Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02298647 |
| Other study ID # |
BioGM1 / BioGM2 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 20, 2018 |
| Est. completion date |
February 28, 2021 |
Study information
| Verified date |
February 2023 |
| Source |
CENTOGENE GmbH Rostock |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Development of a new MS-based biomarker for the ear-ly and sensitive diagnosis of GM1/GM2
from blood
Description:
Gangliosidosis:
Gangliosides are complex compunds consisting of a glycosphingolipid and a sialic acid and are
located at the cell surface where they are responsible for detecting extracellular molecules.
Gangliosides are mainly located in the nervous system.
If gangliosides accumulate pathologically throughout the body this is known as
Gangliosidosis. There are two main sub-types of Gangliosidosis depending on the deficient
enzyme, which are known as GM1 and GM2.
GM1-Gangliosidosis GM1-Gangliosidosis is an autosomal recessive disease. Genetic counselling
should be provided to affected families. The disorder is caused by mutations in the GLB1-gene
coding for beta-galactosidase. To day, more than 165 mutations have been identified.
Deficient enzyme activity leads to toxic accumulation of gangliosides in body tissues, and
particularly in the central nervous system (CNS).
The disorder is pan-ethnic, however the worldwide prevalence is not known. Prevalence at
birth is estimated to be approximately 1:100,000 to 200,000 live births. High prevalence has
been found in Malta and Brazil, and in the Cypriot and Roma populations.
Deficiency of the lysosomal hydrolase, acid β-galactosidase, causes GM1.Three clinical
sub-types of GM1-Gangliosidosis are recognized, classified by age of onset, as follows:
- Infantile (type 1): In the most common infantile form, coarse facial features,
hepato-splenomegaly, generalized skeletal dysplasia (dysostosis multiplex), macular
cherry-red spots, and developmental delay/arrest (followed by progressive neurologic
deterioration) usually occur within the first 6 months of life. Nonimmune hydrops
fetalis has been reported. An increased incidence of Mongolian spots has also been
described. A wide spectrum of variability is observed in the appearance and progression
of the typical dysmorphic features. As many as 50% of affected infants have a macular
cherry-red spot.
- Juvenile (type 2): The juvenile form is characterized by a later age of onset, less
hepatosplenomegaly (if any), fewer cherry-red spots (if any), dysmorphic features, or
skeletal changes (vertebral dysplasia may be detected radiographically).
- Adult (type 3): The adult form is characterized by normal early neurologic development,
with variable age of clinical presentation. Slowly progressing dementia with
parkinsonian features and extrapyramidal disease is common. Intellectual impairment may
be initially absent or mild but progresses with time. Generalized dystonia with speech
and gait disturbance is the most frequently reported early feature. Typically, no
hepato-splenomegaly, cherry-red spots, dysmorphic features, or skeletal changes are
present aside from scoliosis (mild vertebral changes may be revealed with radiography),
but short stature is common.
GM2-Gangliosidosis The GM2-Gangliosidosis are a group of lysosomal lipid storage disorders
caused by mutations in at least 1 of 3 recessive genes: HEXA, HEXB, and GM2A. Normal products
of all 3 genes are required for normal catabolism of the GM2 ganglioside substrate. Deficient
activity of these enzymes leads to accumulation of the substrate inside neuronal lysosomes,
leading to cell death. The products of the 3 genes are, respectively, the alpha subunits of
b-hexosaminidase A (Hex A). Hex A is a dimer and has the structure alpha-beta.
β-Hexosaminidase B (Hex B) is a dimer of beta chains. It hydrolyzes GM2 and its neutral
asialo derivative GA2. Both subunit precursors acquire the mannose 6-phosphate marker for
recognition by lysosomes.
Hexosaminidase S (Hex S) is a dimer of alpha chains; it is a normal constituent of plasma and
degrades a wide range of glycoconjugates containing β-linked N-acetylhexosaminyl residues.
With lack of beta-subunits the increased polymerization of alpha subunits leads to the
in-creased formation of Hex S in Tay - Sachs disease.
GM2A is a cofactor required for the normal function of Hex A; it´s disruption likewise leads
to a reduced function of Hex A.
Disease classification:
Tay-Sachs disease Tay-Sachs disease (also known as GM2-Gangliosidosis or hexosaminidase-A
deficiency) is an autosomal recessive genetic disorder. In its most common variant (known as
infantile Tay-Sachs disease), it causes a progressive deterioration of mental and physical
abilities that commences around six months of age and usually results in death by the age of
four. The dis-ease occurs when harmful quantities of cell membrane components known as
gangliosides accumulate in the brain nerve cells, eventually leading to the premature death
of the cells. A ganglioside is a form of sphingolipid, which makes Tay-Sachs-Gangliosidosis a
member of the Sphingolipidosis. There is no known cure or treatment.
Tay-Sachs disease is caused by a genetic mutation in the HEXA gene on (human) chromosome 15.
A large number of HEXA mutations have been discovered, and new ones are still being reported.
These mutations reach significant frequencies in specific populations. French Canadians of
south-eastern Quebec have a carrier frequency similar to that seen in Ashkenazi Jews, but
carry a different mutation. Cajuns of southern Louisiana carry the same mutation that is seen
most commonly in Ashkenazi Jews. HEXA mutations are rare and are most seen in genetically
isolated populations. Tay-Sachs can occur from the inheritance of either two simi-lar, or two
unrelated, causative mutations in the HEXA gene.
Tay-Sachs disease is classified into several forms, which are differentiated based on the
onset age of neurological symptoms.
- Infantile Tay-Sachs disease: Infants with Tay-Sachs disease appear to develop normally
for the first six months after birth. Then, as neurons become distended with
gangliosides, a relentless deterioration of mental and physical abilities begins. The
child becomes blind, deaf, unable to swallow, atrophied, and paralytic. Death usually
occurs before the age of four.
- Juvenile Tay-Sachs disease: Juvenile Tay-Sachs disease is rarer than other forms of
Tay-Sachs, and usually is initially seen in children between two and ten years old.
People with Tay-Sachs disease develop cognitive and motor skill deterioration,
dysar-thria, dysphagia, ataxia, and spasticity; they typically die between five and
fifteen years old.
- Adult/Late-Onset Tay-Sachs disease: A rare form of this disease, known as Adult-Onset or
Late-Onset Tay-Sachs disease usually has its first symptoms during the 30s or 40s. In
contrast to the other forms, late-onset Tay-Sachs disease is usually not fatal as the
effects can stop progressing. It is frequently misdiagnosed. It is characterized by
unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset
Tay-Sachs disease which typically begin to be seen in adolescence or early adulthood -
include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive
decline, and psychiatric illness, particularly a schizophrenia-like psychosis. People
with late-onset Tay-Sachs disease frequently become full-time wheelchair users in
adulthood.
Until the 1970s and 1980s, when the disease's molecular genetics became known, the juvenile
and adult forms of the disease were not always recognized as variants of Tay-Sachs disease.
Post-infantile Tay-Sachs was often misdiagnosed as other neurological disorders.
Sandhoff disease Sandhoff disease is a lipid storage disorder characterized by a progressive
deterioration of the central nervous system. The clinical symptoms of Sandhoff disease are
identical to Tay-Sachs disease. Sandhoff disease is an autosomal recessive genetic disorder
caused by an abnormal gene for the beta subunit of the hexosaminidase B enzyme. This gene
abnormality results in a deficiency of hexosaminidase A and B that results in accumulation of
fats (lipids) called GM2 gangliosides in the neurons and other tissues.
Sandhoff disease, also known as Sandhoff-Jatzkewitz disease, variant 0 of GM2-Gangliosidosis
or Hexosaminidase A and B deficiency, is a lysosomal genetic, lipid storage disorder caused
by the inherited deficiency to create functional beta-hexosaminidases A and B. These
catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2,
its derivative GA2, the glycolipid globoside in visceral tissues, and some oligosaccharides.
Accumulation of these metabolites leads to a progressive destruction of the central nervous
system and eventually to death. The rare autosomal recessive neurodegenera-tive disorder is
clinically almost indistinguishable from Tay-Sachs disease, another genetic disorder that
disrupts beta-hexosaminidases A and S.
There are three different types of Sandhoff disease, classic infantile, juvenile, and adult
late onset. Each form is classified by the severity of the symptoms as well as the age in
which the patient shows these symptoms:
- Classic infantile form: Classic infantile form of the disease is classified by the
development of symptoms anywhere from 2 months to 9 months of age. It is the most severe
of all of the forms and will lead to death before the patient reaches the age of three.
This is the most common and severe form of Sandoff disease. Infants with this disorder
typically appear normal until the age of 3 to 6 months, when development slows and
muscles used for movement weaken. Affected infants lose motor skills such as turning
over, sitting, and crawling. As the disease progresses, infants develop seizures, vision
and hearing loss, mental retardation, and paralysis. An eye abnormality called a
cherry-red spot, which can be identified with an eye examination, is characteristic of
this disorder. Some infants with Sandhoff disease may also have enlarged organs
(or-ganomegalie) or bone abnormalities. Children with the severe form of this disorder
usually live only into early childhood.
- Juvenile form: Juvenile form of the disease shows symptoms starting at age 3 ranging to
age 10 and although the child usually dies by the time they are 15, it is possible for
them to live longer if they are under constant care.
- Adult onset form: Adult onset form of the disease is classified by its occurrence in
older individuals and has an effect on the motor function of these individuals and it is
not yet known if Sandhoff Disease will cause these individuals to have a decrease in
their life span.
Both Juvenile and Adult onset forms of Sandhoff disease are very rare. Signs and symptoms can
begin in childhood, adolescence, or adulthood and are usually milder than those seen with the
infantile form of Sandhoff disease. As in the infantile form, mental abilities and
coordination are affected. Characteristic features include muscle weakness, loss of muscle
coordination (ataxia) and other problems with movement, speech problems, and mental illness.
These signs and symptoms vary widely among people with late-onset forms of Sandhoff disease.
Sandhoff disease symptoms are clinically indeterminable from Tay-Sachs disease. The classic
infantile form of the disease has the most severe symptoms and is incredibly hard to diagnose
at this early age. The first signs of symptoms begin before 6 months of age and the parents'
notice when the child begins digressing in their development. If the children had the ability
to sit up by themselves or crawl they will lose this ability. This is caused by a slow
deterioration of the muscles in the child's body from the build-up of GM2 gangliosides. Since
the body is unable to create the enzymes it needs within the central nervous system, it is
unable to attach to these gangliosides to break them apart and make them non-toxic. With this
build-up there are several symptoms that begin to appear such as muscle/motor weakness, sharp
reaction to loud noises, blindness, deafness, inability to react to stimulants, respiratory
problems and infections, mental retardation, seizures, cherry red spots in the retina,
enlarged liver and spleen (hepatosplenomegaly), pneumonia, or bronchopneumonia.
The other two forms of Sandhoff disease have similar symptoms but to a lesser extent. Adult
and juvenile forms of Sandhoff disease are rarer then the infantile form. In these cases
victims suffer cognitive impairment (retardation) and a loss of muscle coordination that
impairs and eventually destroys their ability to walk; the characteristic red spots in the
retina also develop. The adult form of the disease, however, is sometimes milder, and may
only lead to muscle weakness that impairs walking or the ability to get out of bed.
New methods, like mass-spectrometry give a good chance to characterize specific metabolic
alterations in the blood of affected patients that allow diagnosing in the future the disease
earlier, with a higher sensitivity and specificity.
Therefore it is the goal of the study to validate this new biochemical marker from the blood
of the affected patients helping to benefit other patients by an early diagnose and thereby
with an earlier treatment.
