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

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.

FIGURE 1

Chest X‐ray with cardiomegaly

FIGURE 2

Heart: Panel a: The heart was enlarged and globoid‐shaped, panel b: On the cut section, the heart showed thickened ventricular walls, panel c: Cardiomyocytes with loss of striations, and microvacuolated cytoplasm (all H&E, original magnification × 100). Panel d: Ultra‐structurally, lysosomes‐containing mono‐particulate glycogen were observed (EM; original magnification × 10,000)

FIGURE 3

Muscle: Panel a: Extensive cytoplasm vacuolization of muscle cells and loss of striations of the tongue (H&E; original magnification × 40), panel b: Similar changes in the diaphragm and the major psoas muscle (H&E; original magnification × 100)

FIGURE 4

Liver: Panel a: Hepatocytes with microvesicular steatosis and granular cytoplasm (H &E, original magnification × 40), panel b: Cytoplasmic PAS‐positive granules (PAS stain, original magnification × 40), panel c: Cathepsin D was positive in the cytoplasm of hepatocytes (original magnification × 20), panel d: Lysosomes‐containing granular glycogen (electronic microscopy. Original magnification × 5000)

FIGURE 5

Brain: Panels a and b: Encephalic atrophy characterized by deep brain grooves and dilatation of ventricles, panels c and d: Enlarged neurons with prominent vacuolization of the cytoplasm, panels e and f: Vacuoles containing PAS‐positive material. Panel g and h: Cathepsin D (g) and lysosomal integral membrane protein (h) reveal that vacuoles correspond to lysosomes