Phosphoglycerate mutase deficiency: case report of a manifesting heterozygote with a novel E154K mutation and very late onset

Abstract

Phosphoglycerate mutase (PGAM) deficiency is a rare glycogen storage disease (glycogenosis type X) due to recessive mutations in the muscle-specific isoform PGAMM. We present a 67-year-old German patient with exercise-induced cramps and myalgia for 1 year but no attacks of rhabdomyolysis. CK was 2.5-folds increased and forearm exercise test was normal. Sections of the muscle biopsy stained with PAS showed moderate glycogen accumulation. Gomori-trichome and NADH showed subsarcolemmal depositions (0.01% of the fibres) suggesting tubular aggregates (Fig. 1). PGAM activity in muscle homogenate [4] was moderately reduced (141 U/g wet weight, normal 332 ± 88). Deficiencies of alpha-glucosidase, myophosphorylase, CPT and MAD were excluded biochemically. The PGAM-M gene was amplified [5] and directly sequenced. A novel G to A transition at nucleotide position 460, resulting in exchange of amino acid glutamic acid at codon 154 to lysine, was identified in heterozygous state. This was confirmed by reverse sequencing. RFLP analysis in 70 normal controls from the same ethnic origin did not show the mutation. There are several lines of evidence suggesting that the patient is a manifesting heterozygous carrier. The E154K mutation is considered pathogenic because: (1) the mutation was not identified in normal controls, (2) it affects a highly conserved amino acid (Fig. 2), (3) it results in changing of an acidic amino acid to a basic amino acid with larger side chain, (4) it was the only mutant change identified in the coding region and exon– intron boundaries of the PGAM-M gene. However, it cannot be excluded that the patient carries a large deletion or a deep intronic mutation on the second allele. The biochemical result with half the normal enzyme activity, however, seems consistent with just one mutant allele. Finally, glycogen storage and tubular aggregates in muscle (in very low degree, though) are typical findings of PGAM deficiency. These histological changes might be scarce, even in cases with two mutant alleles. We identified another case of PGAM deficiency (with the typical phenotype of exercise-induced myalgia with rhabdomyolysis starting at age 35 years) with moderate glycogen accumulation and very few fibres suggestive of tubular aggregates (0.02% of total fibres). This patient of African origin had very reduced PGAM activity (9.6 U/g wet weight, normal 332 ± 88) and carried the homozygous W78X stopmutation that was identified in several African patients with PGAM deficiency [3, 6]. The patient had incomplete raise of lactate in the forearm test, as described for PGAM deficiency [1, 3, 7]. The manifesting heterozygote patient, however, had normal forearm exercise test, suggesting that 50% residual activity is enough so that the metabolic impairment is undetectable in this test. In both of our patients electron microscopy was unable to identify fibres with tubular aggregates because they were very scarce and abnormal fibres were not seen in semi-thin sections because of the small piece of muscle that is analysed. P. R. Joshi M. Knape S. Zierz M. Deschauer Neurologische Universitatsklinik, Halle, Germany