Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.

What is a Monocyte?

Monocytes are a vital part of your immune system, quietly working behind the scenes to keep your body healthy. As one of the five main types of white blood cells—alongside lymphocytes, basophils, neutrophils, and eosinophils—they play a crucial role in defending against infections and clearing out damaged cells.

These cells are produced in the bone marrow and released into the bloodstream, where they circulate for just a few hours. From there, monocytes migrate into different tissues like the lungs, liver, and spleen, where they mature into either macrophages or dendritic cells. Macrophages work to remove harmful microorganisms, even destroying cancer cells, and removing dead or damaged tissue. Dendritic cells, on the other hand, help coordinate the immune response by presenting antigens—foreign substances that alert the immune system to a threat.

Although monocytes are the largest of all white blood cells, they are relatively few in number. However, their function is significant. When an infection or injury occurs, these cells spring into action. Once they’ve matured into macrophages, they send out signals to other immune cells, directing them to the site of infection. This coordinated response helps the body fight off pathogens and heal from injury.

How monocytes are made

Monocytes are produced in the bone marrow from basic blood cells called stem cells. These stem cells have not yet specialized into specific types of cells. Once they are ready,  monocytes are released into the bloodstream, where they circulate for about one to three days before migrating into various tissues, such as those in the lungs, liver, and spleen.

Though present and circulating, monocytes remain inactive until triggered by the presence of pathogens—substances that cause disease. This activation prompts their transformation into macrophages, which are highly effective immune cells. Once fully activated, macrophages or dendritic cells  release chemicals that can eliminate harmful bacteria or infected cells. They are also capable of digesting pathogens, particularly those that have been marked by antibodies by other white blood cells.

In this way, monocytes are primed to respond to infections by clearing harmful substances and maintaining the body’s defenses.

What is Monocyte Count?

Monocyte count is the measure of how many monocytes are present in a specific volume of blood. This count is usually determined through a complete blood count (CBC) with differential, a test that also looks at different types of white blood cells to help assess overall health.

How Do You Measure Monocyte Count?

Monocyte count is typically measured using a complete blood count (CBC) with differential, a common blood test that provides a detailed overview of your blood components. Often referred to as a full blood count or blood cell count, including the red blood cells,  this test helps your doctor assess various aspects of your health, such as the presence of infections or conditions like anemia.

The differential part of the CBC specifically counts each type of white blood cell and assesses their proportions. It checks for any imbalances or abnormal cells, providing insights into your immune system’s status.

To determine your absolute monocyte count, the lab calculates the number of monocytes by multiplying their percentage from the CBC by the total number of white blood cells in your blood. This figure helps your doctor determine whether your monocyte count is within the normal range or if it is too high or too low.

The test is performed by drawing a blood sample from a vein in your arm. Generally, no special preparation is required unless additional tests are ordered. Your doctor will provide specific instructions if fasting or other preparations are needed.

What is the Normal Monocyte Count?

Normal monocyte levels can differ slightly based on the lab’s methods and individual factors like age, sex, and health. Generally, the standard ranges are:

• Absolute Monocyte Count: Typically between 100 and 700 cells per cubic millimeter of blood.
• Monocyte Percentage: Usually 2% to 8% of the total white blood cell count.

These ranges help assess whether your monocyte count is normal or if it might indicate potential health issues.

What Does it Mean if You Have High/Low Monocyte Count?

High Monocyte Count (Monocytosis):

When the number of monocytes in your blood exceeds the normal range, it’s referred to as monocytosis. This condition is identified when the absolute monocyte count reaches 1 × 10^9 or more per liter of blood. While monocytosis itself typically doesn’t cause symptoms, it is often a sign of an underlying condition. The symptoms you may experience are usually related to the root cause of the elevated monocyte levels.

Monocytosis can be linked to a wide variety of health conditions. Infections, for instance, are a common cause, particularly long-lasting or severe viral infections like mononucleosis or COVID-19, as well as bacterial infections such as tuberculosis. Autoimmune diseases like lupus or inflammatory  bowel disease (IBD) can also trigger a rise in monocytes. Blood disorders, such as sickle cell disease or hemolytic anemia, and certain cancers, especially leukemias and lymphomas, may also contribute to higher monocyte counts.

It’s important to note that not all causes of monocytosis are serious. Temporary increases in monocytes can occur due to physical or emotional stress, or even intense physical activity. Pregnancy is another factor that can cause a temporary rise in monocytes. Additionally, some medications, particularly steroids, are known to elevate monocyte levels.

Common Causes of High Monocyte Count:

• Infections: Both short-term and long-term, including viral infections like COVID-19 and bacterial infections such as tuberculosis.
• Blood Disorders: Conditions like sickle cell disease or hemolytic anemia.
• Autoimmune or Inflammatory Disorders: Such as inflammatory bowel disease, sarcoidosis, and lupus.
• Stress: Both physical (intense exercise) and emotional stress.
• Medications: Certain drugs, including steroids.
• Pregnancy: Can cause temporary increases in monocyte levels.
• Splenectomy: Removal of the spleen.
• Cancer: Particularly leukemias and lymphomas.

A high monocyte count often indicates a response to these conditions or factors, and further testing may be required to pinpoint the exact cause.

Low Monocyte Count (Monocytopenia):

A low monocyte count, or monocytopenia, occurs when monocyte levels fall below 0.5 × 10^9 monocytes per liter of blood. While this condition often doesn’t cause direct symptoms, it can point to underlying issues that affect the immune system, making the body more susceptible to infections. 

Several factors can lead to monocytopenia, including:

• Infections: Infections with viruses like Epstein-Barr virus (EBV), adenovirus, and HIV can lower monocyte levels.
• Severe Bloodstream Infections: Conditions such as bacterial sepsis can cause a significant drop in monocytes.
• Cancer Treatments: Chemotherapy and radiation therapy can damage bone marrow, leading to reduced white blood cell production, including that of monocytes.
• Medications: Steroids and immunosuppressive drugs can also lower monocyte levels.
• Surgery: Procedures on the stomach or intestines may temporarily reduce immune cell counts.
• Hemodialysis: Regular dialysis treatments can suppress the production of certain white blood cells.
• Bone Marrow Disorders: Conditions like aplastic anemia reduce the bone marrow’s ability to produce monocytes.
• Burn Injuries: Extensive burn injuries can deplete white blood cells.
• Certain Cancers: Blood cancers such as leukemia, lymphomas (including Hodgkin’s lymphoma), and hairy cell leukemia.
• Chronic Conditions: Autoimmune diseases like systemic lupus erythematosus (SLE) can result in lower monocyte levels.

Low monocyte counts can weaken the immune system, making it harder for the body to fight infections. This condition can be linked to bone marrow disorders, overwhelming infections, or immune-suppressing treatments. Conditions like sepsis, bone marrow damage, or cancer therapies may lead to monocytopenia.

In some cases, monocytopenia is a temporary response to medical treatments or severe infections. Regardless, low monocyte counts require further evaluation to determine the underlying cause and decide on appropriate treatment.

Genetic Factors Influencing Monocyte Count

Genetic diversity plays a significant role in shaping how our immune system functions, especially in response to diseases. For instance, conditions like tuberculosis (TB), autoimmune hepatitis, and systemic lupus erythematosus (SLE) are known to affect populations differently, depending on their ancestry. Research by Nédélec et al. points out that both environmental pressures and genetic factors contribute to variations in inflammatory responses, particularly between populations of African and European descent.

Your ancestry doesn’t just influence the overall number of white blood cells, including neutrophils, lymphocytes, eosinophils, and monocytes—it can also affect specific subsets of monocytes. A large study across different ethnic groups found that people of European descent generally have higher monocyte counts than  African American and Japanese individuals. This suggests that ancestry and ethnicity, combined with other factors, plays a key role in how our immune system behaves.

There’s also an interesting interplay between sex and ethnicity when it comes to monocyte counts. For example, white men tend to have more monocytes than their American counterparts with African ancestry, but this difference isn’t seen in women.

Digging deeper into specific monocyte subsets, a recent study revealed that whites in America  tend to have more classical monocytes and fewer non-classical monocytes compared to those with African ancestry. The same study also highlighted an increase in CX3CR1 expression in whites. This receptor is essential for the adhesion and survival of non-classical monocytes, meaning that a higher expression of CX3CR1 could lead to more of these cells staying attached to blood vessel walls and fewer circulating in the bloodstream.

Monocyte function also varies by ethnicity. For instance, when exposed to Mycobacterium tuberculosis, monocyte-derived cells from Filipino, Chinese, and non-Hispanic white individuals produced different levels of cytokines, signaling molecules important for immune responses. 

Non-Genetic Factors Influencing Monocyte Count

While genetics play a role in determining monocyte counts, non-genetic factors such as diet, sleep, exercise, and age  also have a significant impact.

Diet 

What you eat can directly affect your monocytes. Diets high in calories, fat, and sugar—common in Western eating patterns—are linked to chronic conditions like atherosclerosis, type 2 diabetes, and non-alcoholic fatty liver disease, all of which are tied to systemic inflammation. Research has shown that a high-fat diet can increase monocyte levels in both the bloodstream and spleen, a result of enhanced myelopoiesis in the bone marrow. In mice, switching back to a healthier diet normalizes monocyte levels but leaves classical monocytes in a heightened state of activation, indicating long-lasting effects.

In humans, a high-fat meal, like fast food, leads to an immediate spike in monocyte counts, particularly non-classical monocytes. This is more pronounced in people with higher body weight. On the flip side, fasting reduces both classical and non-classical monocytes by curbing their release from the bone marrow. Results of the research even show that fasting improves outcomes in autoimmune diseases, hinting at its potential benefits in controlling inflammation.

Sleep

Monocyte levels follow a daily rhythm tied to the sleep/wake cycle. Cortisol, a hormone that peaks shortly after waking and decreases throughout the day, influences immune cells, including monocytes. Research has found that monocyte levels drop during sleep and rise upon waking, with some people showing peak levels in the morning, while others peak in the evening. Disrupted sleep or sleep deprivation increases monocyte counts, but the natural daily fluctuation remains. Seasonal changes also affect monocyte function, with winter seeing higher phagocytic activity, possibly due to indoor crowding and less sunlight exposure.

Exercise

Exercise, both in the short and long term, affects monocyte levels and function. Physical activity can temporarily raise different monocyte subsets, depending on the intensity and type of exercise. For instance, high-intensity exercise increases the release of non-classical monocytes from blood vessel walls. Long-term exercise has been shown to reduce inflammatory monocytes (CD16+), improve monocyte phagocytic capacity, and promote an anti-inflammatory state, indicating the beneficial effects of regular activity on immune health.

Age

Monocyte counts change significantly over a lifetime. Newborns have higher monocyte levels than adults, which rise during the early weeks of life as part of  the immune system development. As we age, a phenomenon called “inflamm-aging” occurs, marked by increased pro-inflammatory markers. Older adults often have higher levels of intermediate and non-classical monocytes, contributing to chronic inflammation. However, in very old age, classical monocytes decline while non-classical monocytes—associated with inflammatory responses—rise, increasing susceptibility to age-related diseases.

Improving Monocyte Function

Optimizing your monocyte function can be supported by leading a healthy lifestyle. Since monocytes play a key role in your immune system, these steps may help strengthen your body’s defense mechanisms:

• Maintain a Balanced Diet: Eating a variety of nutrient-rich foods , including fruits, vegetables, lean proteins, and whole grains, provides essential vitamins and minerals that support monocyte activity and overall immune health.
• Exercise Regularly: Engaging in regular physical activity helps regulate your immune system, including monocyte production. Moderate exercise has been shown to improve immune cell circulation, making it easier for monocytes to respond to infections.
• Manage Stress: Chronic stress can negatively affect immune function and may lower monocyte efficiency. Practices such as meditation, deep breathing, and other relaxation techniques can help reduce stress levels and promote healthier immune responses.
• Avoid Smoking: Smoking weakens the immune system and reduces monocyte function, making it harder for your body to defend against infections. Quitting smoking can significantly improve overall immune health.
• Limit Alcohol consumption: Excessive alcohol use can impair immune cells, including monocytes, reducing their ability to fight infections. Drinking in moderation can help keep your immune system functioning properly.
• Practice Good Hygiene: Regularly washing your hands and avoiding contact with sick individuals can help reduce your exposure to infections. This minimizes the workload on your immune system, including that of monocytes, allowing them to function more effectively when needed.

If your monocyte count is out of balance due to a medical condition or treatment, it’s important to follow your doctor’s advice. In some cases, your healthcare provider may recommend additional strategies to support immune function, such as specific supplements or other targeted therapies.

• References:
  https://www.webmd.com/a-to-z-guides/what-to-know-about-high-monocyte-count
• https://my.clevelandclinic.org/health/diseases/22726-monocytosis 
• https://www.healthline.com/health/monocytes-high#what-are-monocytes 
• https://www.healthline.com/health/monocytes-high#typical-range 
• https://www.healthline.com/health/absolute-monocytes#summary 
• https://www.verywellhealth.com/high-monocyte-count-5219055 
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854020/ 
• https://www.cell.com/cell/fulltext/S0092-8674(16)31307-1?ref=toiest 
• https://academic.oup.com/hmg/article/23/25/6944/571379 
• https://academic.oup.com/jcem/article/101/11/4195/2764976 
• https://journals.aai.org/jimmunol/article/196/6/2466/111934 

Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.

What is ARSACS?

ARSACS stands for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay. It is a rare genetic disorder that affects the muscle control and movement. People with ARSACS may experience symptoms such as muscle stiffness, difficulty balancing, and problems with coordination. This disorder was first identified in the Charlevoix-Saguenay region of Quebec, Canada, but it is now recognized to affect individuals around the world.

What Causes ARSACS?

ARSACS is caused by mutations in the SACS gene, which encodes a protein called sacsin. Sacsin plays a key role in helping nerve cells function correctly by ensuring other proteins fold into the right shapes, especially in the brain’s cerebellum—the area responsible for movement regulation and coordination. Mutations in the SACS gene prevent sacsin from working correctly, leading to the nerve and muscle issues seen in ARSACS.

In 2000, researchers identified and cloned the SACS gene, enabling a clearer understanding of ARSACS and the development of a mouse model for further study. This model has been critical for exploring potential treatments, as it shows how SACS mutations impact brain cells similarly to how they do in humans.

What are the first signs of ARSACS?

The first signs of ARSACS usually show up between 12 and 18 months when a child starts to walk. Parents might notice that the child has trouble balancing, walks unsteadily, or needs extra support. These balance and coordination problems are often the earliest signs that something might be affecting the child’s motor skills.

As the child grows, other symptoms like muscle stiffness can develop, making movement harder. Recognizing these early signs helps doctors identify ARSACS sooner and guide families toward the right support and resources.

What symptoms are associated with ARSACS?

Each symptom associated with ARSACS directly connects to the progressive impacts of mutations in the SACS gene, affecting nerve cells that control movement, coordination, and muscle function. Here are some known symptoms: 

• Muscle Stiffness: ARSACS affects the part of the brain (the cerebellum) that controls smooth movements. Because of this, muscles in the arms and legs often feel tight and stiff, making movement harder.
• Balance and Coordination Issues: Damage to the cerebellum also affects balance and coordination. This makes activities like walking or holding small objects challenging, as movements may look clumsy or unsteady.
• Nerve Problems in the Limbs: The nerves in the arms and legs may not work well, causing feelings of weakness, numbness, or tingling. This can make it harder to sense touch or temperature and leads to more movement difficulties.
• Muscle Shrinking: Since nerve signals to the muscles are weak, muscles can gradually shrink and lose strength over time. This mostly affects the muscles in the arms and legs.
• Uncontrolled Eye Movements: The cerebellum also helps control eye movement, so people with ARSACS may have difficulty focusing because their eyes move on their own (nystagmus).
• Swallowing Problems: Weak throat muscles can make swallowing difficult, which increases the risk of choking while eating or drinking.
• Speech Difficulties: When muscles in the mouth and throat are affected, speech can become slow or slurred, making it harder for others to understand.
• High-Arched Feet: Muscle and nerve issues in the feet can lead to high arches, which may make walking uncomfortable and finding well-fitting shoes harder.
• Curved Spine (Scoliosis): Weak back muscles combined with nerve issues can cause the spine to curve, which can lead to back pain and poor posture.
• Yellow Streaks in the Eyes: During an eye exam, yellow streaks in the back of the eyes are often a sign of ARSACS. These streaks don’t affect vision but can help doctors make a diagnosis.
• Bladder Issues: Problems with nerve function can make it harder to control the bladder, which might lead to frequent urination or accidents.
• Learning and Development Delays: Some people with ARSACS may experience mild challenges with learning or memory, though many have typical cognitive functions.
• Hearing Loss: Hearing can be affected, as nerves related to hearing don’t work well. Hearing aids or other devices may be needed.
• Seizures: Some people with ARSACS experience seizures, which require medication to manage.
• Walking Problems: Problems with coordination, muscle stiffness, and nerve control make walking difficult, even from a young age, and often get worse over time. Many people eventually need aids like walkers or wheelchairs.

Each of these symptoms shows how ARSACS affects nerves and muscles throughout the body, especially in areas that control movement, balance, and coordination. Early diagnosis and support can help people with ARSACS manage these symptoms and improve their quality of life.

What is the inheritance pattern of ARSACS?

ARSACS is inherited in an autosomal recessive manner. This means that both parents must carry one copy of the mutated gene for a child to inherit ARSACS. Each child of two carrier parents has a 25% chance of inheriting both mutated genes and developing the disorder, a 50% chance of becoming a carrier (like their parents), and a 25% chance of inheriting no mutations.
Carriers of ARSACS have only one copy of the mutated gene and generally do not have symptoms. In the Charlevoix-Saguenay region, where the mutation is more common, approximately 1 in 22 people is a carrier. Identifying carriers is important for family planning, as they can pass the gene mutation to their children.

Genetics and ARSACS

In 2000, A study led by Engert and his team made a major discovery by identifying and cloning the gene that causes ARSACS, known as the SACS gene. To pinpoint SACS, the researchers first located it on chromosome 13. By analyzing the DNA of people with ARSACS, they narrowed down this location until they confirmed that mutations in the SACS gene caused the disease. Specifically, they found that these mutations disrupted the gene’s ability to produce a normal, functioning protein called sacsin, which is a molecular chaperone

This gene is important for nerve cells to work properly by helping other proteins fold into their correct shapes. Sacsin is found in many tissues, including the brain, where ARSACS symptoms are most noticeable. To study ARSACS more deeply, scientists also identified the same gene in mice and created a mouse model of the disease. This mouse model allowed them to examine the effects of SACS gene mutations, especially in the cerebellum—the part of the brain that controls movement and coordination. Over time, more than 170 different mutations in the SACS gene have been found in ARSACS patients, helping scientists understand how this disease works and improving diagnosis.

The ARSACS mouse model has provided valuable insights into the disease. Researchers have observed problems in cerebellar cells similar to those found in people with ARSACS. These findings make it possible to test new treatments to modify the effects of the gene mutation. With further research and clinical testing, scientists are hopeful that effective therapies can be developed to manage ARSACS symptoms and improve the quality of life for those affected. This genetic insight also guides research toward developing potential treatments and supports families in understanding inheritance patterns and planning for the future.

How Is ARSACS Diagnosed? 

Diagnosing ARSACS involves clinical assessments, genetic testing, and imaging. Doctors first check for symptoms like muscle stiffness, balance issues, and movement problems common in ARSACS. Reviewing family medical history is also helpful, especially if other family members show similar signs.

Genetic testing confirms ARSACS by identifying mutations in the SACS gene, setting it apart from similar conditions. MRI scans can reveal typical changes in the brain and spine, like shrinkage in a part of the cerebellum and distinct patterns in the brainstem. These combined methods provide a clear diagnosis and important information for families.

Are there any treatments available for ARSACS?

While there is currently no cure for ARSACS, several treatments can help manage its symptoms to help improve a patient’s quality of life. Early intervention and ongoing support can make a significant difference in daily functioning.

• Physical Therapy: Regular physical therapy can help manage muscle stiffness and improve balance and coordination. Exercises focus on strengthening muscles, increasing flexibility, and preventing joint contractures, which are the shortening and hardening of muscles over time.
• Occupational Therapy: Occupational therapy can help individuals with ARSACS learn practical strategies for daily activities, from dressing and eating to using adaptive tools for greater independence.
• Mobility Aids: Devices such as braces, walkers, and wheelchairs can support mobility as the condition progresses. Using these aids can help reduce strain and maintain mobility for as long as possible.
• Speech Therapy: Some people with ARSACS experience speech difficulties. Speech therapy can assist with articulation and help improve communication skills.
• Medications for Muscle Stiffness: Medications such as muscle relaxants may be prescribed to help manage muscle stiffness or spasticity, easing discomfort and enhancing mobility.

Although these treatments don’t address the underlying genetic cause, they provide critical support for managing symptoms and maintaining quality of life.

Managing Daily Life with ARSACS 

Living with ARSACS poses unique challenges, but comprehensive care and support can make a significant difference in daily life. Understanding what to expect and preparing for mobility, communication, and self-care changes can improve quality of life and maintain independence longer.

Home Adaptations for Accessibility

As mobility and muscle strength decrease, making changes at home is essential. Adding ramps and handrails, as well as widening doorways, can make it easier for wheelchair users to get around. In the bathroom, using shower chairs and grab bars can improve safety and comfort. Simple tools, like grips for utensils and button hooks for clothing, can help make everyday tasks easier.

Planning for Emotional and Psychological Support

Living with a progressive condition like ARSACS can be tough emotionally, both for the person affected and their family. Support groups, counseling, and mental health services are vital for dealing with these challenges. Joining peer support groups can provide a sense of community and understanding, helping to reduce feelings of loneliness.

Educational Support and Vocational Training

For young people diagnosed with ARSACS, having the right educational support is very important. Schools can collaborate with occupational therapists to ensure students have the tools they need for effective learning. Vocational training can also help individuals prepare for jobs that match their abilities, allowing them to maintain a sense of purpose and independence.

Planning for Long-Term Care Needs

As ARSACS progresses, it’s wise for individuals and their families to plan for future care needs. This could involve looking into care facilities or in-home assistance that cater to specific physical and medical needs. Starting these discussions early helps families make informed choices and find the best support.

By following these strategies, individuals with ARSACS and their families can better manage the physical and emotional effects of the condition. 

Summary: 

• ARSACS (Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay) is a rare genetic disorder that affects the nervous system, leading to progressive issues with movement, muscle control, and coordination.
• First identified in the Charlevoix-Saguenay region of Quebec, Canada, where it is more common due to a higher frequency of the gene mutation in that population. However, cases are now found worldwide.
• Symptoms typically appear in early childhood, around 12-18 months, when a child is learning to walk. Delayed walking, difficulty balancing, and unsteady movements often prompt early evaluations.
• ARSACS is a progressive condition, meaning symptoms worsen over time, leading to increasing difficulties with motor skills, speech, and other physical functions. 
• Over time, ARSACS significantly impacts daily living. The need for physical support increases as motor skills diminish. 
• Challenges like muscle tightness, balance issues, and speech difficulties can make both daily tasks and communication challenging, necessitating regular therapy and assistance.
• Inherited in an autosomal recessive manner, requiring two copies of the mutated SACS gene—one from each parent.
• Parents who are carriers have one mutated gene but do not show symptoms, as two copies are required for the disease to manifest.
• In the Charlevoix-Saguenay area, about 1 in 22 individuals carries the mutation, increasing the likelihood of ARSACS in the region. 
• ARSACS is linked to mutations in the SACS gene on chromosome 13. 
• The SACS  gene produces a protein called sacsin, essential for helping nerve cells function properly.
• Sacsin aids in protein folding and maintenance within nerve cells, especially in the cerebellum, the part of the brain responsible for coordination and movement. 
• Disruption in sacsin affects these cells’ ability to function normally, which manifests as the symptoms seen in ARSACS.
• MRI scans can reveal characteristic brain changes, such as cerebellar shrinkage and distinct structural patterns in the brainstem, which aid in diagnosis.
• Physical, occupational, and speech therapies help manage symptoms and improve independence. 
• Physical therapy addresses muscle stiffness and helps maintain joint flexibility, while occupational therapy offers practical support for daily activities.
• Devices such as braces, walkers, and wheelchairs support mobility and reduce strain, helping individuals retain independence longer.
• Muscle relaxants may help manage stiffness and discomfort, improving quality of life and making movement less taxing.

References:

• https://pmc.ncbi.nlm.nih.gov/articles/PMC7313614/#:~:text=Autosomal%20recessive%20spastic%20ataxia%20of%20Charlevoix%2DSaguenay%20(ARSACS)%20is,with%20finger%20and%20foot%20deformities).
• https://medlineplus.gov/genetics/condition/autosomal-recessive-spastic-ataxia-of-charlevoix-saguenay/
• https://radiopaedia.org/articles/autosomal-recessive-spastic-ataxia-of-charlevoix-saguenay-1
• https://www.ataxia.org/scasourceposts/hunting-for-a-needle-in-a-haystack-scientists-identify-the-gene-that-causes-arsacs/
• https://www.ajnr.org/content/28/8/1606
• https://www.sciencedirect.com/science/article/abs/pii/S0888754399960032

Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.

Hereditary amyloidosis is a genetic disorder and one of the subtypes of amyloidosis. It is characterized by abnormal accumulation of amyloids, or protein aggregates in various tissues and organs due to mutations that happen in certain genes. This accumulation disrupts normal organ function which can- lead to serious health complications. While hereditary amyloidosis may not be widely known like other genetic conditions, it is crucial to understand its causes, symptoms, types, and treatment options. Early diagnosis can significantly affect patient outcomes and quality of life. In this comprehensive article, we will explore the key aspects of hereditary amyloidosis to provide a clear understanding for those who are not familiar with this rare condition.

What is Hereditary Amyloidosis?

Hereditary amyloidosis, often referred to as familial amyloidosis occurs due to genetic mutations that lead to the misfolding of specific proteins. These misfolded proteins aggregate into amyloid fibrils, which then deposit in various organ tissues and can later lead to disruption of their normal function. The most common type of hereditary amyloidosis is transthyretin amyloidosis (ATTRv), caused by mutations in the transthyretin (TTR) gene. Understanding hereditary amyloidosis is vital, especially for individuals with a family history of the condition or those experiencing unexplained symptoms that could indicate amyloid deposition.

Types of Hereditary Amyloidosis

Hereditary amyloidosis is a group of genetic disorders where abnormal protein aggregates called amyloids build up in organs and tissues, causing them to function poorly. This happens because certain gene mutations cause proteins to fold incorrectly, allowing them to form clumps that the body cannot break down. These different types are named after the specific protein involved, each affecting the body in unique ways.

1. Transthyretin Amyloidosis (ATTRv)

ATTRv is the most common type of hereditary amyloidosis caused by mutations in the TTR gene, which  causesperipheral sensorimotor and/or autonomic neuropathy.  The TTR gene is responsible for creating transthyretin, a protein made in the liver that helps transport thyroid hormones, particularly thyroxine (T4), as well as retinol (vitamin A) in the blood. Mutated transthyretin – causes amyloid deposits  in various organ tissues and later affects their vital functions.

2. Apolipoprotein A-I Amyloidosis

Apolipoprotein AI amyloidosis is linked to mutations in the APOA1 gene, a gene that aids in the production of  a high-density lipoprotein (HDL)  component called apolipoprotein A-I , a protein responsible for cholesterol and phospholipids transport through the bloodstream. When mutation is present, this protein misfold causing  amyloid deposits, primarily affecting the heart and kidneys.

3. Gelsolin Amyloidosis

This type of amyloidosis is caused by mutations in the GSN gene, which helps maintain the structure of cells. When the GSN gene is mutated, amyloid deposits can form in the skin and nervous system affecting skin structure, motor, and sensory function.

4. Lysozyme Amyloidosis

Lysozyme amyloidosis stems from mutations in the LYZ gene, a gene that encodes the lysozyme enzyme. This enzyme is synthesized through hepatocytes and macrophages and helps the body fight harmful bacteria. When mutation is present, it causes the lysozyme to build up as amyloid, particularly affecting renal, cardiac, and gastrointestinal health.

5. Fibrinogen Aα-chain Amyloidosis

Mutations in the FGA gene lead to fibrinogen Aα-chain amyloidosis. The protein produced by this gene is involved in blood clotting (coagulation) to prevent excessive bleeding. But when mutated, the protein  can accumulate as amyloid deposits in the kidneys and liver.

6. Cystatin C Amyloidosis

This type results from mutations in the CST3 gene, responsible for producing cystatin C, a protein involved in regulating other proteins in the body. When it misfolds due to genetic mutation, cystatin amyloids can build up in the nervous system and kidneys.

Risk Factors for Hereditary Amyloidosis

Hereditary amyloidosis is primarily determined by genetic factors, with several considerations influencing its development:

• Family History: Having a family member with hereditary amyloidosis significantly increases the risk. The condition follows an autosomal dominant inheritance pattern, meaning a mutation in just one copy of the gene can lead to disease manifestation.
• Age: Symptoms typically begin in adulthood, with the age of onset varying based on the specific type of amyloidosis.
• Genetic Mutations: Specific mutations in the TTR gene and other related genes are directly linked to different forms of hereditary amyloidosis. Genetic testing can identify individuals at risk.
• Ethnicity: Certain populations, particularly those of Scandinavian and African descent, are more likely to carry mutations associated with hereditary amyloidosis, especially ATTRv.

Complications of Hereditary Amyloidosis

The complications arising from hereditary amyloidosis can vary based on the type of amyloidosis and the organs affected. Here are some common complications:

1. Cardiac Complications
   Amyloid deposits in the heart can lead to serious complications. Heart failure may develop as the amyloid buildup weakens the heart’s ability to pump blood efficiently, resulting in fatigue and fluid retention. Additionally, arrhythmias, or irregular heart rhythms, can arise from disruptions in the heart’s electrical pathways. These abnormal rhythms can pose severe risks, potentially leading to dangerous cardiac events that require careful monitoring and medical intervention.
2. Kidney Damage
   The kidneys are particularly vulnerable to amyloid deposits, which can impair their function over time. One of the first signs of kidney involvement is proteinuria, or increased protein levels in the urine, which suggests that the kidneys are struggling to filter waste properly. As amyloid accumulation progresses, it can lead to kidney failure, making dialysis or even a kidney transplant necessary to sustain kidney function and overall health.
3. Neurological Issues
   Amyloidosis can also damage the nervous system, leading to various neurological symptoms. Peripheral neuropathy, characterized by tingling, numbness, and pain in the hands and feet, can make daily tasks challenging. In some cases, autonomic neuropathy occurs, affecting the involuntary functions of the body, like blood pressure control and digestion, which can lead to dizziness, changes in sweating, and digestive difficulties.
4. Gastrointestinal Complications
   Amyloid deposits may affect the gastrointestinal system, disrupting normal digestion and causing symptoms like nausea and vomiting, often due to nerve damage affecting gut motility. Some individuals may experience diarrhea or constipation as well, which can result from autonomic nerve involvement that disrupts the regular rhythm of the digestive tract, making it difficult for the body to process food comfortably and consistently which could lead to poor nutrient absorption and low energy.

Symptoms of Hereditary Amyloidosis

1. Heart Issues
   Hereditary amyloidosis can cause a variety of heart-related problems as amyloid protein aggregates accumulate in heart tissue. This buildup can weaken the heart muscle, leading to heart failure, a condition where the heart cannot pump blood effectively. This often results in fatigue, shortness of breath, and swelling in the legs and feet due to fluid retention. Additionally, amyloid deposits may interfere with the heart’s electrical signals, causing arrhythmias, or irregular heartbeats, which can sometimes be life-threatening if not addressed early and managed properly.
2. Kidney Problems
   The kidneys are commonly affected by amyloid deposits, which can damage their ability to filter waste from the blood. This often leads to proteinuria, where excess protein appears in the urine, signaling that the kidneys are under strain. Over time, kidney function may progressively decline, leading to kidney failure in severe cases. This can necessitate treatments such as dialysis or, in some cases, a kidney transplant, to help maintain essential kidney function.
3. Neuropathy
   Amyloid deposits can impact the nervous system, particularly the peripheral nerves, which are responsible for sensation and movement in the limbs. Peripheral neuropathy often develops, leading to symptoms like tingling, numbness, and pain in the hands and feet. This can make everyday activities difficult and uncomfortable. In addition, amyloid deposits may affect the autonomic nerves, which control involuntary bodily functions, causing autonomic neuropathy. This can lead to dizziness, digestive issues, and other disruptions in bodily functions like blood pressure regulation.
4. Gastrointestinal Symptoms
   Amyloidosis can affect the gastrointestinal tract, resulting in digestive issues that disrupt normal eating and digestion patterns. Many people experience symptoms such as nausea and vomiting, often due to nerve damage that slows food movement through the digestive tract. This condition, called gastroparesis, can make it difficult to eat comfortably. Additionally, people may experience diarrhea or constipation, both of which can result from nerve involvement in the digestive system and lead to unpredictable bowel habits.
5. Eye Problems
   In certain types of hereditary amyloidosis, amyloid deposits can affect eye structures, potentially causing vision issues. This may lead to clouding of the cornea, difficulty focusing, or even retinal damage in severe cases. The presence of amyloid in the eyes may cause discomfort or blurred vision and could potentially require specialized ophthalmologic care to manage these symptoms and protect vision.
6. Skin Changes
   In some individuals, amyloidosis may cause noticeable changes to the skin. This can include thickening or waxy areas on the skin, particularly around the eyes. The skin might also bruise more easily than usual due to the impact of amyloid on blood vessel integrity. These skin changes, while not life-threatening, can be distressing and may require management by a dermatologist.
7. Carpal Tunnel Syndrome
   A common symptom in hereditary amyloidosis is carpal tunnel syndrome, which occurs when amyloid deposits accumulate around the median nerve in the wrist. This can lead to numbness, tingling, and pain in the hands, often making it difficult to grip objects or perform fine motor tasks. Carpal tunnel syndrome can be an early symptom, sometimes appearing years before other signs of amyloidosis, and may require intervention such as wrist splints or surgery to relieve symptoms.

Diagnosis of Hereditary Amyloidosis

Diagnosing hereditary amyloidosis involves a multi-faceted approach, often requiring several tests and evaluations:

1. Medical History and Physical Examination: A healthcare provider will review the patient’s medical and family history, alongside a physical examination to identify any symptoms or signs of organ involvement.
2. Blood Tests: These can help assess kidney and liver function and detect abnormal protein levels, such as that of the  Transthyretin (TTR).
3. Urine Tests: A 24-hour urine collection may be conducted to check for protein levels, particularly light chains indicative of amyloid involvement.
4. Imaging Studies: Techniques such as echocardiograms, MRI, or CT scans can help assess the extent of organ involvement.
5. Biopsy: A definitive diagnosis often requires a biopsy of affected tissue to confirm the presence of amyloid deposits. Common biopsy sites include fat tissue, bone marrow, or organs suspected to be involved.
6. Genetic Testing: Genetic testing is crucial for confirming hereditary amyloidosis and identifying specific mutations. This information is valuable for family members regarding their risk of developing the condition.

Treatment Options for Hereditary Amyloidosis

Although there is no cure for hereditary amyloidosis, treatment options have been researched with an aim to manage symptoms by addressing the root cause of amyloid buildup. The approach can vary depending on the specific amyloidosis type and affected organs. Here are some common treatment options to help manage this condition:

Targeting the Underlying Genetic Cause
For transthyretin amyloidosis (ATTRv), the goal is to target the genetic root of the disorder.

• Medications: New treatments aim to stabilize or reduce amyloid deposits by targeting the TTR protein. For example, patisiran (an RNA interference therapy) and inotersen (an antisense oligonucleotide) can lower the production of abnormal TTR proteins, potentially slowing disease progression.
• Diflunisal: This is a nonsteroidal anti-inflammatory drug that can also stabilize the TTR protein, helping to delay the progression of the condition.
• Liver Transplantation: Since the liver produces the abnormal TTR protein in ATTRv, a liver transplant may be considered in severe cases to replace the source of amyloid production, reducing amyloid deposits and improving symptoms.

Supportive Care
Overall supportive care is vital for improving quality of life in hereditary amyloidosis.

• Nutritional Support: Ensuring that patients have adequate nutrition can help manage weight loss and general weakness often associated with the disease.
• Counseling and Emotional Support: Living with hereditary amyloidosis can be challenging, so counseling and psychological support can help patients and their families navigate the emotional aspects of the condition, improve coping skills, and enhance overall well-being.

Living with Hereditary Amyloidosis

Managing life with hereditary amyloidosis involves multiple aspects to ensure physical, emotional, and overall well-being. Here are some key areas of focus:

1. Medical Management
   Routine medical care is essential for monitoring the progression of amyloidosis and managing symptoms. Regular check-ups, blood tests, and imaging studies can help track the impact on organs like the heart, kidneys, and nervous system. Staying in close contact with a healthcare provider allows for adjustments in treatment and medication as needed, ensuring patients receive timely care and interventions.
2. Diet and Nutrition
   Nutrition plays an important role in managing hereditary amyloidosis, especially when vital organs such as the kidneys are affected. A well-balanced diet tailored to individual needs can support overall health, and a low-salt or low-protein diet may help reduce strain on the heart and kidneys. Consulting with a dietitian will help in choosing nutrient-rich foods that align with the dietary restrictions, helping to manage symptoms and maintain energy levels.
3. Physical Activity and Mobility
   Staying active can help maintain muscle strength, improve circulation, and support heart health, even as symptoms progress. For individuals with neuropathy or cardiac symptoms, engaging in gentle, regular physical activities like walking or stretching may help preserve mobility and reduce discomfort. A physical therapist can recommend exercises tailored to each person’s needs, ensuring safe and effective movement practices.
4. Emotional and Psychological Support
   Living with a chronic illness can take an emotional toll, so psychological support is vital. Connecting with support groups or mental health counselors provides patients and families with an understanding of community and professional guidance. Talking about the challenges and emotions associated with amyloidosis can help reduce feelings of isolation and provide strategies for coping.
5. Adaptations for Daily Living
   Over time, hereditary amyloidosis can impact physical abilities, making daily tasks more challenging. Home adaptations, such as handrails, shower chairs, and ramps, can create a safer environment, while assistive devices like button hooks and grip aids help with daily tasks. Occupational therapists can provide recommendations for home modifications that increase independence and comfort.
6. Building a Support Network
   Having a strong support system of family, friends, and caregivers is invaluable for individuals with hereditary amyloidosis. A support network provides practical help, such as assistance with medical appointments, daily needs, and emotional encouragement. For both patients and their families, this network is key to navigating the journey and finding comfort during challenging times.
7. Planning for the Future
   As hereditary amyloidosis is a progressive condition, it’s important to plan for future healthcare needs. This may include discussing long-term care options, such as home health services or care facilities, with family and healthcare providers. Planning ahead can help reduce stress and ensure that support is available when needed, enabling patients and families to feel more prepared and in control of their care journey.

Each of these strategies can help individuals with hereditary amyloidosis manage the complexities of the condition and live as fully and independently as possible.

References:

• https://www.hopkinsmedicine.org/health/conditions-and-diseases/amyloidosis#:~:text=Amyloidosis%20is%20a%20rare%20disease,in%20one%20organ%20or%20several.
• https://www.amyloidosis.org/facts/familial
• https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178
• https://www.mountsinai.org/health-library/diseases-conditions/hereditary-amyloidosis
• https://rarediseases.info.nih.gov/diseases/6611/hereditary-amyloidosis
• https://arci.org/about-amyloidosis/hereditary-attr-amyloidosis/
• https://www.ncbi.nlm.nih.gov/books/NBK1194/