Pompe Disease

Pompe disease is a rare inherited metabolic disorder classified as Glycogen Storage Disease Type II. It is caused by a deficiency or malfunction of the enzyme acid alpha-glucosidase (GAA), leading to the accumulation of glycogen in the lysosomes of cells due to impaired breakdown. This buildup damages various tissues, including muscles and the heart, resulting in a wide range of symptoms such as progressive muscle weakness, cardiac complications, and respiratory difficulties. Without appropriate treatment, especially in infants, the disease can lead to life-threatening outcomes.

Pompe disease is broadly categorized into two types: Infantile-Onset Pompe Disease (IOPD) and Late-Onset Pompe Disease (LOPD). Each type presents with distinct clinical features depending on the age of onset and severity of enzyme deficiency.

Infantile-Onset Pompe Disease (IOPD) typically begins before 12 months of age. It is the more severe form of the disease, characterized by early and rapid progression of symptoms. A hallmark feature is cardiomegaly, often caused by hypertrophic cardiomyopathy, which may lead to heart failure if untreated. Affected infants frequently show severe hypotonia (floppiness) and profound weakness of the trunk and limb muscles, resulting in poor head control and an inability to maintain posture. Feeding difficulties, failure to thrive, and delayed growth are common, accompanied by high-pitched crying. Respiratory muscles are also significantly weakened, leading to tachypnea, chest wall retractions, and episodes of sleep apnea, which increase the risk of recurrent respiratory infections and rapidly progressive respiratory failure. In addition, some patients may exhibit hepatomegaly or macroglossia. Without early enzyme replacement therapy, most infants with IOPD die during infancy or early childhood due to cardiorespiratory complications.

Late-Onset Pompe Disease (LOPD), on the other hand, can present anytime from childhood to adulthood. Unlike IOPD, cardiac involvement is rare. The disease progresses more slowly and is often misdiagnosed as other neuromuscular conditions due to its nonspecific symptoms. The most common features include progressive muscle weakness, especially in the proximal muscles of the lower limbs and trunk. This leads to difficulty climbing stairs, rising from a chair, or walking long distances. Postural instability may develop, sometimes resulting in scoliosis or lumbar lordosis. As the disease advances, respiratory muscles become affected, resulting in sleep-disordered breathing, daytime sleepiness, chronic fatigue, and dyspnea on exertion. In many cases, respiratory symptoms may precede noticeable muscle weakness, and some patients eventually require non-invasive ventilation (NIV) or mechanical support. Additional symptoms such as myalgia, muscle cramps, and visible muscle wasting may also occur. The rate of disease progression varies widely among individuals; in some cases, symptoms may worsen gradually over several decades.

Overall, Pompe disease is a progressive condition, and early diagnosis is critical to initiating treatment that can help slow the disease course and improve quality of life.

Pompe disease is caused by mutations in the GAA gene, which is located on chromosome 17. This gene normally produces the enzyme acid alpha-glucosidase, which plays a key role in breaking down glycogen within the lysosomes. When this enzyme is deficient or nonfunctional due to genetic mutations, glycogen accumulates inside cells, leading to damage in muscles, the heart, and other organs. Pompe disease is inherited in an autosomal recessive manner, meaning that an affected individual must inherit one mutated copy of the gene from each parent to develop the condition.