Classic infantile-onset Pompe disease with histopathological neurologic findings linked to a novel GAA gene 4 bp deletion: A case study

Mol Genet Genomic Med. 2022 Jul;10(7):e1957. doi: 10.1002/mgg3.1957. Epub 2022 May 9.

Abstract

Pompe disease (PD) is an autosomal recessive disorder by a deficiency of acid α-glucosidase (GAA) with intralysosomal glycogen accumulation in multiple tissues. We present the case of a 5-month-old male with hypertrophic cardiomyopathy, hypotony, feeding difficulties, and oxygen requirement since birth. At 3 months of age, he develops heart failure, respiratory impairment, and neurological deterioration. The echocardiogram revealed concentric hypertrophic cardiomyopathy with left-diastolic dysfunction. We found increased creatine-phosphokinase, lactate dehydrogenase, and urinary glucose tetrasaccharide levels, 50% of PAS-positive vacuolated lymphocytes in the peripheral blood smear, and low GAA activity. Sequencing of coding exons and flanking intronic sequences revealed a novel homozygous 4 bp deletion in exon 15 of the GAA gene (c.2066_2069delAGCC/p.Glu689Glyfs*6). IOPD was diagnosed. At 5 months old, we started enzyme replacement therapy with an alpha-alglucosidase of 20 mg/kg weekly and immunomodulation with intravenous immunoglobulin. He developed two cardiorespiratory arrests with subsequent neurologic deterioration, convulsive crisis, and respiratory failure and died at 9 months old. We found the usual PD hallmarks in the heart, striated muscle, and liver but also we found neuronal lesions characterized by cytoplasm vacuolization with PAS-positive granules in the central nervous system and myenteric plexus. We describe a novel GAA gene pathogenic variant with a particular phenotype characterized by classic IOPD and neurologic histopathological findings. Enhancing the knowledge of lysosomal diseases is critical to improving the diagnosis and treatment of these patients.

Keywords: GAA gene; acid alpha-glucosidase; c.2066_2069delAGCC; infantile-onset Pompe disease; neurologic; p.Glu689Glyfs*6.

Publication types

  • Case Reports

MeSH terms

  • Cardiomyopathy, Hypertrophic* / genetics
  • Enzyme Replacement Therapy
  • Glycogen Storage Disease Type II* / diagnosis
  • Glycogen Storage Disease Type II* / genetics
  • Glycogen Storage Disease Type II* / pathology
  • Humans
  • Male
  • Muscle, Skeletal / pathology
  • alpha-Glucosidases / genetics

Substances

  • alpha-Glucosidases