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.[4] In early childhood, they begin to exhibit signs of 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.[5]
Signs and symptoms
The disease manifests in young children, with symptoms usually beginning to appear between two and six years of age.[6] Affected infants appear normal, although some mild facial dysmorphism may be noticeable; however, compared to all other MPS diseases, Sanfilippo syndrome produces the fewest physical anomalies. After an initial symptom-free interval, patients usually present with a slowing of development and/or behavioural problems, followed by a progressive intellectual decline, resulting in severe dementia and progressive motor disease.[7]Acquisition of speech is often slow and incomplete.[8]
The disease progresses to increasing behavioral disturbances, including temper tantrums, hyperactivity, destructiveness, aggressive behavior, pica, difficulties with toilet training, and sleep disturbances. Initially, as affected children retain normal muscle strength and mobility, unique behavioral disturbances may be difficult to manage. Irregular sleep patterns, in particular, present significant challenges to families and care providers.[citation needed]
In the final phase of the illness, children become increasingly immobile and unresponsive, often requiring a wheelchair or other form of supported transport, and may develop swallowing difficulties or seizures. Usually, the lifespan of an affected child does not extend beyond the late teens or into the early twenties.[9]
Individuals with MPS type III tend to have mild skeletal anomalies; osteonecrosis of the femoral head may be present in severe cases.[10]Optic nerveatrophy, deafness, and otitis can be seen in moderate to severe cases. Other characteristics include coarser facial features, thicker lips, synophrys, and stiff joints.[11]
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 its early onset, rapid clinical progression (with severe symptoms), and short survival rate.[12] The median age of death for children afflicted with type A is 15.4 ± 4.1 years.[13]
It is important that simple and treatable conditions, such as ear infections or toothaches, not be overlooked due to behavioral challenges that may make physical exams difficult; additionally, children with MPS type III often have an increased tolerance to pain, leading to potentially minor conditions becoming worse with time. Bumps, bruises, or ear infections that would typically be painful for other children, and even adults, often go unnoticed in children with MPS type III. Some children with MPS type III may also have a blood-clotting problem during and after surgery.[6]
Genetics
Mutations in four different genes can lead to Sanfilippo syndrome. This disorder is inherited in an autosomal recessive pattern. People with two working copies of the gene are unaffected. People with one working copy are genetic carriers of Sanfilippo syndrome. They have no symptoms but may pass down the defective gene to their children. People with two defective copies will develop Sanfilippo syndrome.[14]
Structure of heparan sulfate, one of the molecules that builds up in the tissues of people with Sanfilippo syndrome
Glycosaminoglycans (GAGs) are chains of sugar molecules. They are found in the extracellular matrix and the cell membrane, 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.[12]
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.[citation needed]
A urinalysis can show elevated levels of heparan sulfate in the urine.[14] 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 urine test due to dilution, it is important that a urine sample be taken first thing in the morning.[citation needed]
The diagnosis may be confirmed by enzyme assay of skin fibroblasts and white blood cells. 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.[citation needed]
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 and therefore cannot treat the neurological manifestations of the disease. Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system.[citation needed]
Several promising therapies are in development. Allievex was conducting a phase II/III clinical trial on Enzyme Replacement Therapy for MPSIIIB (former Biomarin clinical trail),[16][17] but negotiations to buy Allievex failed in December 2023, and the company abruptly terminated trials that had been reported to greatly improve child patients' condition as it could not raise enough money to support a new trial. This has been attributed largely to the economic difficulties in producing drugs for rare diseases, estimated to cost about five times more than treatments for common conditions.[18]
Ultragenyx (former Abeona clinical trial) and Lysogene of a gene therapy-based treatment for MPSIIIA.[19][20] Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the blood–brain barrier, stabilisation 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[when?] 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.[citation needed] The flavonoid genistein decreases the accumulation of GAGs.[21]In vitro, animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein.[22] Despite its reported beneficial properties, genistein also has toxic side effects.[23]
Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome.[24][25][26][27][28][excessive citations]
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.[29]
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.[30]
Epidemiology
Incidence of Sanfilippo syndrome varies geographically, with approximately 1 case per 280,000 live births in Northern Ireland,[31] 1 per 66,000 in Australia,[32] and 1 per 50,000 in the Netherlands.[33]
The Australian study estimated the following incidence for each subtype of Sanfilippo syndrome:
The first-ever global consensus clinical care guidelines for Sanfilippo syndrome were published in Orphanet Journal of Rare Diseases[34] in late 2022. It represents a consensus set of basic clinical care guidelines that are accessible to clinicians and families globally. The guidelines consist of evidence-based, expert-led recommendations for how to approach Sanfilippo syndrome-specific care management and monitoring of disease-related changes. These clinical care guidelines are intended for use by anyone providing medical care, rehabilitative care, or support services for individuals with Sanfilippo syndrome. Additionally, the guidelines are a practical resource for families to be well-informed advocates and for them to share with their local care team, who may not have previous experience with this rare disease.
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.[36]
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.[36]
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.[36]
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."[36]
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."[36]
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.[37][38]
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.
Sly syndrome, also called mucopolysaccharidosis type VII (MPS-VII), is an autosomal recessive lysosomal storage disease caused by a deficiency of the enzyme β-glucuronidase. This enzyme is responsible for breaking down large sugar molecules called glycosaminoglycans. The inability to break down GAGs leads to a buildup in many tissues and organs of the body. The severity of the disease can vary widely.
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.
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.
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.
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.
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.
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.
Farber disease is an extremely rare, progressive, autosomal recessive lysosomal storage disease caused by a deficiency of the acid ceramidase enzyme. Acid ceramidase is responsible for breaking down ceramide into sphingosine and fatty acid. When the enzyme is deficient, this leads to an accumulation of fatty material in the lysosomes of the cells, leading to the signs and symptoms of this disorder.
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
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.
Pseudo-Hurler polydystrophy, also referred to as mucolipidosis III, is a lysosomal storage disease closely related to I-cell disease. This disorder is called Pseudo-Hurler because it resembles a mild form of Hurler syndrome, one of the mucopolysaccharide (MPS) diseases.
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.
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.
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.
In enzymology, a N-sulfoglucosamine sulfohydrolase (EC 3.10.1.1), otherwise known as SGSH, is an enzyme that catalyzes the chemical reaction
N-sulphoglucosamine sulphohydrolase is an enzyme that in humans is encoded by the SGSH gene.
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.
Emil Kakkis is an American medical geneticist known for his work to develop treatments for ultra rare disorders. He is the Founder of the Everylife Foundation for Rare Disease and Founder, CEO and President of Ultragenyx Pharmaceutical Inc.
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.
↑ Tardieu, Marc (February 2014). "Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial". Human Gene Therapy. 25 (6): 506–516. doi:10.1089/hum.2013.238. PMID24524415.
↑ Halliday, Josh (27 December 2023). "Sheffield family plead for help after drug trial for boy, 11, is abruptly stopped". The Guardian. Tom Mathers, the chief executive of Allievex, said: "The hardest decision that I have ever had to make was to pause our ongoing treatment of children with this devastating disease. It is most frustrating because we have a treatment that we know works.
↑ Poorthuis BJ, Wevers RA, Kleijer WJ, etal. (1999). "The frequency of lysosomal storage diseases in The Netherlands". Hum. Genet. 105 (1–2): 151–6. doi:10.1007/s004390051078. PMID10480370.
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