Rare metabolism disorder
Medical condition
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.
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.
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. Between the ages of one and four is when the disease typically manifests. 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.
After an initial symptom-free interval, symptoms may arise during the early years of development, from the age of one to three. Children usually present with delayed cognitive development and/or behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease. Acquisition of speech is often slow and incomplete. Although delayed cognitive development may occur, it tends to be mild in individuals with Sanfilippo syndrome.
Between the ages of three and ten, the disease progresses to increasing behavioral disturbance including temper tantrums, hyperactivity, destructive behavior, 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. The disordered sleep in particular presents a significant problem to care providers. People with this disorder may stay in this phase for five to ten years. After that, the behavioral disturbances subside. However, 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. Persons with Sanfilippo Syndrome tend to regress to an unresponsive or vegetative state until they pass away. The life-span of a severely affected person does not usually extend beyond late teens to early twenties. However, patients with less severe phenotypes of the disease have varied life spans, with some cases even surviving into their seventies.
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. 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.
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.
Individuals with Sanfilippo syndrome are born within normal physiological ranges. At around age 2, individuals with Sanfilippo syndrome are significantly taller than children without the condition. By the age of 4, mostly male children with Sanfilippo syndrome were still taller than unaffected children. 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.
It is difficult to clinically distinguish symptomatic differences among the four types of Sanfilippo syndrome, although each of the types can vary in severity. Type A is usually the most severe subtype, characterized by the earliest onset, rapid clinical progression with severe symptoms, and short survival, with patients averaging between 15 and 18 years old. Type B is considered slightly less aggressive than type A, but still displays rapid clinical progression and short survival, with patients averaging between 17 and 19 years old. Type C is considered the least aggressive form of Sanfilippo syndrome, with patients' average life expectancy between 19 and 34 years of age, depending on the study. Type D is a rare subtype of Sanfilippo syndrome, and no data has been published on average life expectancy.
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. 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.
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.
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. 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.
Mechanism.
Symptoms due to Sanfilippo Syndrome arise because the body cannot break down a type of sugar chain called heparan sulfate. 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). 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; how it works is not fully understood. Heparan sulfate may also accumulate outside of cells or be excreted in urine. 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.
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.
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. 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.
A urinalysis can show elevated levels of heparan sulfate in the urine. 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. 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. Aside from confirming diagnosis, genetic testing is also recommended to determine carriers and to understand development of the disease.
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. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. 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. 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.
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 as there is overlap of behaviors with these conditions. 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. 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.
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. 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.
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.
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. Evidence for medications that effectively manage behavioral problems and seizures in children with Sanfilippo syndrome are limited. 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.
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. 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. 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. Patients that underwent bone marrow transplant before the age of two showed neurocognitive function stabilization. Although the missing enzyme can be manufactured and given intravenously (also known as enzyme