Sandhoff disease
Sandhoff disease, is a lysosomal genetic, lipid storage
disorder caused by the inherited deficiency to create
functional beta-hexosaminidases A and B.[1][2] These
catabolic enzymes are needed to degrade the neuronal
membrane components, ganglioside GM2, its derivative
GA2, the glycolipid globoside in visceral tissues,[1] and
some oligosaccharides. Accumulation of these
metabolites leads to a progressive destruction of the
central nervous system and eventually to death.[1][3] The
rare autosomal recessive[4][5] neurodegenerative disorder
is clinically almost indistinguishable from Tay–Sachs
disease, another genetic disorder that disrupts betahexosaminidases A and S. There are three subsets of
Sandhoff disease based on when first symptoms appear:
classic infantile, juvenile and adult late onset.
Sandhoff disease
Other
names
Sandhoff–Jatzkewitz disease,
Variant 0 of GM2-gangliosidosis
or Hexosaminidase A and B
deficiency
Contents
Symptoms
Causes
Mutations and polymorphism
Pathophysiology
Diagnosis
Types
Treatment
History
See also
References
External links
Symptoms
Sandhoff disease is inherited via an autosomal
recessive manner
Specialty Endocrinology
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.[6] The first signs of symptoms begin before 6 months of age
and the parents’ notice when the child begins regressing 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 buildup 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 buildup 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.[7]
The other two forms of Sandhoff disease have similar symptoms but to a lesser extent. Adult and juvenile
forms of Sandhoff disease are more rare than the infantile form.[8] 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.[9]
Causes
Two parents carrying a mutated gene and passing it on to their offspring cause the disease. Even with both
parents carrying the disease in their genome, there is only a 25% chance that they will have a child
containing the genetic coding for the disease (see figure right).[10]
Each form of the disease is caused by the differences in the various mutations of the genome, in particular
the codons on the 14 exons in the HEX B gene located within chromosome 5 (see figure bottom), leading to
the differences in severities of the symptoms.[6] The difference in the codons has the consequence of
inhibiting two enzymes located in the lysosomes of the neurons of the central nervous system. Lysosomes
contain various enzymes to break down byproducts and toxins to ensure they do not accumulate enough to
interfere with the function of the central nervous system.[7]
Using restriction enzymes, it was discovered that a mutation on chromosome 5 particularly within the
C1214T allele caused the adult onset form of Sandhoff Disease. For the patient showing symptoms of the
infantile or juvenile form they have a mutation on exon I207V from their father, and a 16 base pair deletion
from their mother which can be located on as many as five exons, exons 1–5.[11]
Mutations and polymorphism
Articles regarding Sandhoff disease frequencies among distinct groups of people contain discrepancies from
one another. More than 25 mutations have been reported other than novel mutations.[5]
One article says that Sandhoff disease is found commonly in individuals with a non-Jewish descent.[12]
Others say that it is more commonly in:
the Creole population of northern Argentina[13]
the indigenous Métis in Saskatchewan[10]
Christian Maronite communities from Cyprus[14]
Discovery of several mutations in Ashkenazi Jews may reflect ascertainment bias rather than a high
population frequency, because Ashkenazi Jews were the targeted population in a mass screening program for
Tay-Sachs disease. Several rare SD mutations were discovered as researchers resolved cases of enzyme
deficiency among suspected TSD carriers, but no cases of the disease itself have been reported.[5][15]
However, since it is an autosomal recessive disease, it is likely found in any ethnic group passing from
generation to generation through carriers without being expressed in their offspring. Even though the family
may not have a history of Sandhoff disease, it is possible for two individuals to have a child with the
disease. Since Sandhoff disease was only discovered in 1968, there are years the disease has gone
undetected because of misdiagnoses.
Pathophysiology
Biallelic pathogenic variants in the HEXB gene cause Sandhoff disease. The gene provides instructions for
making a protein crucial to the enzymes beta-hexosaminidase A and beta-hexosaminidase B,[16] which
function in nerve cells to break down fatty substances, complex sugars, and molecules that are linked to
sugars. In particular, beta-hexosaminidase A breaks down a fatty compound called GM2 ganglioside.
Mutations in the HEXB gene disrupt the activity of these enzymes, preventing the breakdown of GM2
ganglioside and other molecules.
As a result, progressive damage caused by the resulting buildup of GM2 ganglioside leads to the destruction
of nerve cells, causing the signs and symptoms associated with Sandhoff disease.
Diagnosis
Sandhoff disease can be detected through the following procedures (before it is apparent through physical
examination): a biopsy removing a sample of tissue from the liver, genetic testing, molecular analysis of
cells and tissues (to determine the presence of a genetic metabolic disorder), enzyme assay, and occasionally
a urinalysis to determine if the above-noted compounds are abnormally stored within the body. For a child to
suffer from this disease, both parents must be carriers, and both must transmit the mutation to the child.
Thus, even in the case where both parents have the mutation, there is only a 25 percent chance their child
will inherit the condition. Frequently, parents are given the opportunity to have a DNA screening if they are
at high risk, to determine their carrier status before they have children. However, it is also highly
recommended to undergo testing even for those parents who do not have a family history of Sandhoff
disease. Over 95% of the families that have children with Sandhoff disease had no known prior family
history of the condition, as the mutation in the HEXB gene does not cause clinical symptoms when only one
copy is present, and often passed undetected from one generation to the next[6] Naturally, if an individual
carries the mutation, he or she has a risk of transmitting it to the unborn child. Genetic counseling is
recommended for those who have the mutation.
It is possible for parents who are about to have a child or had a child with Sandhoff Disease can have a PGD
or PEGD. PEGD is pre-embryonic genetic diagnosis for the parents that would not benefit from a preimplantation genetic diagnosis because of their religion or negative attitude for the discarding of embryos.
PEGD sequences the genome of the embryo to be produced by two parents if they were to conceive a child.
If the family has a history of Sandhoff disease it is recommended they have their genome sequenced to
ensure they are not carriers or to sequence the genome of their child.[17]
Types
There are three types of Sandhoff disease: classic infantile, juvenile, and adult late onset.[16] Each form is
classified by the severity of the symptoms as well as the age at which the patient shows these symptoms.[18]
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.[19] This is the most common and severe
form of Sandhoff 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, dementia, 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 have enlarged organs (organomegaly) or
bone abnormalities. Children with the severe form of this disorder usually live only into early
childhood.
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.[20] Symptoms include autism, ataxia, motor skills regression,
spacticity, and learning disorders.[21]
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. It is not yet known if Sandhoff disease will
cause these individuals to have a decrease in their life span.[6]
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.
Treatment
Currently Sandhoff disease does not have any standard treatment and does not have a cure. However, a
person suffering from the disease needs proper nutrition, hydration, and maintenance of clear airways. To
reduce some symptoms that may occur with Sandhoff disease, the patient may take anticonvulsants to
manage seizures or medications to treat respiratory infections, and consume a precise diet consisting of
puree foods due to difficulties swallowing. Infants with the disease usually die by the age of 3 due to
respiratory infections. The patient must be under constant surveillance because they can suffer from
aspiration or lack the ability to change from the passageway to their lungs versus their stomach and their spit
travels to the lungs causing bronchopneumonia. The patient also lacks the ability to cough and therefore
must undergo a treatment to shake up their body to remove the mucus from the lining of their lungs.
Medication is also given to patients to lessen their symptoms including seizures.
Currently the government is testing several treatments including N-butyl-deoxynojirimycin in mice, as well
as stem cell treatment in humans and other medical treatments recruiting test patients.[11] A Sandhoff
disease study showing proof of principle for gene therapy in a human model system using CRISPR and
virus gene correction gives the chance for clinical trials to cure the disease. The ultra-rare occurrence is a
main hurdle to overcome for clinical trials.[22][23]
History
Sandhoff disease is one of several forms of what was
formerly known as amaurotic idiocy. This inherited disease
is characterized by the accumulation of lipid-containing
cells in the viscera and in the nervous system, mental
retardation, and impaired vision or blindness. The chemical
and enzymatic analysis of various patients with amaurotic
idiocy by Konrad Sandhoff (1939- ), a German Biochemist,
who led to the identification of several biochemically
distinct diseases: The first biochemical description of
GM1-gangliosidosis in 1963,[24] Sandhoff disease in
1968,[1] Tay-Sachs-Disease,[2][25] the AB-variant of GM2Gangliosidosis[2][26] and the B1-variant of GM2gangliosidosis.[27]
Sphingolipidoses
It came to the discovery of the molecular defect in
Sandhoff disease, when Konrad Sandhoff studied the
biochemistry of sphingolipids and gangliosides in the laboratory of Prof. Horst Jatzkewitz (1912–2002), a
German Biochemist (Max- Planck-Institute for Psychiatry, Munich). In October 1966, he obtained deepfrozen autopsy material from an infantile case with amaurotic idiocy. The glycolipid analysis soon
demonstrated differences from all the cases studied before. Besides the neuronal storage of GM2, the storage
of GA2 was much more pronounced, and different from all cases of Tay-Sachs disease studied so far,
globoside accumulated in the visceral organs and, most importantly, hexosaminidase activity was almost
completely absent. The disease causing catabolic enzyme deficiency of hexosaminidases was demonstrated
with four different substrates (p–nitrophenyl-β-D-N-acetylglucosaminide, p-nitrophenyl-β-D-Nacetylgalactosaminide, glycolipid [3H]GA2 and [3H]globoside) in four different organs and published in
1968.[1]
See also
GM2-gangliosidosis, AB variant
globoside
References
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exceptional case of Tay-Sachs disease with additional storage of kidney globoside in visceral
organs". Life Sci. 7 (6): 283–8. doi:10.1016/0024-3205(68)90024-6 (https://doi.org/10.1016%2
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2. Sandhoff K (August 1969). "Variation of beta-N-acetylhexosaminidase-pattern in Tay-Sachs
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Hexosaminidase-Defekt (Klinische, morphologische und biochemische Befunde bei einem Fall
mit viszeraler Speicherung von Nierenglobosid)". Dtsch Med Wochenschr. 93 (39): 1833–9.
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13. Kleiman FE, et al. (1994). "Sandhoff disease in Argentina: high frequency of a splice site
mutation in the HEXB gene and correlation between enzyme and DNA-based tests for
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M.; Golebiowski, Diane; Sena-Esteves, Miguel; Tifft, Cynthia J.; Proia, Richard L. (2018-0122). "Cerebral organoids derived from Sandhoff disease induced pluripotent stem cells exhibit
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idiocy". Biochim Biophys Acta. 70: 354–6. doi:10.1016/0006-3002(63)90764-9 (https://doi.org/1
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13957544).
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This article incorporates some public domain text from The U.S. National Library of Medicine (http://ghr.nl
m.nih.gov)
External links
Sandhoff (https://www.ninds.nih.gov/Disorders/All-Disorders/ Classification ICD-10: E75.0 (htt D
Sandhoff-Information-Page) at NINDS
ps://icd.who.int/bro
wse10/2019/en#/E7
5.0) · ICD-10-CM:
E75.01 (https://icdc
odelookup.com/icd10/codes/E75.01) ·
ICD-9-CM: 330.1 (h
ttp://www.icd9data.c
om/getICD9Code.a
shx?icd9=330.1) ·
OMIM: 268800 (http
s://omim.org/entry/2
68800) · MeSH:
D012497 (https://w
ww.nlm.nih.gov/cgi/
mesh/2015/MB_cg
i?field=uid&term=D
012497) ·
DiseasesDB:
29469 (http://www.d
iseasesdatabase.co
m/ddb29469.htm)
External
resources
Orphanet: 796 (htt
p://www.orpha.net/c
onsor/cgi-bin/OC_E
xp.php?lng=en&Exp
ert=796)
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