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Generalized arterial calcification of infancy

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Generalized arterial calcification of infancy
Other namesIdiopathic infantile arterial calcification (IIAC), arterial calcification of infancy, idiopathic arterial calcification of infancy (IACI), occlusive infantile arterial calcification, occlusive infantile arteriopathy[1]
SpecialtyMedical genetics

Generalized arterial calcification of infancy (GACI) is an extremely rare[2] genetic disorder. It is caused by mutations in the ENPP1 gene in 75% of the subjects[3] or in mutations in the ABCC6 genes in 10% of patients.[4] However, sometimes individuals affected with GACI do not have mutations in the ENPP1 or ABCC6 gene and in those cases the cause of the disorder is unknown.[4]

The condition usually affects infants during the first 6 months of life. This condition is inherited as an autosomal recessive pattern. It is characterized by generalized calcification of the arterial internal elastic lamina, leading to rupture of the lamina and occlusive changes in the tunica intima with stenosis and decreased elasticity of the vessel wall.[5] Unfortunately, many infants die of vaso-occlusive disease, especially of the coronary arteries.[6]

Types

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There are 2 forms of GACI that can be indicated on a genetic test:

GACI Type 1 is caused by mutations in the ENPP1 gene. It is called ENPP1 Deficiency. Patients with the ENPP1 Deficiency are at risk of developing Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2).  ARHR2 can cause weakening in the bones, pain in bones and joints bone deformities (knocked knees, bowed legs), dental problems, calcification of ligaments and short stature. With proper treatment the bones can be strengthened and side effects minimized.[7][8][9]

GACI Type 2 is caused by mutations in the ABCC6 gene. It is called ABCC6 Deficiency. As children affected by GACI due to ABCC6 Deficiency get older, they can develop characteristics similar to pseudoxanthoma elasticum (PXE). This condition affects the elastic tissue of the skin, the eye, cardiovascular and gastrointestinal systems.[7][8][9]

Signs and symptoms

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Clinical presentation is variable. First symptoms usually occur at birth but can take place in the first 6 months of life or in utero.[2]

Clinical Signs for GACI can include:

Cause

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GACI is inherited in an autosomal recessive pattern.

The condition results from an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1 gene) or the ATP-binding C member 6 (ABBC6 gene), leading to decreased inorganic pyrophosphate (PPi).[7] This is a potent inhibitor of calcium deposition in the vessel wall. These mutations allow for unregulated calcium deposition within muscular arteries. The symptoms are caused by calcification of large and medium-sized arteries, including the aorta, coronary arteries, and renal arteries.[citation needed]

Recently, homozygous or compound heterozygous mutations for ENPP1 gene were reported as causative for the disorder. ENPP1 regulates extracellular inorganic pyrophosphate (PPi), a major inhibitor of extracellular matrix calcification.[16]

The critical period for babies affected by GACI is during the first 6 months after birth. This is due to calcium continuing to build up in the artery walls. If blood flow becomes restricted it can become life threatening.[7]

GACI affects males and females equally and occurs in populations all across the world. It is estimated to occur in approximately 1 out of every 391,000 births with the carrier rate being 1:312. Survival statistics vary greatly.[7]

Diagnosis

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Generalized arterial calcification of infancy should always be considered in infants and children presenting with hypertension, cardiac failure, or sudden death.[17] Plain radiography,[18] sonography[19] and MRI[20] can aid in the diagnosis. Postnatal gray-scale and color Doppler echocardiographic and sonographic examinations allowed noninvasive diagnosis, assessment of severity, and monitoring of progression.[21] Contrast-enhanced MR angiography with breath-hold and cardiac gating techniques can allow evaluation of the extent of the disease.[22]

Prevention

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  • Potential role of genetic markers in the identification of persons at risk.[30] There is a 75% probability to identify the two ENPP1 mutations or 10% with ABCC6 mutations (one paternal, one maternal) that cause GACI.[4] Once the mutations are identified, preimplantation genetic diagnosis (PGD) or chorionic villus sampling (CVS) are possible options to identify the condition, either before or during pregnancy.
  • At week 20 of gestation, it is possible to detect an Echogenic intracardiac focus (EIF)[31] or intravascular calcifications, particularly in the iliac and [abdominal aorta]. EIF is a small bright spot seen in the baby's heart on an ultrasound exam. This is thought to represent mineralization, or small deposits of calcium hydroxyapatite,[32] in the muscle of the heart. EIFs are found in about 3-5% of normal pregnancies and cause no health problems.[citation needed]
  • Ultrasound can show subtle intravascular calcifications, particularly in the abdominal aorta at week 23.[33]
  • Calcification has been detected at 33 weeks' gestation.[34]
  • The earliest detected manifestation (echogenic foci in the mitral valve Hepatic vascular) of the disease was prenatally at 14 weeks gestation.[7]

Treatment

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  • Currently, there is no curative treatment for GACI. However, in recent years, better medical treatment has led to increased survival rates.[7]
  • Use of bisphosphonates appears to significantly increase survival. Etidronate, a non-nitrogen-containing bisphosphonate, is the most commonly used based on its potent antimineralization effect.[7]
  • Prenatal[35] and postnatal treatment with low-dose, cyclical bisphosphonates, also called diphosphonate, resulted in a complete resolution of vascular calcifications in some cases using disodium pamidronate and risedronate.[36][37][38][39][40]
  • Sodium Thiosulfate (STS) is a calcium-chelating agent. It is typically used by patients who have excess calcium in their arteries due to kidney disease. In recent years, STS has also been used to treat patients with GACI.Proposed mechanism of STS action includes  chelation or increased solubility of over mineralized calcium in arteries to be removed from the body. STS is typically administered intravenously through a central line in the chest. The dosage amount and length of time for STS treatment is determined by the patient's medical team.[7]
  • PGE1 infusion is a possible therapeutic alternative for babies with idiopathic arterial calcification complicated by severe hypertension refractory to conventional treatment.[41]
  • Infants must reach a certain weight to allow for a transplant, commonly not reached.[42] There is minimal information available about heart transplants in patients with GACI. There is some clinical evidence that heart transplants can be successful, without recurrence of calcifications. Heart transplant for individuals with GACI has occurred in at least 3 known cases. In 2014, there was a follow up report about a 4 year old child with GACI who had a successful heart transplant.[43]

Prognosis

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  • Survival to adulthood has been reported,[44][45] sometimes with persistent hypertension and cardiovascular sequelae.
  • Spontaneous regression of arterial calcifications can occur, and antihypertensive treatment can be tapered off gradually. In some patients, the natural course of GACI may be more favourable than previously assumed.[46][47]
  • Despite the same genotype and similar sonographic and radiographic features in early infancy, the phenotype of GACI can vary to a great extent within one family.[48]

Research

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In 2015, Demetrios Braddock, MD, PhD, a pathologist and professor from Yale University along with his team published an article in Nature Communications.[49] Their research revealed when mice with GACI were given a replacement version of the enzyme, it helped to reduce the calcifications and prevented the animals from dying.[49][50][51] This discovery has led to the development of Inozyme Pharma[51][9] a biotechnology company developing new medicines to treat rare disorders of calcification including GACI.[52]

See also

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References

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  1. ^ Witzleben, C.L (1970). "Idiopathic infantile arterial calcification—A misnomer?". The American Journal of Cardiology. 26 (3): 305–9. doi:10.1016/0002-9149(70)90798-8. PMID 4196111.
  2. ^ a b Chong, Curtis R.; Hutchins, Grover M. (2008). "Idiopathic Infantile Arterial Calcification: The Spectrum of Clinical Presentations". Pediatric and Developmental Pathology. 11 (5): 405–15. doi:10.2350/07-06-0297.1. PMID 17990935. S2CID 9031166.
  3. ^ Rutsch, Frank; Ruf, Nico; Vaingankar, Sucheta; Toliat, Mohammad R.; Suk, Anita; Höhne, Wolfgang; Schauer, Galen; Lehmann, Mandy; et al. (2003). "Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification". Nature Genetics. 34 (4): 379–81. doi:10.1038/ng1221. PMID 12881724. S2CID 12784972.
  4. ^ a b c "Generalized arterial calcification of infancy". Genetic Home Reference-US National Library of Medicine.
  5. ^ Greenberg, S. Bruce; Gibson, James (2005). "New Findings in Idiopathic Arterial Calcification of Infancy Detected by MDCT". American Journal of Roentgenology. 185 (2): 530–2. doi:10.2214/ajr.185.2.01850530. PMID 16037532.
  6. ^ Rutsch, Frank; Boyer, Petra; Nitschke, Yvonne; Ruf, Nico; Lorenz-Depierieux, Bettina; Wittkampf, Tanja; Weissen-Plenz, Gabriele; Fischer, Rudolf-Josef; et al. (2008). "Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated with Survival Beyond Infancy in Generalized Arterial Calcification of Infancy". Circulation: Cardiovascular Genetics. 1 (2): 133–40. doi:10.1161/CIRCGENETICS.108.797704. PMC 2794045. PMID 20016754. {{cite journal}}: |first17= has generic name (help)
  7. ^ a b c d e f g h i j k l m n o p q r s Ferreira, Carlos; Ziegler, Shira; Gahl, William A. (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Generalized Arterial Calcification of Infancy", GeneReviews®, University of Washington, Seattle, PMID 25392903, retrieved 2019-10-17
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  30. ^ Eller, Philipp; Hochegger, Kathrin; Feuchtner, Gudrun M.; Zitt, Emanuel; Tancevski, Ivan; Ritsch, Andreas; Kronenberg, Florian; Rosenkranz, Alexander R.; et al. (2007). "Impact of ENPP1 genotype on arterial calcification in patients with end-stage renal failure". Nephrology Dialysis Transplantation. 23 (1): 321–7. doi:10.1093/ndt/gfm566. PMID 17848394.
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  36. ^ Ramjan, Kim A; Roscioli, Tony; Rutsch, Frank; Sillence, David; Munns, Craig FJ (2009). "Generalized arterial calcification of infancy: Treatment with bisphosphonates". Nature Clinical Practice Endocrinology & Metabolism. 5 (3): 167–72. doi:10.1038/ncpendmet1067. PMID 19229237. S2CID 24401990.
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  40. ^ Culling, Bronwyn; Loughran-Fowlds, Alison; Munns, Craig; Sillence, David; Walsh, Corrina; Taylor, Peter; Buckley, Michael; Rutsch, Frank; Roscioli, Tony (August 6–10, 2006). Infantile Arterial Calcification: Successful Treatment with Bisphosphonate. 11th International Congress of Human Genetics. Brisbane, Australia. Archived from the original on May 12, 2006.
  41. ^ Ciana, G.; Colonna, F.; Forleo, V.; Brizzi, F.; Benettoni, A.; de Vonderweid, U. (1997). "Idiopathic Arterial Calcification of Infancy: Effectiveness of Prostaglandin Infusion for Treatment of Secondary Hypertension Refractory to Conventional Therapy: Case Report". Pediatric Cardiology. 18 (1): 67–71. doi:10.1007/s002469900114. PMID 8960499. S2CID 1520872.
  42. ^ Glatz, Andrew C.; Pawel, Bruce R.; Hsu, Daphne T.; Weinberg, Paul; Chrisant, Maryanne R. K. (2006). "Idiopathic infantile arterial calcification: Two case reports, a review of the literature and a role for cardiac transplantation". Pediatric Transplantation. 10 (2): 225–33. doi:10.1111/j.1399-3046.2005.00414.x. PMID 16573612. S2CID 42109157.
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  47. ^ Thomas, Philomena; Chandra, Manju; Kahn, Ellen; McVicar, Melinda; Naidich, James; Lacorte, Michael (1990). "Idiopathic arterial calcification of infancy: A case with prolonged survival". Pediatric Nephrology. 4 (3): 233–5. doi:10.1007/BF00857661. PMID 2400650. S2CID 40660217.
  48. ^ Cheng, Kun-Shan; Chen, Ming-Ren; Ruf, Nico; Lin, Shuan-Pei; Rutsch, Frank (2005). "Generalized arterial calcification of infancy: Different clinical courses in two affected siblings". American Journal of Medical Genetics Part A. 136A (2): 210–3. doi:10.1002/ajmg.a.30800. PMID 15940697. S2CID 22783574.
  49. ^ a b Albright, Ronald A.; Stabach, Paul; Cao, Wenxiang; Kavanagh, Dillon; Mullen, Isabelle; Braddock, Alexander A.; Covo, Mariel S.; Tehan, Martin; Yang, Guangxiao; Cheng, Zhiliang; Bouchard, Keith (December 2015). "ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy". Nature Communications. 6 (1): 10006. Bibcode:2015NatCo...610006A. doi:10.1038/ncomms10006. ISSN 2041-1723. PMC 4686714. PMID 26624227.
  50. ^ "Demetrios Braddock > Doctor at Yale Medicine". Yale Medicine. Retrieved 2019-10-17.
  51. ^ a b "News + Media for 10/2019 | Office of Cooperative Research". ocr.yale.edu. Retrieved 2019-10-17.
  52. ^ "Inozyme Pharma, Inc. - Massachusetts Biotechnology Council". www.massbio.org. Retrieved 2019-10-17.
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