Generalized arterial calcification of infancy (GACI) is an ultra-rare disorder with an estimated birth prevalence of around 1 in 400,000.1 GACI is generally fatal before birth or within the first six months after birth. The cause of death is frequently myocardial infarction or stroke. GACI is strongly associated with inactivating mutations in ectonucleotide pyrophosphate/ phosphodiesterase 1 (ENPP1). Many patients with GACI, including some without an ENPP1 mutation also present with mutations in adenosine triphosphate binding cassette transporter protein subfamily C member 6 (ABCC6). Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and pseudoxanthoma elasticum (PXE) are believed to be closely related to GACI. ARHR2 is caused by mutations in the ENPP1 gene and PXE is caused by mutations in the ABCC6 gene, with both being observed among patients with GACI. The natural history of GACI and in particular its long term morbidity and mortality are poorly understood. The primary objective of this study is to characterize overall survival among patients with GACI, over time from birth.

Population

Probands with proven history of generalized arterial calcification of infancy.

Brief Title

Natural History of GACI With or Without ARHR2 or PXE

Official Title

The Natural History of Generalized Arterial Calcification of Infancy (GACI) With or Without Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2) or Pseudoxanthoma Elasticum (PXE)

Brief Summary

Generalized arterial calcification of infancy (GACI) is an ultra-rare disorder with an<br /> estimated birth prevalence of around 1 in 400,000.1 GACI is generally fatal before birth or<br /> within the first six months after birth. The cause of death is frequently myocardial<br /> infarction or stroke. GACI is strongly associated with inactivating mutations in<br /> ectonucleotide pyrophosphate/ phosphodiesterase 1 (ENPP1). Many patients with GACI, including<br /> some without an ENPP1 mutation also present with mutations in adenosine triphosphate binding<br /> cassette transporter protein subfamily C member 6 (ABCC6). Autosomal recessive<br /> hypophosphatemic rickets type 2 (ARHR2) and pseudoxanthoma elasticum (PXE) are believed to be<br /> closely related to GACI. ARHR2 is caused by mutations in the ENPP1 gene and PXE is caused by<br /> mutations in the ABCC6 gene, with both being observed among patients with GACI. The natural<br /> history of GACI and in particular its long term morbidity and mortality are poorly<br /> understood. The primary objective of this study is to characterize overall survival among<br /> patients with GACI, over time from birth.

Detailed Description

Background:

Generalized arterial calcification of infancy (GACI) is an ultra-rare disorder with an
estimated birth prevalence of around 1 in 400,000.1 GACI is characterized by extensive
arterial calcifications, arterial stenosis, myointimal proliferation and periarticular
calcifications. Individuals with GACI also experience calcification in other body areas, such
as joints and organs. GACI is generally fatal before birth or within the first six months
after birth. The cause of death is frequently myocardial infarction or stroke. GACI is
strongly associated with inactivating mutations in ectonucleotide pyrophosphate/
phosphodiesterase 1 (ENPP1); around three quarters of GACI cases investigated had one or
several ENPP1 mutations. Many patients with GACI, including some without an ENPP1 mutation
also present with mutations in adenosine triphosphate binding cassette transporter protein
subfamily C member 6 (ABCC6). Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and
pseudoxanthoma elasticum (PXE) are believed to be closely related to GACI. ARHR2 is caused by
mutations in the ENPP1 gene5 and PXE is caused by mutations in the ABCC6 gene,3 with both
being observed among patients with GACI. The natural history of GACI and in particular its
long term morbidity and mortality are poorly understood, but a strong understanding of the
condition will be crucial for further therapy development and drug testing. This study aims
to address this knowledge gap.

Objectives:

The primary objective of this study is to characterize overall survival among patients with
GACI, over time from birth.

Secondary objectives are to:

- Characterize the patient and disease characteristics;

- Describe symptomology at diagnosis and the change in symptomology over time;

- Describe treatment patterns specific to GACI or rickets

- Characterize mental/physical impairment, education, and employment situation;

- Characterize the sequelae of the disease;

- Prevalence of rickets; and

- Growth velocities.

Eligibility:

- GACI genotype (mutation in ENPP1 and/or ABCC6) confirmed through mutational analysis of
the patient and a GACI phenotype confirmed by imaging or biopsy; or

- GACI phenotype confirmed with imaging, biopsy, or mutational analysis of the parents
indicating a GACI genotype (mutation in ENPP1 and/or ABCC6) coinciding with symptoms of
the patient.

Data will be collected for both living and deceased patients

Design:

Retrospective multicenter chart review

Outcome Measures

Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.