Hereditary Angiopathy with Nephropathy, Aneurysms, and Muscle Cramps (HANAC) Syndrome
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Disease Entity
Introduction
Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) Syndrome is a rare systemic phenotype caused by COL4A1 mutations, leading to significant impacts on renal, muscular, vascular, and ocular function. It was first extensively characterized by Plaisier et al. originally in 1993, and again in early 2000s, through linkage analysis among three French families exhibiting features distinct from other COL4A1-related diseases.[1] Bilateral retinal arteriolar tortuosity is considered a characteristic finding of the syndrome and may lead to transient vision changes.[1] [2] [3]
Pathophysiology
HANAC is an autosomal dominant condition caused by COL4A1 mutations, which encode for the alpha-1 chain of type IV collagen. Alpha-1 chains are one of the three major networks of type IV collagen that constitute basement membranes that are ubiquitous throughout the body.[4] In contrast to other COL4A1-related disorders, HANAC mutations specifically impact glycine residues in exons 24 and 25 localized to the CB3[IV] domain, which are critical for integrin binding and mediate interactions between cells and the basement membrane.[5] Mutations in the glycine region of the collagenous portion of the triple helix disrupt protein folding and function, underlying the systemic effects seen in HANAC.[5]
Diagnosis
HANAC presents most often with spontaneous, unprovoked muscle cramps beginning in early childhood, typically lasting several minutes and causing discomfort for the following one to two days.[6] Hematuria is typically microscopic but can rarely present with gross findings.[2] Raynaud phenomenon and headaches have been closely associated among some HANAC patients.[2] Patients may report a history of palpitations and tachycardia as supraventricular arrhythmias have also been associated with the syndrome.[5][7]
Ophthalmic Presentation
Among previously studied families, 100% of individuals exhibited bilateral retinal arteriolar tortuosity.[2] Tortuosity of the retinal vessels has been described as affecting distal retinal arterioles while sparing the central arcades.[3] Recurrent retinal hemorrhages due to the fragility of tortuous vessels may result in transient vision loss with excellent visual progress.[1][2][3] Optical Coherence Tomography -Angiography in HANAC may show tortuosity localized to the superficial retinal plexus.[7] Cataracts and Axenfeld-Rieger anomalies have also been previously associated with COL4A1 mutations though not specifically reported among those with HANAC.[8]
Diagnostic Procedures
Diagnosis of HANAC is confirmed by genetic testing for COL4A1 mutations, which can be completed through single gene sequencing or with multigene studies that include other genes of interest. Providers should evaluate for a history of muscle cramps, spontaneous vision loss, retinal hemorrhages, nephropathy, cardiac arrhythmias, cerebral aneurysms, and known white matter changes on MRI. A thorough family history is critical as the disease is inherited in an autosomal dominant pattern and thus, a similar systemic phenotype will typically be observed throughout a family tree, although up to 27% of COL4A1 mutations may be sporadic.[9]
Further work-up should evaluate for further signs and sequelae from the syndrome. Creatine kinase is typically elevated among those with HANAC and may be the first diagnostic clue in a patient initially presenting with muscle cramps.[10] Brain MRI in HANAC often shows leukoencephalopathy in periventricular, subcortical, and pontine distributions and may show evidence of previous lacunar infarcts and dilated perivascular spaces.[11] Small vessel disease in the brain in HANAC rarely presents with symptoms and has a lower risk of intracranial hemorrhage when compared with other COL4A1 disorders like familiar porencephaly.[11] Intracranial aneurysms in HANAC predominantly affect the internal carotid artery at level of the carotid siphon, a tortuous segment of the artery that marks its bifurcation into the middle cerebral artery and anterior cerebral artery.[11][12] Metabolic panels may show decreased GFR with elevated creatinine and urinalysis with microscopic reflex should be used to screen for hematuria.[1] Renal ultrasounds are warranted to evaluate for the presence of renal cysts.[1] ECGs and/or Holter monitors are indicated as supraventricular arrhythmias have also been reported.[1][7]
Differential Diagnosis
•Ehlers-Danlos Syndromes (EDS)
•Familial Retinal Arteriolar Tortuosity (FRAT)
•Sickle Cell Retinopathy
•Retinal Vasculopathy with Cerebral Leukodystrophy (includes CRV, HERNS, and HVR)
•Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
•Hereditary Infantile Hemiparesis, Retinal Arteriolar Tortuosity, and Leukoencephalopathy
•Loeys-Dietz Syndrome
•Fabry Disease
Management
Treatment
Like other COL4A1-related disorders, no cure currently exists for HANAC and treatment is focused on symptomatic management as well as prevention of complications from the syndrome, such as nephropathy, cardiac arrhythmias, and cerebral aneurysms.[9]
Prognosis
Prognosis for HANAC has yet to be formally described. Among patients with COL4A1 disorders, the prognosis is widely variable depending on the mutation, phenotype, and the level of systemic and cerebral involvement.[9][13][14]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Plaisier E, Gribouval O, Alamowitch S, et al. COL4A1 Mutations and Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps. N Engl J Med. 2007;357(26):2687–2695. doi:10.1056/NEJMoa071906
- ↑ 2.0 2.1 2.2 2.3 2.4 Plaisier E, Alamowitch S, Gribouval O, et al. Autosomal-dominant familial hematuria with retinal arteriolar tortuosity and contractures: A novel syndrome. Kidney Int. 2005;67(6):2354–2360. doi:10.1111/j.1523-1755.2005.00341.x
- ↑ 3.0 3.1 3.2 Jordan MA, Pierpont ME, Johnston RH, Lee MS, McClelland CM. Hereditary Angiopathy With Nephropathy, Aneurysm, and Muscle Cramps (HANAC) Syndrome Presenting to Neuro-Ophthalmology With Metamorphopsia. Journal of neuro-ophthalmology. 2019;39(4):506–510. doi:10.1097/WNO.0000000000000812
- ↑ Chen Z, Migeon T, Verpont M, et al. HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease. Journal of the American Society of Nephrology. 2016;27(4):1042–1054. doi:10.1681/ASN.2014121217
- ↑ 5.0 5.1 5.2 Plaisier E, Chen Z, Gekeler F, et al. Novel COL4A1 mutations associated with HANAC syndrome: A role for the triple helical CB3[IV] domain. American journal of medical genetics.Part A. 2010;152A(10):2550–2555. doi:10.1002/ajmg.a.33659
- ↑ Haga S, Takeguchi R, Tanaka R, et al. Clinical characteristics of muscle cramps in hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome associated with a novel COL4A1 pathogenic variant: A family case study. Brain & development (Tokyo.1979). 2023;45(7):390–394. doi:10.1016/j.braindev.2023.02.008
- ↑ 7.0 7.1 7.2 FerreiraFelipe de QT, Nascimento de QueirozMarjorie Fd, Ayres da FonsecaAndré Luis, Holanda de FreitasAna CL, NascimentoMaurício Abujamra. Atypical Macular Presentation in a FRAT Case and HANAC Syndrome, A Case Report. The Open Ophthalmology Journal. ;15. doi:10.2174/1874364102115010246
- ↑ Coupry I, Sibon I, Mortemousque B, Rouanet F, Mine M, Goizet C. Ophthalmological Features Associated With COL4A1 Mutations. Archives of ophthalmology (1960). 2010;128(4):483–489. doi:10.1001/archophthalmol.2010.42
- ↑ 9.0 9.1 9.2 Meuwissen MEC, Halley DJJ, Smit LS, et al. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med. 2015;17(11):843–853. doi:10.1038/gim.2014.210
- ↑ Tonduti D, Pichiecchio A, La Piana R, et al. COL4A1-Related Disease: Raised Creatine Kinase and Cerebral Calcification as Useful Pointers. Neuropediatrics. 2012;43(5):283–288. doi:10.1055/s-0032-1325116
- ↑ 11.0 11.1 11.2 ALAMOWITCH S, PLAISIER E, FAVROLE P, et al. Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome. Neurology. 2009;73(22):1873–1882. doi:10.1212/WNL.0b013e3181c3fd12
- ↑ Bogunović H, Pozo JM, Cárdenes R, et al. Automated landmarking and geometric characterization of the carotid siphon. Med Image Anal. 2012;16(4):889–903. doi:10.1016/j.media.2012.01.006
- ↑ Zagaglia S, Selch C, Nisevic JR, et al. Neurologic phenotypes associated with COL4A1/2 mutations. Neurology. 2018;91(22):e2078–e2088. doi:10.1212/WNL.0000000000006567
- ↑ Weng Y, Sonni A, Labelle-Dumais C, et al. COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage. Ann Neurol. 2012;71(4):470–477. doi:10.1002/ana.22682
