Elsevier

The Journal of Pediatrics

Volume 175, August 2016, Pages 130-136.e8
The Journal of Pediatrics

Original Article
Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency

https://doi.org/10.1016/j.jpeds.2016.04.021Get rights and content

Objective

To define phenotypic groups and identify predictors of disease severity in patients with phosphoglucomutase-1 deficiency (PGM1-CDG).

Study design

We evaluated 27 patients with PGM1-CDG who were divided into 3 phenotypic groups, and group assignment was validated by a scoring system, the Tulane PGM1-CDG Rating Scale (TPCRS). This scale evaluates measurable clinical features of PGM1-CDG. We examined the relationship between genotype, enzyme activity, and TPCRS score by using regression analysis. Associations between the most common clinical features and disease severity were evaluated by principal component analysis.

Results

We found a statistically significant stratification of the TPCRS scores among the phenotypic groups (P < .001). Regression analysis showed that there is no significant correlation between genotype, enzyme activity, and TPCRS score. Principal component analysis identified 5 variables that contributed to 54% variance in the cohort and are predictive of disease severity: congenital malformation, cardiac involvement, endocrine deficiency, myopathy, and growth.

Conclusions

We established a scoring algorithm to reliably evaluate disease severity in patients with PGM1-CDG on the basis of their clinical history and presentation. We also identified 5 clinical features that are predictors of disease severity; 2 of these features can be evaluated by physical examination, without the need for specific diagnostic testing and thus allow for rapid assessment and initiation of therapy.

Section snippets

Methods

We evaluated 27 patients (18 children and 9 adults) with confirmed diagnosis of PGM1-CDG. The diagnosis was based on enzyme and molecular analysis. Patient age ranged from 2 to 43 years at the time of assessment, with 17 male and 10 female patients in the cohort. None of the patients exhibited severe motor or cognitive impairment. We obtained patient data by using a specific survey on informed consent (institutional review board reference #13-533377) and collected data on clinical features,

Results

Although the majority of the patients have been reported previously,4, 8, 12 we recruited 6 new patients, 5 with novel PGM1 mutations (patient 5, 7, 11, 14, and 17) and 1 with a previously reported mutation (patient 27).4 There was a great diversity in the phenotypic spectrum. Hepatopathy is the most frequent clinical manifestation in the cohort (100%), followed by hypoglycemia (89%), congenital malformation (85%), and growth retardation (85%). The type and frequency of congenital malformation

Discussion

Although our patient cohort is small (n = 27), we demonstrated that by assessing the presence and absence of congenital malformation and dilated cardiomyopathy, 2 of the most common clinical features that are consequences of in utero developmental anomaly, we were able to classify the patients into 3 phenotypic groups; mild, moderate, and severe. Furthermore, we proved that our classification approach is clinically and statistically meaningful by using TPCRS, a simple screening tool we tailored

References (36)

  • S. Timal et al.

    Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing

    Hum Mol Genet

    (2012)
  • L.C. Tegtmeyer et al.

    Multiple phenotypes in phosphoglucomutase 1 deficiency

    N Engl J Med

    (2014)
  • T. Stojkovic et al.

    Muscle glycogenosis due to phosphoglucomutase 1 deficiency

    N Engl J Med

    (2009)
  • W.H. Thomson et al.

    Skeletal muscle glycogenosis: an investigation of two dissimilar cases

    J Neurol Neurosurg Psychiatry

    (1963)
  • B. Pérez et al.

    A novel congenital disorder of glycosylation type without central nervous system involvement caused by mutations in the phosphoglucomutase 1 gene

    J Inherit Metab Dis

    (2013)
  • L.J. Beamer

    Mutations in hereditary phosphoglucomutase 1 deficiency map to key regions of enzyme structure and function

    J Inherit Metab Dis

    (2015)
  • S. Achouitar et al.

    Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression

    J Inherit Metab Dis

    (2011)
  • N. Ondruskova et al.

    Glycogen storage disease-like phenotype with central nervous system involvement in a PGM1-CDG patient

    Neuro Endocrinol Lett

    (2014)
  • Cited by (42)

    • Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots

      2020, Molecular Genetics and Metabolism
      Citation Excerpt :

      To compare the description of early presentation with literature and to identify possible age-related clinical presentations of PGM1 deficiency, we performed a systematic literature review on clinical symptoms in PGM1-CDG. The systematic review of the literature led to 198 papers (Table S2), of which 17 case reports were included [1,4–6,8,11,16,21–31]. The article by Radenkovic et al. [12] was also included despite being a review as it provided unreported clinical details on previously published patients, with particular attention for CNS symptoms.

    View all citing articles on Scopus

    Supported by the National Institute of General Medical Sciences of the National Institutes of Health (1 U54 GM104940), which funds the Louisiana Clinical and Translational Science Center. T.H. is supported by General University Hospital in Prague, Czech Republic (RVO-VFN 64165), and the Ministry of Health of the Czech Republic (MZ CR AZV 16-31932A). The authors declare no conflicts of interest.

    View full text