Novel probable pathological variant c.1249A>C in exon 7 of the GAA gene associated with Pompe disease in adults

Dear Editor,

Pompe disease is a rare genetic disorder affecting lysosomal storage. Acid alpha-glucosidase (GAA) is a lysosomal enzyme necessary for glycogen degradation. Decreased enzyme activity results in glycogen accumulation, mainly in muscles.¹ This autosomal recessive disorder is caused by mutations in the gene coding for GAA, located on chromosome 17q25.3. Over 450 GAA mutations have been described (http://cluster15.erasmusmc.nl/klgn/pompe/mutations.html). The type of mutation affects residual enzyme activity, which in turn determines the severity of symptoms: residual enzyme activity is below 1% in infantile forms and below 40% in adult forms.² We present the case of a Spanish man with late-onset Pompe disease and a novel allelic variant of GAA in heterozygosis.

The patient was a man who began to experience weakness in the pelvis at the age of 57. The weakness first affected his ability to practice sport. The patient never experienced muscle pain, muscle spasms, respiratory insufficiency, or bulbar symptoms. The neurological examination revealed weakness in hip flexion (3-4/5), hip abduction and adduction (4/5), and shoulder abduction (4+/5) (Medical Research Council scale). Lower limb reflexes were abolished.

A laboratory test showed sustained hyperCKaemia (500-800 U/L; normal range, 0-190) and elevated levels of lactate (27.0 mg/dL; normal range, 4.5-19.8), GOT (50 U/L; normal range, 0-37), GPT (69 U/L; normal range, 0-41), LDH (449 U/L; normal range, 160-480), and aldolase (8.7 U/L; normal range, 1.3-2). An electromyography study revealed myopathic motor unit action potentials with early recruitment and spontaneous activity, especially in the quadriceps. The echocardiogram showed asymmetric septal left ventricular hypertrophy with preserved ventricular function. Respiratory function was normal. A biopsy of the biceps and deltoid muscles revealed muscle atrophy; histochemical staining techniques showed no abnormalities. Electron microscopy showed free glycogen deposition in the sarcoplasm, fibrillary deposits in the cytoplasm, lipid deposition, and focal disorganisation of sarcomeres.

Dried blood spot testing revealed pathological decreases in GAA inhibitory activity (AαGIA) (0.64 and 0.68 μmol/L/h; normal range, 0.75-5.0). Diagnosis was confirmed with an analysis of enzyme activity in isolated lymphocytes (0.8 nmol/min/mg protein; normal range, 0.15-1.0). A genetic study revealed that the patient was heterozygous for a variant of uncertain clinical significance, p.Asn417His (p.N417H), in position 1249 (c.1249A>C) of exon 7 of GAA. This nucleotide change has not been described previously in the HGMD, ClinVar, dbSNP, ExAC, or ESP databases, either as a mutation or as a polymorphism associated with any disease. Various in silico prediction algorithms, which predict the impact of an amino acid change on protein function, predicted that the variant was probably pathogenic (PolyPhen-2 score: 0.905, damaging; MutationTaster score: 0.505894, disease-causing; MutationAssessor score: 1.78, low impact).

The patient's children also underwent genetic testing. One of his daughters showed decreased GAA activity both in dried blood spot testing and in isolated lymphocytes (0.14 nmol/min/mg protein). She was asymptomatic. A biochemical study revealed slightly elevated transaminases and normal creatine kinase levels. The genetic study showed that the patient's daughter was a heterozygous carrier of the same GAA variant.

We have identified a patient with a possibly pathogenic mutation of GAA. The characteristic symptoms of Pompe disease and decreased GAA activity in isolated lymphocytes suggest that the mutation may be responsible for the findings. The hypothesis of the pathogenicity of this variant is supported by the results of several in silico prediction algorithms; furthermore, the cosegregation study of family members revealed that one of the patient's daughters, who showed decreased GAA activity, was also a heterozygous carrier of the variant.

Interestingly, the patient was heterozygous but showed unequivocal signs of myopathy. Asymptomatic hyperCKaemia secondary to mild enzyme deficiency had previously been described in mutation carriers.³ We propose 2 possible hypotheses for our patient's case: 1) the patient may carry an undetected mutation in a non-coding region of the other allele,⁴ or 2) certain epigenetic or environmental factors may have an impact on final enzyme activity, as shown by the mutation c.-32-13T>G.^5–7 An enzyme replacement therapy approved in 2006 poses new clinical dilemmas,^8,9 especially in late-onset cases, in which patients may remain asymptomatic for decades, and in heterozygous cases, as the one presented here, whose clinical expression is difficult to predict.^10,11