Sanfilippo syndrome
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Sanfilippo syndrome, also known as
mucopolysaccharidosis Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosome, lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within ...
type III (MPS III), is a rare
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
lysosomal storage disease Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
that primarily affects the
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
and
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
. It is caused by a buildup of large sugar molecules called
glycosaminoglycans Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
(AKA GAGs, or mucopolysaccharides) in the body's
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
s. Affected children generally do not show any signs or symptoms at birth, although some early indicators can be respiratory issues at birth, large head size, and umbilical hernia. In early childhood, they begin to develop developmental disability and loss of previously learned skills. In later stages of the disorder, they may develop seizures and movement disorders. Patients with Sanfilippo syndrome usually live into adolescence or early adulthood.


Signs and symptoms

The disease manifests in young children. Symptoms usually begin to appear between two and six years of age. Affected infants appear normal, although some mild
facial dysmorphism A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, genetic syndrome or birth defect. Dysmorphology is the study of dysm ...
may be noticeable. Of all of the MPS diseases, Sanfilippo syndrome produces the fewest physical abnormalities. After an initial symptom-free interval, patients usually present with a slowing of development and/or behavioral problems, followed by progressive intellectual decline resulting in severe
dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
and progressive motor disease.
Acquisition of speech Speech acquisition focuses on the development of vocal, acoustic and oral language by a child. This includes motor planning and execution, pronunciation, phonological and articulation patterns (as opposed to content and grammar which is language). ...
is often slow and incomplete. The disease progresses to increasing behavioral disturbance including
temper tantrums A tantrum, temper tantrum, lash out, meltdown, fit or hissy fit is an emotional outburst, usually associated with those in emotional distress, that is typically characterized by stubbornness, crying, screaming, violence, defiance, angry rant ...
, hyperactivity, destructiveness, aggressive behavior, pica, difficulties with toilet training, and sleep disturbance. As affected children initially have normal muscle strength and mobility, the behavioral disturbances may be difficult to manage. Disordered sleep in particular presents a significant problem to care providers. In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. The life-span of an affected child does not usually extend beyond late teens to early twenties. Individuals with MPS type III tend to have mild skeletal abnormalities; osteonecrosis of the femoral head may be present in severe cases. Optic nerve atrophy, deafness, and otitis can be seen in moderate to severe cases. Other characteristics include coarse facial features, thick lips, synophrys, and stiff joints. It is difficult to clinically distinguish differences among the four types of Sanfilippo syndrome. However, type A is usually the most severe subtype, characterized by earliest onset, rapid clinical progression with severe symptoms, and short survival. The median age of death for children afflicted with type A is 15.4 ± 4.1 years. It is important that simple and treatable conditions such as ear infections and toothaches not be overlooked because of behavior problems that make examination difficult. Children with MPS type III often have an increased tolerance to pain. Bumps, bruises, or ear infections that would be painful for other children often go unnoticed in children with MPS type III. Some children with MPS type III may have a
blood-clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The m ...
problem during and after surgery.


Genetics

Mutations in four different genes can lead to Sanfilippo syndrome. This disorder is inherited in an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
pattern. People with two working copies of the gene are unaffected. People with one working copy are
genetic carrier A hereditary carrier (genetic carrier or just carrier), is a person or other organism that has inherited a recessive allele for a genetic trait or mutation but usually does not display that trait or show symptoms of the disease. Carriers are, ho ...
s of Sanfilippo syndrome. They have no symptoms but may pass down the defective gene to their children. People with two defective copies will suffer from Sanfilippo syndrome.


Mechanism

Glycosaminoglycans (GAGs) are chains of sugar molecules. They are found in the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
and the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
, or stored in the secretory granules. GAGs are stored in the cell lysosome, and are degraded by enzymes such as glycosidases, sulfatases, and acetyltransferases. Deficiency in these enzymes lead to the four subtypes of MPS III.


Diagnosis

Sanfilippo syndrome types A, B, C, and D are considered to be clinically indistinguishable, although mutations in different genes are responsible for each disease. The following discussion is therefore applicable to all four conditions. A
urinalysis Urinalysis, a portmanteau of the words ''urine'' and ''analysis'', is a panel of medical tests that includes physical (macroscopic) examination of the urine, chemical evaluation using urine test strips, and microscopic examination. Macroscopic e ...
can show elevated levels of heparan sulfate in the urine. All four types of Sanfilippo syndrome show increased levels of GAGs in the urine; however, this is less true of Sanfilippo syndrome than other MPS disorders. Additionally, urinary GAG levels are higher in infants and toddlers than in older children. In order to avoid a
false negative A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test result ...
urine test due to
dilution Dilution may refer to: * Reducing the concentration of a chemical * Serial dilution, a common way of going about this reduction of concentration * Homeopathic dilution * Dilution (equation), an equation to calculate the rate a gas dilutes *Tradema ...
, it is important that a urine sample be taken first thing in the morning. The diagnosis may be confirmed by
enzyme assay Enzyme assays are laboratory methods for measuring enzymatic activity. They are vital for the study of enzyme kinetics and enzyme inhibition. Enzyme units The quantity or concentration of an enzyme can be expressed in molar amounts, as with a ...
of skin
fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
and
white blood cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
. The enzyme assay is considered to be the most credible diagnostic tool because it detects whether or not the enzymes that are normally present in the cellular pathway that is responsible for breaking down heparan sulfate are present or not, thereby providing a definitive answer. This test is also ideal for younger patients in which collecting a viable urine sample is difficult or impossible. Another diagnostic tool can be gene sequencing. However, if the genetic mutation they carry has never been seen or recorded, the patient would receive a false negative.
Prenatal diagnosis Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of ...
is possible by
chorionic villus sampling Chorionic villus sampling (CVS), sometimes called "chorionic ''villous'' sampling" (as "villous" is the adjectival form of the word "villus"), is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus. It ent ...
or
amniocentesis Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is ne ...
.


Treatments

Treatment remains largely supportive. The behavioral disturbances of MPS-III respond poorly to medication. If an early diagnosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
and therefore cannot treat the neurological manifestations of the disease. Along with many other
lysosomal storage disease Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
s, MPS-III exists as a model of a monogenetic disease involving the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
. Several promising therapies are in development. The French company Lysogene is conducting a phase II/III clinical trial of a
gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
-based treatment. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis. The flavonoid
genistein Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen. It was first isolated in 1899 from the dyer's bro ...
decreases the accumulation of GAGs. ''In vitro'', animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein. Despite its reported beneficial properties,
genistein Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen. It was first isolated in 1899 from the dyer's bro ...
also has toxic side effects. Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome. Participants in the first-ever "Caregiver Preference Study for Sanfilippo Syndrome" advocated for clinical trials that shift focus from primary cognitive outcomes to other multisystem endpoints, and perceptions of non-curative therapies revealed a preference for treatment options that stop or slow the disorder progression to maintain the child’s current function to ensure quality of life; thus, parents express high risk tolerance and a desire for broader inclusion criteria for trials.


Prognosis

According to a study of patients with Sanfilippo syndrome, the median life expectancy varies depending on the subtype. In Sanfilippo syndrome type A, the mean age at death (± standard deviation) was 15.22 ± 4.22 years. For type B, it was 18.91 ± 7.33 years, and for type C it was 23.43 ± 9.47 years. The mean life expectancy for type A has increased since the 1970s.


Epidemiology

Incidence of Sanfilippo syndrome varies geographically, with approximately 1 case per 280,000 live births in Northern Ireland, 1 per 66,000 in Australia, and 1 per 50,000 in the Netherlands. The Australian study estimated the following incidence for each subtype of Sanfilippo syndrome:


History

The condition is named after Sylvester Sanfilippo, the
pediatrician Pediatrics ( also spelled ''paediatrics'' or ''pædiatrics'') is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, paediatrics covers many of their youth until the ...
who first described the disease in 1963.


Caregiver impact

Caregivers for children with Sanfilippo syndrome face a unique set of challenges because of the disease's complex nature. There is little understanding among clinicians of the family experience of caring for patients with Sanfilippo and how a caregiver's experiences change and evolve as patients age. The burden and impact on caregivers' quality of life is poorly defined and best-practice guidance for clinicians is lacking. Material was copied from this source, which is available under
Creative Commons Attribution 4.0 International License
A best-practice guidance to help clinicians understand the challenges caregivers face was published July 2019 in the ''Orphanet Journal of Rare Diseases'' by a group of international clinical advisors with expertise in the care of pediatric patients with Sanfilippo, lysosomal storage disorders, and life as a caregiver to a child with Sanfilippo. The group reviewed key aspects of caregiver burden associated with Sanfilippo B by identifying and quantifying the nature and impact of the disease on patients and caregivers. Recommendations were based on findings from qualitative and quantitative research. The article's authors reported, "Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties ... Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress." Additionally, the authors call for changing the narrative associated with Sanfilippo: "The panel agreed that the perceived aggressive behavior of the child may be better described as 'physical impulsiveness' and is often misunderstood by the general public. Importantly, the lack of intentionality of the child’s behavior is recognized and shared by parents and panel members ... Parents may seek to protect their child from public scrutiny and avoid situations that may engender criticism of their parenting skills."


Society and culture

The community of Sanfilippo families, foundations, scientists and researchers, and industry partners and collaborators around the world have dedicated November 16 as World Sanfilippo Awareness Day. orld Sanfilippo Awareness Dayhttps://curesanfilippofoundation.org/worldsanfilippoawarenessday/ World Sanfilippo Awareness Day is about spreading awareness and sparking conversations globally about Sanfilippo syndrome. This day of awareness is in honor of the children around the world living with Sanfilippo syndrome today, and those who have died. It also honors the families of the children with Sanfilippo syndrome. November 16, 2019, was the first year observing World Sanfilippo Awareness Day.


See also

*
Mucopolysaccharidosis Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosome, lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within ...
*
Hurler syndrome Hurler syndrome, also known as mucopolysaccharidosis Type IH (MPS-IH), Hurler's disease, and formerly gargoylism, is a genetic disorder that results in the buildup of large sugar molecules called glycosaminoglycans (GAGs) in lysosomes. The inab ...
( MPS I) *
Hunter syndrome Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is a rare genetic disorder in which large sugar molecules called glycosaminoglycans (or GAGs or mucopolysaccharides) build up in body tissues. It is a form of lysosomal storage disease. ...
(MPS II) *
Morquio syndrome Morquio syndrome, also known as Mucopolysaccharidosis Type IV (MPS IV), is a rare metabolic disorder in which the body cannot process certain types of sugar molecules called glycosaminoglycans (AKA GAGs, or mucopolysaccharides). In Morquio syndr ...
(MPS IV) *
List of neurological conditions and disorders This is a list of major and frequently observed neurological disorders (e.g., Alzheimer's disease), symptoms (e.g., back pain), signs (e.g., aphasia) and syndromes (e.g., Aicardi syndrome). There is disagreement over the definitions and criteria ...


References


External links

* {{Mucopolysaccharidoses Autosomal recessive disorders Proteoglycan metabolism disorders Rare diseases Syndromes with craniofacial abnormalities Syndromes with intellectual disability Syndromes affecting the nervous system Rare syndromes