1st Natural History Study in Korea: Sanfilippo Type A Most Common

Understanding disease's natural history may allow early diagnosis, researchers say

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by Steve Bryson, PhD |

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Sanfilippo syndrome type A was found to be the most predominant form of the rare genetic disorder in Korea in the country’s first natural history study of this patient population.

A potential Sanfilippo syndrome diagnosis should be considered when patients show neurodegenerative symptoms such as language and motor delays, or hyperactivity, according to researchers.

The team noted that greater knowledge of the disease’s natural history may “support outcome measures of future clinical trials” for Korean patients with Sanfilippo.

“Better understanding of the natural history … might allow early diagnosis and timely management of the disease” — which could improve survival, the researchers noted.

The study, “Natural History and Molecular Characteristics of Korean Patients with Mucopolysaccharidosis Type III,” was published in the Journal of Personalized Medicine.

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Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is caused by defects in enzymes that break down the complex sugar molecule heparan sulfate. Such defects lead to a toxic buildup of heparan sulfate inside cells, causing damage systemwide and especially in the brain.

There are four types of Sanfilippo, each resulting from mutations in different genes that encode these enzymes. Types A and B are more common and more severe, while types C and D occur less often and are usually more mild.

Symptoms of the condition, a form of childhood dementia, usually appear between the ages of 2 and 6, and include behavioral problems, especially hyperactivity, sleeping difficulties, and developmental delays, particularly delayed speech.

Studying Sanfilippo in Korea

To date, studies describing the natural history of Sanfilippo have focused on Caucasian patients. The natural course of the condition in Asian populations has not been adequately studied.

To fill that knowledge gap, researchers based at the Sungkyunkwan University School of Medicine, in South Korea, collected clinical data from 34 Korean Sanfilippo patients. Among them, 58.9% were male and 41.1% were female. More than half — 18 patients or 52.9% — were diagnosed with Sanfilippo type A, while 14, or 41.2%, had type B. Two patients 5.9% had type C.

“This is the first study that analysed the genetic and clinical characteristics of [Sanfilippo syndrome] patients in Korea,” the team wrote.

The mean age at symptom onset was 2.8 years, and the mean age at diagnosis was 6.3 years. Slow neurodevelopment was the most common early symptom (88.2%), followed by language and motor delays (76.5%), then behavioral abnormalities.

All type A and B patients were diagnosed before age 6 and/or were associated with severe disease and considered rapidly progressing.

There were no significant observed clinical differences between types A and B, with the exception that children with type B started walking on their own later (median 1.55 years) than those with type A (median 1.25 years). Language delays were the most common initial symptoms in type A, while motor delays were noted first in type B children.

The most common additional symptoms after diagnosis were behavioral abnormalities and speech impairment. Falls due to walking difficulties occurred in 91.2% of patients, and hearing impairment was reported in 17 (50%), of whom seven used hearing aids.

Data showed 30 participants (88.2%) had coarse facial features, and most (85.3%) had unusual facial hair or bluish skin (Mongolian) spots (64.7%).

Most of those who underwent heart tests showed some type of heart dysfunction. Among the 21 patients who had an ultrasound of the abdomen, 17 had enlarged organs. Most (70.6%) underwent at least one surgical procedure, including the implant of feeding and breathing tubes, hernia repair, or tonsil or adenoid removal.

Regarding neurodegenerative symptoms, those with either Sanfilippo syndrome type A or type B showed a rapid cognitive decline at a mean age of 4.4 years.

Within this group, the onset of speech delays was seen at a median age of 3.9 years (range 2.1–5 years). Motor decline was observed at a median of 5.4 years (range 3–13 years), while the average age at onset was 4.4 years (range 1.5–11 years) for cognitive decline.

Severe regression in speech abilities was noted at a median of 7.3 years (range 2–10 years), motor fitness at a median of 10.4 years (range 7–15 years), and cognitive capacity at a median of 8.2 years (range 5–13 years).

Epilepsy first began in 78.8% of patients at a mean of 10.0 years. Episodes were controlled with one or two medications.

Walking difficulties began at a median age of 10 years (range 4.6–15 years), while swallowing problems started at a median age of 12 (range 5.4–16 years). By the mean age of 15.1 years, patients were entirely bedridden.

The two Sanfilippo type C patients were siblings, with the younger sibling diagnosed at 2.3 years and the older sibling at 5.1 years. The siblings were considered to have slowly progressing disease, with loss of speech, walking, and cognitive abilities occurring after 10 years of age.

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Survival with Sanfilippo

In a survival analysis of the 18 patients with Sanfilippo syndrome type A, six died (33.3%) over a mean follow-up period of 12.6 years. Seven of the 14 type B patients (50%) also died during the follow-up period.

Overall, the mean age of death was 14 years. Eight of the children died of pneumonia, one from epilepsy, and four from unknown causes. There was no difference in survival rates between those with type A or type B.

Although the age at symptom onset was similar, the mean age at diagnosis was significantly older in the non-survival group than in the survival group (7.3 vs. 5.6 years). Time to diagnosis in the nonsurvivor group was significantly longer (4.8 vs. 2.8 years), and the use of anti-seizure medications was significantly more frequent (100% vs. 61.9%).

Previously reported SGSH gene mutations were found in seven Sanfilippo type A patients, while four carried novel mutations. Six known NAGLU gene mutations were seen in type B patients, with three newly reported mutations. Both type C siblings had two known HGSNAT mutations.

“[Sanfilippo type A] is the most predominant in Korea,” the researchers concluded, noting, “[Sanfilippo] should be considered when a patient shows neurodegenerative symptoms such as language retardation, motor retardation, or hyperactivity.”

“Early diagnosis is important to increase the survival rate for this population,” the researchers added. “Our findings can be used to develop quality of care strategies and provide guidance for clinical trial endpoint evaluations.”