Sanfilippo syndrome

Last updated

Sanfilippo Syndrome (MPS III)
Other names Mucopolysaccharidosis III; MPS III
Hadar Sanfilippo.jpg
12-year-old girl with Sanfilippo Syndrome Type A
Pronunciation
  • /ˌsanfɪˈliːpəʊz/
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Progressive intellectual disability; hyperactivity; dementia; loss of mobility
Usual onsetBirth; symptoms usually become apparent between ages 1-4
DurationLifelong
TypesSanfilippo Syndrome Types A, B, C, and D
CausesInherited enzyme deficiency
Diagnostic method MPS urine screen (initial test), confirmed by blood test
TreatmentThere is no cure; only symptom management
Prognosis Lifespan is reduced; most patients survive until the early teenage years, but some may reach their 30s
Frequency1 in 70,000 [1]

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare lifelong genetic disease that mainly affects the brain and spinal cord. It is caused by a problem with how the body breaks down certain large sugar molecules called glycosaminoglycans (also known as GAGs or mucopolysaccharides). In children with this condition, these sugar molecules build up in the body and eventually lead to damage of the central nervous system and other organ systems. [2]

Contents

Children with Sanfilippo syndrome do not usually show any problems at birth. As they grow, they may begin having trouble learning new things and might lose previously learned skills. As the disease progresses, they may develop seizures and movement disorders. Most children with Sanfilippo syndrome live into adolescence or early adulthood. [3]

Signs and symptoms

The age of onset, severity, and progression of the disease can vary greatly between patients with different subtypes and within the same subtype. Development during the prenatal and early post-natal stages progresses normally. [4] Between the ages of one to four is when the disease typically manifests. [5] Affected infants appear normal, although some mild facial dysmorphism may be noticeable. Of all of the MPS diseases, Sanfilippo syndrome produces the fewest physical abnormalities. Possible clinical somatic symptoms, although rare, include coarse facial features with broad eyebrows, dark eyelashes, dry and rough hair, and skeletal pathology that affects growth. [6]

After an initial symptom-free interval, symptoms may arise during the early years of development, from the age of one to three. [6] Children usually present with delayed cognitive development and/or behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease. [7] Acquisition of speech is often slow and incomplete. Even though delayed cognitive development may occur, it tends to be mild in individuals with Sanfilippo syndrome. [8]

Between the ages of three to ten, the disease progresses to increasing behavioral disturbance including temper tantrums, hyperactivity, destructive behavior, aggressive behavior, pica, difficulties with toilet training, and sleep disturbance. [9] As affected children initially have normal muscle strength and mobility, the behavioral disturbances may be difficult to manage. The disordered sleep in particular presents a significant problem to care providers. [10] People with this disorder may stay in this phase for five to ten years. [6] After that, their behavior subsides, but patients start to become increasingly immobile and unresponsive as individuals with Sanfilippo syndrome will gradually lose their motor skills, often require wheelchairs, and develop swallowing difficulties and seizures. [11] Persons with Sanfilippo Syndrome tend to regress to an unresponsive or vegetative state until they pass away, which can occur anywhere between early teen years to their seventies. [6] The life-span of a severely affected person does not usually extend beyond late teens to early twenties. [12] However, persons with less severe phenotypes of the disease have varied life spans, some cases surviving into their seventies. [10]

The most common symptoms seen in individuals with Sanfilippo syndrome are neurological and may include intellectual disabilities, impaired language development, abnormal movements, and trouble sleeping; however, other symptoms commonly seen are excessive hair growth, chronic ear infections, respiratory infections, and poor nutrient absorption. [13] Other signs less frequently seen in persons with Sanfilippo syndrome include behavioral changes and musculoskeletal changes such as increased muscle and joint stiffness and changes in bone growth or density. [13] [9]

Children with Sanfilippo syndrome 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 Sanfilippo syndrome. Some children with Sanfilippo syndrome may have a blood-clotting problem during and after surgery. [5]

Individuals with Sanfilippo syndrome are born within normal physiological ranges. At around age 2, individuals with Sanfilippo syndrome are significantly taller than children without. [14] By the age of 4, mostly male children with Sanfilippo syndrome were still taller than children without. [14] Growth velocity decelerates dramatically after the age of 5, and by the time children with Sanfilippo syndrome reach 17, all individuals are significantly shorter than their reference groups. [14]

It is difficult to clinically distinguish symptomatical differences among the four types of Sanfilippo syndrome. Although, each of the types can vary in severity. [15] Type A is usually the most severe subtype, characterized by earliest onset, rapid clinical progression with severe symptoms, and short survival with patients averaging between 15 to 18 years old. [15] Type B is considered slightly less aggressive than type A, but still display rapid clinical progression, and short survival with patients averaging between 17 to 19 years old. [15] Type C is considered the less aggressive form of Sanfilippo syndrome with a patient's average life expectancy between 19 to 34 years of age, depending on the study. [15] Type D is the rarity subtype of Sanfilippo syndrome and no data has been published on average life expectancy. [15]

Genetics

Mutations in four different genes can lead to Sanfilippo syndrome. Each gene codes for a specific enzyme responsible for the breakdown of heparan sulfate. [10] This disorder is inherited in an autosomal recessive pattern meaning a person must have two copies of the mutated gene (one from each parent) to develop the disorder. People with two working copies of the gene are unaffected. People with one working copy are genetic carriers of Sanfilippo syndrome and do not show symptoms, but they may pass down the affected gene to their children. People with two affected copies will suffer from Sanfilippo syndrome. [16]

Genetics of MPS-III
Sanfilippo syndrome typeGeneEnzymeChromosomal regionNumber of known mutations causing this type
Type A SGSH heparan N-sulfatase [16] 17q25.3155 [17]
Type B NAGLU Alpha-N-acetylglucosaminidase [16] 17q21.2229 [17]
Type C HGSNAT acetyl-CoA:alpha-glucosaminide N-acetyltransferase [16] 8p11.2177 [17]
Type DGNS N-acetylglucosamine-6-sulfatase [16] 12q14.325 [17]

Risk factors for the Sanfilippo Syndrome are a family history of MPS disease(s), individuals who are from regions that have a high incidence of Sanfilippo syndrome, and individuals carrying the defective allele(s), as stated above. [18]

Sanfilippo syndrome can also appear as a 5th mutation, type E. This mutation results from a deficiency in the N-glucosamine 3-O-sulfatase, ARSG, gene. [6] Although it has been characterized on a molecular level and seen within dogs and mouse models, the genetic mutation has not been seen to manifest in humans. [6]

Mechanism

Symptoms due to Sanfilippo Syndrome arise because the body cannot break down a type of sugar chain called heparan sulfate. [6] [19] These chains of sugar molecules, known as glycosaminoglycans or GAGs, are found in different parts of cells and tissues, such as the extracellular matrix and the cell membrane, or stored in the secretory granules (which are small particles inside cells). [20] Normally, special enzymes found in lysosomes, the cell's recycling centers, break down these sugar chains. These degrading enzymes include glycosidases, sulfatases, and acetyltransferases and a deficiency or absence in any one of these enzymes can lead to improper breakdown of heparan sulfate. The sugar chains buildup in the cell's lysosomes eventually causing cell damage, dysfunction, and death; [21] how it works is not fully understood. [22] Heparan sulfate may also accumulate outside of cells or be excreted in urine. [23] The build up of these sugar molecules can occur in the brain, spinal cord, and connective tissue of various organ systems which are what led to the range of symptoms associated with Sanfilippo syndrome. [18] [24]

The Sanfilippo Syndrome is associated with a wide range of symptoms is due to the protein heparan sulfate is attached to, heparan sulfate proteoglycans (HSPGs). HSPGs are key players in various signaling pathways, controls neural progenitor proliferation, and other essential processes within the CNS. [22]

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. Another subtype has been identified, but it has only been found in mice. [15] The following discussion is therefore applicable to all four conditions. Thus, there are two main ways that can be used to confirm if an individual has Sanfilippo syndrome: a urinalysis and genetic testing. [25] [9]

A urinalysis can show elevated levels of heparan sulfate in the urine. [16] All four types of Sanfilippo syndrome show increased levels of GAGs in the urine, so there is no distinction between the Sanfilippo syndrome subtypes based on a urinalysis alone; however, in MPS IIIA and IIIB patients, the plasma and CSF were also found to be elevated. [26] Additionally, urinary GAG levels are higher in infants and toddlers than in older children. In order to avoid a false negative urine test due to dilution, it is important that a urine sample be taken first thing in the morning. The diagnosis may be confirmed by enzyme assay of skin fibroblasts and white blood cells, as well as gene sequencing. Through gene sequencing, known genetic defects can be detected in order to identify the disease. [25] Aside from confirming diagnosis, genetic testing is also recommended to determine carriers and to understand development of the disease. [10]

There are various stages in a child's life in which they can be diagnosed with Sanfilippo syndrome. Diagnosing a child prior to presentation of symptoms is integral for experimental treatments to be beneficial. [27] Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. [28] Newborn diagnosis is also a possibility; however, no country has mandated testing for this specific disease. Testing for newborns includes examining their blood to locate the mutation. [27] Although there is no current standard, largely due to economical reasons, a whole genome sequencing may prove to be beneficial in the future. This method can shorten the route for accurate diagnosis, which can ultimate help the individual and their families. [25]

A diagnosis of Sanfilippo syndrome should be considered by providers if a child presents with symptoms associated with other disorders such as behavioral or attention deficit disorders or autism spectrum disorder [11] as there is overlap of behaviors with these conditions. [29] Diagnosing individuals with Sanfilippo syndrome can be challenging because of the rarity of the disease and variability of the presentation in early symptoms and an accurate diagnosis may take years. Due to the neurological symptoms presented in Sanfilippo syndrome, misdiagnoses can occur, such as developmental delays, attention deficit/hyperactivity disorder (ADHD), or autism spectrum disorder (ASD) diagnoses being made. [30] Moreover, other medical conditions that present with physical symptoms such as juvenile idiopathic arthritis or behavioral issues such as Landau - Kleffner syndrome can be mistaken for the disease and prevent early diagnosis of Sanfilippo. Additionally, screening for Sanfilippo syndrome is not a routine procedure, which can also delay a proper diagnosis to have the best possible management. [25]

Once a diagnosis has been made, it is important that children are monitored and seen regularly by their healthcare provider to assess the progression of disease, decline of normal function, and to identify other health issues associated with Sanfilippo syndrome such as cardiac, musculoskeletal, and gastrointestinal problems. [10] Testing to monitor disease progression includes magnetic resonance imaging (MRI), x-rays, electroencephalography (EEG), electrocardiogram (ECG), and abdominal imaging. These tests are more specifically used to determine the source of neurological pain, cognitive and behavioral changes, physical symptoms of pain, cardiac abnormalities, and symptoms of gastroesophageal reflux disease (GERD). Examples of routine monitoring includes physical, eye, ear, nutritional, and dental exams. [10]

Treatment

While treatment remains largely supportive, research advancements are being made in the fields of pharmacology, stem cell, and genetics to address the disease. Currently, there is no cure for any subtype of Sanfilippo syndrome. [31] [32]

Supportive therapies to manage Sanfilippo syndrome include the use of medications, physical therapy, medical equipment, surgery, and occupational therapy to treat behavioral and cognitive delays, musculoskeletal damage, and to improve overall quality of life. [2] Evidence for medications that effectively manage behavioral problems and seizures in children with Sanfilippo syndrome are limited. [2] [10] Occupational and physical therapy can assist children with any movement restrictions. Staying up to date with vaccines against pneumococcal disease is also recommended due to the increased risk of contracting respiratory infections. Surgical interventions can be used to minimize ear infections, scoliosis, and other complications that occur during the disease progression. Due to the disease's impact on different organs and systems, healthcare professionals from various fields are involved and integral in managing the child's symptoms. [10]

Pharmacological interventions for the management of symptoms associated with Sanfilippo syndrome vary depending on the affected organ system. These may include gastrointestinal medications, antibiotics, anticholinergics, melatonin for sleep disorders, or neurological medications to help modify behaviors or control seizures. [10] It is important to note that behavioral disturbances of Sanfilippo syndrome may vary in response to medication, as each individual may react differently to the medications that are intended to treat the individual's mental state. [25] However, medication usage can still be pursued to treat an individual’s symptoms instead of managing Sanfilippo syndrome to improve their quality of life.

If an early diagnosis is made, bone marrow replacement may be beneficial. [33] Patients that underwent bone marrow transplant before the age of two showed neurocognitive function stabilization. [34] Although the missing enzyme can be manufactured and given intravenously (also known as enzyme replacement therapy) to help treat other non-neurological lysosomal storage diseases and Sanfilippo syndrome with minor neurological impacts, it cannot penetrate the blood–brain barrier and therefore cannot treat the moderate to severe neurological manifestations of MPS-III. [17] Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system. [25]

Gene therapy in particular is under Phase I/II clinical trial in France since October 2011 under the leadership of Paris-based biotechnology company Lysogene. [35] [36] Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the blood–brain barrier, stabilization of abnormal but active enzyme to prevent its degradation, and implantation of stem cells 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.

Another treatment currently being studied is enzyme replacement therapy, which works by replacing the enzyme that is not present or deficient by infusing the enzyme into the body. [37] However, a challenge of this treatment option is that the enzymes being replaced do not have the ability to cross the blood-brain barrier, one of the places sulfate heparan accumulates. [6] Additionally, antibodies that can break down the added enzyme are present in individuals with Sanfilippo syndrome, which can reduce the efficacy of enzyme replacement therapy. [17] In studies, injection of the enzyme sulfamidase into the brain or cerebrospinal fluid of mice has been shown to reduce symptoms of the Sanfilippo Syndrome. Interestingly, injecting sulfamidase in places outside the CNS has not shown to be as effective.

Substrate reduction therapy (SRT) is also currently being studied to treat Sanfilippo syndrome. Since Sanfilippo syndrome occurs due to the body's inability to break down GAGs, SRT functions by targeting the genes responsible for the synthesis of GAGs to restore the balance of production and breakdown of GAGs. [17] While this therapy is innovative, the technology to deliver the therapy to ensure effectiveness is not yet available. A part of SRT, genistein is also believed to play a role in reducing GAG synthesis in cells by blocking hormones that are responsible for enhancing GAG production. [38] [17] The safety of oral genistein has been confirmed in clinical trials with children; [38] however, results on its effectiveness are inconclusive. One clinical trial showed reduction of heparan sulfate but no clinical benefit, while another trial showed behavioral improvement due to reduction in heparan sulfate and neuroinflammation. [4] There is currently one clinical trial ongoing on genistein therapy. [39]

Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome. [40] [41] [42] [43] [44]

Prognosis

According to a study of people 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. [45] In severe cases of Sanfilippo syndrome, less than twenty percent of people survive past 20 years of age. [11]

Epidemiology

It is estimated that approximately 1 in 70,000 newborns are born with Sanfilippo syndrome. [46] The point prevalence (the proportion of people in a population that has the trait at a given point of time) can vary from 1 to 9 in 1,000,000 people. [46] Sanfilippo syndrome varies geographically, with approximately 1 case per 280,000 live births in Northern Ireland, [47] 1 per 66,000 in Australia, [48] and 1 per 50,000 in the Netherlands. [49] Globally, there are an estimated 12,000 to 19,000 individuals living with types A, B, and C. [50] Subtypes A and B are predominately found in Europe, with subtype A specific to the northern region and subtype B specific to the southern region. [15]

Studies were performed across several countries assessing the mean age of diagnosis for each type of Sanfilippo syndrome. [46] For patients with Sanfilippo syndrome type A, mean age at diagnosis was found to between 3.5 to 4.9 years of age. For patients with Sanfilippo syndrome type B, mean age at diagnosis was found to be between 3.5 to 4.9 years of age. For patients with Sanfilippo syndrome type C, mean age at diagnosis was found to be between 4.5 and 19 years of age. For patients with Sanfilippo syndrome type D, mean age at diagnosis was found to be between 8.2 and 8.3 years of age. [46]

Worldwide, Sanfilippo syndrome Type A and B affects the most people with Types C and D seen less commonly; however, the actual number of persons affected may be more than reported due to incorrect or delayed diagnosis of the disorder. [11] An Australian study estimated the following incidences for each subtype of Sanfilippo syndrome in the Australian population:

Sanfilippo syndrome typeApproximate incidencePercentage of casesAge of onset
A1 in 100,000 [48] 60%1.5-4
B1 in 200,000 [48] 30%1–4
C1 in 1,500,000 [48] 4%3–7
D1 in 1,000,000 [48] 6%2–6

Over 50% of individual with Sanfilippo syndrome type A's die from pneumonia. [45] The remaining causes of death for type A are spread out between cardiorespiratory failure, gastrointestinal complications, central nervous system complications, and other. [45] Pneumonia is also the primary cause of death for Sanfilippo syndrome type B. [45] Over 30% of individuals with Sanfilippo syndrome type B die from pneumonia. The remaining causes of death for type B are spread out between cardiorespiratory failure, gastrointestinal complications and other. [45] Due to the rarity of Sanfilippo syndrome type C and D, not enough data was collected to estimate mortality rates. [45]

History

The condition is named after Sylvester Sanfilippo, the pediatrician who first described the disease in 1963. [5] [28] [51]

Society and culture

The economic burden of Sanfilippo syndrome worldwide has not been studied; however new research shows the disease's impact in monetary and DALYs terms in the United States. DALYs stands for disability adjusted life years and the article describes it as "...years of life lost from early death and the years lived with a disability or ill-health, compared to a typical healthy life." [52] The disease is estimated to cost the U.S $1.55 billion in the next twenty years, and due to the heavy burden caregivers of children with Sanfilippo syndrome carry, they were estimated to lose an average of 2.08 DALYs (father) or 4.08 DALYs (mother), with an economical loss of $4.54 million and $5.61 million DALYs. A child diagnosed with the disease loses 53 (male) or 58 DALYs (female). [52]

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; [12] however, quantitative data revealed that parents of children with Sanfilippo syndrome have reported they would like to see therapies that target both behavioral issues such as lack of communication, hyperactivity, and frustration, as well as physical symptoms such as motor and sleep issues. They believe these types of treatments would greatly reduce the burden for both parties. Parents also specified their willingness to try experimental treatments, but were disappointed that most clinical trials limited access to younger children with less disease progression. [53]

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. [12]

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. [12]

The article's authors reported that: "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." [12]

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 many engender criticism of their parenting skills." [12]

See also

Related Research Articles

<span class="mw-page-title-main">Macrocephaly</span> Abnormally large head size

Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.

<span class="mw-page-title-main">Mucopolysaccharidosis</span> Medical condition

Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. GAGs are also found in the fluids that lubricate joints.

<span class="mw-page-title-main">Lysosomal storage disease</span> Medical condition

Lysosomal storage diseases 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 parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation, the large molecules accumulate within the cell, eventually killing it.

<span class="mw-page-title-main">Alpha-mannosidosis</span> Medical condition

Alpha-mannosidosis is a lysosomal storage disorder, first described by Swedish physician Okerman in 1967. In humans it is known to be caused by an autosomal recessive genetic mutation in the gene MAN2B1, located on chromosome 19, affecting the production of the enzyme alpha-D-mannosidase, resulting in its deficiency. Consequently, if both parents are carriers, there will be a 25% chance with each pregnancy that the defective gene from both parents will be inherited, and the child will develop the disease. There is a two in three chance that unaffected siblings will be carriers. In livestock alpha-mannosidosis is caused by chronic poisoning with swainsonine from locoweed.

<span class="mw-page-title-main">Hurler syndrome</span> Genetic disorder

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 inability to break down these molecules results in a wide variety of symptoms caused by damage to several different organ systems, including but not limited to the nervous system, skeletal system, eyes, and heart.

<span class="mw-page-title-main">Morquio syndrome</span> Medical condition

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 syndrome, the specific GAG which builds up in the body is called keratan sulfate. This birth defect, which is autosomal recessive, is a type of lysosomal storage disorder. The buildup of GAGs in different parts of the body causes symptoms in many different organ systems. In the US, the incidence rate for Morquio syndrome is estimated at between 1 in 200,000 and 1 in 300,000 live births.

<span class="mw-page-title-main">Hunter syndrome</span> X-linked recessive genetic condition

Hunter syndrome, or mucopolysaccharidosis type II, is a rare genetic disorder in which large sugar molecules called glycosaminoglycans build up in body tissues. It is a form of lysosomal storage disease. Hunter syndrome is caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The lack of this enzyme causes heparan sulfate and dermatan sulfate to accumulate in all body tissues. Hunter syndrome is the only MPS syndrome to exhibit X-linked recessive inheritance.

The GM1 gangliosidoses, usually shortened to GM1, are gangliosidoses caused by mutation in the GLB1 gene resulting in a deficiency of beta-galactosidase. The deficiency causes abnormal storage of acidic lipid materials in cells of the central and peripheral nervous systems, but particularly in the nerve cells, resulting in progressive neurodegeneration. GM1 is a rare lysosomal storage disorder with a prevalence of 1 to every 100,000 to 200,000 live births worldwide, although rates are higher in some regions.

An osteochondrodysplasia, or skeletal dysplasia, is a disorder of the development of bone and cartilage. Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. These disorders lead to disproportionate short stature and bone abnormalities, particularly in the arms, legs, and spine. Skeletal dysplasia can result in marked functional limitation and even mortality.

Iduronidase, sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan α-L-iduronohydrolase. It catalyses the hydrolysis of unsulfated α-L-iduronosidic linkages in dermatan sulfate.

<span class="mw-page-title-main">Maroteaux–Lamy syndrome</span> Lysosomal storage disease

Maroteaux–Lamy syndrome, or Mucopolysaccharidosis Type VI (MPS-VI), is an inherited disease caused by a deficiency in the enzyme arylsulfatase B (ARSB). ASRB is responsible for the breakdown of large sugar molecules called glycosaminoglycans. In particular, ARSB breaks down dermatan sulfate and chondroitin sulfate. Because people with MPS-VI lack the ability to break down these GAGs, these chemicals build up in the lysosomes of cells. MPS-VI is therefore a type of lysosomal storage disease.

<span class="mw-page-title-main">Iduronate-2-sulfatase</span> Class of enzymes

Iduronate 2-sulfatase is a sulfatase enzyme associated with Hunter syndrome. It catalyses hydrolysis of the 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate and heparin.

<span class="mw-page-title-main">N-acetylglucosamine-6-sulfatase</span> Protein-coding gene in the species Homo sapiens

N-acetylglucosamine-6-sulfatase (EC 3.1.6.14, glucosamine (N-acetyl)-6-sulfatase, systematic name N-acetyl-D-glucosamine-6-sulfate 6-sulfohydrolase) is an enzyme that in humans is encoded by the GNS gene. It is deficient in Sanfilippo Syndrome type IIId. It catalyses the hydrolysis of the 6-sulfate groups of the N-acetyl-D-glucosamine 6-sulfate units of heparan sulfate and keratan sulfate

<span class="mw-page-title-main">Scheie syndrome</span> Medical condition

Scheie syndrome is a disease caused by a deficiency in the enzyme iduronidase, leading to the buildup of glycosaminoglycans (GAGs) in the body. It is the most mild subtype of mucopolysaccharidosis type I; the most severe subtype of this disease is called Hurler Syndrome.

<span class="mw-page-title-main">N-sulfoglucosamine sulfohydrolase</span> Class of enzymes

In enzymology, a N-sulfoglucosamine sulfohydrolase (EC 3.10.1.1), otherwise known as SGSH, is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">SGSH</span> Protein-coding gene in the species Homo sapiens

N-sulphoglucosamine sulphohydrolase is an enzyme that in humans is encoded by the SGSH gene.

<span class="mw-page-title-main">HGSNAT</span> Protein-coding gene in the species Homo sapiens

Heparan-α-glucosaminide N-acetyltransferase is an enzyme that in humans is encoded by the HGSNAT gene.

<span class="mw-page-title-main">Mucopolysaccharidosis type I</span> Medical condition

Mucopolysaccharidosis type I is a spectrum of diseases in the mucopolysaccharidosis family. It results in the buildup of glycosaminoglycans due to a deficiency of alpha-L iduronidase, an enzyme responsible for the degradation of GAGs in lysosomes. Without this enzyme, a buildup of dermatan sulfate and heparan sulfate occurs in the body.

<span class="mw-page-title-main">NAGLU</span> Protein-coding gene in the species Homo sapiens

N-acetylglucosaminidase, alpha is a protein that in humans is encoded by the NAGLU gene.

Maria Luisa Escolar is a pediatrician, clinical professor, and researcher who specializes in pediatric neurodevelopmental disabilities. She is Founder and Director of the Program for the Study of Neurodevelopment in Rare Disorders at Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center. Escolar is nationally and internationally known for her research and clinical care of children with leukodystrophies, lysosomal storage diseases, and other inherited metabolic diseases.

References

  1. ↑ "MPS III (Sanfilippo syndrome)". National MPS Society. 2024. Retrieved 26 July 2024.
  2. 1 2 3 Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE (2019). "Mucopolysaccharidosis Type III". europepmc.org. Europe PMC. PMID   31536183 . Retrieved 2024-07-26.
  3. ↑ "Mucopolysaccharidosis type III". medlineplus.gov. 2022-11-07. Retrieved 2024-07-26.
  4. 1 2 Pearse Y, Iacovino M. A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise. Med Res Arch. 2020 Feb 1;8(2):10.18103/mra.v8i2.2045. doi: 10.18103/mra.v8i2.2045. Epub 2020 Feb 21. PMID 32733997; PMCID: PMC7391468.
  5. 1 2 3 "A Guide to Understanding MPS III" (PDF). web.archive.org. Archived from the original (PDF) on 8 July 2011. Retrieved 13 March 2019.
  6. 1 2 3 4 5 6 7 8 Fedele AO (2015-11-25). "Sanfilippo syndrome: causes, consequences, and treatments". The Application of Clinical Genetics. 8: 269–281. doi: 10.2147/TACG.S57672 . PMC   4664539 . PMID   26648750.
  7. ↑ Valstar MJ, Bruggenwirth HT, Olmer R, Wevers RA, Verheijen FW, Poorthuis BJ, et al. (December 2010). "Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype". Journal of Inherited Metabolic Disease. 33 (6): 759–767. doi:10.1007/s10545-010-9199-y. PMC   2992652 . PMID   20852935.
  8. ↑ Heon-Roberts R, Nguyen AL, Pshezhetsky AV (2020-01-27). "Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease". Journal of Clinical Medicine. 9 (2): 344. doi: 10.3390/jcm9020344 . ISSN   2077-0383. PMC   7074161 . PMID   32012694.
  9. 1 2 3 Wagner VF, Northrup H (1993), Adam MP, Feldman J, Mirzaa GM, Pagon RA (eds.), "Mucopolysaccharidosis Type III", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   31536183 , retrieved 2024-07-27
  10. 1 2 3 4 5 6 7 8 9 Muschol N, Giugliani R, Jones SA, Muenzer J, Smith NJ, Whitley CB, et al. (October 2022). "Sanfilippo syndrome: consensus guidelines for clinical care". Orphanet Journal of Rare Diseases. 17 (1): 391. doi: 10.1186/s13023-022-02484-6 . PMC   9612603 . PMID   36303195.
  11. 1 2 3 4 "Orphanet: Mucopolysaccharidosis type 3". www.orpha.net. Retrieved 2024-07-27.
  12. 1 2 3 4 5 6 Shapiro E, Lourenço CM, Mungan NO, Muschol N, O'Neill C, Vijayaraghavan S (July 2019). "Analysis of the caregiver burden associated with Sanfilippo syndrome type B: panel recommendations based on qualitative and quantitative data". Orphanet Journal of Rare Diseases. 14 (1): 168. doi: 10.1186/s13023-019-1150-1 . PMC   6615275 . PMID   31287005. CC-BY icon.svg Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  13. 1 2 "Mucopolysaccharidosis type 3 - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2024-07-27.
  14. 1 2 3 Muschol NM, Pape D, Kossow K, Ullrich K, Arash-Kaps L, Hennermann JB, et al. (2019-05-02). "Growth charts for patients with Sanfilippo syndrome (Mucopolysaccharidosis type III)". Orphanet Journal of Rare Diseases. 14 (1): 93. doi: 10.1186/s13023-019-1065-x . ISSN   1750-1172. PMC   6498678 . PMID   31046785.
  15. 1 2 3 4 5 6 7 Benetó N, Vilageliu L, Grinberg D, Canals I (2020-10-22). "Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches". International Journal of Molecular Sciences. 21 (21): 7819. doi: 10.3390/ijms21217819 . ISSN   1422-0067. PMC   7659972 . PMID   33105639.
  16. 1 2 3 4 5 6 Edens Hurst AC, Zieve D, Conaway B (1 May 2017). "Mucopolysaccharidosis type III". United States National Library of Medicine . Retrieved 20 June 2019.
  17. 1 2 3 4 5 6 7 8 Alyazidi AS, Muthaffar OY, Baaishrah LS, Shawli MK, Jambi AT, Aljezani MA, et al. (April 2024). "Current Concepts in the Management of Sanfilippo Syndrome (MPS III): A Narrative Review". Cureus. 16 (4): e58023. doi: 10.7759/cureus.58023 . PMC   11087936 . PMID   38738088.
  18. 1 2 Spahiu L, Behluli E, Peterlin B, Nefic H, Hadziselimovic R, Liehr T, et al. (September 2021). "Mucopolysaccharidosis III: Molecular basis and treatment". Pediatric Endocrinology, Diabetes, and Metabolism. 27 (3): 201–208. doi:10.5114/pedm.2021.109270. PMC   10228206 . PMID   34743503.
  19. ↑ Kaczor-Kamińska M, Kamiński K, Wróbel M (2022-03-30). "Heparan Sulfate, Mucopolysaccharidosis IIIB and Sulfur Metabolism Disorders". Antioxidants. 11 (4): 678. doi: 10.3390/antiox11040678 . ISSN   2076-3921. PMC   9026333 . PMID   35453363.
  20. ↑ Sasarman F, Maftei C, Campeau P, Brunel Guitton C, Mitchell G, Allard P (2016). "Biosynthesis of glycosaminoglycans: associated disorders and biochemical tests". Journal of Inherited Metabolic Disorders. 39 (2): 173–188. doi:10.1007/s10545-015-9903-z. ISSN   0141-8955. PMID   26689402.
  21. ↑ Zhou J, Lin J, Leung WT, Wang L (February 2020). "A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management". Intractable & Rare Diseases Research. 9 (1): 1–9. doi:10.5582/irdr.2020.01011. PMC   7062595 . PMID   32201668.
  22. 1 2 Benetó N, Vilageliu L, Grinberg D, Canals I. Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches. Int J Mol Sci. 2020 Oct 22;21(21):7819. doi: 10.3390/ijms21217819. PMID 33105639; PMCID: PMC7659972.
  23. ↑ Minami K, Morimoto H, Morioka H, Imakiire A, Kinoshita M, Yamamoto R, et al. (2022). "Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses". International Journal of Molecular Sciences. 23 (19): 11724. doi: 10.3390/ijms231911724 . ISSN   1422-0067. PMC   9570396 . PMID   36233030.
  24. ↑ Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML (June 2015). "Sanfilippo syndrome: Overall review". Pediatrics International. 57 (3): 331–338. doi:10.1111/ped.12636. PMID   25851924.
  25. 1 2 3 4 5 6 Cyske Z, Anikiej-Wiczenbach P, Wisniewska K, Gaffke L, Pierzynowska K, Mański A, et al. (2022-09-19). "Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach". Journal of Multidisciplinary Healthcare. 15: 2097–2110. doi: 10.2147/JMDH.S362994 . PMC   9505362 . PMID   36158637.
  26. ↑ Saville JT, Flanigan KM, Truxal KV, McBride KL, Fuller M. Evaluation of biomarkers for Sanfilippo syndrome. Mol Genet Metab. 2019 Sep-Oct;128(1-2):68-74. doi: 10.1016/j.ymgme.2019.05.005. Epub 2019 May 9. PMID 31104888.
  27. 1 2 Winner LK, Rogers ML, Snel MF, Hemsley KM (August 2023). "Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia". Journal of Neurochemistry. 166 (3): 481–496. doi: 10.1111/jnc.15891 . PMID   37357981.
  28. 1 2 Defendi GL (23 May 2018). "Sanfilippo Syndrome (Mucopolysaccharidosis Type III)". Medscape . Retrieved 20 June 2019.
  29. ↑ Wolfenden C, Wittkowski A, Hare DJ (2017). "Symptoms of Autism Spectrum Disorder (ASD) in Individuals with Mucopolysaccharide Disease Type III (Sanfilippo Syndrome): A Systematic Review". Journal of Autism and Developmental Disorders. 47 (11): 3620–3633. doi:10.1007/s10803-017-3262-6. ISSN   0162-3257. PMC   5633638 . PMID   28856504.
  30. ↑ Wijburg FA, Węgrzyn G, Burton BK, Tylki-Szymańska A (May 2013). "Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder". Acta Paediatrica. 102 (5): 462–470. doi:10.1111/apa.12169. ISSN   0803-5253. PMC   3654162 . PMID   23336697.
  31. ↑ Spahiu L, Behluli E, Peterlin B, Nefic H, Hadziselimovic R, Liehr T, et al. (2021). "Mucopolysaccharidosis III: Molecular basis and treatment". Pediatric Endocrinology, Diabetes, and Metabolism. 27 (3): 201–208. doi:10.5114/pedm.2021.109270. PMC   10228206 . PMID   34743503.
  32. ↑ Seker Yilmaz B, Davison J, Jones SA, Baruteau J (January 2021). "Novel therapies for mucopolysaccharidosis type III". Journal of Inherited Metabolic Disease. 44 (1): 129–147. doi:10.1002/jimd.12316. PMC   8436764 . PMID   32944950.
  33. ↑ Wolf DA, Banerjee S, Hackett PB, Whitley CB, McIvor RS, Low WC (February 2015). "Gene Therapy for Neurologic Manifestations of Mucopolysaccharidoses". Expert Opinion on Drug Delivery. 12 (2): 283–296. doi:10.1517/17425247.2015.966682. ISSN   1742-5247. PMC   4393078 . PMID   25510418.
  34. ↑ Muñoz-Rojas, M.V., Bay, L., Sanchez, L. et al. Clinical manifestations and treatment of mucopolysaccharidosis type I patients in Latin America as compared with the rest of the world. J Inherit Metab Dis 34, 1029–1037 (2011). https://doi.org/10.1007/s10545-011-9336-2
  35. ↑ Koberstein W (November 7, 2018). "Lysogene: Mother of Invention". Life Science Leader. United States: VertMarkets.
  36. ↑ Intracerebral Gene Therapy for Sanfilippo Type A Syndrome on clinicaltrials.gov
  37. ↑ "LiverTox: Clinical and Research Information on Drug-Induced Liver Injury". 2012. PMID   31644103 . Retrieved 26 July 2024.
  38. 1 2 Gaffke L, Pierzynowska K, Piotrowska E, Węgrzyn G (2018). "How close are we to therapies for Sanfilippo disease?". Metabolic Brain Disease. 33 (1): 1–10. doi:10.1007/s11011-017-0111-4. ISSN   0885-7490. PMC   5769821 . PMID   28921412.
  39. ↑ Alyazidi AS, Muthaffar OY, Baaishrah LS, Shawli MK, Jambi AT, Aljezani MA, et al. (2024). "Current Concepts in the Management of Sanfilippo Syndrome (MPS III): A Narrative Review". Cureus. 16 (4): e58023. doi: 10.7759/cureus.58023 . ISSN   2168-8184. PMC   11087936 . PMID   38738088.
  40. ↑ Cure Sanfilippo Foundation, funding research to accelerate discovery of a cure to Sanfilippo Syndrome
  41. ↑ Jonah's Just Begun - Foundation to Cure Sanfilippo, Inc.
  42. ↑ Phoenix Nest, Inc., a biotech company seeking treatments and cures for Sanfilippo Syndrome
  43. ↑ Phunk Phenomenon HipHop For Hope Archived 2018-09-01 at the Wayback Machine , a dance crew in Boston raising awareness for Sanfilippo Syndrome
  44. ↑ Team Sanfilippo Foundation, a medical research foundation created by parents of children with Sanfilippo Syndrome
  45. 1 2 3 4 5 6 Lavery C, Hendriksz CJ, Jones SA (October 2017). "Mortality in patients with Sanfilippo syndrome". Orphanet Journal of Rare Diseases. 12 (1): 168. doi: 10.1186/s13023-017-0717-y . PMC   5654004 . PMID   29061114.
  46. 1 2 3 4 Zelei T, Csetneki K, Vokó Z, Siffel C (2018-04-10). "Epidemiology of Sanfilippo syndrome: results of a systematic literature review". Orphanet Journal of Rare Diseases. 13 (1): 53. doi: 10.1186/s13023-018-0796-4 . ISSN   1750-1172. PMC   5891921 . PMID   29631636.
  47. ↑ Nelson J (December 1997). "Incidence of the mucopolysaccharidoses in Northern Ireland". Human Genetics. 101 (3): 355–358. doi:10.1007/s004390050641. PMID   9439667.
  48. 1 2 3 4 5 Meikle PJ, Hopwood JJ, Clague AE, Carey WF (January 1999). "Prevalence of lysosomal storage disorders". JAMA. 281 (3): 249–254. doi:10.1001/jama.281.3.249. PMID   9918480.
  49. ↑ Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, et al. (1999). "The frequency of lysosomal storage diseases in The Netherlands". Human Genetics. 105 (1–2): 151–156. doi:10.1007/s004390051078. PMID   10480370.
  50. ↑ Kong W, Wu S, Zhang J, Lu C, Ding Y, Meng Y (October 2021). "Global epidemiology of mucopolysaccharidosis type III (Sanfilippo syndrome): an updated systematic review and meta-analysis". Journal of Pediatric Endocrinology & Metabolism. 34 (10): 1225–1235. doi:10.1515/jpem-2020-0742. PMID   34271605.
  51. ↑ Sanfilippo SJ, Podosin R, Langer L, Good RA (October 1963). "Mental retardation associated with acid mucopolysacchariduria (heparitin sulfate type)". The Journal of Pediatrics. 63 (4): 837–838. doi:10.1016/S0022-3476(63)80279-6.
  52. 1 2 "Insights into the economic impact of Sanfilippo syndrome". Sanfilippo. Retrieved 2024-07-30.
  53. ↑ Porter KA, O'Neill C, Drake E, Parker S, Escolar ML, Montgomery S, et al. (2021). "Parent Experiences of Sanfilippo Syndrome Impact and Unmet Treatment Needs: A Qualitative Assessment". Neurology and Therapy. 10 (1): 197–212. doi:10.1007/s40120-020-00226-z. PMC   8139994 . PMID   33263924.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.