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Natural history of Sanfilippo syndrome type A

Significance Statement

Mucopolysaccharidosis (MPS) type III, also known as Sanfilippo syndrome, is a rare inherited disorder caused by deficiency of one of the four enzymes involved in heparan sulfate metabolism.  The most severe form, Sanfilippo type A, is caused by insufficient heparan-N-sulfatase activity. As undegraded heparan sulfate accumulates in the lysosome, progressive neurodegeneration occurs, manifesting as developmental delays, behavioral problems, and sleep disturbances; other problems include recurrent infections, diarrhea, hearing impairment, and seizures.  Initial symptoms of the disease appear between birth and 36 months with death occurring before the second decade of life.  Although there is currently no effective treatment, there are several clinical trials underway involving gene therapy, hematopoietic stem cell transplantation, recombinant human heparan N-sulfatase, and substrate reduction therapy.  Unfortunately, it is challenging to understand the efficacy of treatments in a disease where there is rapid cognitive decline. Sanfilippo syndrome mainly affects the central nervous system.  The brain is especially vulnerable to disease within the first three years of life where there is an increase in growth and brain development.  Therefore, significant damage occurs early in life and damage may not be reversible even in treatments able to reverse the pathology of the disease. In addition, most genetic mutations are private contributing to the poor correlation between genotype and phenotype of the disease. Our study highlights the importance of understanding the variability of disease presentation and impact of treatment according to time of diagnosis.  A well-defined natural history study is able to detect variability in the population, slope of cognitive decline and unique characteristics of the disease, all of which are important in understanding if a treatment is effective. A natural history study can also identify meaningful endpoints that represent functional levels of the child. A consistent finding across many lysosomal storage diseases is that early diagnosis and treatment leads to better outcomes, as it is easier to prevent than correct damage. This study highlights the currently unacceptable delay in diagnosis, which occurs after regression is noted by the parents. As with all rare diseases, cohorts of patients are small, therefore measures need to be very reliable with the least possible introduction of error. Standardized protocols with good inter and intra rater reliability should be used and individuals experienced with the disease process should administer the testing. In this study, the same methods were repeated longitudinally in an effort to reduce error and effectively evaluate this small number of patients.  Studies similar to this will become more complex as multiple treatments become available, since most patients will be receiving treatment and the opportunity to understand how each therapy compares to the natural history of the disease will be lost.

Natural history of Sanfilippo syndrome type A. - Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Buhrman D, Thakkar K, Poe M, Escolar ML.

J Inherit Metab Dis. 2014 May;37(3):431-7.

University of Pittsburgh and Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Ave, Pittsburgh, PA, 15213, USA.

 

Abstract

 OBJECTIVE:

To describe the natural history of Sanfilippo syndrome type A.

METHODS:

We performed a retrospective review of 46 children (21 boys, 25 girls) with Sanfilippo syndrome type A evaluated between January 2000 and April 2013. Assessments included neurodevelopmental evaluations, audiologic testing, and assessment of growth, adaptive behavior, cognitive behavior, motor function, and speech/language skills. Only the baseline evaluation was included for patients who received hematopoietic stem cell transplantation.

RESULTS:

Median age at diagnosis was 35 months, with a median delay between initial symptoms to diagnosis of 24 months. The most common initial symptoms were speech/language delay (48%), dysmorphology (22%), and hearing loss (20%). Early behavioral problems included perseverative chewing and difficulty with toilet training. All children developed sleep difficulties and behavioral changes (e.g., hyperactivity, aggression). More than 93% of the children experienced somatic symptoms such as hepatomegaly (67%), abnormal dentition (39%), enlarged tongue (37%), coarse facial features (76%), and protuberant abdomen (43%). Kaplan-Meier analysis showed a 60% probability of surviving past 17 years of age.

CONCLUSIONS:

Sanfilippo type A is characterized by severe hearing loss and speech delay, followed by a rapid decline in cognitive skills by 3 years of age. Significant somatic disease occurs in more than half of patients. Behavioral difficulties presented between 2 and 4 years of age during a rapid period of cognitive decline. Gross motor abilities are maintained during this period, which results in an active child with impaired cognition. Sleep difficulties are concurrent with the period of cognitive degeneration. There is currently an unacceptable delay in diagnosis, highlighting the need to increase awareness of this disease among clinicians.

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