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| ANGIOPATHY, HEREDITARY, WITH NEPHROPATHY, ANEURYSMS, AND MUSCLE CRAMPS; HANAC | ||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that this disorder is caused by missense mutations in the COL4A1 gene (120130). | ||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||
| Plaisier et al. (2005) described a 4-generation French Caucasian family presenting with autosomal dominant hematuria associated with extrarenal manifestations. All affected patients presented with association of renal involvement, retinal arterial tortuosities, and muscular contractures. Retinal arterial tortuosities were present bilaterally; affected family members also experienced episodes of superficial intraretinal hemorrhages with transient visual impairment which resolved spontaneously, without visual sequelae. Muscle contractures were painful and paroxysmal, lasting from a few seconds to minutes, and occasionally to a few hours. Three patients suffered from recurrent headaches, and one presented with a generalized seizure. Gekeler et al. (2006) reported a father and 2 daughters with retinal arterial tortuosity associated with tortuosity of nail bed capillaries. Only second- and third-order arteries were affected, whereas first-order arteries and the venous system were normal. Symptomatic retinal hemorrhage occasionally followed minor stress or trauma, but no leakage was seen on fluorescein angiography, and all 3 patients had good visual acuity. One of the daughters had an episode of transient microhematuria of unknown origin, and the father had a stroke with speech disturbances 8 years earlier but reported no residual adverse effects. No associated systemic disease was found in any of the 3 patients. Gekeler et al. (2006) noted that the high degree of tortuosity of capillaries observed on nailfold capillaroscopy indicated systemic vascular pathology, but stated that the syndrome in these patients was distinct from that described by Plaisier et al. (2005). Plaisier et al. (2007) characterized the renal and extrarenal phenotypes of subjects from 3 families with autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps, including the one previously described by them (Plaisier et al., 2005). Plaisier et al. (2007) proposed the acronym HANAC for this syndrome. The clinical renal manifestations of the HANAC syndrome in these families included hematuria and bilateral large cysts. Histologic analysis revealed complex basement membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appeared to affect both small vessels and large arteries. Muscle cramps occurred in 2 of the 3 families and affected members of all 3 showed elevated creatine kinase levels. Retinal arteriolar tortuosity leading to repeated retinal hemorrhages was a frequent finding. Microscopic hematuria occurred in most affected individuals and gross hematuria in some. Supraventricular cardiac arrhythmia and Raynaud phenomenon were also observed. Changes of leukoencephalopathy were found frequently on brain scans. Among 14 patients from 3 families with HANAC, Alamowitch et al. (2009) found that only 2 had clinical cerebrovascular symptoms: a minor ischemic stroke at age 47 years and a small posttraumatic hemorrhage under anticoagulants at age 48 years. However, 8 of 9 adult patients studied using brain MRI and magnetic resonance angiography (MRA) were found to have cerebrovascular lesions, including 5 with intracranial aneurysms of the carotid siphon, and 7 with cerebral small vessel disease characterized by deep white matter changes (7 of 7), dilated perivascular spaces (5 of 7), and lacunar infarcts (4 of 7). None had hemiplegia, major stroke, or porencephaly. Skin biopsies of 3 patients showed alterations of basement membranes at the dermoepidermal junction associated with expansion of extracellular matrix between smooth vascular cells in the arteriolar wall, indicating a systemic vasculopathy. These imaging findings indicated that the cerebrovascular phenotype in HANAC includes both small vessel disease and large vessel disease, but with a low incidence of hemorrhagic stroke compared to other COL4A1-related disorders, such as brain small vessel disease (607595) and familial porencephaly (175780). | ||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||
| Plaisier et al. (2007) performed linkage analysis in the original family described by them with HANAC, which showed that all affected subjects shared a common haplotype at the COL4A1-COL4A2 locus (120130, 120090). Sequence analysis of COL4A1 cDNA from skin-fibroblast specimens from the subjects demonstrated a missense mutation in each of the 3 families converting glycine to another amino acid in exon 24 or exon 25 of the COL4A1 gene (120130.0007, 120130.0008, 120130.0009). A suggestion by Plaisier et al. (2007) that the phenotype of the HANAC syndrome may be caused by dominant-negative effects of the mutations was supported by findings from several animal models (Gould et al., 2005; Gould et al., 2007). In affected members of 3 families exhibiting key features of HANAC, 1 of which was previously reported by Gekeler et al. (2006), Plaisier et al. (2010) identified 3 different heterozygous missense mutations in the COL4A1 gene (120130.0012-120130.0014). Plaisier et al. (2010) stated that age of examination could account for the partial penetrance or variable severity of several symptoms, and concluded that these results confirmed HANAC as a distinct clinical entity among the COL4A1-related disorders. Van Agtmael et al. (2010) showed that animals with a Col4a1 missense mutation (Col4a1+/Raw) display focal detachment of the endothelium from the media and age-dependent defects in vascular function including a reduced response to norepinephrine. Age-dependent hypersensitivity to acetylcholine was abolished by inhibition of nitric oxide synthase (NOS) activity, indicating that Col4a1 mutations affected vasorelaxation mediated by endothelium-derived nitric oxide. These defects were associated with a reduction in basal NOS activity and the development of heightened nitric oxide sensitivity of the smooth muscle. The vascular function defects were physiologically relevant as they maintained, in part, the hypotension in mutant animals, which was primarily associated with a reduced red blood cell volume due to a reduction in red blood cell number, rather than defects in kidney function. The deposition of collagen type IV in the basement membrane was defective, and the mutation was found to lead to activation of the unfolded protein response. | ||||||||||||||||||||||||
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