Global Patient Testing Programs
Rostock International Parkinson's Disease Study (ROPAD)
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders world-wide. Due to the loss of dopaminergic neurons the patients affected with PD develop characteristic motor symptoms that worsen over time. In the vast majority of cases the etiology of the disease is unknown and it is likely heterogeneous and complex with genetic and environmental factors involved. The ROPAD study aims at screening 10,000 PD patients for genetic mutations in PD associated genes with a special focus on LRRK2. This observational study will help understanding the molecular mechanisms of PD and lead to the development of better diagnosis and treatments for PD.
European Alpha-Mannosidosis Patient Epidemiological Program (EUMAP)
Alpha-Mannosidosis is a very rare, hereditary lysosomal storage disorder, closely related to Mucopolysaccharidoses, which is estimated to occur in approximately 1 in 500,000 people worldwide. Mutations in the MAN2B1 gene interfere with the activity of the alpha-mannosidase enzyme, which results in accumulation mannose-containing oligosaccharides in the lysosomes. Tissues and organs are damaged by the abnormal accumulation of these complex sugars, leading to the characteristic and diverse signs and symptoms of Alpha-Mannosidosis.
It is the goal of this international, multicentre, epidemiological study to further explore and analyse the prevalence of Alpha-Mannosidosis disease in a clinical study cohort of 1.000 patients with a suspicion of suffering from Alpha-Mannosidosis disease, based on the patient's clinical symptoms.
Alpha-Mannosidosis is an extremely rare lysosomal storage disorder of the Glycoprotein disease family and is closely related to Mucopolysaccharidoses. Alpha-Mannosidosis was first described by Dr Oekerman, from Lund in Sweden in 1967.
Alpha-Mannosidosis is an autosomal-recessive inherited disorder that causes problems in many organs and tissues of the body. Affected individuals may have intellectual disability, distinctive facial features, and skeletal abnormalities. Characteristic facial features can include a large head, prominent forehead, low hairline, rounded eyebrows, large ears, flattened bridge of the nose, protruding jaw, widely spaced teeth, overgrown gums, and large tongue. The skeletal abnormalities that can occur in this disorder, including reduced bone density, thickening of the bones at the top of the skull (calvaria), deformations of the bones in the spine (vertebrae), bowed legs or knock knees, as well as deformation of the breastbone and joints.
The course of the disease is progressive in general, although symptoms can vary significantly between individual patients. Alpha-Mannosidosis has been categorized into three subtypes, based on severity of the symptoms and age of onset.
- Type 1: Mild form, recognized after age ten years, with absence of skeletal abnormalities, muscle problems (myopathy), and slow disease progression
- Type 2: Moderate form, recognized before age ten years, with presence of skeletal abnormalities, myopathy, and slow disease progression. This is the most common form
- Type 3: Severe form, often leading to early death of the affected patients, progressive central nervous system involvement
Mutations in the MAN2B1 gene cause Alpha-Mannosidosis. This gene provides instructions for making the enzyme alpha-mannosidase. This enzyme works in the lysosomes, which are compartments that digest and recycle materials in the cell. Within lysosomes, the enzyme helps break down complexes of sugar molecules (oligosaccharides) attached to certain proteins (glycoproteins). In particular, alpha-mannosidase helps break down oligosaccharides containing a sugar molecule, called mannose.
Mutations in the MAN2B1 gene interfere with the ability of the alpha-mannosidase enzyme to perform its role in breaking down mannose-containing oligosaccharides. These oligosaccha-rides accumulate in the lysosomes and cause cells to malfunction and eventually die. Tissues and organs are damaged by the abnormal accumulation of oligosaccharides and the resulting cell death, leading to the described, characteristic features of Alpha-Mannosidosis.
Modern methods, as DBS based mass-spectrometry give a great opportunity to:
- Simplify the diagnostic process
- Simplify the logistics
- Increases stability and reproducibility
- Characterize specific metabolic alterations in the blood of affected patients that allow diagnosing the disease earlier, with a higher sensitivity and specificity
A more specific diagnosis that permits earlier detection of the disease, as well as assessment of the disease activity and progression, would also permit improved chances for earlier treatment of those patients suffering from the disease, e.g. via recombinant human alpha-mannosidase (rhLAMAN) Enzyme Replacement Therapy (ERT).
Therefore, it is the goal of this international, multicentre, epidemiological study to explore and analyse the prevalence of Alpha-Mannosidosis disease in a cohort of 1.000 patients with a suspicion of Alpha-Mannosidosis disease, based on the patient’s clinical symptoms and/or positive family anamnesis of Alpha-Mannosidosis.
- Informed consent from the patients and/or the parents/legal guardian
- Patients aged <18 years, parent/legal guardian and assent of the minor where applicable, is necessary
- Patients of both genders older than 2 months
- Patients with a suspicion of Alpha-Mannosidosis
- Suspicion present, if one or more inclusion criteria, of unknown etiology, are valid:
- Positive family anamnesis for Alpha-Mannosidosis disease
- Immunodeficiency, recurrent infections
- Unclear skeletal abnormalities
- Hearing impairment or deafness
- Impairment of mental functions
- Unclear progressive neurological symptoms
- Gingival hypertrophy, facial dysmorphia
- Motoric disturbances
- No Informed consent from the patient or the parents/legal guardian (Patients aged <18 years)
- Patients of both gender younger than 2 months
- No valid criteria for profound suspicion of Alpha-Mannosidosis disease, as stated above
Epidemiological Analysis for the Hereditary Angioedema Disease (EHA)
Hereditary angioedema (HAE) is a rare disease characterized by bradykinin-mediated angioedema. It is an autosomal dominant disease resulting from mutations in the SERPING1 gene, leading to the deficient (type 1) or nonfunctional (type 2) C1 inhibitor protein. Clinical manifestations in all HAE types include acute attacks of non-urticarial edemas affecting the upper airway, face, extremities, genitals, and gastrointestinal system. Abdominal symptoms occur in 93% of individuals with HAE and may be the only manifestation of the disease. However, individuals experiencing gastrointestinal symptoms are rarely considered for HAE, leading to the disease being misdiagnosed for an average of eight years. In general, the epidemiological data on HAE is scarce, with an estimated prevalence of 1:50,000 to 1:70.000 worldwide.
HAE is a condition presenting as recurrent attacks of angioedema usually without symptoms of pruritus or urticaria. It is an autosomal dominant condition typically presenting in childhood, characterized by edema of subcutaneous and mucosal tissues and usually associated with the upper respiratory and gastrointestinal systems. Patients may experience nausea, vomiting, diarrhea, pain syndromes, and laryngeal swelling that may be life threatening. This topic review will focus on the gastrointestinal complications of HAE as a potential area of misdiagnosis leading to surgical morbidity.
Common prodromal symptoms include nausea abdominal pain, rash, fatigue, muscle aches, numbness, and tingling. Prodromal skin changes can be described as a nonurticarial erythem-atous discoloration on the extremities and trunk with reticulate and serpentine appearance sim-ilar to that of erythema marginatum. Cutaneous attacks of HAE typically involve swelling of the skin, which was present in 97% of episodes in one study with 221 patients. Face, genitals and upper extremities, more often than lower extremities, are affected. The neck and trunk were rarely the most notable locations of swelling. Laryngeal edema is the most serious complica-tion that can become life threatening but is a relatively rare event. Only 0.9% of all edema epi-sodes involved laryngeal edema. However, 51% of patients did admit to experiencing some sensation of tightness in the throat, hoarseness, and aphonia/dysphonia in their lifetime. Lar-yngeal edema can occur alone or with simultaneous swelling of the soft palate, tongue, and uvula . There have also been reports of attacks manifesting as headaches, temporary neu-rologic deficits, swelling and spasms of the urethra and bladder, joint swelling, chest tightness and pain, and renal colic.
Gastrointestinal, abdominal tract involvement is an important feature and one of the most common in HAE. The difficulty in recognizing gastrointestinal symptoms as being relat-ed to HAE often leads to a delay in diagnosis and to unnecessary surgical procedures. The most common symptoms include varying degrees of nausea, vomiting, diarrhea, and ab-dominal pain, which are the result of intestinal edema. The abdominal pain can present acutely or as recurrent pain and is described by patients to be cramping and colicky in nature. The pain patients experience can be moderate to severe in intensity and is usually present in 43–93% of all HAE attacks. Many of these abdominal pain symptoms can occur for many years without any associated respiratory or cutaneous involvement. Not only does the transient ede-ma of the bowel wall cause the aforementioned symptoms, but it may also lead to intestinal pseudoobstruction. The entire gastrointestinal tract can be involved in HAE attacks leading to a wide range of clinical manifestations (Table 1).
Table 1: Gastrointestinal manifestations of Hereditary Angioedema (data from CENTOGENE AG/ August 2017)
|n = 378 pts (2015-6/2017) (w/o MENA and others)||Europe||Latam|
|Age groups diagnosed HAE patients||< 5||5,1-15||> 15||< 5||5,1-15||> 15|
|Numbers of patients in total||28||41||67||22||57||61|
|Asymmetric swelling attacks extremities||39%||66%||52%||57%||22%||47%|
|Positive family history for any symptom||29%||66%||44%||32%||55%||61%|
|1-5 hospital stays before Dx||92%||27%||11%||77%||67%||14%|
|6-10 hospital stays before Dx||4%||18%||28%||19%||21%||39%|
|> 10 hospital stays before Dx||0%||23%||41%||8%||11%||5%|
The oropharynx and esophagus can be involved which leads to feeling of dysphagia. Stomach and small intestinal involvement cause nonspecific findings of abdominal pain, vomiting, and diarrhea. Liver involvement can lead to elevated transaminases, exudative ascites, and re-versible parenchymal changes. Pancreatic edema can cause partial duct obstruction, which can present as recurrent episodes of pancreatitis. Constipation was a common finding when there was colonic involvement, with only a few reported cases of intussusception. Severe con-sequences such as circulatory collapse may occur due to a combination of vasodilation, fluid loss from emesis and diarrhea, and fluid extravasation from bowel wall edema and ascites. This can lead to considerable hypovolemia and hemoconcentration. The majority of abdominal attacks last 2–4 days with preceding symptoms of irritability, fatigue, hunger, aggressiveness, and erythema marginatum.
Based on own epidemiological numbers we can calculate the following frequency of HAE in specific countries: 1:17.525 (Turkey/KSA); 1:36.600 Germany (analysis of 140,200 WES/WGS data sets from Turkey and KSA: identification of 8 HAE/SERPING1 patients; 13 HAE pts in a cohort of 1,040 appendectomized patients in Rostock University; 140,000 appendectomized pts/year in Germany; 80 mill population, resulting in at least 2,200 HAE pts in Germany.
The angioedema in HAE develops secondary to excess bradykinin production due to low levels of functionally active C1 inhibitor (C1 INH). This leads to the activation of the kallikrein-kinin system causing the release of vasoactive peptides and ultimately angioedema formation. Sev-eral types of HAE resulting from a genetic disorder have been identified that are not related to acquire C1 inhibitor deficiency or drug induced angioedema. Type 1 HAE is the cause of the disease in about 85% of HAE patients due to deficiency of the C1 INH protein (quantitative defect). Type 2 HAE comprises the majority of the remaining 15% of patients with HAE with a normal or elevated level of the C1 INH protein but with a functional deficiency (qualitative de-fect). Both types 1 and 2 are a result of a mutation in the C1 INH gene. A third type of HAE has been found, primarily in women, with normal C1 INH protein and the mutation is actually in the coagulation factor XII gene.
The prognosis for patients with HAE before current treatment modalities reached as high as 25–50% in some families with the cause of death almost always secondary to laryngeal edema and fatal asphyxiation. A recent study found that mortality was 29% in patients with undiag-nosed HAE compared to 3% in patients with a known diagnosis of HAE. This stresses the im-portance of early diagnosis and that patient education and access to treatment can greatly reduce mortality.
The diagnosis is complicated because HAE is extremely rare and most physicians typically never see a patient with the disorder. In addition, most cases of angioedema are caused by an allergic reaction. Abdominal attacks may be mistaken for conditions such as appendicitis and often results in unnecessary exploratory surgery. Often, patients are misdiagnosed as having psychosomatic symptoms and are inappropriately referred for psychiatric evaluation.
- Informed consent will be obtained from the participant
- Participants with previous episodes of abdominal pain of no obvious aetiology or angioedema
- Participants aged between 16 and 60 years
- Previous diagnosis of HAE
- Inability to provide informed consent
- The etiology of abdominal pain attacks is determined
- Participants that are younger than 16 years old and older than 60 years old
- Previously enrolled in the study
- Participant in custodyAngioedema clearly allergic in nature
Epidemiological Analysis for the Hereditary Transthyretin-Related Amyloidosis (TRAM2)
Transthyretin (TTR) amyloidosis (A-TTR) is a rare protein misfolding, autosomal dominant inherited disease with variable penetrance. It presents with a wide spectrum of clinical manifestations. TTR, the protein implicated in A-TTR, is a tetrameric transport protein. Misfolded TTR protein forms amyloid fibrils causing tissue damage by direct compression and obstruction. In the earliest stages of the disease the symptoms comprise autonomic and/or sensory symptoms. The clinical spectrum of A-TTR (Amyloidosis TTR) varies widely from an exclusive neurological involvement to a predominant cardiac presentation.
The clinical spectrum of A-TTR (Amyloidosis TTR) varies widely from an exclusive neurological involvement to a predominant cardiac presentation (Rapezzi 2013). In the first case, the disease is called TTR familial amyloid polyneuropathy, in the second case, the disease is called TTR amyloid cardiomyopathy; new nomenclature uses hATTR. Most likely this classification does not really make sense furtheron, since the clinical picture is in the majority of the patients (>62%) overlapping.
Screening for the Transthyretin-Related Familial Amyloidotic Small Fiber Polyneuropathy (TRAP)
The study focuses on TTR-FAP (OMIM: #105210, OMIM: #176300), whose prevalence shall be determined in a cohort of 500 patients with polyneuropathy of unknown etiology. The TTR-FAP is an autosomal dominant disease, the exact prevalence of which is unknown but estimated to be around 1:100,000 to 1:1,000,000 in the normal population (Orphanet, ORPHA 85447).
Diseases of diverse etiology can be correlated to the term „polyneuropathy“ (PNP).
Neuropathies are generalised disorders of the peripheral nervous system, due to deranged function of the peripheral motor, sensory and autonomic neurons, their fibres or their myelin sheath. Dysfunction of unmyelinated C and myelinated Aδ fibres causes symptoms like insensitivity or hypersensitivity to heat and/or cold and neuropathic pain. These fibres have slow conduction velocities, carrying temperature feeling and pain sensations from nociceptors and thermoreceptors respectively. An isolated disturbance of these fibres leads usually to the diagnosis of small fibre neuropathy (SFN).
The pathogenesis of SFN may be of inflammatory, autoimmune, metabolic, toxic or hereditary nature. Careful clinical and electrodiagnostic assessment, with attention to the pattern of involvement and the types of nerve fibers most affected, narrows the differential diagnosis and helps to focus the laboratory evaluation.
Beside the frequent genetic etiologies in PNP (pmp22, MFN2) one cause of a genetic polyneuropathy may be a hereditary amyloidosis. These have been described as endemic in Sweden, Portugal or Japan. The most common form of the hereditary familial amyloidotic neuropathy (FAP) is the Transthyretin-related FAP, however two other amyloidogenic proteins have been described: Apolipoprotein A-I and Gelsolin (Ando et al., 2005; Adams et al., 2010).
This study focuses on TTR-FAP (OMIM: #105210, OMIM: #176300), whose prevalence shall be determined in a cohort of 500 patients with polyneuropathy of unknown etiology. The TTR-FAP is an autosomal dominant disease, the exact prevalence of which is unknown but estimated to be around 1:100,000 to 1:1,000,000 in the normal population (Orphanet, ORPHA 85447).
While the diagnosis of the amyloidotic neuropathy can be conducted histologically, a molecular genetic approach is necessary to diagnose TTR-FAP. Even though more than 100 point mutations are known to cause the disease, the most common amino acid change is V30M.
The mutation in the TTR gene causes the destabilization of the physiologically tetrameric protein. Usually transthyretin consists of four identical monomeric subunits and binds the thyroxin circulating in the blood plasma. The monomeric subunits exhibit a pronounced β-sheet structure which leads to the accumulation of unsoluble β-fibrils when they are destabilised as in TTR-FAP.
This accumulation of misfolded TTR can lead to three phenotypes known as:
- Cardiac TTR amyloidosis
- Leptomeningeal TTR amyloidosis and the
The TTR-FAP has a very heterogeneous phenotype which can manifest starting at the age of 18 and may lead to death within 10 years. The symptoms can be categorized in three groups (Ando et al. 2005):
Dysfunction of peripheral nerves
- Dissociated anesthesia
- Muscle paresis and atrophy
- Dysaesthesia and paraesthesia
- Reduced skin temperature
- Orthostatic dysregulation
- Erectile dysfunction
- Weight loss
The currently available therapeutic approaches are either liver transplantation (as the liver mainly produces transthyretin this is a feasible approach) or as of more recently also a TTR-tetramer stabilizing agent (Tafamidis). Tafamidis (Vyndaqel®) gained the European approval under „exceptional circumstances“ in November 2011 for treating FAP in adults with a symptomatic polyneuropathy.
In light of the potential therapy of this very rare disease this study aims to determine the prevalence of TTR-FAP in a selected, clinical sub-population.
- Informed consent will be obtained from the patient before any study related procedures
- Patients aged older than 18 years
- Patients with small fiber polyneuropathy of undetermined etiology based on: the normal results of laboratory data (CRP, glucose, electrolytes, urea, transaminases, TSH, immunoglobulins, vitamin B12, RF, ANA, antibodies against Lyme borrelia)
- Presence of an electrophysiological examination for N. Peroneus and N. Suralis
- No obvious apparent cause of neuropathy
- No anamnesis for carcinoma
- No continuous alcohol consumption
- No light-chain-amyloidosis
- No anamnesis for heavy metal exposure
- Progressive idiopathic small fiber polyneuropathy
- No Informed Consent from the patient before any study related procedures
- Patients younger than 18 years
- The etiology of the small fiber polyneuropathy is already known based on: significant pathological results for any of the following laboratory data (CRP, glucose, electrolytes, urea, transaminases, TSH, immunoglobulins, vitamin B12, RF, ANA, antibodies against Lyme borrelia)
- No presence of an electrophysiological examination for N. Peroneus and N. Suralis
- Obvious apparent cause of neuropathy
- Positive anamnesis for carcinoma
- Continuous alcohol consumption
- Anamnesis for heavy metal exposure
- No progression of idiopathic small fiber polyneuropathy within the last two years