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 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' life expectancy 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' life expectancy 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.
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