Table 2). Among them, only Savasta and collaborators identified a mutation in COL5A1 gene, which was detected in a 1year-old female affected by afebrile generalized seizures and cEDS with a good response to valproate treatment. The brain MRI revealed unilateral PH, neurological condition associated for the first time with this clinical phenotype [20]. On the other hand, in the remaining cases, mutations occurred in COL3A1 gene. In particular, an already known splice-site variant (c. 1662 + 1 G > A) was identified in a vEDS 46-year-old woman presenting with generalized tonic-clonic seizures and cerebral infarction with micro-bleeds. This splicing mutation resulted in exon 24 skipping
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F. Cortini, C. Villa / Seizure 57 (2018) 1–4
[21]. Recently, Horn and collaborators described a case of two vEDS siblings carrying the missense mutation p.Pro49Ala in homozygous state. They both suffered from generalized epilepsy and the cerebral MRI showed bilateral frontoparietal polymicrogyria [22]. Their clinical data were in accordance with the findings in knockout mice in which the type III collagen seems to play a relevant role in cerebral cortical development in addition to its known contribution to the organization of ECM [23]. Interestingly, the same bi-allelic mutation was previously detected also in other two individuals who presented seizures, suggesting a link between epilepsy and defects in collagen production [24]. A similar case of those reported by Horn et al. was described in a 20-year-old male with familial history of vEDS, confirmed by genetic testing of COL3A1 gene. He also showed generalized seizures, probably generated by bilateral frontoparietal polymicrogyria, as revealed by brain MRI. The patient was resistant to valproate treatment, so the addition of clobazam was required [25]. Another research group reported a vascular EDS case of a 4year-old female presenting with focal convulsions, which was successfully managed with valproate and levetiracetam as anticonvulsant drugs [26]. An important study that examined a series of 42 epileptic individuals affected by EDS was performed subdividing them according to the presence or absence of brain lesions, mainly PH. The large majority of the enrolled patients had the classical type of EDS, except three with the vascular form. After a long-term followup (at least five years), the outcome of epilepsy will be evaluated. Interestingly, the response to antiepileptic drug (AEDs) monotherapy was favorable in all individuals without brain lesions, whereas a worse outcome was observed in those with central nervous system (CNS) abnormalities, confirming that the epilepsy in the presence of cerebral structural anomalies is more frequent drug resistant [27]. 2. Conclusions Epilepsy is an important cause of morbidity in EDS and should be taken in consideration for the care of these patients. The type, the severity and the age at onset of seizures are very variable. However, the pathological mechanisms leading to epilepsy are not clear: some authors hypothesised that the existence of brain lesions (e.g. PH or polymicrogyria) was considered the main cause [27]. Biochemical and genetic anomalies of the connective tissue probably underlie the pathogenesis of neurological manifestation of EDS. It would be interesting to understand if there is any possible correlation between different EDS subtypes and the various epileptic manifestations, but, unfortunately, the most of discussed cases showed the cEDS. It is important to carefully evaluate patients showing asymptomatic or unrecognised anomalies to better define their prognosis. In this regard, MRI, EEG recording and neuropsychological tests may represent useful tools for defining diagnosis and caring for individuals affected by both EDS and epilepsy. Indeed, in most cases, the treatment with different AEDs in patients without brain abnormalities obtained good results. A better understanding of the mechanisms underneath the origin of seizures is useful to improve therapy and the out-come of these patients. Declaration of interest We declare we have no financial interests.
References [1] Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997: Ehlers-Danlos national foundation (USA) and Ehlers-Danlos support group (UK). Am J Med Genet 1998;77:31–7. [2] Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers Danlos syndromes. Am J Med Genet C Semin Med Genet 2017;175:8–26. [3] Castori M, Voermans NC. Neurological manifestations of Ehlers-Danlos syndrome(s): A review. Iran J Neurol 2014;13:190–208. [4] Savasta S, Merli P, Ruggieri M, Bianchi L, Spartà MV. Ehlers-Danlos syndrome and neurological features: a review. Childs Nerv Syst 2011;27:365–71. [5] Verrotti A, Monacelli D, Castagnino M, Villa MP, Parisi P. Ehlers-Danlos syndrome: a cause of epilepsy and periventricular heterotopia. Seizure 2014;23:819–24. [6] Savasta S, Crispino M, Valli M, Calligaro A, Zambelloni C, Poggiani C. Subependymal periventricular heterotopias in a patient with Ehlers-Danlos syndrome: a new case. J Child Neurol 2007;22:317–20. [7] Kim ST, Brinjikji W, Lanzino G, Kallmes DF. Neurovascular manifestations of connective-tissue diseases: a review. Interv Neuroradiol 2016;22:624–37. [8] Savasta S, Salpietro V, Spartà MV, Foiadelli T, Laino D, Lobefalo L, et al. Stickler syndrome associated with epilepsy: report of three cases. Eur J Pediatr 2015;174:697–701. [9] Beighton P, De Paepe A, Hall JG, Hollister DW, Pope FM, Pyeritz RE, et al. Molecular nosology of heritable disorders of connective tissue. Am J Med Genet 1992;42:431–48. [10] Herrero F. Ehlers–Danlos syndrome and epilepsy: a case study. Epilepsia 1995;36:240. [11] Cupo LN, Pyeritz RE, Olson JL, McPhee SJ, Hutchins GM, McKusick VA. EhlersDanlos syndrome with abnormal collagen fibrils, sinus of Valsalva aneurysms, myocardial infarction, panacinar emphysema and cerebral heterotopias. Am J Med 1981;71:1051–8. [12] Thomas P, Bossan A, Lacour JP, Chanalet S, Ortonne JP, Chatel M. Ehlers-Danlos syndrome with subependymal periventricular heterotopias. Neurology 1996;46:1165–7. [13] Pretorius ME, Butler IJ. Neurologic manifestations of Ehlers-Danlos syndrome. Neurology 1983;33:1087–9. [14] Jacome DE. Epilepsy in Ehlers-Danlos syndrome. Epilepsia 1999;40:467–73. [15] Echaniz-Laguna A, de Saint-Martin A, Lafontaine AL, Tasch E, Thomas P, Hirsh E, et al. Bilateral focal polymicrogyria in Ehlers-Danlos syndrome. Arch Neurol 2000;57:123–7. [16] Palmeri S, Mari F, Meloni I, Malandrini A, Ariani F, Villanova M, et al. Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism. Clin Genet 2003;63:510–5. [17] Gómez-Garre P, Seijo M, Gutiérrez-Delicado E, Castro del Río M, de la Torre C, Gómez-Abad C, et al. Ehlers-Danlos syndrome and periventricular nodular heterotopia in a Spanish family with a single FLNA mutation. J Med Genet 2006;43:232–7. [18] Reinstein E, Frentz S, Morgan T, García-Miñaúr S, Leventer RJ, McGillivray G, et al. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. Eur J Hum Genet 2013;21:494–502. [19] Sheen VL, Jansen A, Chen MH, Parrini E, Morgan T, Ravenscroft R, et al. Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. Neurology 2005;64:254–62. [20] Savasta S, Verrotti A, Spartà MV, Foiadelli T, Villa MP, Parisi P. Unilateral periventricular heterotopia and epilepsy in a girl with Ehlers-Danlos syndrome. Epilepsy Behav Case Rep 2015;4:27–9. [21] Kim JG, Cho WS, Kang HS, Kim JE. Spontaneous carotid-cavernous fistula in the type IV Ehlers-Danlos syndrome. J Korean Neurosurg Soc 2014;55:92–5. [22] Horn D, Siebert E, Seidel U, Rost I, Mayer K, Abou Jamra R, et al. Biallelic COL3A1 mutations result in a clinical spectrum of specific structural brain anomalies and connective tissue abnormalities. Am J Med Genet A 2017;173:2534–8. [23] Liu X, Wu H, Byrne M, Krane S, Jaenisch R. Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A 1997;94:1852–6. [24] Vandervore L, Stouffs K, Tanyalçin I, Vanderhasselt T, Roelens F, HolderEspinasse M, et al. Bi-allelic variants in COL3A1 encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts. J Med Genet 2017;54:432–40. [25] Sakka S, Machraoui R, Bouzidi N, Damak M, Mhiri C. Ehlers Danlos syndrome and polymicrogyria: an uncommon association. J Neurol Disord Stroke 2017;5:1119. [26] Ahmed S, Ali SR, Nadeem N, Hamid M. Vascular Ehlers-Danlos syndrome: a rare disorder presenting with focal convulsions. J Coll Physicians Surg Pak 2014;24(Suppl 3):S262–34. [27] Verrotti A, Spartà MV, Monacelli D, Porto R, Castagnino M, Russo Raucci A, et al. Long-term prognosis of patients with Ehlers-Danlos syndrome and epilepsy. Epilepsia 2014;55:1213–9.
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Review
Ehlers-Danlos syndromes and epilepsy: An updated review Francesca Cortinia,b , Chiara Villac,* a
Department of Clinical Sciences and Community Health, University of Milan, IRCCS Ca' Granda Foundation, Milan, Italy Genetics Laboratory, IRCCS Ca' Granda Foundation, Milan, Italy c School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy b
A R T I C L E I N F O
Article history: Received 1 February 2018 Received in revised form 17 February 2018 Accepted 23 February 2018 Available online xxx Keywords: Ehlers-Danlos syndromes Epilepsy Seizure Genetics
A B S T R A C T
The Ehlers-Danlos syndromes (EDS) comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs), characterised by joint hypermobility, hyperextensibility of the skin and tissue fragility that can induce symptoms from multiple organ systems. The latest EDS nosology distinguished thirteen subtypes with an overlap of phenotypic features, making the clinical diagnosis rather difficult and highlighting the importance of molecular diagnostic confirmation. Although the nervous system is not considered a primary target of the underlying molecular defect, recently, increasing attention has been focused on neurological manifestations of EDS. Among them, epilepsy represents a frequent cause of morbidity in these syndromes and can influence the long-term evolution of these patients, but the mechanisms are needed to be clarified. The aim of this review is to give a comprehensive overview and to analyze a possible association between EDS and epilepsy, focusing on the various brain anomalies and the types of epilepsy reported in patients affected by EDS. © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
1. Introduction The term Ehlers-Danlos syndromes (EDS) refers to a heterogeneous group of heritable connective tissue disorders (HCTDs), mainly affecting skin, ligaments, joints and blood vessels. EDS is characterised by genetic heterogeneity and phenotypic variability: while the past Villefranche classification delineated six subtypes, most of which caused by mutations in genes encoding the collagen structure or biosynthesis [1], recent advances in genetics led to a revised EDS classification in thirteen subtypes [2], including defects in both non-collagenous extracellular matrix (ECM) proteins and intracellular processes. Although the main features of EDS are generally recognised by specialists, emerging evidences define a wide spectrum of neurological manifestations that are unexpectedly common and potentially disabling: headache, fatigue, cerebrovascular disorders, chronic pain syndrome, peripheral neuropathy, plexopathy, spontaneous intracranial hypotension and epilepsy [3]. The severity of these manifestations ranges from very mild findings to severe debilitating illness [4]. Among the principal neurological features of EDS, epilepsy has been frequently described in
* Corresponding author. E-mail address: [email protected] (C. Villa).
literature, due mainly to structural anomalies often associated with periventricular heterotopia (PH) [5], a group of neuronal migration disorders characterised by abnormal neuronal positioning that also includes bilateral nodular heterotopia (PNH). Concerning this association, it is important to note a particular case of an EDS 12-year-old girl with PH, which reported sudden headache as first symptom of presentation [6]. Both generalized or focal seizures with various electroencephalography (EEG) features were found in these patients, associated with different kinds of epilepsy and specific brain malformations investigated by magnetic resonance imaging (MRI). In this review, we report and analyze all cases of patients affected by EDS and epilepsy from both a clinical and genetic point of view. 1.1. Classification The recent EDS nosology recognised thirteen subtypes based on clinical findings, inheritance pattern and molecular defects, as outlined in Table 1 [2]. All phenotypes show the basic clinical hallmarks of EDS, such as hypermobility, skin hyperextensibility and tissue fragility. The spectrum of joint hypermobility ranges from asymptomatic conditions to severe disabling symptoms. Given a great phenotypic and genetic EDS variability and the clinical overlap with the EDS subtypes or other HCTDs, a final
https://doi.org/10.1016/j.seizure.2018.02.013 1059-1311/© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
2
F. Cortini, C. Villa / Seizure 57 (2018) 1–4
Table 1 Clinical classification of Ehlers-Danlos Syndromes: inheritance pattern, genes and main functions of involved proteins. EDS subtypes (subtypes)
Inheritance pattern
Genes
Proteins
Main protein functions
Classical EDS (cEDS)
AD
COL5A1, COL5A2,
type V collagen
Classical-like EDS (clEDS)
AR
COL1A1 TNXB
type I collagen tenascin XB
Cardiac-valvular EDS (cvEDS) Vascular EDS (vEDS)
AR AD
COL1A2 COL3A1,
type I collagen type III collagen
Hypermobile EDS (hEDS) Arthrochalasia EDS (aEDS) Dermatosparaxis EDS (dEDS) Kyphoscoliotic EDS (kEDS)
AD AD AR AR
COL1A1 unknown COL1A1, COL1A2 ADAMTS2 PLOD1,
type I collagen unknown type I collagen ADAMTS-2 LH1
Brittle Cornea syndrome (BCS)
AR
FKBP14 ZNF469, PRDM5
FKBP22 ZNF469 PRDM5
Spondylodysplastic EDS (spEDS)
AR
B4GALT7, B3GALT6,
b4GalT7, b3GalT6,
SLC39A13
ZIP13
fibrillation of types I and III collagen and nucleation of collagen fibrillogenesis fibril-forming collagen in most connective tissues maintaining the integrity of the scaffold in which the collagen lays down and regulation the stability of the body’s elastic fibers fibril-forming collagen in most connective tissues fibril-forming collagen frequently in association with type I collagen fibril-forming collagen in most connective tissues unknown fibril-forming collagen in most connective tissues processing procollagen molecules into mature collagen hydroxylation of lysyl residues in collagen-like peptides into hydrolysine, essential to forming cross-links between individual of collagen chains acceleration the folding of proteins during protein synthesis regulating collagen fiber synthesis or organization regulating the expression of proteins involved in ECM development and maintenance synthesis of different glycosylated and saccharide structures transport of zinc into the cell, essential to the healthy function of connective tissues transfer of sulfate groups between different molecules production of a specific glycosaminoglycan, important in filling in connective tissue gaps, lending cohesion and stability. modifying the interactions between collagen I fibrils and the surrounding matrix if associated with type I collagen complement subcomponents, important for immune function
Musculocontractural EDS (mcEDS)
AR
CHST14, DSE
D4ST1 DSE
Myopathic EDS (mEDS)
AD or AR
COL12A1
collagen XII
Periodontal EDS (pEDS)
AD
C1R, C1S
C1r, C1s
AD: autosomal dominant; AR: autosomal recessive; ECM: extracellular matrix.
diagnosis requires molecular confirmation with the identification of causative genetic variant, except for the hypermobile (hEDS), based on only clinical findings. Both autosomal dominant and recessive inheritance patterns are found among different forms of EDS. These inheritance patterns are also common in other disorders that overlap clinical features with EDS. The genetic analysis can confirm or modify the clinical diagnosis and is thus essential for evaluating prognosis, making decisions on treatment and management strategies. Most of genes associated with EDS encode different types of collagen (COL1A1, COL1A2, COL1A3, COL5A1, COL5A2 and COL12A1) or proteins interacting with it or modifying enzymes (ADAMTS2, PLOD1, PRDM5, TNXB and ZNF469). Type-specific genetics, the involved proteins and their main functions are summarized in Table 1. The most common subtype of EDS is the hEDS, followed by the classical (cEDS) and the vascular (vEDS). The classification is very important for the management and counseling to the patients and their family. The subtypes are distinct from each other not only in their genetic causes, but also in their symptoms which can vary between individuals even in the same family. 1.2. EDS and epilepsy Epilepsy was reported in people affected by EDS, especially in cases with structural brain abnormalities, such as PH or polymicrogyria. However, the mechanisms linking seizures to a hereditary defect of the connective tissue remain likely heterogeneous and poorly studied. A possible explanation of this association may be related to the fact that collagen plays an important role in neurological growth, migration, metabolism and differentiation [7]. A further evidence supporting this hypothesis is that seizures also occurred in three reported cases of patients
affected by Stickler syndrome (STL), another connective tissue disorder [8]. Moreover, it has also been demonstrated the interaction between epidermal growth factor and the ECM is needed for the differentiation of cortical neurons [9]. So, a defect in collagen or in other ECM proteins in EDS patients may result in a structural failure of the cortical organization. The disruption in the link between the ECM and the cytoskeleton generates anomalies in cellular migration during development that can lead to malformations in vessels and brain parenchyma, contributing to seizures in EDS cases. In the literature, patients affected by EDS syndrome and epilepsy have been frequently reported, as summarized in Table 2. After the first case described by Herrero in 1972 [10], some years later, Cupo et al. reported a 30-year-old woman with EDS and grand mal seizures who died of an intractable ventricular fibrillation due to myocardial infarction (aneurysms of the sinuses of Valsalva) [11]. She also presented cerebral heterotopias that probably generated the seizure disorder. Other authors described a similar case of EDS and myocardial infarction in a 24-year-old woman with complex partial and right sensory motor seizures associated to PH [12]. Afterwards, in 1983 a 22-year-old female patient with EDS presented chronic focal seizures that began generalized, probably related to a congenital structural defect in the brain, as revealed by computed tomography (CT) [13]. Jacome reported seven cases affected by EDS and epilepsy with seizures onset in the childhood. Among them, two were affected by occipital horn syndrome, which is not included in EDS spectrum anymore, and focal seizures associated to frontal gliosis and Dandy-Walker malformation occurring in the cerebellum. The remaining five individuals with more stringent diagnosis of EDS showed different brain complications that probably caused seizures, such as basilar artery hypoplasia, left hemispheric
F. Cortini, C. Villa / Seizure 57 (2018) 1–4
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Table 2 Reported cases of patients affected by EDS and epilepsy: clinical features and identified mutations. Authors
Cases Sex, age (yr)
Type of seizures
Gene mutations
MRI findings
Treatment
Herrero, 1972 Cupo, 1981 Pretorius, 1983 Thomas, 1996 Jacome, 1999
#1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12
n.a F, 30 F, 22 F, 24 M, 36 M, 29 F, 70 F, 28 M, 69 F, 35 F, 68 M, 29
n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.
n.a. PH n.a. PH frontal gliosis partial Dandy-Walker malformation basilar artery hypoplasia left hemispheric hypotrophy parietal venous angioma perisylvian encephalomalacia perisylvian encephalomalacia bilateral frontal polymicrogyria
#13
F, 22
n.a. grand mal focal and generalized focal focal focal focal focal focal and generalized focal generalized focal with secondary generalization generalized
n.a.
#14
F, 48
grand mal
#15
F, 24
generalized tonic-clonic
Sheen, 2005
#16 #17 #18 #19 #20 #21 #22
F,7 F, 24 F, 25 F, 53 M, 18 F, 29 F, 15
single seizure n.a. generalized n.a. focal generalized focal
Gòmez-Garre, 2006
#23
F, 68
#24
F, 19
focal with secondary generalization generalized
Ahmed, 2014 Kim, 2014
#25 #26
F, 4 F, 46
focal generalized tonic-clonic
p. Gly833Val COL3A1 p. Gly833Val COL3A1 n.a. n.a. n.a. n.a. n.a. n.a. p. Ala39Gly FLNA p. Ala128Val FLNA p. Ala128Val FLNA n.a. c. 1662 + 1 G>A COL3A1
bilateral congenital perisylvian syndrome with polymicrogyria n.a.
n.a. n.a. n.a. phenobarbital carbamazepine carbamazerpine and valproate carbamazepine and phenytoin AEDs valproate and phenytoin valproate phenobarbital phenobarbital, valproate, carbamazepine n.a.
Savasta, 2015 Horn, 2017
#27 #28
F,1 F, 5
afebrile generalized generalized
#29
M, 4
generalized
#30
M, 20
generalized tonic
Echaniz-Laguna, 2000
Palmeri, 2003
Sakka, 2017
COL5A1 p. Pro49Ala COL3A1 p. Pro49Ala COL3A1 COL3A1
n.a.
normal
n.a.
bilateral PNH PH PH PH PH PH bilateral PNH and megacisterna magna
n.a. n.a. n.a. n.a. n.a. n.a. n.a.
bilateral PNH
n.a.
bilateral PNH and megacisterna magna
n.a.
n.a. venous infarction at the right anterior insular cortex and right frontal lobe with micro-bleeds unilateral PH bilateral frontoparietal polymicrogyria
valproate and levetiracetam n.a.
bilateral frontoparietal polymicrogyria
n.a.
bilateral frontoparietal polymicrogyria
valproate and clobazam
valproate n.a.
MRI: magnetic resonance imaging; n.a: not available; PH: periventricular heterotopia; AEDs: antiepileptic drugs; PNH: bilateral nodular heterotopia.
atrophy, venous parietal angioma, intracranial bleed and a previous stoke [14]. In 2000, for the first time, some authors described two EDS cases, showing bilateral polymicrogyria as a cause of epilepsy. The first patient was a 29-year-old male with focal seizures that evolved then into generalized and well controlled only by the adding of carbamazepine to the phenobarbital and valproate treatment. The second, a 22-year-old female, presented intractable seizures that were drug resistant [15]. Among family studies, it is important to note an interesting case of a parental mosaicism: a point mutation p. Gly833Val in COL3A1 gene (coding the type III collagen) was detected not only in the family proband and in her mother, both affected by epileptic seizures, but unexpectedly also in the asymptomatic maternal grandmother, as a mosaic in somatic tissues [16]. Another family study was reported by Gòmez-Garre and collaborators in a Spanish family with three individuals affected by EDS, but only two of them had a history of seizures. The first, a 68-year-old woman, showed complex focal epilepsy followed by secondary tonic-clonic generalized seizures and the brain MRI revealed bilateral PNH. The second one, her 19-year-old grand-daughter, was affected by generalized epilepsy and had PNH associated with mega cisterna magna. Genetic analysis resulted in the identification of a novel missense mutation (p.Ala128Gly) in FLNA gene, encoding filamin A,
an actin binding protein involved in cytoskeletal organization [17]. These most common clinical manifestations among patients, carrying FLNA mutations and affected by EDS and PH, led some authors to suggest a separate syndrome, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH) [17–19]. Nevertheless, the latest EDS nosology excluded this rare variant from the spectrum disorder. Previously, Sheen et al. also reported a case with similar clinical features due to the p. Ala39Gly FLNA mutation in a study in which seven EDS patients with seizures and PH were described, further suggesting the strong association between epilepsy and this cerebral malformation [19]. Some authors described patients carrying mutations in genes encoding collagen, leading thus to an aberrant efficiency of protein secretion (Table 2). Among them, only Savasta and collaborators identified a mutation in COL5A1 gene, which was detected in a 1year-old female affected by afebrile generalized seizures and cEDS with a good response to valproate treatment. The brain MRI revealed unilateral PH, neurological condition associated for the first time with this clinical phenotype [20]. On the other hand, in the remaining cases, mutations occurred in COL3A1 gene. In particular, an already known splice-site variant (c. 1662 + 1 G > A) was identified in a vEDS 46-year-old woman presenting with generalized tonic-clonic seizures and cerebral infarction with micro-bleeds. This splicing mutation resulted in exon 24 skipping
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[21]. Recently, Horn and collaborators described a case of two vEDS siblings carrying the missense mutation p.Pro49Ala in homozygous state. They both suffered from generalized epilepsy and the cerebral MRI showed bilateral frontoparietal polymicrogyria [22]. Their clinical data were in accordance with the findings in knockout mice in which the type III collagen seems to play a relevant role in cerebral cortical development in addition to its known contribution to the organization of ECM [23]. Interestingly, the same bi-allelic mutation was previously detected also in other two individuals who presented seizures, suggesting a link between epilepsy and defects in collagen production [24]. A similar case of those reported by Horn et al. was described in a 20-year-old male with familial history of vEDS, confirmed by genetic testing of COL3A1 gene. He also showed generalized seizures, probably generated by bilateral frontoparietal polymicrogyria, as revealed by brain MRI. The patient was resistant to valproate treatment, so the addition of clobazam was required [25]. Another research group reported a vascular EDS case of a 4year-old female presenting with focal convulsions, which was successfully managed with valproate and levetiracetam as anticonvulsant drugs [26]. An important study that examined a series of 42 epileptic individuals affected by EDS was performed subdividing them according to the presence or absence of brain lesions, mainly PH. The large majority of the enrolled patients had the classical type of EDS, except three with the vascular form. After a long-term followup (at least five years), the outcome of epilepsy will be evaluated. Interestingly, the response to antiepileptic drug (AEDs) monotherapy was favorable in all individuals without brain lesions, whereas a worse outcome was observed in those with central nervous system (CNS) abnormalities, confirming that the epilepsy in the presence of cerebral structural anomalies is more frequent drug resistant [27]. 2. Conclusions Epilepsy is an important cause of morbidity in EDS and should be taken in consideration for the care of these patients. The type, the severity and the age at onset of seizures are very variable. However, the pathological mechanisms leading to epilepsy are not clear: some authors hypothesised that the existence of brain lesions (e.g. PH or polymicrogyria) was considered the main cause [27]. Biochemical and genetic anomalies of the connective tissue probably underlie the pathogenesis of neurological manifestation of EDS. It would be interesting to understand if there is any possible correlation between different EDS subtypes and the various epileptic manifestations, but, unfortunately, the most of discussed cases showed the cEDS. It is important to carefully evaluate patients showing asymptomatic or unrecognised anomalies to better define their prognosis. In this regard, MRI, EEG recording and neuropsychological tests may represent useful tools for defining diagnosis and caring for individuals affected by both EDS and epilepsy. Indeed, in most cases, the treatment with different AEDs in patients without brain abnormalities obtained good results. A better understanding of the mechanisms underneath the origin of seizures is useful to improve therapy and the out-come of these patients. Declaration of interest We declare we have no financial interests.
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