Cognitive and adaptive functioning of children with infantile Pompe disease treated with enzyme replacement therapy: Long-term follow-up† ‡§
How to cite this article: Spiridigliozzi GA, Heller JH, Kishnani PS. 2012. Cognitive and adaptive functioning of children with infantile pompe disease treated with enzyme replacement therapy: Long-term follow-up. Am J Med Genet Part C Semin Med Genet 160C:22–29.
Gail A. Spiridigliozzi and James H. Heller have worked on research supported by Genzyme Corporation. Priya S. Kishnani has received research/grant support and honoraria from Genzyme Corporation. She is also a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation.
The authors have collaborated on several studies conducted through the Duke Pompe Program, under the direction of Dr. Kishnani.
Abstract
This report documents the long-term cognitive and adaptive outcome of children with infantile Pompe disease. Specifically, we describe the cognitive and adaptive functioning of seven children with classic infantile Pompe disease and two children with atypical infantile Pompe disease who have received enzyme replacement therapy (Myozyme®) for an average of 6 years, 8 months and 4 years, 1. 5 months, respectively. Multiple assessments of cognitive functioning were completed over time by means of individualized intelligence (IQ) testing. Adaptive functioning was measured by means of the Vineland Adaptive Behavior Scales-Second Edition (VABS-II). Consistent with our earlier findings regarding infants treated with ERT, children with classic infantile Pompe disease (ages 4 years, 11 months to 8 years, 11 months) were functioning at the lower end of the average range in comparison to their typical peers on their most recent IQ test. There was no evidence of a decline in their cognitive abilities over time. In contrast, the two children with atypical infantile Pompe disease (ages 5 years, 4 months and 5 years, 11 months) obtained above average IQ scores and demonstrated significant gains in IQ over time. For all children where adaptive functioning was assessed, their overall level of adaptive functioning on the VABS-II was lower than their Full Scale IQ scores on cognitive testing. Motor function appears to be an important factor impacting on reduced adaptive behavior. The implication of these findings on our understanding of a possible relationship between CNS status in children with Pompe and their adaptive and cognitive function is discussed. © 2012 Wiley Periodicals, Inc.
INTRODUCTION
Pompe disease (glycogen storage disease type II) is a rare, progressive, autosomal recessive neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Children with the classic infantile-onset form of the disease have a complete or nearly complete lack of GAA enzyme activity and the most severe disease symptoms. With GAA deficiency, an excessive amount of glycogen accumulates in various tissues, especially heart, skeletal, smooth, and bulbar muscles. Infants with Pompe disease have significant hypertrophic cardiomyopathy, hypotonia, macroglossia, feeding and swallow difficulties, and respiratory compromise. Untreated, the infantile form of the disease is fatal, with death occurring usually within the first 1–2 years of life. The availability of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme®) in 2006 changed the course of the disease, allowing most children with the infantile form of Pompe the opportunity for a full life.
While Pompe disease is considered a neuromuscular disease, glycogen is known to be present in the central nervous system (CNS) of individuals with this disease. Autopsy reports have identified glycogen deposits in the anterior horn cells of the spinal cord and medulla [Teng et al., 2004] and the motor neurons of the spinal cord [Martin et al., 1973; Martini et al., 2001]. In an autopsy report of a 14-month-old infant treated with ERT for 10 months, Thurberg et al. [2006] described glycogen accumulation in Purkinje cells of the cerebellum, in cortical neurons, and in the motor neurons of the ventral horn in the spinal cord. Glycogen deposits have been described in oligodendrocytes as early as the second trimester [Chen et al., 2004] and early delays in myelination have been described in neonates [Chien et al., 2006]. In a knockout mouse model of Pompe disease, excess glycogen was present within large neurons of the hindbrain, spinal cord, and sensory ganglia at 1 month, followed by progressive accumulation throughout many types of cells of the CNS and behavioral decline [Sidman et al., 2008].
The possible presence of glycogen in the CNS of young children with Pompe disease raises important developmental concerns. Specifically, (i) Is glycogen present in the CNS of infants with Pompe disease? If so, to what degree does glycogen in the CNS impair cognitive function?; (ii) Whether or not glycogen is present in the CNS of infants with Pompe disease, does the glycogen accumulate and/or redistribute as the children get older? If so, does cognitive function decline in individuals with Pompe disease over time? Since ERT does not cross the blood–brain barrier [Kaye, 2001; Desnick, 2004], ERT should not directly reduce the level of glycogen in the CNS.
It is important to note that there may not be a direct relationship between glycogen in the CNS and cognitive function. Cognitive delay in infancy and/or the delayed progression of cognitive development is not necessarily indicative of the presence of glycogen in the CNS. Similarly, the lack of any cognitive delay does not mean that glycogen build up in the CNS is not occurring or is not a health concern. Currently, there are no tools to measure the accumulation of glycogen in the CNS of these children.
In an effort to document the development of cognitive function in children with Pompe disease, we examined the cognitive function of a group of infants with Pompe disease prior to ERT and over the initial 12 month period of ERT [Spiridigliozzi et al., in press]. All participants were 6 months of age or younger at the initiation of ERT (alglucosidase alfa—Myozyme®). The results suggested that, for the infants who responded to ERT, (i) there was no difference between the level of cognitive functioning prior to ERT and following 12 months of ERT and (ii) the level of cognitive function following 12 months of ERT was at the lower end of the normal range in comparison to same-aged peers. Based on these results, we concluded that these infantile survivors maintained cognitive abilities with no evidence of decline. Furthermore, if there was an accumulation of glycogen over the 12 month treatment period, it did not have a significant deleterious effect on cognitive function. Infants who showed a minimal response to ERT had much lower scores on the cognitive measure after 12 months of ERT and extremely delayed motor skills. The lower scores on cognitive testing obtained by these children may have been due to a variety of factors, including their poor health status and motor skills as well as the motor requirements of the test items.
In this study, we report on the cognitive and adaptive abilities of seven children with classic infantile Pompe disease and two children with atypical infantile Pompe disease who are followed in our Medical Genetics Clinic at Duke. Children with atypical Pompe disease present in the first year of life but have a less rapid progression of disease manifestations than children with classic infantile Pompe disease.
In this study, we report on the cognitive and adaptive abilities of seven children with classic infantile Pompe disease and two children with atypical infantile Pompe disease who are followed in our Medical Genetics Clinic at Duke. Children with atypical Pompe disease present in the first year of life but have a less rapid progression of disease manifestations than children with classic infantile Pompe disease. Also, they do not have cardiac involvement. Here, the children with classic infantile Pompe disease have received ERT for an average of 6 years, 8 months. Those with atypical infantile Pompe disease have received ERT for an average of 4 years, 1.5 months. This information is important for understanding the emerging cognitive phenotype and to explore whether or not there is evidence of a cognitive decline over time. Such a decline could be an indicator of glycogen accumulation in the CNS impacting on cognition. This information is also important to corroborate the results of the cognitive function testing obtained in early childhood due to the known limitations of measuring cognition in that young age [Aylward, 2004; Hack et al., 2005].
METHODS
Patients
This study includes seven children (5 boys and 2 girls) with classic infantile Pompe disease (median age = 7 years, 1 month; range = 4 years, 11 months to 8 years, 11 months) who were started on ERT (Myozyme®) within the first 6 months of age (range = 0.2–6 months) and two boys with atypical infantile Pompe disease (ages 5 years, 4 months and 5 years, 11 months) who were started on ERT between 1 and 2 years of age (Table I). All patients were enrolled in a long-term natural history study at Duke University Medical Center approved by the Duke Institutional Review Board. None of the children require invasive or non-invasive ventilation. Most children live outside of the Southeast region of the United States and return to Duke for evaluation intermittently.
| Patient | Gender | Race | Corrected gestational age at ERT start (months) | Age at testing (year, month) | Ambulates independently (with or without AFOs) | Dysarthria | Sensorineural hearing loss | Other |
|---|---|---|---|---|---|---|---|---|
| A | M | Caucasian | 0.2 | 4, 11 | Yes | No | Yes | Hearing aids, glasses, ASD diagnosis |
| B | F | Caucasian | 6 | 5, 6 | No | Yes | No | Supplemental G-tube feedings |
| C | M | Caucasian | 2.9 | 6, 7 | Yes | Yes | No | Hearing aids, G-tube feedings |
| D | M | Hispanic | 6 | 8, 0 | No | Yes | Yes | Hearing aids |
| E | F | Hispanic | 4.9 | 7, 10 | Yes | Yes | Yes | Hearing aids, glasses, G-tube feedings |
| F | M | Caucasian | 1.0 | 7, 1 | Yes | Yes | No | |
| G | M | Asian-Indian | 3.1 | 8, 11 | Yes | Yes | Yes | |
| H | M | Caucasian | 20.8 | 5, 4 | Yes | Yes | No | |
| I | M | African-American | 16.7 | 5, 11 | Yes | No | No |
- ERT, enzyme replacement therapy; AFO, ankle–foot orthosis; ASD, autism spectrum disorder.
Only two patients (D and E) participated in our previous study of the cognitive function of children with Pompe disease [Spiridigliozzi et al., in press]. All patients over the age of 5 years received ERT prior to FDA approval through participation in early clinical trials of Myozyme®.
Six of the nine children were based in regular education classrooms that were appropriate for their age (Table II). One child had repeated a grade and another was receiving instruction at home on a short-term basis due to medical issues. One child had been diagnosed with an autism spectrum disorder and was attending a special education preschool classroom. Seven subjects qualified for special education support services and had an Individualized Education Program (IEP). Five patients were receiving speech-language therapy through the public school system and/or a hospital-based clinic. Six children were receiving physical therapy services and three were receiving occupational therapy services.
| Patient | Age at testing (year, month) | Grade level | Classroom placement | IEP | Speech-language therapy | Occupational therapy | Physical therapy |
|---|---|---|---|---|---|---|---|
| A | 4, 11 | Preschool | Self-contained EC Preschool Class | Yes | School | School | School |
| B | 5, 6 | Kindergarten | Regular Classroom | Yes | School and Hospital | School | School and Hospital |
| C | 6, 7 | Kindergarten | Homebound Services | Yes | School and Hospital | Hospital | School and Hospital |
| D | 8, 0 | Grade 1 | Regular Classroom and EC Support Services | Yes | School | No | School and Home-Based |
| E | 7, 10 | Grade 2 | Regular Classroom and EC Support Services | Yes | Hospital | No | Hospital |
| F | 7, 1 | Grade 2 | Regular Classroom | No | No | No | No |
| G | 8, 11 | Grade 4 | Regular Classroom | No | No | No | No |
| H | 5, 4 | Preschool | Regular Classroom | No | No | No | No |
| I | 5, 11 | Grade 1 | Regular Classroom | Yes | No | No | Home-Based |
- EC, Exceptional Children; IEP, Individualized Education Program.
Procedure
Cognitive assessments
Multiple assessments of cognitive functioning were completed over time. Cognitive assessment was completed by means of an individualized intelligence (IQ) test using standardized test administration procedures. Whenever possible, testing was completed in a non-medical, low-stimulation room while the child's parent(s) observed via a two-way mirror. Sessions were scheduled in the morning to minimize the possible impact of fatigue on test performance. All tests were administered by the same clinical child psychologist (GAS).
Consistent with the standard protocol for patients followed through the Duke Pompe program, the Bayley Scales of Infant Development, Second or Third Edition [Bayley, 1993 and Bayley, 2006, respectively] or the Mullen Scales of Early Learning, AGS Edition [Mullen, 1995] were administered to children through 3 years of age; the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III) [Wechsler, 2002] was administered to children 3–6 years of age, and the Wechsler Scale of Intelligence for Children, Fourth Edition (WISC-IV) [Wechsler, 2003] was administered to children older than 6 years of age. Children 3 years of age and older with significant hearing and/or speech and language problems were administered the Visualization and Reasoning Battery of the Leiter International Performance Scale-Revised (Leiter-R) [Roid and Miller, 1997] rather than the WPPSI-III or the WISC-IV. The Leiter-R is designed to measure IQ independent of language ability. An overall composite or Full Scale IQ score was computed for each test. These standardized scores have a mean of 100 and a standard deviation of 15. Scores between 85 and 115 are considered to be in the average or normal range in comparison to typically developing, same-aged peers. Scores between 70 and 84 are in the borderline range between average intelligence and mild intellectual disability.
Adaptive functioning
Adaptive functioning was assessed using the Vineland Adaptive Behavior Scales, Second Edition, Survey Interview Form (VABS-II) [Sparrow et al., 2005]. The VABS-II scoring is based on a semi-structured interview conducted with a child's parent or caregiver to provide information regarding their everyday functioning in the following domains: motor skills (up to age 7 years), communication, daily living skills, and socialization. Age standard scores are computed for each domain as well as an overall Adaptive Behavior Composite (ABC) score. The VABS-II ABC score and the domain scores have a mean of 100 and a standard deviation of 15. Consistent with the cognitive measures, ABC scores between 85 and 115 are in the average or normal range in comparison to typically developing, same-aged peers.
Analysis
The analysis of cognitive functioning was based on the Full Scale IQ score from the most recent IQ test. Verbal IQ and Performance IQ scores were also computed for patients assessed with the WPPSI-III or the WISC-IV. The median Full Scale IQ scores for the group of seven children with classic infantile-onset Pompe disease and the two children with atypical infantile-onset Pompe disease were determined. In order to capture the within subject variability of IQ over time, we report on the range of MDI or Full Scale IQ scores (low to high) obtained from multiple assessments of each child and the child's age at testing (Table III).
| Patient | Age at testing (year, month) | Test administered | Full Scale IQ | No. of cognitive tests over time | Lowest MDI/IQ (age y, m) | Highest MDI/IQ (age y, m) | VABS-II ABC |
|---|---|---|---|---|---|---|---|
| A | 4, 11 | WPPSI-III | 73 | 5 | 73 (4, 11) | 102 (2 weeks) | 72 |
| B | 5, 6 | WPPSI-III | 83 | 3 | 64 (9, 3) | 100 (3, 10) | 79 |
| C | 6, 7 | WISC-IV | 83 | 8 | 82 (9, 11) | 95 (2, 23) | 73 |
| D | 8, 0 | Leiter-R | 85 | 4 | 75 (1, 9) | 96 (4, 2) | 80 |
| E | 7, 10 | Leiter-R | 88 | 6 | 86 (1, 8) | 121 (3, 8) | |
| F | 7, 1 | WISC-IV | 96 | 3 | 95 (2, 7) | 114 (5, 11) | |
| G | 8, 11 | WISC-IV | 109 | 2 | 100 (5, 4) | 109 (8, 11) | 105 |
| (7, 1) | Median Score (median age) | 85 | 82 (4, 11) | 102 (3, 10) | 79 | ||
| H | 5, 4 | WPPSI-III | 122 | 3 | 68 (1, 8) | 122 (5, 4) | |
| I | 5, 11 | WPPSI-III | 127 | 4 | 80 (1, 4) | 127 (5, 11) | 93 |
- MDI, Mental Development Index, Bayley Scales of Infant Development; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence-Third Edition; WISC-IV, Wechsler Intelligence Scale for Children-Fourth Edition; Leiter-R, Leiter International Performance Scale-Revised; VABS-II ABC, Vineland Adaptive Behavior Scales-Second Edition, Adaptive Behavior Composite score.
The analysis of adaptive functioning was based on the ABC score from the most recent VABS-II administration. Standard scores on the Communication, Daily Living Skills, Socialization, and Motor Skills domains were also computed.
RESULTS
Cognitive Function
The median Full Scale IQ of the children with classic infantile Pompe disease was 85 (range = 73–109) (Table III). This score is considered to be at the low end of the normal range of intellectual functioning. The median Full Scale IQ of the two children with atypical infantile Pompe disease was 124.5 (122 and 127). This score is in the above average range of intellectual functioning (i.e., Full Scale IQs > 115).
Within Subject IQ Variability
The total number of IQ assessments per child varied from 2 to 5 (Table III). Within subject variability was remarkably high for all patients. The average (median) difference between the lowest and highest IQ score per patient was 19. No consistent pattern of IQ development was apparent for the classic infantile-onset group. The lowest IQ score for three of the seven children was obtained when they were younger than 3 years of age. However, the highest IQ score for one subject was obtained when the child was less than 1-month old. In contrast, the pattern of IQ development for the two atypical children was consistent across patients and dramatic. Both patients demonstrated gains in IQ over time, from their lowest measured IQ score at approximately 1½ years of age (68 and 80, respectively) to their remarkably high IQ score obtained at their most recent assessment at 5 years of age (122 and 127, respectively).
Adaptive Function
The VABS-II was completed for five of seven children with classic infantile Pompe disease at the time of their IQ testing (Table IV). The median ABC score for these patients was 79 (range = 72–105). This score is considered to be in the borderline range between average and significantly impaired functioning (i.e., 70–84). The ABC score for the one child with atypical Pompe was 93. This score is considered to be at the lower end of the normal range of functioning in comparison to same-aged peers. For all patients, their ABC scores were lower than the Full Scale IQ scores obtained from cognitive testing.
| Patient | Age at testing (year, month) | Test administered | Full Scale IQ | Vineland-II Adaptive Behavior Composite | Vineland-II Domain Standard Scores | |||
|---|---|---|---|---|---|---|---|---|
| Communication | Daily Living Skills | Socialization | Motor Skills | |||||
| A | 4, 11 | WPPSI-III | 73 | 72 | 76 | 81 | 74 | 70 |
| B | 5, 6 | WPPSI-III | 83 | 79 | 95 | 77 | 95 | 64 |
| C | 6, 7 | WISC-IV | 83 | 73 | 76 | 83 | 83 | 64 |
| D | 8, 0 | Leiter-R | 85 | 80 | 82 | 81 | 83 | |
| E | 7, 10 | Leiter-R | 88 | |||||
| F | 7, 1 | WISC-IV | 96 | |||||
| G | 8, 11 | WISC-IV | 109 | 105 | 96 | PR 123 | 100 | |
| Median Score | 85 | 79 | 82 | 81 | 83 | 64 | ||
| H | 5, 4 | WPPSI-III | 122 | |||||
| I | 5, 11 | WPPSI-III | 127 | 93 | 97 | 93 | 101 | 88 |
- Vineland II, Vineland Adaptive Behavior Scales- Second Edition; PR, prorated based on the responses to two of the three Daily Living Skills subdomains.
An analysis of VABS-II median domain scores of the children with classic infantile-onset Pompe disease (see Table IV) suggests stable performance across communication, daily living skills and socialization and significantly lower scores on motor skills. An important part of the discrepancy between IQ and adaptive behavior can be explained by the substantial deficit in motor skills demonstrated by this population as measured by the VABS-II Motor Skills domain and by the inability of these children to complete motor skills embedded in the assessment of the other domains (e.g., bathing independently on the Daily Living Skills domain).
DISCUSSION
In addition to our original work [Spiridigliozzi et al., in press], this is the second study that has found the average or median IQ of a group of children with classic infantile onset Pompe to be in the lower end of the normal range of intellectual functioning, with no evidence of cognitive decline over time. The consistency of the IQ results of the two studies suggests that IQ remains stable across the early childhood years.
The mean Mental Development Index (analogous to IQ) of the children in the first study (ages 1.5–2.5 years) responding to ERT was 89.8 and the median IQ of the children with classic infantile Pompe disease in this study (ages 4 year, 11 months to 8 years, 11 months) was 85. The similarity between the two studies with different cohorts is noteworthy. In both investigations, the average IQ performance of the children was approximately one standard deviation below the mean for their age. Likely possibilities for this finding include fluctuations in the children's health status, reduced motor function, speech and hearing status, and/or the variable demands of different IQ measures. Still, the possibility of glycogen accumulation in the CNS of these children remains. Additional research, including autopsy and neuroimaging studies, will be important to further our understanding of cognitive function in long-term infantile survivors.
In addition to investigating the cognitive function of young children with infantile Pompe disease, our previous study documented the correlation of motor progress to performance on a cognitive measure. The IQ scores of most patients remained stable, while motor function improved substantially throughout the 12 month period of ERT. In the present study, we found that motor ability continues to be a challenge for these children. On the VABS-II, parent reports of fine and gross motor ability lagged behind the development of communication, socialization and daily living skills and had a major impact on overall adaptive functioning.
The motor function of the two children with atypical infantile Pompe disease was less affected than the others with classic infantile Pompe disease. However, both subjects had significant gross motor involvement in comparison to same-aged peers. The cognitive development of these children was particularly remarkable. Both subjects with atypical infantile Pompe disease exhibited a dramatic increase in their Full Scale IQ scores from age 1½ to 5 years. At age 5, their IQ scores were not only significantly above the average of children with classic infantile onset Pompe disease; they were significantly above the average of their normally developing peers. Should the developmental trajectory of children with atypical infantile Pompe be confirmed with additional research, the continued investigation of these two groups of children could potentially yield important clues to the protective function associated with some residual enzyme production.
Of note, all children enrolled in this study were Cross Immunization Material-Positive (CRIM positive), that is, at birth they naturally produced a limited amount of the GAA enzyme. This was due to the fact that there are no long-term CRIM negative survivors in the patients followed at Duke. The data on CRIM negative survivors are currently limited. Prior to the development of immune modulation protocols, these patients had very poor outcomes despite ERT. In a recent series of four CRIM negative cases treated with immune modulation, two patients (ages 17 and 31 months) had normal MRIs of the brain, one showed new deep white matter changes (age 54 months), and one did not have an MRI done [Messinger et al., in press]. In addition, there is a report of a 44-month-old CRIM negative survivor receiving ERT who showed a positive response in skeletal and cardiac muscle, but has white matter brain changes [Rohrbach et al., 2010]. This child also has cognitive and language delays and hearing loss. With current immune modulation treatment protocols, CRIM negative patients are living longer. It will be important to investigate the development of this cohort to identify any differences in the cognitive profiles of these children versus the children who are CRIM positive.
It is very reassuring to know that the majority of our subjects are in age-appropriate, regular education classroom settings, despite the chronicity of this condition and associated features in some children, such as a hearing impairment, articulation difficulties, and feeding issues
It is very reassuring to know that the majority of our subjects are in age-appropriate, regular education classroom settings, despite the chronicity of this condition and associated features in some children, such as a hearing impairment, articulation difficulties, and feeding issues
(see Table II). The fact that they have an Individualized Education Program (IEP) with the public school system allows them to access therapies and services targeting their specific areas of weakness while receiving instruction in the standard curriculum. Over time, more subtle learning difficulties may become apparent, particularly as the demands for written production increase. For example, an examination of the subtest scores on the WISC-IV showed a relative weakness on the Processing Speed composite for some patients (see Table V). Since both Processing Speed subtests are timed and require the use of a pencil, the scores can be impacted negatively by relatively low muscle tone, weak motor skills and/or decreased stamina among other factors. Although these observations must be interpreted with extreme caution due to the limited sample size, they suggest the importance of looking beyond an overall measure of cognitive functioning to determine patients' relative strengths and weaknesses and evaluating a variety of cognitive skills over time.
| Patient | Test administered | Full Scale IQ | Verbal IQ | Performance IQ | Processing Speed | Working Memory |
|---|---|---|---|---|---|---|
| A | WPPSI-III | 73 | 78 | 73 | a | |
| B | WPPSI-III | 83 | 86 | 82 | 88 | |
| C | WISC-IV | 83 | 96 | 84 | 78 | 86 |
| D | Leiter-R | 85 | ||||
| E | Leiter-R | 88 | ||||
| F | WISC-IV | 96 | 104 | 100 | 88 | 88 |
| G | WISC-IV | 109 | 104 | 106 | 106 | 110 |
| H | WPPSI-III | 122 | 116 | 129 | 104 | |
| I | WPPSI-III | 127 | 129 | 125 | 104 |
- WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence-Third Edition; WISC-IV, Wechsler Intelligence Scale for Children-Fourth Edition; Leiter-R, Leiter International Performance Scale-Revised.
- Working Memory Composites can be calculated only for the WISC-IV
- a A Processing Speed composite could not be computed for this patient.
CONCLUSION
In a series of two studies, we have described the cognitive functioning of children with classic infantile Pompe disease and as well as two children with atypical infantile Pompe disease. Even though the total number of patients is relatively small, the results of the cognitive testing have been remarkably consistent. Despite the challenges of health status, motor limitations, and hearing and speech impairments, these children have IQ scores within the lower range of normal with no evidence of a cognitive decline. Motor function appears to be a major factor impacting on reduced adaptive behavior.
Additionally, we have attempted to explore a possible relationship between CNS status and cognitive function. Across our two studies, we have found consistency in level of cognitive function in infancy through school-age. This consistent result suggests that glycogen may not accumulate in the CNS over this time period or if it does, the effect on overall cognitive function is negligible. At this point, we cannot rule out a specific deleterious effect on cognition that is not detected by our current measures. This possible effect warrants further investigation including continued long-term study of the development of cognitive function in this population.
We also propose that investigating the development of related populations, for example, individuals with atypical infantile Pompe disease and individuals with infantile Pompe disease who are CRIM negative, who are now living longer through the use of concomitant immune modulation therapy [Messinger et al., in press], could lead to a greater understanding of the relationship between ERT, enzyme production, enzyme presence in the CNS and development. Clearly, more questions are raised than are answered. However, we suggest that this early research provides important insights into the developing phenotype of children living with infantile Pompe disease and a foundation for additional research in this area.
Acknowledgements
We thank the patients who participated in this clinical study and their families. We also thank the following health care providers for their assistance in collecting and assembling the data: Michelle Canfield, Stephanie DeArmey, Joanne Mackey, Laura Case, Gwendolyn O'Grady, Sean Prater, and Suhrad Banugaria. We thank Elizabeth Wait for assistance with manuscript preparation.
