Overview of Autosomal Dominant Disorders

Autosomal dominant disorders are a class of genetic diseases caused by dominant gene mutations on chromosomes. This means that just one mutated gene is sufficient to cause disease manifestations without the corresponding gene on another homologous chromosome also being mutated. The disease can be passed from parents to children, with each child having a 50% chance of inheriting the mutated gene. Autosomal dominant disorders can be divided into two types: fully dominant and partially dominant. Full dominance means that the mutated gene completely masks the normal gene, causing all individuals carrying the mutated gene to display the characteristics of the disease. Incomplete dominance means that there is a certain degree of interaction between the mutated gene and the normal gene, resulting in individuals carrying the mutated gene displaying different degrees or types of disease characteristics. Autosomal dominant disorders include many disorders of different types and severities, such as neurological diseases, musculoskeletal diseases, metabolic diseases, and tumor syndromes. Several common autosomal dominant disorders include Huntington's disease, Marfan syndrome, Neurofibromatosis type 1, Polycystic kidney disease, and Familial hypercholesterolemia.

Huntington’s Disease

Huntington's disease is an inherited neurological disorder caused by a mutation in a gene. The disease causes nerve cells in the brain to gradually degenerate and die, affecting movement, thinking, emotions and personality. Huntington's disease is caused by repeated mutations in a gene on chromosome 4 (HTT gene), resulting in an overlong sequence encoding the huntingtin protein. This abnormal huntingtin aggregates inside nerve cells, interfering with their normal function and causing apoptosis.

Fig.1 The difference in structure of a normal brain and one with Huntington's disease

Symptoms of Huntington's disease usually begin in middle age and gradually worsen over time, eventually leading to death. Specifically, Huntington's disease typically presents with involuntary dance-like movements (called chorea), which include rapid, involuntary movements of the fingers, extremities, face, or trunk. This movement is exacerbated by stress or distraction and becomes more intense and pronounced as the disease progresses. In addition, stiffness (called catalepsy), tremor, abnormal eye movements, problems with balance and coordination, decreased muscle coordination, and difficulty swallowing and speaking may also occur. In addition, Huntington's disease can cause decreased concentration, impaired judgment, impaired thinking, planning, and organizational skills, memory loss, impulsivity or loss of self-control, stubborn or repetitive thinking (called persistence), communication disorders (difficulty speaking or finding words), difficulty learning new things, etc. These cognitive impairments become more severe as the disease progresses, until the patient is unable to function, drive, or take care of himself normally. When cognitive impairment is severe enough to interfere with daily life, it is called dementia. Some patients also experience mood swings, personality changes, a lack of motivation and initiative, impulsive behavior, compulsive behavior, anxiety, depression, irritability, aggression, a lack of empathy, decreased personal hygiene, and schizophrenia.

There is currently no cure for Huntington's disease, only drugs and other treatments can be used to relieve symptoms and improve quality of life. Drug therapy is mainly used to control chorea and psychobehavioral problems. Commonly used drugs include nerve blockers that inhibit the action of dopamine, NMDA receptor antagonists that inhibit the action of glutamate, anticholinergics that inhibit the action of acetylcholine, alpha-adrenoceptor antagonists that inhibit the action of norepinephrine, and selective serotonin reuptake inhibitors that modulate the action of serotonin. Non-drug treatments mainly include physical therapy, speech therapy, occupational therapy, and psychotherapy. Gene therapy, an experimental treatment for the underlying cause of Huntington's disease, is currently in clinical trials. The goal of gene therapy is to prevent or slow down the damage to nerve cells by changing or replacing the mutated HTT gene or its products.

Marfan Syndrome

Marfan syndrome affects connective tissue in various parts of the body, including the heart, blood vessels, bones, joints, eyes, skin, and lungs. Marfan syndrome occurs due to a mutation in a gene on chromosome 15 (the FBN1 gene), resulting in an abnormality in the sequence encoding fibronectin-1. Fibronectin-1 is an important connective tissue component involved in the formation of elastic fibers and microfibrils that support and anchor various organs and structures in the body. Fibronectin-1 also regulates a protein called transforming growth factor-beta (TGF-beta), which plays an important role in processes such as cell proliferation, differentiation, and migration. In patients with Marfan syndrome, mutations in the FBN1 gene lead to defective or insufficient fibronectin-1, which affects the elasticity and strength of connective tissue as well as the level and activity of TGF-β. People with Marfan syndrome are usually tall and thin, with unusually long and thin limbs, fingers, and toes, hyperflexible joints, and an abnormal curvature of the spine. The most serious complications involve the heart and aorta, increasing the risk of mitral valve prolapse and aortic dissection.

Unfortunately, there is currently no cure for Marfan syndrome, other than medication and other treatments to manage symptoms and prevent complications. Drug therapy is mainly used to lower blood pressure and heart rate, reduce the pressure on the aorta, and delay the occurrence of aortic dilatation or dissection. Commonly used drugs are β-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors. Surgery is mainly used to repair aortic dilation or dissection, and prevent aortic rupture or dissection from progressing. Surgical methods include artificial blood vessel replacement and artificial intracardiac stent placement. The timing of surgery depends on factors such as aortic diameter, dilatation rate, and family history. Other treatments include physical therapy, eye treatment, dental treatment, and psychotherapy. Gene therapy for Marfan syndrome is currently in clinical trials. The goal of gene therapy is to restore the function or quantity of normal fibronectin-1 and regulate the level and activity of TGF-β by changing or replacing the mutated FBN1 gene or its products.

Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) occurs due to a mutation in a gene on chromosome 17 (the NF1 gene), resulting in an abnormality in the sequence encoding the neurocellulose protein. Neurofibrillin is an important nervous system component involved in regulating processes such as cell proliferation, differentiation, and migration. In patients with NF1, due to mutations in the NF1 gene, functional defects or insufficient amounts of neurofibrillin are caused, which affect the normal development and function of the nervous system. NF1 causes tumors to grow along nerves in the skin, brain, and elsewhere. These tumors are usually benign (not cancerous) but can cause a range of symptoms, such as café au lait spots, Lisch nodules, and others.

Similarly, NF1 currently has no cure. Treatment options include drug therapy, surgery, psychotherapy, and gene therapy. Drug therapy is mainly used to relieve headaches, control seizures, and reduce intraocular pressure. Commonly used drugs are painkillers, antiepileptic drugs, and antiglaucoma drugs. The main purpose of surgery is to remove skin or subcutaneous neurofibromas that affect vision or aesthetics, remove intracranial or spinal cord tumors, and repair bone deformities. In addition, gene therapy targeting the underlying cause of NF1 is currently still in clinical trials. The goal of gene therapy is to restore the function or quantity of normal neurofibrillin and regulate cell proliferation, differentiation and migration by changing or replacing the mutated NF1 gene or its products.

Polycystic Kidney Disease

Polycystic kidney disease (PKD) is an inherited kidney disease caused by mutations in one or more genes. The cause of PKD is due to the mutation of one or more genes (such as PKD1, PKD2, and PKHD1) on the chromosome, resulting in an abnormal sequence encoding polycystin. Polycystin is an important renal component involved in maintaining the structure and function of renal tubules. Due to gene mutations in PKD patients, polycystin function defects or insufficient quantities result, which affects the normal development and operation of renal tubules. There are two main types of PKD—autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD). ADPKD is usually diagnosed in adulthood, whereas ARPKD can be diagnosed in utero or in infancy. This disease causes many fluid-filled cysts to grow on the kidneys. If there are too many or large cysts, the kidneys can be damaged. PKD can reduce kidney function and even lead to kidney failure. PKD can also cause other complications, such as high blood pressure, cysts in the liver, and blood vessel problems in the brain and heart.

Treatment options for PKD include drug therapy, surgery, dialysis, and kidney transplantation. Drug therapy is mainly aimed at lowering blood pressure and controlling infection. Commonly used drugs are ACEI class, ARB class, antibiotics. Surgery is mainly used to remove large cysts that affect function or appearance, remove malignant tumors, repair aneurysms or dissections, etc. Timing of surgery depends on the size, location, and extent of impact of the cyst or tumor. Dialysis is a method of replacing kidney function that removes excess water and waste from the body; transplantation is a method of replacing a damaged kidney and restoring normal kidney function. Both dialysis and transplantation require regular checkups and monitoring, and specific medications to prevent infection or rejection. Gene therapy for PKD is to restore the function or quantity of normal polycystin and regulate the development and function of renal tubules by changing or replacing the mutated gene or its product, and it is still in the stage of clinical trials.

Familial Hypercholesterolemia

Hypercholesterolemia (FH) is an inherited blood disorder caused by mutations in one or more genes. The cause of FH is due to mutations in one or more genes on the chromosome (such as LDLR, APOB, and PCSK9), resulting in abnormal sequences encoding LDL receptors or other proteins that regulate cholesterol metabolism. The LDL receptor is an important cell surface molecule involved in the clearance of LDL-C from the blood. Due to gene mutations in FH patients, a functional defect or insufficient quantity of LDL receptors is caused, which affects the normal metabolism and excretion of cholesterol. There are two main types of FH—autosomal dominant FH (ADFH) and autosomal recessive FH (ARFH). ADFH is usually diagnosed in adulthood, whereas ARFH can be diagnosed in childhood. FH can lead to high levels of low-density lipoprotein cholesterol (LDL-C) in the blood, which increases the risk of cardiovascular disease and premature myocardial infarction. LDL-C is known as the "bad" cholesterol because it builds up plaque on artery walls, hardening and narrowing the arteries. This excess cholesterol is sometimes deposited in places such as the skin, tendons, and around the iris of the eye.

Fig.2 Familial hypercholesterolemia. (Safarova, 2016)

Several treatment options, including medication, surgery, lifestyle intervention, and nutritional supplementation, can be used to control blood cholesterol levels and prevent cardiovascular complications caused by FH. The main purpose of drug treatment is to reduce LDL-C levels and total cholesterol levels and increase HDL-C levels. Commonly used drugs include statins, fibrates, PCSK9 inhibitors, particulate carriers, and bile acid binders. Surgery is primarily used to remove xanthomas or corneal arcs that impair function or aesthetics. Lifestyle interventions, including smoking cessation, limiting alcohol consumption, weight control, and increased exercise, can help lower blood pressure and improve blood lipid levels. Nutritional supplements include eating foods rich in unsaturated fatty acids, cellulose, plant sterols, and other beneficial ingredients, which can help reduce LDL-C levels and total cholesterol levels. The goal of gene therapy strategies for FH being developed and tested is to restore the function or amount of normal LDL receptors or other proteins that regulate cholesterol metabolism and reduce LDL-C levels and total cholesterol levels.

References

1. McColgan P, et al. Huntington's disease: a clinical review. Eur J Neurol. 2018 Jan;25(1):24-34.
2. Tabrizi SJ, et al. Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities. Lancet Neurol. 2022 Jul;21(7):645-658.
3. Underwood BR, et al. Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240.
4. Coelho SG, et al. Marfan syndrome revisited: From genetics to the clinic. Rev Port Cardiol (Engl Ed). 2020 Apr;39(4):215-226. English, Portuguese.
5. Zeigler SM, et al. Pathophysiology and Pathogenesis of Marfan Syndrome. Adv Exp Med Biol. 2021;1348:185-206.
6. Milewicz DM, et al. Marfan syndrome. Nat Rev Dis Primers. 2021 Sep 2;7(1):64.
7. Ly KI, et al. The Diagnosis and Management of Neurofibromatosis Type 1. Med Clin North Am. 2019 Nov;103(6):1035-1054.
8. Wilson BN, et al. Neurofibromatosis type 1: New developments in genetics and treatment. J Am Acad Dermatol. 2021 Jun;84(6):1667-1676.
9. Fisher MJ, et al. Management of neurofibromatosis type 1-associated plexiform neurofibromas. Neuro Oncol. 2022 Nov 2;24(11):1827-1844
10. Cornec-Le Gall E, et al. Autosomal dominant polycystic kidney disease. Lancet. 2019 Mar 2;393(10174):919-935.
11. Colbert GB, et al. Update and review of adult polycystic kidney disease. Dis Mon. 2020 May;66(5):100887.
12. Tokgozoglu L, et al. Familial Hypercholesterolemia: Global Burden and Approaches. Curr Cardiol Rep. 2021 Sep 4;23(10):151.
13. Raal FJ, et al. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 2018 Oct;277:483-492.
14. Safarova, Maya S., and Iftikhar J. Kullo. "My approach to the patient with familial hypercholesterolemia." Mayo Clinic Proceedings. Vol. 91. No. 6. Elsevier, 2016.