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Motor function decline and motor apraxia in Sanfilippo syndrome type A
S34
Abstracts
11 Hurler patients, 4 attenuated MPSI patients, and 3 Hunter syndrome patients. The memory tests included measures of rote verbal memory, story or contextual memory, and memory for visual designs. There was an immediate memory and delayed memory component to the measures given. There were some missing variables due to the range of ages included. The IQ and memory tests administered were chosen based on the subject's age and some of the measures could not be administered to children falling outside the age range for which the measure was normed. Results: IQ is lowest in Hurler group but not significant in looking at memory differences between the three groups. Story/contextual memory results fell within the average range across all three groups and there were no significant differences between the three groups. Memory for visual information/designs was lower in both MPS I Hurler and MPS I attenuated when compared to the MPS II group. The ability to encode new information is statistically significantly poorer in subjects with MPS I Hurler. Conclusions: Early in childhood the differences in memory function are not large between the three groups, except in rote memory. These results are similar to findings that we see in older children with these same diseases, only more dramatic. We acknowledge that the small sample sizes is a limiting factor and we will continue to collect this data via the longitudinal study of MPS I, II, and VI. doi:10.1016/j.ymgme.2012.11.067
54 Motor function decline and motor apraxia in Sanfilippo syndrome type A Kathleen Delaneya, Igor Nestrasila, Brianna Yunda, Kelly Kinga, Chester Whitleya, Kyle Rudsera, Patrick Haslettb, Elsa Shapiroa, aUniversity of Minnesota, Minneapolis, MN, USA, bShire HGT, Lexington, MA, USA We examined the changes, over 12 months, of motor function in a group of children participating in an ongoing longitudinal natural history study (NCT01047306) of mucopolysaccharidosis, type IIIA (Sanfilippo syndrome type A). In addition, we documented clinical data pertaining to signs of motor apraxia, an aspect of the disease that has not previously been defined in Sanfilippo syndrome. This is the first study utilizing longitudinal data from direct measurement of the child's fine and gross motor performance in subjects with Sanfilippo type A. Methods: Of the 25 children with MPSIII‐A enrolled in the study, 19 subjects were selected based on early age of diagnosis (b6 years), since this corresponds to a phenotype with relatively rapid disease progression. Cognitive data have been presented and suggest rapidly progressing disease characterized by an arrest in neurocognitive development at approximately 30 months of age, followed by regression. To assess gross and fine motor changes over time, we used the motor scales on the Bayley Scales of Infant Development (Third Edition) and parental report of motor function via a standard parent interview and survey form, Vineland Adaptive Behavior Scales (VABS‐II). Observational data were used to identify those subjects with signs of motor apraxia. Results: The course of motor decline varies more than that of cognitive skill loss. Fine motor skills decline more rapidly than gross. There is no definitive period in which decline is universal in fine motor function but there was a ceiling of fine motor development observed at 41 months of age both on direct measurement and parental report. The loss of fine motor skills was observed in some, but not all subjects over this 12‐month period. Gross motor skills are impaired, but stable, and do not decline significantly until later in the disease. A discrepancy between direct measurement (maximum
developmental level of 31 months) and parent report (maximum development of 46 months) of gross motor skills was found. This may be explained by the occurrence of motor apraxia in most subjects, such that they are able to perform gross motor activities spontaneously (observed and reported by parents), but not upon instruction or by imitation during formal assessment. doi:10.1016/j.ymgme.2012.11.068
55 Along the “deDuve-ian” trail: Research with colleagues & fellows on the path toward LSD delineation and treatment Robert Desnick, Mount Sinai School of Medicine, New York, New York, USA This award is dedicated to my outstanding mentors, colleagues, and especially the fellows and students whose efforts resulted in our accomplishments. In 1964, Christian deDuve challenged researchers and clinicians to delineate the diseases of the lysosome and to correct their defects… he suggested that the metabolic defect in Pompe disease “could be treated by replacing the defective enzyme with its normal counterpart”. Early attempts in the late 60s and 70s to meet deDuve's challenge resulted in various animal model and clinical approaches to treat the lysosomal storage diseases (LSD) by enzyme replacement therapy (ERT). Continued pursuit led to safe and effective ERT for Gaucher type 1 disease using purified placental enzyme, which was FDA-approved in 1991. Clearly, the last 50 years have witnessed major advances in the delineation and treatment of the lysosomal diseases. However, it took the efforts of many outstanding investigators with the mantra of “pursuit and persistence” to overcome various obstacles and to achieve the successes to date. Advances in cell and molecular biology led to the identification of lysosomal enzyme receptor-mediated uptake, isolation/characterization of lysosomal cDNAs and their genes, identification of naturally-occurring animal models and generation of KO and KI mice, development of methods to over-express and selectively secrete lysosomal enzymes, and identification and characterization of the causative mutations in the LSD and their phenotypic consequences. Today, ERTs using recombinant human enzymes are available for six LSD and under development for several others. The trail to Fabry ERT included incredible mentors, colleagues and fellows. This pursuit required mastering new technologies and continuous funding. The successes along the way overcame the moments of frustration, and as always, the patients and their families kept the focus. The future for new approaches to treat this and other LSD includes pharmacologic chaperones, substrate inhibitors, stopcodon read-through, as well as gene and stem cell strategies. Advances in iPS technology may personalize treatments for certain diseases. Today, prenatal and premarital carrier screening are available, newborn screening for LSD is evolving, and eventually targeted exomic or genomic sequencing will further facilitate the prevention and/or early intervention of these diseases…it is likely that the paths to prevention and treatment will be synergistic. The trail is open for young investigators to be innovative and to reach our therapeutic goals of helping families to effectively treat, cure, and/or prevent these diseases, especially the many with neurodegenerative manifestations. Suffice it to say, basic and clinical research in the LSD has never been better! The future for the development of treatments, and even cures, for these diseases is bright, and we need to train the next generation of investigators to pursue them. doi:10.1016/j.ymgme.2012.11.069
Abstracts
11 Hurler patients, 4 attenuated MPSI patients, and 3 Hunter syndrome patients. The memory tests included measures of rote verbal memory, story or contextual memory, and memory for visual designs. There was an immediate memory and delayed memory component to the measures given. There were some missing variables due to the range of ages included. The IQ and memory tests administered were chosen based on the subject's age and some of the measures could not be administered to children falling outside the age range for which the measure was normed. Results: IQ is lowest in Hurler group but not significant in looking at memory differences between the three groups. Story/contextual memory results fell within the average range across all three groups and there were no significant differences between the three groups. Memory for visual information/designs was lower in both MPS I Hurler and MPS I attenuated when compared to the MPS II group. The ability to encode new information is statistically significantly poorer in subjects with MPS I Hurler. Conclusions: Early in childhood the differences in memory function are not large between the three groups, except in rote memory. These results are similar to findings that we see in older children with these same diseases, only more dramatic. We acknowledge that the small sample sizes is a limiting factor and we will continue to collect this data via the longitudinal study of MPS I, II, and VI. doi:10.1016/j.ymgme.2012.11.067
54 Motor function decline and motor apraxia in Sanfilippo syndrome type A Kathleen Delaneya, Igor Nestrasila, Brianna Yunda, Kelly Kinga, Chester Whitleya, Kyle Rudsera, Patrick Haslettb, Elsa Shapiroa, aUniversity of Minnesota, Minneapolis, MN, USA, bShire HGT, Lexington, MA, USA We examined the changes, over 12 months, of motor function in a group of children participating in an ongoing longitudinal natural history study (NCT01047306) of mucopolysaccharidosis, type IIIA (Sanfilippo syndrome type A). In addition, we documented clinical data pertaining to signs of motor apraxia, an aspect of the disease that has not previously been defined in Sanfilippo syndrome. This is the first study utilizing longitudinal data from direct measurement of the child's fine and gross motor performance in subjects with Sanfilippo type A. Methods: Of the 25 children with MPSIII‐A enrolled in the study, 19 subjects were selected based on early age of diagnosis (b6 years), since this corresponds to a phenotype with relatively rapid disease progression. Cognitive data have been presented and suggest rapidly progressing disease characterized by an arrest in neurocognitive development at approximately 30 months of age, followed by regression. To assess gross and fine motor changes over time, we used the motor scales on the Bayley Scales of Infant Development (Third Edition) and parental report of motor function via a standard parent interview and survey form, Vineland Adaptive Behavior Scales (VABS‐II). Observational data were used to identify those subjects with signs of motor apraxia. Results: The course of motor decline varies more than that of cognitive skill loss. Fine motor skills decline more rapidly than gross. There is no definitive period in which decline is universal in fine motor function but there was a ceiling of fine motor development observed at 41 months of age both on direct measurement and parental report. The loss of fine motor skills was observed in some, but not all subjects over this 12‐month period. Gross motor skills are impaired, but stable, and do not decline significantly until later in the disease. A discrepancy between direct measurement (maximum
developmental level of 31 months) and parent report (maximum development of 46 months) of gross motor skills was found. This may be explained by the occurrence of motor apraxia in most subjects, such that they are able to perform gross motor activities spontaneously (observed and reported by parents), but not upon instruction or by imitation during formal assessment. doi:10.1016/j.ymgme.2012.11.068
55 Along the “deDuve-ian” trail: Research with colleagues & fellows on the path toward LSD delineation and treatment Robert Desnick, Mount Sinai School of Medicine, New York, New York, USA This award is dedicated to my outstanding mentors, colleagues, and especially the fellows and students whose efforts resulted in our accomplishments. In 1964, Christian deDuve challenged researchers and clinicians to delineate the diseases of the lysosome and to correct their defects… he suggested that the metabolic defect in Pompe disease “could be treated by replacing the defective enzyme with its normal counterpart”. Early attempts in the late 60s and 70s to meet deDuve's challenge resulted in various animal model and clinical approaches to treat the lysosomal storage diseases (LSD) by enzyme replacement therapy (ERT). Continued pursuit led to safe and effective ERT for Gaucher type 1 disease using purified placental enzyme, which was FDA-approved in 1991. Clearly, the last 50 years have witnessed major advances in the delineation and treatment of the lysosomal diseases. However, it took the efforts of many outstanding investigators with the mantra of “pursuit and persistence” to overcome various obstacles and to achieve the successes to date. Advances in cell and molecular biology led to the identification of lysosomal enzyme receptor-mediated uptake, isolation/characterization of lysosomal cDNAs and their genes, identification of naturally-occurring animal models and generation of KO and KI mice, development of methods to over-express and selectively secrete lysosomal enzymes, and identification and characterization of the causative mutations in the LSD and their phenotypic consequences. Today, ERTs using recombinant human enzymes are available for six LSD and under development for several others. The trail to Fabry ERT included incredible mentors, colleagues and fellows. This pursuit required mastering new technologies and continuous funding. The successes along the way overcame the moments of frustration, and as always, the patients and their families kept the focus. The future for new approaches to treat this and other LSD includes pharmacologic chaperones, substrate inhibitors, stopcodon read-through, as well as gene and stem cell strategies. Advances in iPS technology may personalize treatments for certain diseases. Today, prenatal and premarital carrier screening are available, newborn screening for LSD is evolving, and eventually targeted exomic or genomic sequencing will further facilitate the prevention and/or early intervention of these diseases…it is likely that the paths to prevention and treatment will be synergistic. The trail is open for young investigators to be innovative and to reach our therapeutic goals of helping families to effectively treat, cure, and/or prevent these diseases, especially the many with neurodegenerative manifestations. Suffice it to say, basic and clinical research in the LSD has never been better! The future for the development of treatments, and even cures, for these diseases is bright, and we need to train the next generation of investigators to pursue them. doi:10.1016/j.ymgme.2012.11.069