Hereditary Angiopathy With Nephropathy Aneurysm and Muscle Cramps (HANAC) Syndrome Presenting to Neuro-Ophthalmology With Metamorphopsia

Clinical Correspondence Hereditary Angiopathy With Nephropathy, Aneurysm, and Muscle Cramps (HANAC) Syndrome Presenting to NeuroOphthalmology With Metamorphopsia Michael A. Jordan, MD, Mary Ella Pierpont, MD, PhD, Richard H. Johnston, MD, Michael S. Lee, MD, Collin M. McClelland, MD H ereditary angiopathy with nephropathy, aneurysm, and muscle cramps (HANAC) syndrome is a rare autosomal dominant disorder of Type 4 collagen affecting the vasculature of multiple organ systems including the brain, skin, muscles, kidneys, and retina (1). HANAC syndrome was first described in 2007 in a report of 3 families with varying manifestations attributable to 3 distinct genetic mutations in exons 24 and 25 of the collagen Type IV alpha 1 chain (COL4A1) gene (1). Although the literature on this syndrome is limited to small series in the general medical and neurology literature and 1 case report in a French ophthalmology journal, HANAC syndrome may present with a variety of neuro-ophthalmic sequelae including retinal arteriolar tortuosity and fragility predisposing to spontaneous intra-retinal hemorrhage, intracranial aneurysms, prominent microvascular T2 hyperintensities in the white matter on MRI, and early-onset hemorrhagic or ischemic cerebral stroke (1–3). We report a patient with HANAC syndrome associated with a COL4A1 gene variant who presented with persistent metamorphopsia after resolution of spontaneous macular hemorrhages. CASE REPORT A 58-year-old woman presented with a complaint of fixation splitting and central metamorphopsia in her right eye for the past 4 years after visual recovery from an acute macular hemorrhage. She recalled numerous previous episodes of spontaneous retinal hemorrhage beginning at age 13 years that caused paracentral or central scotomas before completely recovering over months. She was followed at a university ophthalmology practice from ages 13– Department of Ophthalmology and Visual Neurosciences (MAJ, MEP, RHJ, MSL, CMM), University of Minnesota School of Medicine, Minneapolis, Minnesota; Division of Genetics and Metabolism (MEP), Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota; and Edina Retina Consultants, PA (RHJ), Edina, Minnesota. The authors report no conflicts of interest. Address correspondence to Collin McClelland, MD, Department of Ophthalmology and Visual Neurosciences, University of Minnesota School of Medicine, Minneapolis, MN 55455; E-mail: [e-mail] 506 26 years with an ill-defined diagnosis of “autosomal dominant retinal tortuosity” with recurrent spontaneous hemorrhages. Four years before her presentation at our institution, she saw a retina provider for acute painless vision loss and was noted to have telangiectatic retinal vessels and numerous macular hemorrhages in the right eye. There were similarappearing vessels with a mild hemorrhage in the left eye (Fig. 1). Fluorescein angiography at that time revealed no leakage from her tortuous retinal vessels. Over 6 weeks, her hemorrhages and vision loss in the right eye dramatically improved, although she had permanent metamorphopsia. The patient’s medical history included a prior cardiac arrest for which she received implantation of a cardioverter– defibrillator, a renal cyst without renal dysfunction, and 2 asymptomatic cerebral aneurysms found incidentally on work-up of a remote transient ischemic attack. She denied family history of consanguinity. Her family history was remarkable for retinal arteriolar tortuosity, severe diffuse muscle cramps, and polycystic kidney disease in her 48year-old brother. Her mother had lifelong muscle cramps, suffered a myocardial infarction at age 37, and died at age 57 of an unknown heart problem. It was not known whether the patient’s mother had been diagnosed polycystic kidney disease or retinal arteriolar tortuosity. The patient had 5 children; 3 underwent normal neuro-ophthalmic examinations by our team with no history or symptoms of HANAC syndrome. Two sons were unavailable for examination, including one 38-year-old known to have lifelong muscle cramps and retinal arteriolar tortuosity. Visual acuities were 20/30 in the right eye and 20/20 in the left eye with correction. The patient identified 11/11 Ishihara color plates in both eyes. Extraocular motility, alignment, slit lamp examination, and pupils were unremarkable. Funduscopic examination was significant for extreme tortuosity of the distal branch arterioles, most prominent in the maculas of both eyes (Fig. 2). Spectral-domain optical coherence tomography of the right eye demonstrated a small subfoveal intraretinal cyst corresponding to the location of the patient’s metamorphopsia (Fig. 3). Review of an MRI of the brain with and without intravenous contrast (performed for vertigo 4 Jordan et al: J Neuro-Ophthalmol 2019; 39: 506-510 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Color fundus photos of both eyes at the time of acute vision loss, 4 years before neuro-ophthalmology evaluation. These demonstrate branch retinal arteriolar tortuosity with looping and numerous scattered intraretinal macular hemorrhages in the right eye. The left fundus shows identical vascular tortuosity with a single asymptomatic inferonasal macular hemorrhage (arrow). months before) revealed prominent nonenhancing T2 hyperintensities in the subcortical, periventricular, and deep white matter regions, consistent with extensive microvascular disease (Fig. 4). A recent magnetic resonance angiogram of the brain and computed tomographic angiogram of the brain (Fig. 5) showed a stable 5-mm saccular aneurysm at the cavernous–supraclinoid junction of the internal carotid artery and a 2-mm internal carotid artery aneurysm at the origin of the left ophthalmic artery. The patient was referred to the genetics clinic for consideration of HANAC syndrome testing. A novel heterozygous variant of probable clinical significance was detected in exon 24 of the COL4A1 gene resulting in an aspartate substitution for glycine. In combination with the patient’s other unique symptoms and findings fitting the classic features of HANAC syndrome, the genetic variant provided additional evidence to support the clinical diagnosis. and cystic nephropathy in most cases (1). Renal disease can manifest as gross hematuria with or without normal renal function or an asymptomatic decreased glomerular filtration rate. Other variably associated features include cardiac arrhythmias and Raynaud phenomena (1). Findings of retinal arteriolar tortuosity similar to our patient are universally present in HANAC syndrome and often lead to recurrent, symptomatic, spontaneous hemorrhages (1). The severely tortuous morphology of distal branch retinal arterioles forming loops with relative sparing of the arcade arterioles is highly characteristic of HANAC. These changes are distinct from the far less prominent arteriolar tortuosity seen in the family of TREX-1–associated cerebroretinal vasculopathy (CRV) disorders which classically demonstrate progressive findings of retinal ischemia not seen in HANAC syndrome, including cotton wool spots, microaneurysms, and perifoveal capillary nonperfusion (4). DISCUSSION Reported as a novel syndrome only 12 years ago, our understanding of HANAC syndrome continues to evolve. Affected individuals typically become symptomatic by middle age (40–60 years), and central nervous system radiographic findings are present in virtually all by age 40 years (2). Cerebrovasculopathic features of HANAC syndrome include early onset of T2 white matter hyperintensities on MRI with a particular predilection for the periventricular, deep, and subcortical white matter regions, ischemic or hemorrhagic stroke, and internal carotid artery aneurysms (2). Similar to our patient, HANAC syndrome–associated intracranial aneurysms typically form along both the intradural and extradural segments of the internal carotid siphon. Although long-term follow-up data are limited, the literature suggests that there is a lower risk of aneurysm rupture associated with COL4A1 mutations and HANAC syndrome (2). The phenotype of HANAC syndrome also includes elevated creatine kinase levels, prominent muscle cramps, Jordan et al: J Neuro-Ophthalmol 2019; 39: 506-510 FIG. 2. Color fundus photograph of the right eye 4 years after the most recent macular hemorrhage; this shows complete resolution of hemorrhages and stable retinal vessel tortuosity. 507 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 3. Spectral-domain optical coherence tomography scan through the fovea of the right eye demonstrating a small subfoveal region of decreased signal and contour irregularity (arrow) bordered by 2 spots of increased signal that potentially correspond to the patient’s symptom of metamorphopsia. In the initial study describing HANAC syndrome, 3 families were found to have missense mutations in either exon 24 or 25 of the COL4A1 gene (1). One family was found to have a c.1493-.T in exon 24 responsible for a glycine-to-valine substitution. The second had a c.1555G-.A missense mutation in exon 24 causing a glycine-to-arginine substitution. Finally, the third had a c.1583G-.A mutation in exon 25 resulting in the substitution of glutamic acid for glycine (1). Similarly, our patient harbored a novel c.1502G-.A variant in exon 24 of the COL4A1 gene resulting in an aspartate substitution for glycine. Computer modeling and the striking similarities FIG. 4. Axial T2 FLAIR sequence MRI demonstrating numerous T2 hyperintensities in the periventricular and deep white matter regions. These did not enhance on postcontrast T1 images. 508 of our patient’s missense variant to those described in the literature strongly suggest pathogenicity. In addition to HANAC syndrome, there are a few other well-described hereditary systemic vasculopathy syndromes with ocular and cerebral sequelae, including cerebroretinal vasculopathy; hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS); hereditary vascular retinopathy (HVR), and cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy (CADASIL). The clinical characteristics of these syndromes are summarized in Table 1. Originally described in the literature as unique syndromes, CRV, HERNS, and HVR have since been reclassified as varying phenotypes along the spectrum of a single genetic disease termed retinal vasculopathy with cerebral leukodystrophy (5). Linkage analysis has identified a single locus on chromosome 3p21.1-p21.3 for CRV, HERNS, and HVR, supporting this notion (6). Subsequently, mutations in the TREX1 gene encoding a DNA exonuclease were found to be the cause for retinal vasculopathy with cerebral leukodystrophy (5). In a study by Stam et al, 84% of TREX1 mutation carriers were found to have vascular retinopathy, with manifestations of brain disease present in 81 percent of carriers. Brain sequelae included focal neurological deficits (56%), migraine (53%), cognitive impairment (47%), psychiatric disturbances (39%), and seizures (14%) (7). The most common neuroradiologic findings present were punctate hyperintense white matter lesions with or without nodular enhancement; these were present in 92% of mutation carriers. The systemic features most commonly present were liver disease, anemia, nephropathy, hypertension, Raynaud’s phenomenon, and gastrointestinal bleeding. CADASIL is a monogenic cause of cerebral small vessel disease as the result of a mutation in the NOTCH3 gene located on 19p13.2-13.1. The typical clinical FIG. 5. Brain CT angiography with contrast demonstrates a 5-mm saccular aneurysm (arrow) at the junction of the right cavernous and supraclinoid segments of the internal carotid artery. Not visualized here is a 2-mm internal carotid aneurysm at the origin of the left ophthalmic artery. Jordan et al: J Neuro-Ophthalmol 2019; 39: 506-510 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence TABLE 1. Clinical characteristics of cerebroretinal vasculopathies Syndrome HANAC RVCL (Encompasses CRV, HERNS, and HVR) CADASIL Gene mutation COL4A1 TREX1 NOTCH3 Inheritance Autosomal dominant Autosomal dominant Autosomal dominant pattern Most common Intracranial aneurysms Focal neurologic deficit Migraine with aura neurologic manifestation Systemic Muscle cramps and nephropathy Liver disease and nephropathy None manifestations Retinal ischemia: microaneurysms, Retinal ischemia (variable-39%): Retinopathy Severe (full loops) branch Cotton wool spots, nerve fiber cotton wool spots, telangiectasias, arteriolar tortuosity and layer defects, mild tortuosity capillary nonperfusion, and spontaneous macular neovascularization of the retina hemorrhages CADASIL, cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy; CRV, cerebroretinal vasculopathy; HANAC, hereditary angiopathy with nephropathy, aneurysm, and muscle cramps; HERNS, hereditary endotheliopathy with retinopathy, neuropathy, and stroke; HVR, hereditary vascular retinopathy; RVCL, retinal vasculopathy with cerebral leukodystrophy. manifestations of CADASIL include migraine with aura, recurrent subcortical ischemic events, mood disturbances, progressive cognitive impairment primarily affecting executive function, and seizures (8). Symptoms vary among affected individuals, and the sequelae of CADASIL are relatively nonspecific and common; this can make early diagnosis challenging. A typical clinical presentation includes progressive small subcortical strokes and cognitive impairment in a middle-aged patient with a family history of early stroke and/or dementia. One study of 18 CADASIL patients who underwent a detailed ophthalmic examination and fluorescein angiogram found retinopathy in 39%; these findings included nerve fiber layer defects (22%), cotton wool spots (17%), and tortuous arteries (5.5%) (9). The combination of profound retinal arterial tortuosity with recurrent spontaneous hemorrhages and severe, lifelong, body cramps is virtually pathognomonic for HANAC syndrome. This constellation of signs and symptoms suggests to the neuro-ophthalmologist a diagnosis of HANAC. Additional HANAC sequelae, including intracranial aneurysms and prominent microvascular white matter changes, may also bring affected individuals to the attention of the neuro-ophthalmologist. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. A. Jordan, M. S. Lee, and C. M. McClelland; b. Acquisition of data: M. A. Jordan, M. E. Pierpont, R. H. Johnston, and C. M. McClelland; c. Analysis and interpretation of data: M. A. Jordan, M. E. Pierpont, R. H. Johnston, and C. M. McClelland. Category 2: a. Drafting the manuscript: M. A. Jordan and C. M. McClelland; b. Revising it for intellectual content: M. A. Jordan, M. E. Pierpont, R. H. Johnston, M. S. Lee, and C. M. McClelland. Category 3: a. Final approval of the completed manuscript: M. A. Jordan, M. E. Pierpont, R. H. Johnston, M. S. Lee, and C. M. McClelland. Jordan et al: J Neuro-Ophthalmol 2019; 39: 506-510 REFERENCES 1. 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