Genetic Diseases

Friedreich’s Ataxia (FRDA) is a progressive, neurodegenerative genetic disorder that typically begins around 10 to 15 years of age. Initial symptoms may include unsteady movements, frequent falls, and progressive difficulty walking due to impaired ability to coordinate voluntary movements (ataxia). Affected individuals often develop slurred speech (dysarthria), characteristic foot deformities, and an irregular curvature of the spine (scoliosis). FRDA is frequently associated with cardiomyopathy, a heart muscle disease that can lead to heart failure or irregular heart rhythms (cardiac arrhythmia). Approximately one-third of people with FRDA develop diabetes mellitus. The symptoms and clinical findings associated with FRDA primarily result from degenerative changes in the sensory nerve fibers at the point where they enter the spinal cord in structures known as dorsal root ganglia. This leads to secondary degeneration of nerve fibers in the spinal cord, resulting in a lack of sensory signals to the cerebellum, the part of the brain that aids in coordinating voluntary movements.

FRDA is caused by abnormalities (mutations) in the FXN gene and is an autosomal recessive disease. In most affected individuals, the FXN gene contains an expanded GAA trinucleotide repeat. In most people with FRDA, both copies of the FXN gene contain excessively long GAA repeat units. Normal individuals without FRDA have fewer than 30 GAA repeats, while individuals with FRDA typically have repeats ranging from 100 to 1300 for each copy of the FXN gene, with most containing >400 repeats. The method used for this test includes PCR, fragment analysis for GAA repeat determination for the FXN gene, FXN gene sequencing, and MLPA analysis for the FXN gene.

Ataxia-Telangiectasia is an inherited disorder that affects the nervous system, immune system, and other systems. This disorder is associated with progressive difficulties, including uncoordinated movements. Affected children typically develop walking difficulties, problems with balance and hand coordination, involuntary movements, etc. Affected individuals have high amounts of a protein called alpha-fetoprotein (AFP) in their blood. They have a weakened immune system and develop chronic lung infections. They also have an increased risk of developing cancer, especially blood-forming cell cancer (leukemia) and immune system cell cancer (lymphoma). Affected individuals are highly sensitive to the effects of radiation, especially X-rays. It is caused by mutations in the ATM gene. This gene codes for the production of a protein that helps control cell division and is involved in DNA regulation. This protein plays an important role in the normal development and activity of many systems, including the nervous and immune systems. Mutations in the ATM gene reduce or eliminate the function of the ATM protein. Without this protein, cells become unstable or die. Timely diagnosis of these mutations is very important as they are indicators for the development of many types of cancer.

Hemophilia is typically an inherited blood disorder in which the blood does not clot properly. This can lead to spontaneous bleeding, especially during injuries or surgeries. Patients with hemophilia have low levels of factor VIII or IX. Low levels of these factors are an indicator of bleeding, leading to serious health problems.

Hemophilia is caused by mutations in the genes that code for the production of proteins necessary for blood clotting. These mutations can lead to a reduction in the production of these proteins or to the production of abnormal proteins. These genes are located on the X chromosome. There are two types of hemophilia that occur more frequently: Hemophilia A, which is caused by a deficiency or reduction of factor VIII. Hemophilia B, which is caused by a deficiency or reduction of factor IX.

Symptoms include:

• Bleeding into joints. This can cause joint pain.

• Bleeding under the skin, causing hematomas.

• Bleeding from the mouth and gums.

• Blood in urine.
• Frequent nosebleeds.

Timely diagnosis is important so that treatment can be initiated as quickly as possible, including blood transfusions, bone marrow transplants, medications, and supplements, etc. Diagnosis can be achieved through physical examination, hemoglobin electrophoresis, or genetic analysis for the detection of mutations in the relevant genes.

Adenosine deaminase deficiency is a metabolic disease that causes immunodeficiency. It is caused by mutations in the ADA gene. As a result, the enzyme, which is most active in white blood cells called lymphocytes, is not produced. It appears in 10-15% of cases in the autosomal recessive form. Diagnosis is important for several reasons;

• Detection of mutations in the ADA gene related to the production of the adenosine deaminase enzyme, which eliminates a molecule called deoxyadenosine that is toxic to lymphocytes.
• Testing of immunoglobulin levels and white blood cells, including T cells, B cells, and natural killer cells.
• Early diagnosis so that treatment can be performed in a timely manner through enzyme replacement, gene therapy, or stem cell transplantation.

Von Willebrand Disease is a blood disorder associated with problems in blood clotting. It is inherited from parents to children. This disorder manifests during injuries, surgeries, in women during menstruation, or during childbirth. This bleeding causes health problems such as pain and anemia (low red blood cell count). In some cases, it can be fatal. This disease is caused by the dysfunction of a protein known as von Willebrand factor (VWF), which aids in blood clotting. A variety of genetic mutations cause a reduction in the production of this protein or the production of an abnormal protein.

Common symptoms include:

• Heavy bleeding after injuries or surgeries

• Persistent nosebleeds

• Bleeding gums after dental treatments

Huntington’s Disease is a progressive, neurodegenerative genetic disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk, and the progressive deterioration of cognitive processes and memory. Neurological movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis. Dementia is usually associated with progressive disorientation and confusion, personality disintegration, impaired memory control, restlessness, anxiety, etc.

Huntington’s Disease is inherited as an autosomal dominant trait. The disease is caused by changes (mutations) in a gene known as ‘huntingtin’ located on the short arm (p) of chromosome 4 (4p16.3). The huntingtin gene contains repeated CAG trinucleotides. Individuals with this disease have over 35 CAG repeats within the huntingtin gene, with most having more than 39. However, individuals without this disorder tend to have around 20 repeats in the gene. The method for performing this test includes PCR, fragment analysis: identification of the length of CAG / CGG repeats for the HTT gene.

Hereditary Breast and Ovarian Cancer syndrome (HBOC) is a genetic syndrome that makes a person more prone to breast, ovarian, or other types of cancer. It is hereditary, meaning that mutations are passed down from one generation to the next. A genetic test helps determine if a personal or family history of cancer is caused by HBOC. This test helps prevent cancer or detect it in a timely manner. HBOC is often caused by mutations in the BRCA1 and BRCA2 genes, but sometimes it is also linked to mutations in other genes. However, many cases of breast or ovarian cancer are not linked to HBOC. In fact, only 3 in 100 cases of breast cancer and 10 in 100 cases of ovarian cancer are caused by mutations in the BRCA1 and BRCA2 genes. If the test is positive for HBOC, the steps to follow to reduce the risk of cancer include:

• Rapid and more frequent cancer screening.
• Taking medications that reduce cancer risk.
• Undergoing prophylactic interventions to remove the breast, ovaries, and fallopian tubes.

Lynch Syndrome is the most common cause of colorectal cancer. It is also known as hereditary non-polyposis colorectal cancer (no polyps present). The causes of Lynch syndrome include inherited genetic mutations. The genes involved are: MLH1, MSH2, MSH6, PMS2, and EPCAM. These genes usually protect the body from various cancers, but a mutation causes these genes to not function properly. People affected with Lynch syndrome are more likely to develop other cancers at an early age (before 50 years old) such as: Uterine (endometrial), Stomach, Liver, Kidney, Brain, and some skin cancers.

MERRF Syndrome (myoclonic epilepsy with ragged red fibers) is an extremely rare disorder that appears in childhood, adolescence, or adulthood after normal early life development. MERRF syndrome affects the nervous system, skeletal muscles, and other body systems. The distinguishing feature in MERRF is muscle twitching (myoclonus), consisting of sudden, brief spasms that can affect the arms, legs, or the entire body. Individuals with MERRF syndrome may also experience seizures (generalized epilepsy), inability to coordinate movements (ataxia), muscle weakness (myopathy), exercise intolerance, and a slow decline in intellectual function. Reduced body height (short stature), vision problems (optic atrophy), hearing loss, heart muscle diseases (cardiomyopathy), and peripheral neuropathy are other common symptoms.

MERRF syndrome is caused by mutations in mitochondrial DNA, in genes that code for tRNA (transfer RNA). More than 90% of MERRF syndrome cases are caused by mutations in the MT-TK gene. A specific MT-TK mutation, called m.8344A>G, accounts for 80% of cases. Mutations in MT-TF, MT-TH, MT-TI, MT-TL1, MT-TP, MT-TS1, and MT-TS2 have also been associated with MERRF syndrome. The method used for performing this test includes PCR-RFLP analysis, quantification, and detection of the m.8344A>G mutation.

Rett Syndrome is a rare genetic neurological disorder that affects brain development, causing a progressive loss of motor skills. It primarily occurs in females, impacting speech, walking, eating, and causing breathing difficulties. Other symptoms include:

• loss of hand use,
• scoliosis,
• sleep disturbances,
• slowed growth of the head, feet, and hands.

Rett Syndrome is caused by mutations on the X chromosome in a gene called MECP2. This gene codes for a protein known as MECP2, which is necessary for brain development. These mutations usually occur spontaneously. The method used for detection is sequencing. This syndrome is typically observed in children aged 6-18 months when they begin to experience developmental regression or lose previously acquired skills.

Fragile X Syndrome (FXS) bears this name due to the X chromosome appearing ‘fragile’ under microscopic observation. FXS is caused by changes in the FMR1 gene, which codes for a protein called FMRP necessary for brain development. The mutation in the FMR1 gene involves a continuous CGG repeat. It is recommended to diagnose during pregnancy.

Thalassemia is an inherited blood disorder that reduces the production of functional hemoglobin (the protein in red blood cells that carries oxygen). This causes a reduction in red blood cells and low oxygen levels in the bloodstream, leading to a range of health problems. Symptoms vary depending on the type of thalassemia, ranging from asymptomatic individuals to moderate to severe symptoms, including:

• slowed growth
• delayed puberty
• bone problems
• enlarged liver
• anemia
• loss of appetite
• dark urine
• skin discolorations
• enlarged heart

There are two types of thalassemia: alpha and beta thalassemia. Beta thalassemia is caused by mutations in the HBB gene, while alpha thalassemia is caused by mutations in the HBA1 and HBA2 genes. Mutations in the HBB gene lead to a reduction in beta globin levels, while deletions in the HBA1 and HBA2 genes lead to a reduction in alpha globin. Timely diagnosis is important so that treatment can be initiated as quickly as possible, including blood transfusions, bone marrow transplants, medications, supplements, etc. Diagnosis can be achieved through physical examination, hemoglobin electrophoresis, or genetic analysis for the detection of mutations in the relevant genes.