An Unusual Cause of Peroneal Neuropathy

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An Unusual Cause of Peroneal Neuropathy Amitha L. Ananth MD, Yaping Yang Ph.D, Seema R. Lalani M.D., Ph.D, Timothy B. Lotze MD

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S1071-9091(14)00025-4 10.1016/j.spen.2014.04.006 YSPEN472

To appear in: Semin Pediatr Neurol

Cite this article as: Amitha L. Ananth MD, Yaping Yang Ph.D, Seema R. Lalani M.D., Ph.D, Timothy B. Lotze MD, An Unusual Cause of Peroneal Neuropathy, Semin Pediatr Neurol , 10.1016/j.spen.2014.04.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

An Unusual Cause of Peroneal Neuropathy Amitha L. Ananth, MD1 Yaping Yang, Ph.D2 Seema R. Lalani, M.D., Ph.D2 Timothy B. Lotze, MD1 Departments of Neurology1 and Genetics2, Baylor College of Medicine

Funding Sources:

None

Author Disclosures: None Keywords: Ehlers-Danlos Type IV, Peroneal Neuropathy, Arterial-Venous Malformation

Corresponding Author: Amitha L. Ananth, MD Department of Child Neurology Baylor College of Medicine 6701 Fannin Clinical Care Center, Suite 950 Houston, TX 77030 Office: 832-822-5046 [email protected]

1 Abstract We present the case of a teenage girl who presented with neurologic symptoms suggestive of a peripheral neuropathy, prior to the development of a central arteriovenous fistula. A 15-year-old patient presented with electromyography and nerve conduction studies indicative of a peroneal motor neuropathy but negative comprehensive genetic studies for common Charcot-Marie-Tooth mutations. After two years of stable symptoms, she presented with unilateral throbbing headache and tinnitus. Magnetic resonance angiography revealed a carotid cavernous fistula, confirmed with conventional angiography. A successful coil embolization of the fistula was performed. Whole-exome sequencing demonstrated a de novo heterozygous c.3158G>A (p.G1056D) mutation in the COL31A gene, consistent with Ehlers-Danlos type IV (EDS4). To our knowledge, this is the first reported case of isolated peroneal motor neuropathy in a patient with EDS4. This case highlights the utility of whole-exome sequencing in the diagnosis of patients with neurologic symptoms who do not fit a clear phenotype.

2 Introduction Ehlers-Danlos syndrome encompasses a group of inherited connective tissue disorders best known for joint hypermobility and skin hyperextensibility. These well recognized signs are not as apparent in type IV, the vascular type. The clinical diagnosis of Ehlers-Danlos syndrome type IV (EDS4; OMIM1300500) is based on four clinical criteria which include 1) thin, translucent skin, 2) easy bruising, 3) characteristic facial appearance (acrogyria), and 4) rupture of arteries, intestines, and/or uterus. EDS4 is estimated to represent 5-10% of cases of EhlersDanlos.1 Perhaps because of this rarity, the diagnosis is often made only after serious vascular complications which carry high morbidity and mortality.2, 3 Joint contractures, peripheral neuropathy, and other neurologic manifestations of EDS4 are described in rare individuals with this condition. Here, we present the case of a young female who initially presented with neurologic symptoms suggestive of a peripheral neuropathy prior to the development of vascular complications associated with EDS4 including central arteriovenous fistula. Whole exome sequencing was performed which excluded primary and/or concurrent neurological disease and identified a novel mutation in COL3A1, consistent with the diagnosis of EDS4. Case Report The patient initially presented at the age of 15 years with findings suggestive of bilateral peroneal motor neuropathy with pes equinus contractures and lower extremity muscle atrophy (Figure 1). In addition, she noted a history of easy bruising and bleeding along with poor wound healing. She additionally reported intermittent headaches characterized as mild migrainous headaches well controlled with amitriptyline.

Physical examination revealed transparent skin

with visible veins over her back and chest. The joints were mildly hyperextensible in the fingers only. Neurological examination noted atrophy of the gastrocnemius muscles bilaterally; however she was noted to have 5-/5 strength bilaterally for foot plantar flexion, and eversion. Foot dorsiflexion was limited by contractures and inversion was noted to be 5/5 bilaterally. Lower extremity reflexes were 3+ in the knee and could not be obtained in the ankles due to contractures. Sensation was intact to light touch, temperature, and proprioception. Vibration was decreased in the bilateral lower extremities to the ankles. Upper extremity strength was noted to be 5/5 bilaterally in deltoids, biceps, triceps, wrist extensors and flexors. Strength was 5-/5 in the finger flexors and extensors.

3 Prior evaluation until this presentation included MRI of the lumbar spine which showed no definite nerve root compression, abnormality of the spinal cord, or other cause for myelopathy. Nerve conduction studies (NCS) demonstrated abnormalities isolated to the bilateral peroneal motor responses with right side more affected than the left. The right peroneal nerve had severely decreased amplitude, prolonged latency but normal nerve conduction velocity. Left peroneal motor study showed prolonged latency, with normal amplitude and velocity. Electromyography (EMG) of the gastrocnemius and extensor hallucis longus demonstrated mixed small amplitude/short duration potentials with large amplitude/long duration potentials as can be seen in chronic myopathy with secondary motor unit remodeling. Basic laboratory studies included normal lactate, pyruvate, CK, and B12. Genetic studies until this point had included normal complete Charcot-Marie-Tooth panel (Cx32, MPZ, PMP22 sequencing/dup/del, EGR2, NFL, PRX, GDAP1, LITAF, MFN2, SH35C2, FIG4, LMNA, RAB7, GARS, HSPB1) and GAA trinucleotide repeat expansion mutation analysis at the FRDA locus for Friedrich ataxia. Clinical whole exome sequencing (WES) was performed using VCRome 2.11, a custom in-house designed solution-based exome capture reagent (Roche/ NimbleGen, https://www.hgsc.bcm.edu/sites/default/files/documents/Illumina_Barcoded_PairedEnd_Capture_Library_Preparation.pdf) The initial WES results were unrevealing for the patient’s neurologic phenotype. Her neuropathy symptoms remained stable over the next two years. She subsequently presented to the ER at the age of 17 with a two day history of a new headache type. The headache was described as left sided, throbbing, 10/10 in severity, and associated with pulsating tinnitus in the left ear. Physical exam revealed a loud bruit over the left orbit which was transmitted to the temples bilaterally as well as into the chest. Non-contrast computed tomography of the head performed in the emergency room was negative. Magnetic resonance imaging and magnetic resonance angiography (MRI/MRA) of the head and neck demonstrated poor delineation of the cavernous segment of the left internal carotid artery with turbulence and disruption of the wall (Figure 2). There was arterialized-appearing flow signal in the venous sinuses on the left including the cavernous sinus, superior and inferior ophthalmic veins. The appearance was suggestive of a left carotid cavernous fistula. While the WES results were undetermined for the patient’s neurologic phenotype, a heterozygous c.3158G>A (p.G1053D) mutation was identified by WES and confirmed by

4 Sanger sequencing in the COL3A1 (NM 000090) gene, associated with dominantly inherited EDS4. This change, which has not been reported in control or patient populations, results in the substitution of glycine 1053 in the triple-helical domain of type III procollagen to aspartate, and is therefore predicted to be likely disease causing. Her asymptomatic parents were negative for the c.3158G>A (p.G1053D) mutation by Sanger sequencing, indicating that the mutation occurred de novo in this patient. The possibility of non-paternity was ruled out based on paternal allele transmission of a few other rare variants observed in this study. The diagnosis was also confirmed by demonstrating the synthesis of abnormal type III procollagen molecules from cultured dermal fibroblasts. The patient was quite debilitated by the pulsatile tinnitus and headache, therefore the neuro-interventional team was consulted. She underwent conventional angiography which confirmed a left type-1 carotid cavernous fistula and had successful coil embolization (Figure 3). Her headache improved after endovascular treatment. Post procedure, she developed a complete left CN VI palsy. She was treated with corticosteroids as the symptoms were thought to be possibly due to post-procedural edema, however the palsy persisted. At most recent follow-up, the patient noted complete resolution of her tinnitus. She was started on celiprolol, a cardioselective beta-blocker with vasodilatory beta-2 agonist properties. Discussion EDS4 is inherited in an autosomal dominant fashion from mutations of the type III procollagen gene, COL3A1.2 About 95% of the mutations result in production of abnormal type III procollagen. There are two major mutation types: point mutations resulting in substitutions of glycine for another amino acid in the triple helical domain and splice site mutations.1, 2, 4 Our patient had a novel point mutation resulting in substitution of a glycine residue for aspartic acid in this triple helical region. The identification of the COL3A1 mutation highlights the importance of interpreting available testing in the context of an evolving clinical picture. WES interrogates the entire coding regions of the genome upfront, making it an ideal platform for reanalyzing an existing variant list based on newly developed disease phenotypes or new disease genes. Our patient presented with an unusual gamut of neurologic deficits to include neuromuscular and neurovascular features. While the EDS complex of disorders is not typically known for neurologic manifestations, EDS4 has a risk for cerebral vasculopathy, which can

5 result in devastating and potentially fatal neurologic complications. In a large cohort of 419 subjects evaluated by Pepin et al in 2000, 43 subjects (approximately 10%) had vascular complications of the central nervous system (CNS) between the ages of 17 and 65 years. 10 subjects (2%) had carotid cavernous fistulae, which was documented as being the most common nonlethal CNS vascular complication.2 In other series, the frequency has been reported from 615 %.5, 6 Other CNS vascular complications include arterial dissection, aneurysms, and arterial rupture. EDS4 may also present with stroke or transient ischemic attack (TIA) due to emboli from carotid dissection and should be considered as a potential cause of stroke in a young person without previously identified risk factors.1, 7 In a prior study of 202 patients, 19 patients (9.4 %) had neurovascular complications. 1 The youngest reported patient with EDS4 and a CNS vascular finding was a 5 year old patient with multiple intracranial aneurysms.8 The recognition of EDS4 is crucial as these patients are at higher risk of complications from endovascular procedures commonly used in the diagnosis and treatment of CNS vascular disease. One study of EDS4 patients treated at Mayo clinic over a 30 year period noted that 3 out of 13 patients (23%) that underwent contrast arteriography developed serious complications.9 These included two patients who developed access site hematomas and one patient who had a carotid artery rupture during attempted endovascular repair of a carotid cavernous fistula. Other sources report 22-35% morbidity and up to 12% mortality associated with diagnostic angiographies.10 Recent reviews discuss that newer technology with smaller diameter catheters and wires which are less traumatic may reduce morbidity associated with these procedures. It is important that these procedures are performed in experienced centers due to the increased risk of complications.11, 12 Our patient had been undergoing evaluation for bilateral peroneal neuropathies at the time of presentation. Peripheral neuropathies including brachial and lumbosacral plexopathies have been reported with EDS, however neuropathies in EDS4 are mostly in association with aneurysm rupture and resultant compression due to compartment syndrome.13-15 Voermans et al performed a cross sectional study of patients with classic, vascular type, TNX deficient, and hypermobility type EDS to evaluate neuromuscular involvement in these entities.16 10 patients of each type were asked to complete questionnaires, and underwent physical exam, electromyography, and nerve conduction studies. While patients with classic and TNX deficient types of EDS were more likely to report neuromuscular symptoms, physical examination

6 revealed normal muscle strength in only 2/10 patients with EDS4. NCS were abnormal in 4 of 9 patients and EMG was abnormal in 8 of 9 patients. These authors suggest that abnormalities of the extracellular matrix such as procollagen III in both muscle and peripheral nerves plays a role in the pathophysiology of peripheral neuropathy when not associated with hyper extensibility or injury to a particular joint. To our knowledge, this is the first reported case of isolated peroneal motor neuropathy in patients with EDS4. Vascular lesions are responsible for the increased morbidity and mortality in patients with EDS4. Patients with EDS4 have been shown to have significantly decreased thickness of arterial wall intima and media and increased carotid circumferential wall stress compared to agematched controls.17 As such, the identification of a treatment to address these vascular risk factors is essential to reducing morbidity and mortality for these patients. The Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) study was a multicenter, prospective, randomized controlled trial to assess the utility of celiprolol in decreasing vascular complications such as dissection or rupture in patients with EDS4.18 Fifty-three patients without prior vascular complications between the ages of 15-65 years were randomized to receive either celiprolol or no treatment. This trial was stopped early due to treatment benefit in the intervention group. Twenty percent of patients treated with celiprolol experienced vascular complications compared to 50% of patients in the control group. These data support celiprolol as a viable option in the prevention of vascular complications for patients with EDS4.12, 18 Conclusion EDS4 is a form of Ehlers-Danlos that is associated with significant morbidity and mortality. Patients may first present to a neurologist’s attention due to vascular complications involving the CNS. EDS4 may also have more indolent neurologic complications which may be unrecognized when not associated with vascular findings. Prompt diagnosis can aid in rapid recognition of the potentially catastrophic complications and help delineate increased risks involved in surgical or endovascular procedures. Use of whole exome sequencing has proven quite useful in the identification of causative mutations in a patient with neurologic symptoms that do not fit a clear phenotype. However, as this case illustrates, exome sequencing must always be interpreted in the context of the evolving clinical picture of the patient.

7 References

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9 Figure Legends Figure 1:

Patient presented with pes equinus contractures (A) and lower extremity muscle atrophy (B).

Figure 2:

MRA of head and neck showing poor delineation of cavernous segment of left internal carotid artery with turbulence. Axial reconstruction (A) and sagittal reconstruction of left internal carotid (B). Note arterialized-appearing flow signal in the cavernous sinus.

Figure 3:

(A) Left carotid injection from conventional angiogram which confirms carotid cavernous fistula. Note contrast pools in fistula and there is poor visualization of MCA and ACA branches. (B) demonstrates left contrast injection post coil embolization.

10 Figure 1.

11 Figure 2.

12 Figure 3.