Browsing by Author "Korlimarla, Aditi"

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    A new look at an old disease: Is Pompe disease a neuromuscular disorder with CNS involvement?
    (Molecular Genetics and Metabolism, 2020-02) Korlimarla, Aditi; Chen, Steven; Austin, Stephanie L; Provenzale, James M; Kishnani, Priya S
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    An emerging phenotype of central nervous system involvement in Pompe disease: from bench to bedside and beyond.
    (Annals of translational medicine, 2019-07) Korlimarla, Aditi; Lim, Jeong-A; Kishnani, Priya S; Sun, Baodong
    Pompe disease (PD) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid-alpha glucosidase (GAA). Pathogenic variants in the GAA gene lead to excessive accumulation of lysosomal glycogen primarily in the cardiac, skeletal, and smooth muscles. There is growing evidence of central nervous system (CNS) involvement in PD. Current research is focused on determining the true extent of CNS involvement, its effects on behavior and cognition, and effective therapies that would correct the disease in both muscle and the CNS. This review article summarizes the CNS findings in patients, highlights the importance of research on animal models, explores the probable success of gene therapy in reversing CNS pathologies as reported by some breakthrough preclinical studies, and emphasizes the need to follow patients and monitor for CNS involvement over time. Lessons learned from animal models (bench) and from the literature available to date on patients will guide future clinical trials in patients (bedside) with PD. Our preliminary studies in infantile PD show that some patients are susceptible to early and extensive CNS pathologies, as assessed by neuroimaging and developmental assessments. This article highlights the importance of neuroimaging which could serve as useful tools to diagnose and monitor certain CNS pathologies such as white matter hyperintense foci (WMF) in the brain. Longitudinal studies with large sample sizes are warranted at this time to better understand the emergence, progression and consequences of CNS involvement in patients with PD.
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    Assessment of Dysphonia in Children with Pompe Disease Using Auditory-Perceptual and Acoustic/Physiologic Methods.
    (Journal of clinical medicine, 2021-08-16) Crisp, Kelly D; Neel, Amy T; Amarasekara, Sathya; Marcus, Jill; Nichting, Gretchen; Korlimarla, Aditi; Kishnani, Priya S; Jones, Harrison N
    Bulbar and respiratory weakness occur commonly in children with Pompe disease and frequently lead to dysarthria. However, changes in vocal quality associated with this motor speech disorder are poorly described. The goal of this study was to characterize the vocal function of children with Pompe disease using auditory-perceptual and physiologic/acoustic methods. High-quality voice recordings were collected from 21 children with Pompe disease. The Grade, Roughness, Breathiness, Asthenia, and Strain (GRBAS) scale was used to assess voice quality and ratings were compared to physiologic/acoustic measurements collected during sustained phonation tasks, reading of a standard passage, and repetition of a short phrase at maximal volume. Based on ratings of grade, dysphonia was present in 90% of participants and was most commonly rated as mild or moderate in severity. Duration of sustained phonation tasks was reduced and shimmer was increased in comparison to published reference values for children without dysphonia. Specific measures of loudness were found to have statistically significant relationships with perceptual ratings of grade, breathiness, asthenia, and strain. Our data suggest that dysphonia is common in children with Pompe disease and primarily reflects impairments in respiratory and laryngeal function; however, the primary cause of dysphonia remains unclear. Future studies should seek to quantify the relative contribution of deficits in individual speech subsystems on voice quality and motor speech performance more broadly.
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    Behavioral, social and school functioning in children with Pompe disease
    (Molecular Genetics and Metabolism Reports, 2020-12) Korlimarla, Aditi; Spiridigliozzi, Gail A; Stefanescu, Mihaela; Austin, Stephanie L; Kishnani, Priya S
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    DOWN SYNDROME
    (2021-02-19) Korlimarla, Aditi; Hart, Sarah; Spiridigliozzi, Gail; Kishnani, Priya
    Down syndrome is the most common identifiable genetic cause of intellectual disability. The facial appearance of individuals with Down syndrome is highly characteristic and is frequently associated with other minor anomalies and malformations of other body systems, most importantly the cardiovascular and gastrointestinal systems. Individuals with Down syndrome also have an increased likelihood of a number of medical complications including those of the thyroid gland, and the gastrointestinal, upper‐respiratory, audiologic, hematological, and neurological systems. It is thus important for persons with Down syndrome to be followed in a systematic fashion and have access to appropriate specialists to anticipate, prevent, or modify potential complications. Current research continues to shed light on many behavioral and medical aspects of Down syndrome, but questions remain about the relationship between the trisomy of chromosome 21, the developmental and behavioral pattern, and the health complications.
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    New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside.
    (Journal of clinical medicine, 2021-07-30) Korlimarla, Aditi; Lim, Jeong-A; McIntosh, Paul; Zimmerman, Kanecia; Sun, Baodong D; Kishnani, Priya S

    Background

    There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease.

    Methods

    To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history.

    Results

    Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18-79 years, median age: 51.55 years; 35 females; 53 on ERT).

    Conclusion

    GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles.
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    New insights into GI manifestations in late-onset Pompe disease: Lessons from the bench and bedside
    Korlimarla, Aditi
    There is growing evidence of smooth muscle involvement in Pompe disease with reports of life-threatening basilar artery and ascending aorta aneurysms, difficulties in swallowing and speech, and gastrointestinal (GI) involvement. We studied the histopathology of the GI tract in Pompe mice (GAAKO 6neo/6neo), and impact of enzyme replacement therapy (ERT) with alglucosidase alfa. We evaluated adult patients with late-onset Pompe disease (LOPD) using Patient-Reported Outcomes Measurements Information System - Gastrointestinal (PROMIS-GI) symptom scales, and a GI-focused medical history. Pompe mice showed extensive and progressive glycogen accumulation in the smooth and striated muscles throughout the GI system (from tongue to rectum), and in the Aurbach's plexus, as early as age 3 months. Long-term (6 months) enzyme replacement therapy (ERT; 20 mg/kg biweekly, age at initiation 2 months) was more effective to clear the glycogen accumulation than short-term (5 weeks) ERT (20 mg/kg weekly, age at initiation 3 months) in Pompe mice. We enrolled 58 patients with LOPD (median age: 51.55 ± 15.5 years, range: 18–79 years; 35 females; 53 on ERT, 4 ERT naïve, 1 off ERT for 3 years; median duration of ERT: 5.5 years; range: 2 months-13 years). The PROMIS-GI (cross-sectional) data from 52 patients suggested a high prevalence of gas/bloating (98%), reflux (94%), constipation (84%), diarrhea (72%), belly pain (68%), nausea/vomiting (61%), disrupted swallowing (54%), and bowel incontinence (40%). Onset of GI symptoms ranged from childhood to seventh decade of life. Longitudinal data (n = 19, followed over 16 months) revealed that most patients had either no change or worsening GI symptoms over time, even after ERT initiation. This study sheds light on the significant disease burden caused by GI manifestations. Clinicians should evaluate GI manifestations during routine clinical visits, and use quantitative tools such as PROMIS-GI measures. The study also highlights the need for next generation therapies that target the smooth muscles.
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    ItemOpen Access
    New insights into GI manifestations in late-onset Pompe disease: Lessons from the bench and bedside
    (Molecular Genetics and Metabolism, 2021-02) Korlimarla, Aditi; Lim, Jeong-A; McIntosh, Paul; Sun, Baodong; Kishnani, Priya S
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    Novel approaches to quantify CNS involvement in children with Pompe disease.
    (Neurology, 2020-06-09) Korlimarla, Aditi; Spiridigliozzi, Gail A; Crisp, Kelly; Herbert, Mrudu; Chen, Steven; Malinzak, Michael; Stefanescu, Mihaela; Austin, Stephanie L; Cope, Heidi; Zimmerman, Kanecia; Jones, Harrison; Provenzale, James M; Kishnani, Priya S
    OBJECTIVE:To characterize the extent of central nervous system involvement in children with Pompe disease using brain magnetic resonance imaging (MRI) and developmental assessments. METHODS:The study included fourteen children (ages 6-18 years) with infantile Pompe disease (IPD) (n=12) or late onset Pompe disease (LOPD) (n=2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach; the individual FS scores from ten anatomical areas were summed to yield a total FS score (range: absent-0 to severe-30) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period. RESULTS:Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age-10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in Processing Speed, Fluid Reasoning, Visual Perception, and receptive vocabulary. The two children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments. CONCLUSION:This study systematically characterized WM hyperintense foci in children with IPD; which could serve as a benchmark for longitudinal follow up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children.
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    Quantitative evaluation of white matter hyperintensities in the central nervous system in infantile Pompe disease
    (Molecular Genetics and Metabolism, 2019-02) Korlimarla, Aditi; Stefanescu, Ela; Austin, Stephanie; Chen, Steven; Provenzale, James M; Kishnani, Priya S