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PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry.

ABSTRACT: OBJECTIVE:To elaborate the diagnostic methods used as "gold standard" in one of the most common glycogen storage diseases (GSDs), Tarui disease (GSDVII). METHODS:Two siblings with disease suggestive of GSD underwent thorough clinical analysis, including muscle biopsy, muscle MRI, exercise tests, laboratory examinations, and whole-exome sequencing (WES). RESULTS:Both siblings had juvenile-onset exercise intolerance with cramping and infrequent myoglobinuria. Muscle biopsy showed extralysosomal glycogen accumulation, but because of normal phosphofructokinase histochemistry, GSDVII was thought to be excluded. However, WES revealed a causative homozygous PFKM gene defect, R39Q, in both siblings, establishing the diagnosis of GSDVII, which was confirmed by very low residual phosphofructo-1-kinase (PFK) enzyme activity in biochemical studies. CONCLUSIONS:We suggest that in patients with suspicion of GSD and extralysosomal glycogen accumulation, biochemical activity assay of PFK followed by molecular genetics should be performed even when enzyme histochemistry is normal.

SUBMITTER: Auranen M

PROVIDER: S-EPMC4821086 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry.

Auranen Mari M Palmio Johanna J Ylikallio Emil E Huovinen Sanna S Paetau Anders A Sandell Satu S Haapasalo Hannu H Viitaniemi Kati K Piirilä Päivi P Tyynismaa Henna H Udd Bjarne B

Neurology. Genetics 20150604 1

<h4>Objective</h4>To elaborate the diagnostic methods used as "gold standard" in one of the most common glycogen storage diseases (GSDs), Tarui disease (GSDVII).<h4>Methods</h4>Two siblings with disease suggestive of GSD underwent thorough clinical analysis, including muscle biopsy, muscle MRI, exercise tests, laboratory examinations, and whole-exome sequencing (WES).<h4>Results</h4>Both siblings had juvenile-onset exercise intolerance with cramping and infrequent myoglobinuria. Muscle biopsy sh ...[more]

PMID: 27066546

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Project description:Glycogen storage diseases (GSD) encompass a group of rare inherited diseases due dysfunction of glycogen metabolism. Hypoglycemia is the most common primary manifestation of GSD, and disturbances in glucose metabolism can cause neurological damage. The aims of this study were to first investigate the metabolic, genetic, and neurological profiles of children with GSD, and to test the hypothesis whether GSD type I would have greater neurological impact than GSD type IX. A cross-sectional study was conducted with 12 children diagnosed with GSD [Types: Ia (n=5); 1, Ib (n=1); 4, IXa (n=5); and 1, IXb (n=1)]. Genetic testing was conducted for the following genes using multigene panel analysis. The biochemical data and magnetic resonance imaging of the brain presented by the patients were evaluated. The criteria of adequate metabolic control were adopted based on the European Study on Glycogen Storage Disease type I consensus. Pathogenic mutations were identified using multigene panel analyses. The mutations and clinical chronology were related to the disease course and neuroimaging findings. Adequate metabolic control was achieved in 67% of patients (GSD I, 43%; GSD IX, 100%). Fourteen different mutations were detected, and only two co-occurring mutations were observed across families (G6PC c.247C>T and c.1039C>T). Six previously unreported variants were identified (5 PHKA2; 1 PHKB). The proportion of GSD IX was higher in our cohort compared to other studies. Brain imaging abnormalities were more frequent among patients with GSD I, early-symptom onset, longer hospitalization, and inadequate metabolic control. The frequency of mutations was similar to that observed among the North American and European populations. None of the mutations observed in PHKA2 have been described previously. Therefore, current study reports six GSD variants previously unknown, and neurological consequences of GSD I. The principal neurological impact of GSD appeared to be related to inadequate metabolic control, especially hypoglycemia.

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PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry.

Publications

PFKM gene defect and glycogen storage disease GSDVII with misleading enzyme histochemistry.

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