Overview

Lysosomal storage diseases (LSDs) represent a group of over 70 rare inherited health conditions that affect the metabolic processes within the body.¹ Metabolic processes are the chemical reactions that occur within the body to keep it functioning. These diseases specifically affect the reactions that break down or recycle certain substances. Typically, LSDs are the result of single gene mutations and manifest before birth or in the early years of childhood.²

In majority of cases, LSDs are the result of a defective enzyme (protein that is meant to break down chemicals in the body). Defective enzyme activators or related proteins, which support enzyme function, are the cause of the condition in other situations. A specific enzyme or activator is produced by each gene on a given chromosome. A protein that is unable to fulfil its supporting function or an enzyme that is inaccurate or inactive can result from a mutation in one of these genes.³ 

Waste products accumulate inside cells as a result of these mutations over time, causing increasing harm to the body.² The cardiovascular system (the heart and blood vessels) and the respiratory system (the lungs and airways), which are vital for preserving general health and quality of life, are frequently significantly impacted by LSDs, as well as other organs within the body.

Why do LSDs affect the heart and lungs?

The heart and lungs are essential for life and the focal parts of the cardiovascular and respiratory systems. These systems team up to ensure that oxygen reaches every single cell, while also getting rid of waste products like carbon dioxide. These systems are packed with blood vessels and depend a lot on the smooth operation of tissues and muscles. The tissues and muscles are the site of a range of metabolic processes.^4,5 Due to LSDs, at the sites, an accumulation of waste products occur in these organs, consequently disrupting normal functioning. Additionally, this buildup can cause tissues to thicken or swell, resulting in blockage, stiffness, or weakness.⁶ This can be especially dangerous when it impacts essential functions like regulating the heartbeat or breathing effectively.

How LSDs affect the heart: cardiovascular complications

Heart muscle thickening (Cardiomyopathy)

 One of the most common heart complications associated with LSDs is the thickening of the heart muscle, which is called cardiomyopathy. Despite this extra muscle placed on the heart, this does not aid the heart’s function but debilitates it. When the heart muscle becomes too thick, an array of issues can occur:⁶

• The heart chambers become smaller, so less blood can enter the space
• The heart has to work tremendously harder to pump the same amount of blood around the body
• Individuals with LSDs often feel tired and short of breath, even with short bouts of activity
• It can lead to heart failure, where the heart cannot pump an adequate amount of blood to meet the needs of the body

This occurs because the enzymes are inactive or not present to recycle the waste from the heart muscle. Subsequently, the cells become bloated and enlarged, causing the structure of the heart muscle to become thicker. Additionally, this affects the conductivity of the heart muscles, causing irregular heartbeats, and the heart cannot meet the body’s demands.⁷

For example, in the LSD pompe disease, it can cause cardiomyopathy at a relatively young age. The breakdown of glycogen, a stored form of sugar, is carried out by the enzyme alpha-glucosidase (GAA), which is deficient in pompe disease. The glycogen accumulation in cardiac muscle cells now causes the heart to grow and the muscular walls to thicken. During the first few months of life, infants with pompe disease frequently experience heart failure, poor weight gain, fast breathing, and feeding issues.⁸ These consequences are frequently fatal if left untreated.

Valve dysfunction

Blood flow between the heart's chambers and the rest of your body is regulated by four valves in your heart.⁹ To guarantee that blood flows in the proper direction, these valves must open and close in a precise order. Storage materials that cannot be adequately broken down start to build up directly on these heart valves in several lysosomal storage illnesses, namely fabry disease and mucopolysaccharidoses (MPS). Over time, this accumulation makes the valve tissue thick and rigid. The capacity of the valves to close entirely is lost when deposits of storage material causes them to thicken.^10,11 Gaps in the valve allow blood to flow backwards through it, rather than creating a tight seal. This backflow is referred to as "leaky valves" or valve regurgitation.¹²

Leaky valves create significant problems for the heart function. The heart must work harder to pump blood because some of the blood it just pumped, flows backward instead of moving forward to the body. This extra workload reduces the heart's overall efficiency at circulating blood throughout the body.

Patients usually experience observable symptoms as valve dysfunction worsens. The inability of the heart to pump enough oxygen-rich blood to meet the body's needs during any physical activity causes shortness of breath (dyspnoea). When the heart muscle itself doesn't get enough oxygen because of inefficient pumping, chest pain may occur as well. As blood backs up in the circulation system, fluid retention becomes common and causes swelling in the legs, ankles, and feet.

Usually, these symptoms appear gradually over several months or years. The rate at which storage materials build up on the valves and the degree to which it impairs valve function determine the progression. Frequent cardiac monitoring helps maintain heart function and improves patient quality of life, by enabling healthcare professionals to monitor valve changes and take action before symptoms worsen.

Irregular heartbeats (arrhythmias)

As the enzymes required to break down waste substances are either absent or malfunctioning, dangerous substances accumulate inside the heart cells of LSDs patients. This accumulation may:

• Disrupt electrical signals: when lysosomal enzymes are deficient, substances like glycolipids (specific to fabry disease), glycogen (specific to pompe disease), or glycosaminoglycans (specific to mucopolysaccharidoses) build up in heart cells. This accumulation disrupts ion channels (e.g., potassium, sodium, calcium) that regulate electrical impulses, causing irregular heartbeats¹³
• Damage to heart tissue: over time, the heart muscle experiences hypertrophy (thickening) and fibrosis (scarring) due to stored material. Glycogen buildup in pompe disease weakens the heart, resulting in conduction abnormalities and ventricular arrhythmias. By interfering with the heart's normal electrical pathways, fibrosis raises the possibility of irregular electrical activity loops, which can result in ventricular tachycardia (a type of irregular heartbeat) or sudden death¹⁴

How LSDs affect the lungs: respiratory complications

Weak respiratory muscles

In LSDs like pompe disease, the accumulation of the substance glycogen weakens the muscles that are responsible for carrying out our breathing functions (the diaphragm and intercostal muscles).¹⁵ Therefore, the lungs may not expand and relax as normal, and this results in symptoms such as shortness of breath, coughs and infections, and fatigue due to low oxygen in the blood.

Narrowed airways 

The tissues in the throat, nose, and airways thicken as a result of some LSDs, particularly the mucopolysaccharidoses. Breathing becomes difficult as a result of the airways narrowing, particularly whilst sleeping.¹⁶

Children with these disorders may have obstructive sleep apnoea, which causes breathing to stop and start repeatedly while they sleep, and they frequently snore loudly. It may also result in noisy or difficult breathing as well as frequent colds or ear infections.¹⁷

Stiff or scarred lungs

The body cannot efficiently break down fatty materials in LSDs: gaucher disease and niemann-pick disease. Rather than being reused or eliminated, the fats get stored in the lung tissue and causes a number of problems:¹⁸

• Fatty material (glucocerebroside in gaucher disease or sphingomyelin in Niemann-Pick disease) accumulates in the microscopic air sacs (alveoli) and lung tissue
• This buildup hardens and fattens up the lungs, like a sponge which has been wetted with sludge,  becoming stiff, and therefore  they cannot expand and contract freely
• Eventually, scarring (fibrosis) takes place, further weakening lung functioning

As the lungs cannot expand completely, the body compensates by breathing more quickly but less deeply. Patients tend to feel that they cannot breathe deeply. Stiff lungs are not good at passing oxygen into the blood, and this leads to tiredness, dizziness, or blue lips/fingertips.

The heart has to work harder to pump oxygen-poor blood, and this can weaken it over time.

Inflammation and scarring of the lungs can lead to chronic pulmonary fibrosis, in which the lung tissue is irreversibly damaged. This increases the risk of life-threatening respiratory failure (lack of oxygen and carbon dioxide exchange), which can be fatal.¹⁹

Summary 

Lysosomal storage disease (LSDs) may be a rare group of conditions, but their impact on vital systems like the cardiovascular and respiratory systems is significant and can be life-threatening. These diseases interfere with the body’s ability to remove or recycle waste materials within many organs. This consequently can cause profound progressive damage to the vital organs, including the heart and lungs. 

In the heart, this can lead to the thickening of the muscle (known as cardiomyopathy), valve dysfunction, or a decrease in its pumping ability, which can cause arrhythmias (irregular heartbeats) and, in the worst-case scenario, heart failure. When it comes to the lungs, weak respiratory muscles or stiff, scarred lung tissue can make breathing a real challenge in addition to narrowed airways in the upper respiratory tract. This can be hazardous, resulting in respiratory failure which can be fatal.

These complications not only diminish quality of life but can also pose serious risks if they go unnoticed and unmanaged. It's essential to understand how these conditions affect these critical systems for timely diagnosis, effective treatment, and ultimately improving the long-term outcomes for those living with these conditions.