Ectonucleotide pyrophosphatase/phosphodiesterase 1 deficiency

ENPP1 Deficiency

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D000071916

ENPP1 Deficiency is a rare genetic disorder that causes serious problems throughout a person’s life, from life-threatening blood vessel calcification in babies to painful bone and joint issues in children and adults.

Table of contents

• What is ENPP1 Deficiency?
• The genetic cause and how the body is affected
• How the disease shows itself at different ages
• How common is the disease
• Getting a diagnosis
• Current treatment and research
• Support and resources

What is ENPP1 Deficiency?

ENPP1 Deficiency is a rare genetic disease that disrupts how the body manages calcium and bone formation^[1]. The disease is caused by problems with a gene called ENPP1, which provides instructions for making an important enzyme in the body^[2].

This enzyme, called ectonucleotide pyrophosphatase/phosphodiesterase 1, plays a critical role in regulating levels of a substance called pyrophosphate (PPi) in the body^[1]. Pyrophosphate is essential for preventing harmful calcium deposits from forming in soft tissues like blood vessels, and it helps ensure that bones develop and stay strong in the right way^[1].

When the ENPP1 enzyme doesn’t work properly, the body cannot maintain the right balance of these substances. This leads to two seemingly opposite problems happening at the same time: too much calcium building up where it shouldn’t be (in blood vessels, joints, and organs) and bones becoming too soft and weak^[11]. This puzzling combination is sometimes called paradoxical mineralization^[11].

The genetic cause and how the body is affected

ENPP1 Deficiency is caused by mutations (changes) in both copies of the ENPP1 gene that a person inherits—one from each parent^[14]. This is called biallelic inheritance, meaning a person must have mutations in both gene copies to develop the disease. Parents who each carry one mutated copy are called carriers and typically don’t have symptoms themselves^[4].

The ENPP1 gene provides instructions for making a protein that sits on the outside of cells and breaks down a molecule called adenosine triphosphate (ATP) when it’s found outside cells^[2]. This breakdown produces two important products: adenosine monophosphate (AMP) and pyrophosphate^[2]. Pyrophosphate acts as a powerful brake that stops calcium and other minerals from depositing in the wrong places^[14].

When someone has ENPP1 Deficiency, their body produces little or no working ENPP1 enzyme^[17]. This means pyrophosphate and adenosine levels become too low. Without enough pyrophosphate to act as a brake, calcium crystals called hydroxyapatite start forming and building up in soft tissues, particularly in the walls of blood vessels, around joints, and in organs^[17]. This abnormal calcium buildup is called ectopic calcification^[17].

At the same time, bones don’t form properly and become soft—a condition called osteomalacia in adults or rickets in children^[1]. The disease also causes problems with blood vessels beyond calcification, including abnormal growth of the inner lining of arteries, which narrows them and blocks blood flow. This process is called neointimal proliferation^[14].

How the disease shows itself at different ages

ENPP1 Deficiency affects people differently depending on their age, and symptoms can vary greatly in severity, even among members of the same family^[17]. The disease tends to progress over a person’s lifetime, with new symptoms appearing at any age^[17]. Doctors recognize three main forms of the disorder based on when and how it appears.

Infants: Generalized Arterial Calcification of Infancy (GACI Type 1)

Babies who show signs of ENPP1 Deficiency before birth or shortly after are typically diagnosed with a condition called Generalized Arterial Calcification of Infancy, or GACI^[1]. This is a serious, life-threatening condition characterized by extensive calcium buildup in the walls of arteries and abnormal thickening of the artery lining^[1].

The calcification stiffens and narrows the arteries, making it extremely difficult for blood to flow properly. As a result, the heart and other organs cannot get enough oxygen-rich blood^[17]. Infants with GACI may experience heart failure, very high blood pressure, breathing difficulties, blue-tinted skin, or trouble gaining weight^[17].

The outlook for infants with GACI is poor. Approximately 45% to 50% of infants with ENPP1 Deficiency die within the first six months of life, despite receiving supportive medical care^[1][14]. The disease can cause heart attacks, strokes, or failure of the heart or other organs^[1].

Children: Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2)

Children with ENPP1 Deficiency who survive infancy, or those who never had cardiovascular symptoms as babies, typically develop bone problems. This form is called Autosomal Recessive Hypophosphatemic Rickets Type 2, or ARHR2^[1].

In ARHR2, children have abnormally low levels of phosphate in their blood, a condition called hypophosphatemia^[17]. The exact reason for this phosphate loss is not fully understood, but it involves increased levels of a hormone called FGF23 that causes the kidneys to lose phosphate^[14]. Low phosphate levels prevent bones from developing properly.

Children with ARHR2 often have weak bones, bowed legs, bone deformities, slowed growth, abnormal walking patterns, and pain^[17]. They may also develop hearing loss^[1]. Some children who had GACI as infants may continue to have high blood pressure throughout childhood^[17].

Adults: Continuing bone and joint problems

Adults with ENPP1 Deficiency continue to experience bone softening (osteomalacia), which can cause bone fractures or significant pain that affects their quality of life^[17]. They may also have short stature, bone deformities, and abnormal walking patterns that remain from childhood^[17].

A major source of disability in adults is pain and stiffness in joints, tendons, and ligaments caused by calcium deposits forming around the knees, hips, ankles, hands, and neck^[17]. This can lead to osteoarthritis and severely limited movement^[17]. Adults may also develop heart valve problems, continue to have high blood pressure, and experience hearing loss^[17]. These musculoskeletal symptoms represent a major cause of ongoing health problems in later life^[14].

How common is the disease

ENPP1 Deficiency is a rare disease. A recent estimate using genetic data from approximately 140,000 individuals suggests the disease occurs in about 1 in 64,000 pregnancies^[4]. This is more than three times higher than an earlier estimate^[4].

Interestingly, the frequency of people who carry one copy of an ENPP1 mutation appears to be highest in East Asian populations, although this is based on a relatively small sample^[4]. These findings suggest that many patients with ENPP1 Deficiency around the world remain undiagnosed^[4].

Because ENPP1 Deficiency can show itself in different ways and at different ages, and because many doctors are not familiar with the condition, it can be difficult to recognize and diagnose^[14]. Low awareness of the disease among healthcare providers, combined with symptoms that can be mistaken for other conditions, means the true number of affected individuals is likely higher than current estimates suggest.

Getting a diagnosis

A confirmed diagnosis of ENPP1 Deficiency requires genetic testing that shows a person has mutations in both copies of their ENPP1 gene^[12]. The genetic test must be performed by a certified laboratory to ensure accuracy^[12].

Early and accurate diagnosis is critical because ENPP1 Deficiency is a devastating, life-long disease^[22]. For infants showing signs of GACI, quick diagnosis can be life-saving. Some babies may show signs of the disease even before birth through routine pregnancy ultrasounds^[12].

Free genetic testing programs are available to help identify individuals with ENPP1 Deficiency. Healthcare providers who suspect a patient may have the condition can access no-cost genetic testing for ENPP1 through programs offered by pharmaceutical companies developing treatments^[16].

If a doctor thinks someone might have ENPP1 Deficiency, the recommended first step is to consult with a specialist, such as an endocrinologist (a doctor who specializes in hormone and metabolic disorders) or a pediatric endocrinologist for children^[16]. These specialists can help coordinate genetic testing and provide guidance on managing the disease.

Current treatment and research

There are currently no approved therapies specifically for ENPP1 Deficiency^[1]. Treatment has been limited to supportive care aimed at managing symptoms and complications as they arise.

However, promising research is underway. Scientists have developed an experimental treatment called enzyme replacement therapy, which works by providing the body with a working version of the ENPP1 enzyme it lacks^[8]. The investigational therapy being tested is called INZ-701, and it is designed to replace the missing or non-functioning ENPP1 enzyme^[1].

Several clinical trials are currently recruiting patients to test INZ-701. These include:

• The ENERGY Study (Study INZ701-104), which is testing the safety and tolerability of INZ-701 in infants with ENPP1 Deficiency^[12]
• The ENERGY 3 Study (Study INZ701-106), a Phase 3 trial evaluating the effectiveness and safety of INZ-701 in children aged 1 to 12 years with ENPP1 Deficiency^[13]
• An earlier Phase 1/2 study in adults with ENPP1 Deficiency, which has reported positive preliminary results for safety and blood markers^[1]
• The ADAPT Study (Study INZ701-304), a long-term safety study for patients who have received INZ-701 in previous clinical trials^[13]

Additionally, researchers have established PROPEL, a global patient registry designed to collect information about the natural history of ENPP1 Deficiency^[7]. This registry aims to systematically gather clinical information to better understand how the disease progresses, its impact on patients, and patient-reported outcomes^[7]. The registry plans to recruit up to 1,000 participants over 10 years across 50 sites worldwide^[7].

Support and resources

For families dealing with an ENPP1 Deficiency diagnosis, especially parents of newly diagnosed babies, connecting with others who understand the disease can be invaluable. Patient advocacy organizations provide support, education, and community for affected individuals and their families.

GACI Global is a patient advocacy organization dedicated to supporting individuals with GACI and ENPP1 Deficiency^[16]. The organization provides resources, connects families, and works to raise awareness about the disease.

These organizations can help families navigate the challenges of living with a rare disease, connect with medical experts, learn about research developments, and find clinical trials that may be appropriate for their situation^[16].