Browsing by Author "El-Gharbawy, Areeg"

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    ItemOpen Access
    A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III.
    (Molecular genetics and metabolism reports, 2021-12) Hijazi, Ghada; Paschall, Anna; Young, Sarah P; Smith, Brian; Case, Laura E; Boggs, Tracy; Amarasekara, Sathya; Austin, Stephanie L; Pendyal, Surekha; El-Gharbawy, Areeg; Deak, Kristen L; Muir, Andrew J; Kishnani, Priya S

    Introduction

    A deficiency of glycogen debrancher enzyme in patients with glycogen storage disease type III (GSD III) manifests with hepatic, cardiac, and muscle involvement in the most common subtype (type a), or with only hepatic involvement in patients with GSD IIIb.

    Objective and methods

    To describe longitudinal biochemical, radiological, muscle strength and ambulation, liver histopathological findings, and clinical outcomes in adults (≥18 years) with glycogen storage disease type III, by a retrospective review of medical records.

    Results

    Twenty-one adults with GSD IIIa (14 F & 7 M) and four with GSD IIIb (1 F & 3 M) were included in this natural history study. At the most recent visit, the median (range) age and follow-up time were 36 (19-68) and 16 years (0-41), respectively. For the entire cohort: 40% had documented hypoglycemic episodes in adulthood; hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients. In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. Older individuals tended to show more severe muscle weakness and mobility limitations, compared with younger adults. Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%. Finally, a urinary biomarker of glycogen storage (Glc4) was significantly associated with AST, ALT and CK.

    Conclusion

    GSD III is a multisystem disorder in which a multidisciplinary approach with regular clinical, biochemical, radiological and functional (physical therapy assessment) follow-up is required. Despite dietary modification, hepatic and myopathic disease progression is evident in adults, with muscle weakness as the major cause of morbidity. Consequently, definitive therapies that address the underlying cause of the disease to correct both liver and muscle are needed.
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    ItemOpen Access
    Beyond predicting diagnosis: Is there a role for measuring biotinidase activity in liver glycogen storage diseases?
    (Molecular genetics and metabolism reports, 2022-06) El-Gharbawy, Areeg; Tolun, Adviye A; Halaby, Carine A; Austin, Stephanie L; Kishnani, Priya S; Bali, Deeksha S

    Introduction

    Biotinidase synthesis is needed to recycle biotin for essential metabolic reactions. Biotinidase activity is lower than normal levels in advanced liver disease but is higher in hepatic glycogen storage disorders (GSDs), however the cause of this association remains unclear.

    Methods

    In this study, biotinidase activity was measured in plasma samples from 45 individuals with hepatic GSDs; GSDI (a, b; n = 25) and GSD III (a, b; n = 20), complemented by a chart review to associate biotinidase activity levels with clinical laboratory and imaging findings known to be implicated in these GSDs.

    Results

    Our findings showed variation in biotinidase activity levels among subjects with GSD I and III; biotinidase activity correlated positively with hypertriglyceridemia in subjects with GSD I (r = 0.47, P = 0.036) and GSD III (r = 0.58, P = 0.014), and correlated negatively with age (r = -0.50, P = 0.03) in patients with GSD III. Additionally, biotinidase activity was reduced, albeit within the normal range in subjects with evidence of fibrosis/cirrhosis, as compared to subjects with hepatomegaly with or without steatosis (P = 0.002).

    Discussions

    These findings suggest that abnormal lipid metabolism in GSD I and III and progressive liver disease in GSD III may influence biotinidase activity levels. We suggest that a prospective, multi-center, longitudinal study designed to assess the significance of monitoring biotinidase activity in a larger cohort with hepatic GSDs is warranted to confirm this observation.

    Take-home message

    Altered lipid metabolism and advancing liver fibrosis/cirrhosis may influence biotinidase activity levels in patients with hepatic glycogen storage disease. Thus, longitudinal monitoring of biotinidase activity, when combined with clinical and other biochemical findings may be informative.
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    ItemOpen Access
    Persistent elevations of alkaline phosphatase as an early indicator of GM1 gangliosidosis.
    (Molecular genetics and metabolism reports, 2025-03) Menkovic, Iskren; Williams, Monika; Makhijani, Neelam; Wei, Ruhan; Young, Sarah P; El-Gharbawy, Areeg; Stiles, Ashlee R
    GLB1-related disorders are autosomal recessive lysosomal diseases caused by enzymatic deficiency of β-galactosidase. Enzymatic deficiency of β-galactosidase may lead to one of two phenotypes, GM1 gangliosidosis or mucopolysaccharidosis IVB (MPS IVB). GM1 gangliosidosis is a neurodegenerative disorder with variable skeletal disease and involvement of other systems. The age of onset correlates with the extent of neurological involvement and established genotype/phenotype correlations. Mucopolysaccharidosis IVB is characterized by a skeletal dysplasia without neurological involvement. Diagnostic work-up for GLB1-related disorders includes enzyme analysis, biomarker analysis, molecular testing, and laboratory imaging studies. We report a patient who presented with persistent elevations of alkaline phosphatase (ALP) and subtle dysmorphic facial features. An initial skeletal survey at birth was unrevealing; however, a repeat at 3 months of age was abnormal with anterior beaking of the lumbar vertebrae and hemivertebrae of the lower cervical spine. Urinary glycosaminoglycan (GAG) analysis revealed a marked elevation of keratan sulfate (KS). Clinical exome sequencing revealed pathogenic heterozygous variants in GLB1, consistent with GLB1-related GM1 gangliosidosis. Our case demonstrates that persistent elevations of ALP may be an early indicator for GM1 gangliosidosis in an infant with progressive multisystem disease, indicating the need for early genetic consultation. This case also highlights the utility of repeat skeletal surveys with abnormalities detected at 3 months of age.