ABCC6 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: multidrug resistance-associated protein 6
  • Transmembrane transporter, although identity of transported substrates not yet fully understood
Clinical phenotype
(OMIM phenotype no.)
  • Pseudoxanthoma elasticum, PXE (#264800)
  • Pseudoxanthoma elasticum, forme fruste (#177850)
  • Generalized arterial calcification of infancy-2, GACI (#614473)
Inheritance
  • Autosomal recessive
Signs for PXE
  • Peau d’orange changes particularly in the temporal macula
  • Angioid streaks
  • Choroidal neovascularization
  • Comet lesions
Signs for GACI
  • Calcification and stenosis of muscular arteries
  • Usually fatal within first 6 months of life due to refractory heart failure
Visual functionPXE
  • Best corrected visual acuity ≤ 20/50 in 73% of patients over age of 52
  • Angioid streaks present between age 15 to 25 in almost all patients
  • Retinal hemorrhage common after age 40
Systemic featuresPXE
  • Typical onset in childhood or adolescence with cutaneous changes
  • Characteristic small yellow papules on the neck and flexural areas which coalesce into plaques over time (cobblestone appearance of the skin); skin loosening in advanced stages
  • Elevated risk of vascular disease (peripheral vascular disease, aneurysms, TIA/stroke, artery stenosis)
  • Gastrointestinal/urinary tract haemorrhage (15% of cases)
Key investigations
  • OCT: Breaks in Bruch’s membrane can be observed along with sub-retinal haemorrhage if CNV is present
  • Near-infrared reflectance imaging is superior to FAF and FA in detecting angiod streaks and peau d’orage changes
  • Systemic assessment with a paediatrician and other relevant specialists
Molecular diagnosisSkin biopsy
  • Positive von Kossa staining showing calcification and fracture of elastic fibers in biopsy material from affected skin
Next generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
ManagementOcular
  • Routine eye examinations
  • Anti-VEGF injections for choroidal neovascularization
Systemic
  • Multidisciplinary approach
Therapies under research
  • None at present
Further information

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Additional information

  • Majority of patients with heterozygous mutations present with limited manifestations of the PXE phenotype
  • In rare cases, heterozygous mutations result in the full PXE phenotype in two successive generations due to pseudodominance. This specific phenotype is known as PXE, forme fruste (#177850)
  • It has been suggested that GACI and PXE represent two ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than two distinct disorders

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References

  1.  Orssaud C, Roche O, Dufier J-L, Germain DP. Visual Impairment in Pseudoxanthoma Elasticum: A Survey of 40 Patients. Ophthalmic Genetics. 2015;36(4):327–32
  2.  Roach ES, Islam MP. Pseudoxanthoma elasticum. Handb Clin Neurol. 2015;132:215‐221
  3.  Finger RP, Charbel Issa P, Ladewig MS, et al. Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches. Surv Ophthalmol. 2009;54(2):272‐285
  4.  Nitschke Y, Baujat G, Botschen U, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012;90(1):25‐39
  5.  Charbel Issa P, Finger RP, Holz FG, Scholl HP. Multimodal imaging including spectral domain OCT and confocal near infrared reflectance for characterization of outer retinal pathology in pseudoxanthoma elasticum. Invest Ophthalmol Vis Sci. 2009;50(12):5913‐5918

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Updated on November 30, 2020
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