Metabolic diseases
Metabolic diseases are a group of disorders that affect the body's ability to process and convert food into energy. These conditions occur due to genetic mutations that disrupt metabolic pathways, and as a group they are known as inborn errors of metabolism (IEM).
The simplified diagram below illustrates this concept: when an error in the genetic code disrupts a metabolic pathway, enzyme X responsible for converting substance A into substance B might be absent, or dysfunctional. As a result, (toxic) accumulation of substance A or a deficiency of essential compound B may occur.
Inborn errors of metabolism can affect various biochemical processes, including the breakdown of carbohydrates, fats, and proteins. While many metabolic diseases are caused by enzyme defects, some involve other proteins crucial for maintaining metabolism, such as transporters, receptors, and cofactors.
Inborn errors of metabolism can cause life-threatening energy deficiencies and severe damage to the body due to the buildup of unprocessed waste products. The impact varies—some children lose their hearing or sight, develop intellectual or physical disabilities, or even regress in their development. Tragically, many children do not survive into adulthood, with 1 in 4 passing away before the age of 18 (1).
To date, 1900 IEMs are known. Individually, these conditions are rare. However, taken together, over 10.000 families in The Netherlands alone are affected by metabolic disease. Everyday a child with an inborn error of metabolism is born. In stark contrast to that, currently for only 15% of these, some form of treatment (including enzyme replacement therapy, dietary management) is available.
At Emma CPM, we aim to change that. By combining forces inside the Amsterdam UMC in research into genetic therapy, medical diets, supplements, and medicines we aim to improve the care and prospects of children and adults with inborn errors of metabolism.
Barth syndrome (BTHS; MIM 302060) was first described by Prof. Peter Barth, a pediatric neurologist from our center, in 1983 (1).BTHS is a rare X-linked inherited mitochondrial disorder that in most affected individuals presents with cardiomyopathy (heart failure), skeletal myopathy (muscle weakness), and neutropenia (immune problem). BTHS is caused by pathogenic variants in the TAFAZZIN gene encoding the tafazzin protein. Tafazzin is involved in the maturation of cardiolipin, a central lipid in mitochondrial physiology.
The prevalence is estimated to be around 1:300.000 to 1:1.000.000.
BTHS is caused by pathogenic variants in the TAFAZZIN gene encoding the tafazzin protein. Tafazzin is involved in the maturation of cardiolipin, a central lipid in mitochondrial physiology.
On a biochemical level, Barth syndrome can be detected with 100% accuracy in blood samples, using mass spectrometry measuring the monolysocardiolipin and cardiolipin ratios (2) (3). This assay is highly specific for individuals with Barth syndrome.
Current treatment strategies focus on symptom management. Despite the severity of the condition, effective (targeted) therapies for Barth syndrome are still lacking.
Novel therapies are currently being evaluated for Barth syndrome both in the laboratories and in the clinic. Together with individuals affected by Barth syndrome, their families and patient foundations, the Emma Center for Personalized Medicine is focused on the development and understanding of emerging therapies for Barth syndrome. To do this, we use a variety of innovative (stem cell-derived) models that can mimic Barth syndrome in a laboratory setting and technical innovations to study mechanisms underlying Barth syndrome and treatments. These models can be highly efficient for evaluating potential therapies, even in a personalized setting. Also, we are developing the clinical care pathway and guidelines to provide the best possible multidisciplinary care for individuals with Barth syndrome.
Cystinosis (MIM 219800) is a disorder in which cystine is accumulated within the lysosomes due to a dysfunction of the cystine transporter cystinosin (1). Cystinosis is caused by bi-allelic mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin (17p13.2).
Prevalence
The prevalence of this disorder is 1:100 000 – 1:200 000.
Standard care and treatment options
The current standard care of cystinosis is symptomatic. Aminothiol cysteamine delays disease progression by reducing lysosomal cystine accumulation but has numerous side effects.
Pathogenesis
The accumulation of cystine leads to crystal formation within all cells, causing multi-organ dysfunction. The process starts in kidneys and eyes and progressively affecting other organs such as thyroid, pancreas, liver, muscles and brain. However, the pathogenesis of cystinosis is more complex than merely cystine accumulation. It involves disturbances in various cellular pathways including increased oxidative stress, altered mTOR signaling and autophagy, mitochondrial dysfunction, and impaired vesicle trafficking.
Our research aims
In close collaboration with cystinosis patients and patient associations, the Emma CPM is focused on better understanding the disease mechanism. We study the dynamic fluxes of metabolites, cystinosis patients cells and cystinosis animal models.
Additionally, we are exploring novel therapeutics to improve therapeutic strategies (2). This includes investigating the potential of different approved drugs to be repurposed for treating cystinosis (cellular) phenotypes. We are also examining mRNA therapy to cure the genetic defect in cystinosis.
Gyrate atrophy of the choroid and retina (GACR; MIM 258870) is a rare genetic metabolic disorder that affects vision. GACR typically occurs at a low incidence, affecting approximately 1 in 1.000.000 individuals. It is caused by mutations in the OAT gene, which leads to a deficiency in the enzyme ornithine aminotransferase.
As a result of this enzyme deficiency, excessive levels of the amino acid ornithine accumulate in the body, leading to progressive degeneration of the choroid (a vascular layer in the eye) and the retina (the light-sensitive inside lining of the eye). This degeneration causes gradual vision loss. Individuals with GACR typically experience night blindness and nearsightedness in early childhood. Over time, they lose their peripheral vision (tunnel vision), and cataracts may develop. If left untreated, most patients become completely blind around 50 years of age.
Currently, there is no standard therapy to cure gyrate atrophy. Management focuses on supportive care, such as low-vision aids and counseling to help patients adapt to vision changes, and in some cases vitamin B6 supplementation. However, none of these treatments halt disease progression, highlighting the urgent need for evidence-based therapies.
At Emma CPM, we focus on addressing this need through a multidisciplinary team approach. We obtain detailed natural history data of affected individuals, use state-of-the-art technologies to investigate the pathophysiology of GACR, and investigate new potential treatments, including nutritional supplements, drugs, and innovative molecular therapies.
The Emma CPM is a center of expertise at the Amsterdam UMC focusing on patients and families with a rare genetic disorder.
A collaboration between the Emma Children's Hospital, the Department of Human Genetics, the Laboratory of Genetic Metabolic Diseases, and various departments and laboratories.