Registry Gangliosidoses
Registry Gangliosidoses
The clinical project "Eight At One Stroke: Attention Gangliosidoses" represents a clinical
 registry for recording the clinical manifestation and the disease progression of
 gangliosidoses. The intention of this project is to better understand the manifestation and
 progression of gangliosidoses and to raise awareness of these disorders in the public health
 service. The patients or their families, respectively, will be integrated in the study in
 order to measure Patient Outcome and to objectify the psychosocial burden for the patient and
 his family. The study has a retrospective and a prospective part. It is planned to transfer
 the data of the study into a continuous registry.
1. 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
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:

 -  The diagnosis of a gangliosidosis has not biochemically or genetically confirmed.

 -  A written informed consent of the patient or parents/acaregiver does not exist.