start date: June 8, 2020
estimated completion: June 7, 2025
last updated: November 12, 2020
size / enrollment: 40
study description: Aim of the Project
The aim of the project is to collect fundamental epidemiological and clinical data, such as prevalence and incidence, but also data regarding phenotype, diagnosis and mutation spectrum.
To understand the natural course of these diseases seems to be very important for individual advice of families and additionally for planning drug studies.
In this study it should also be analyzed how the families and their setting have perceived the disease manifestation. Their perception will be compared to clinical findings and symptoms that were noticed by the physician. The medical history may indicate which symptoms and findings may lead to a well-directed diagnosis.
Clinical and genetic data, that also concern aspects of social medicine, of a greater cohort will raise the awareness of pharmaceutical companies that develop new drugs and will increase the chance of patients to participate in a clinical trial.
The project will enable validation of biomarkers that may be useful for diagnostic purposes and also for monitoring laboratory parameters during a trial.
Patients and their families are involved in the development and procedure of the study. They become a voice and are noticed as partners in the public health service.
3. Background 3.1 Gangliosidoses Gangliosidoses represent autosomal-recessive lysosomal storage disorders, caused by a defect in the lysosomal degradation of gangliosides, resulting in accumulation of these substrates in several organs. Gangliosidoses are divided in eight different diseases according to their biochemical and genetic defect: Four disorders are assigned to GM2-Gangliosidoses, four belong to the Neuraminidase-ß-Galactosidase complex. Gangliosidoses are characterized by more or less pronounced progressive loss of mental and motor capabilities. In patients with a more attenuated phenotype the diagnosis is done often very late, as the typical clinical "classical" features are commonly lacking. Maybe adult patients were never diagnosed.
The diseases result from the accumulation of gangliosides, caused by genetic defects of enzymes or other proteins that are involved in the lysosomal degradation of these complex lipids.
3.2 Classification of Gangliosides GM1-Gangliosidosis - Sialidosis
GM1-Gangliosidosis (1) Morquio B Variant (2) ß-Galactosidase
Sialidosis (3) Neuraminidase
Galactosialidosis (4) Protective Protein/Cathepsin A
GM2-Gangliosidoses
Tay-Sachs Disease (5), incl. B1-Variante (6) Hexosaminidase A
Sandhoff Disease (7) Hexosamidase A&B
GM2-Activator-Deficiency (8) GM2-activator-protein
3.3 Clinical Phenotypes The degree of clinical expression regarding the age of first manifestation, rate of progression and symptoms is extremely heterogeneous and reaches from the lethal hydrops fetalis to the rapidly progressive and to the slowly progressive adult form. The underlying mutations determine the enzyme respectively protein deficiency, in the more attenuated forms, however, the phenotype is additionally influenced by epigenetic factors and the environment. Generally five phenotypic forms are distinguished that differ in the age of first symptoms.
Hydrops fetalis Gangliosidoses can manifest as hydrops fetalis that is defined as fetal fluid accumulation in at least two organ systems, such as ascites, pleural and pericardium effusion and generalized edema. Hydrops fetalis, that mostly leads to intrauterine death, was surprisingly not observed in GM2-gangliosidoses.
Infantile Gangliosidoses Patients with the so-called "classical" infantile form manifest after birth with developmental delay. Between the age of three to six months significant muscular hypotonia becomes obvious. Often, but not exclusively, in GM2-gangliosidoses the parents observe as first symptom an excessive response to an acoustic stimulus with sudden hyperextension of arms and legs and muscle jerks. A cherry-red spot at the eye fundus and a macrocephaly may lead to the diagnosis. A so-called "Hurler-phenotype" is seen in infants with sialidosis, galactosialidosis and GM1-gangliosidoses.
Late-infantile and juvenile Gangliosidoses It is often not possible to differentiate between late.infantile and juvenile gangliosidoses: In young children the parents observe deficits in motor and speech development, later these capabilities get lost. The occurrence of epilpetic seizures implies a bad prognosis. In GM2-gangliosidoses the tetraparesis is hypotonic and floppy, in GM1-gangliosidoses dystonic and spastic. The progressive visual impairment can result in blindness.
Late-onset Gangliosidoses Patients with late-onset (or chronic-adult) type of gangliosidoses present with cerebellar signs such as ataxia, dysarthria and hypotonia. Late-onset GM2-gangliosidoses are characterized by intention tremor and dysmetria, in late-onset GM1-gangliosidoses dystonia and spasticity are the leading neurological symptoms. Prior to the occurrence of neurological symptoms psychoses and episodes of psychosis may appear that later on may dominate the disease manifestation. The cognitive abilities are hardly impaired, due to the severe dysarthria, however, it may be difficult to correctly evaluate the cognitive function. Because in adult gangliosidoses the motor neuron is involved, the patients may resemble individuals with Friedreich-Ataxia ot SMA, for which reason a differentiation between thoMedise disorders may be difficult
primary outcomes:
- Disease progression will be assessed by the 8 in 1 score
Disease progression was assessed by the 8 in 1 score, which is a disease specific instrument adapted from other scores in neurodegenerative and lysosomal diseases (NPC, CLN). The instrument is designed to monitor disease progession and measure disease severity. The 8 in 1 score summarizes 8 domains (partizipation, medical care, ambulation, manipulation, swallowing, speech, epilepsy and cognition) ranging from 0 - 40. A higher score indicates more severe clinical impairment.
- 5 years
secondary outcomes:
- Characterization of the first neurological symptom
5 years
inclusion criteria:
• Eligible Ages: 0 - 120
• Eligible Sexes: all
Inclusion Criteria:
Biochemically and/or genetically affirmed diagnosis of a gangliosidosis
The patient or respectively the parents or the caregiver (for children or older underage patients) have given written informed consent
exclusion criteria: Criteria:
The diagnosis of a gangliosidosis has not biochemically or genetically confirmed.
A written informed consent of the patient or parents/acaregiver does not exist.
