Mucopolysaccharidosis III in Taiwan: Natural history, clinical and molecular characteristics of 28 patients diagnosed during a 21‐year period

Abstract

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) has a variable age of onset and variable rate of progression. However, information regarding the natural history of this disorder in Asian populations is limited. A retrospective analysis was carried out for 28 patients with MPS III (types IIIA [n = 3], IIIB [n = 23], and IIIC [n = 2]; 15 males and 13 females; median age, 8.2 years; age range, 2.7-26.5 years) seen in six medical centers in Taiwan from January 1996 through October 2017. The median age at confirmed diagnosis was 4.6 years. The most common initial symptom was speech delay (75%), followed by hirsutism (64%) and hyperactivity (54%). Both z scores for height and weight were negatively correlated with age (r = -.693 and -0.718, respectively; p < .01). The most prevalent clinical manifestations were speech delay (100%) and intellectual disability (100%), followed by hirsutism (93%), hyperactivity (79%), coarse facial features (68%), sleep disorders (61%), and hepatosplenomegaly (61%). Ten patients (36%) had epilepsy, and the median age at the first seizure was 11 years. Thirteen patients (46%) experienced at least one surgical procedure. At the time of the present study, 7 of the 28 patients had passed away at the median age of 13.0 years. Molecular studies showed an allelic heterogeneity without clear genotype and phenotype correlations. MPS IIIB is the most frequent subtype among MPS III in the Taiwanese population. An understanding of the natural history of MPS III may allow early diagnosis and timely management of the disease facilitating better treatment outcomes.

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

“…Somatic disease is relatively mild in Sanfilippo patients and consists typically of frequent ear-nose-throat infections, episodic diarrhea, hepatomegaly and/or splenomegaly, skeletal abnormalities, hirsutism, and coarse facies [11,[15][16][17][18][31][32][33][35][36][37][38][39][40]. At an early age, MPS III patients are typically taller with an increased head circumference compared to healthy children, but their growth slows around 5 years of age and by their late teens they are generally shorter than average [41].…”

“…The main burden of the disease is the cognitive decline and associated behavioral problems. Indeed, the majority of patients first present with developmental (particularly speech) delay [11,[15][16][17][18][31][32][33][35][36][37][38][39][40]. In a study of 105 MPS IIIA, B, and C patients, the authors found that only 60 children acquired early language skills and that this acquisition was often later than 3 years of age [17].…”

“…Importantly, all subtypes generally included two groups of patients: Those with earlier onset of clinical presentation and higher rate of neurodegeneration and cognitive decline (so called rapid progressing or RP) and those with later onset and slower progress (slow progressing or SP). During the period of rapid decline, the patients start showing behavioral alterations that are difficult to manage, such as uncontrollable hyperactivity, aggression, anxiety, crying spells and sleep disorders, with problems falling asleep and frequent waking [11,[15][16][17][18][31][32][33]35,36,39,40,[47][48][49]. They may also develop autistic behavior as the disease progresses [17,39,50,51], and children with MPS IIIA and MPS IIIB show reduced fear [32], correlating with changes in amygdala volume [52].…”

“…During the later stages of the disease, patients frequently develop seizures [17,32,40]. This progressive cognitive and motor impairment is correlated with cortical and cerebellar atrophy, increased ventricular volume and other brain abnormalities detected by computed tomography-scan (CT-scan) or magnetic resonance imaging (MRI), suggesting that these symptoms are associated with neuronal loss and pathological brain lesions ( Figure 1) [35][36][37][38]40,46,53,54].…”

“…In fact, delays of 1 to 12 years, with an average of 7.6 years, depending on the subtype and severity, have been reported. Unfortunately, these numbers have not been reduced during the last decade [11,33,36,159,160]. This suggests that the awareness of clinicians about Sanfilippo syndrome should be increased allowing them to recognize its clinical pattern, including the presentation of mild somatic symptoms [161].…”