Miyoshi myopathy

Miyoshi myopathy is a rare, inherited muscle disorder characterized by progressive muscle weakness and wasting that begins in the calves before spreading to other parts of the body.

Overview

Miyoshi myopathy is a muscle disorder that begins with weakness in the muscles that are located away from the center of the body (distal muscles), such as those in the legs. During early to mid-adulthood, affected individuals typically begin to experience muscle weakness and wasting (atrophy) in one or both calves. If only one leg is affected, the calves appear different in size (asymmetrical). Calf weakness can make it difficult to stand on tiptoe.

As Miyoshi myopathy slowly worsens, the muscle weakness and atrophy spread up the leg to the muscles in the thigh and buttock and can also involve the upper arm and shoulder muscles. Eventually, affected individuals may have difficulty climbing stairs or walking for an extended period of time. Some people with Miyoshi myopathy may eventually need wheelchair assistance.

Symptoms

The signs and symptoms of Miyoshi myopathy primarily involve progressive muscle dysfunction, including:

• Muscle weakness and wasting (atrophy) in the calves, which may appear asymmetrical
• Difficulty standing on tiptoe
• Muscle weakness spreading to the thighs, buttocks, upper arms, and shoulders
• Difficulty climbing stairs or walking for long periods
• Potential requirement of wheelchair assistance over time
• Rare development of abnormal heart rhythms (arrhythmias)
• Highly elevated blood levels of the enzyme creatine kinase (CK), which typically indicates muscle disease

Frequency

The exact prevalence of Miyoshi myopathy is unknown. In Japan, where the condition was first described, it is estimated to affect 1 in 440,000 individuals.

Causes

Miyoshi myopathy is caused by mutations in the DYSF or ANO5 gene. When Miyoshi myopathy is caused by ANO5 gene mutations, it is sometimes referred to as distal anoctaminopathy; when caused by DYSF gene mutations, it is known as a dysferlinopathy.

The DYSF and ANO5 genes provide instructions for making proteins primarily found in muscles used for movement. The protein produced from the DYSF gene, called dysferlin, is found in the thin membrane called the sarcolemma that surrounds muscle fibers. Dysferlin is thought to aid in repairing the sarcolemma when it becomes damaged or torn due to muscle strain.

The ANO5 gene provides instructions for making a protein called anoctamin-5. This protein is located within the membrane of a cell structure called the endoplasmic reticulum, which is involved in protein production, processing, and transport. Anoctamin-5 is thought to act as a chloride channel, allowing charged chlorine atoms (chloride ions) to flow in and out of the endoplasmic reticulum. The regulation of chloride flow within muscle cells plays a role in controlling muscle tensing (contraction) and relaxation.

Mutations in these genes often result in a decrease or elimination of the corresponding protein. A lack of dysferlin leads to a reduced ability to repair damage done to the sarcolemma of muscle fibers, causing damage to accumulate and lead to atrophy of the muscle fiber. It is unclear why this damage leads to the specific pattern of weakness and atrophy characteristic of Miyoshi myopathy. The effects of the loss of anoctamin-5 are also unclear; while chloride is necessary for normal muscle function, it is unknown how a lack of this chloride channel causes the signs and symptoms of the condition.

Associated Genes

• ANO5
• DYSF

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• Distal muscular dystrophy, Miyoshi type
• Miyoshi distal myopathy
• Miyoshi muscular dystrophy
• MMD

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that causes widespread inflammation in connective tissues, potentially affecting the skin, joints, kidneys, and other major organs.

Overview

Systemic lupus erythematosus (SLE) is a chronic disease that causes inflammation in connective tissues, such as cartilage and the lining of blood vessels, which provide strength and flexibility to structures throughout the body. SLE is one of a large group of conditions called autoimmune disorders, which occur when the immune system attacks the body's own tissues and organs. The signs and symptoms of SLE vary among affected individuals and can involve many organs and systems.

People with SLE experience episodes in which the condition gets worse (exacerbations) and other times when it gets better (remissions). Overall, SLE gradually worsens over time, and damage to major organs can be life-threatening.

Symptoms

The signs and symptoms of SLE can affect multiple systems throughout the body, including:

• Initial systemic symptoms: Extreme tiredness (fatigue), a vague feeling of discomfort or illness (malaise), fever, loss of appetite, and weight loss.
• Musculoskeletal issues: Joint pain (typically affecting the same joints on both sides of the body), muscle pain, and muscle weakness.
• Skin problems: A characteristic flat red "butterfly rash" across the cheeks and bridge of the nose (which generally does not hurt or itch and becomes more pronounced in sunlight), calcium deposits under the skin (calcinosis), damaged blood vessels in the skin (vasculitis), and tiny red spots called petechiae caused by a shortage of clotting cells (platelets).
• Hair and mucosal issues: Hair loss (alopecia) and open sores (ulcerations) in the moist lining of the mouth, nose, or genitals.
• Kidney disease: Inflammation of the kidneys (nephritis), which develops in about a third of people with SLE.
• Heart problems: Inflammation of the sac-like membrane around the heart (pericarditis), abnormalities of the heart valves, and an increased risk of heart disease caused by fatty buildup in blood vessels (atherosclerosis).
• Nervous system damage: Abnormal sensation and weakness in the limbs (peripheral neuropathy), seizures, stroke, and difficulty processing, learning, and remembering information (cognitive impairment).
• Mental health issues: Anxiety and depression.

Frequency

SLE is estimated to affect between 322,000 and 1.5 million people in the United States. The exact prevalence is difficult to determine because many signs and symptoms resemble those of other disorders, which can delay diagnosis for years. Females develop SLE about nine times more often than males, with the condition peaking during childbearing years, though 20 percent of cases occur in people over age 50.

In industrialized Western countries, SLE has become 10 times more common over the past 50 years. While the prevalence of SLE in Africa and Asia is believed to be much lower than in Western nations, people of African and Asian descent living in industrialized Western countries are two to four times more likely to develop SLE than people of European descent. Researchers suggest that factors such as ethnic mixing, tobacco use, and regional infections contribute to these differences. For example, malaria (common in tropical regions) is thought to be protective against SLE, while the Epstein-Barr virus (more common in the West) increases SLE risk.

Causes & Risk Factors

In most cases, multiple genetic factors are thought to be involved in SLE, though normal variations (polymorphisms) in many genes can affect the risk of developing the condition. In rare cases, variants (mutations) in single genes directly cause SLE. Most genes associated with SLE are involved in immune system function, and changes in these genes likely affect the proper targeting and control of the immune response.

Other contributing factors include:

• Sex hormones
• Environmental triggers, including viral infections, diet, stress, chemical exposures, and sunlight
• Drug exposure, which is thought to trigger about 10 percent of SLE cases (with more than 80 associated drugs identified)

In people with SLE, cells that have undergone self-destruction (apoptosis) because they are damaged or no longer needed are not cleared away properly. Researchers suggest these dead cells may release substances that cause the immune system to react inappropriately and attack the body's tissues.

Associated Genes

Some of the primary genes associated with Systemic lupus erythematosus include:

• IRF5
• NCF2
• PTPN22
• STAT4
• TREX1

Additional genes identified by the NCBI include:

• BANK1, C4A, C4B, CR2, CRP, CTLA4, DNASE1, DNASE1L3, FCGR2B, ITGAM, LTK, PDCD1, RASGRP1, RIPK1, TLR5, TNFAIP3, and TNFSF4.

Inheritance

SLE and other autoimmune disorders tend to run in families, but the inheritance pattern is usually unknown. People may inherit a gene variation that alters their risk, but they typically do not inherit the condition itself. Not all people with SLE have a risk-increasing gene variation, and not all people with such a variation will develop the disorder.

A rare, inherited form of SLE follows an autosomal recessive pattern, meaning both copies of the gene in each cell have disease-causing variants. The parents of an individual with this form each carry one copy of the altered gene but typically do not show signs and symptoms of the condition.

Other Names for This Condition

• Disseminated lupus erythematosus
• LE syndrome
• Libman-Sacks disease
• Lupus
• SLE

X-linked infantile spinal muscular atrophy

X-linked infantile spinal muscular atrophy is a severe genetic disorder affecting only boys, characterized by profound muscle weakness, joint deformities, and life-threatening respiratory issues.

Overview

X-linked infantile spinal muscular atrophy is a severe condition that affects only boys. It is characterized by severe muscle weakness and absent reflexes (areflexia). The muscle weakness worsens over time. While affected children may reach some early motor developmental milestones, such as sitting unassisted, these skills are often lost (developmental regression).

Weakness of the chest muscles used for breathing often leads to life-threatening breathing problems. Children with this condition usually do not survive past early childhood due to respiratory failure, though survival into adolescence occurs in rare cases.

Symptoms

The signs and symptoms of X-linked infantile spinal muscular atrophy are present from birth or early infancy and include:

• Severe muscle weakness and absent reflexes (areflexia)
• Multiple joint deformities (contractures) from birth that cause joint stiffness (arthrogryposis) and impair movement
• Broken bones at birth in severe cases
• Developmental regression, such as the loss of the ability to sit unassisted
• An unusually small chin (micrognathia)
• Abnormal curvature of the spine (scoliosis)
• Undescended testes (cryptorchidism)
• Chest muscle weakness leading to severe, life-threatening respiratory problems and respiratory failure

Frequency

X-linked infantile spinal muscular atrophy is thought to be a rare condition; its exact prevalence is unknown.

Causes

Mutations in the UBA1 gene cause X-linked infantile spinal muscular atrophy. The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is necessary for a process that targets damaged or unneeded proteins to be broken down (degraded) within cells, which helps maintain the proper balance of protein production and breakdown (protein homeostasis) required for cell function and survival.

Mutations in the UBA1 gene lead to a decrease in enzyme production or the production of an enzyme with reduced or abnormal function. Consequently, damaged or unneeded proteins build up inside cells instead of being degraded. This buildup disrupts protein homeostasis and impairs normal cell functions by stopping the production of new proteins, ultimately leading to cell death.

Specialized nerve cells that control muscle movement (motor neurons) are particularly susceptible to these disruptions in cell function, likely due to their large size. The loss of these motor neurons causes the characteristic muscle weakness and wasting of the condition.

Associated Genes

• UBA1

Inheritance

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is highly unlikely that females will inherit two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Other Names for This Condition

• AMCX1
• Arthrogryposis multiplex congenita, distal, X-linked
• Arthrogryposis, X-lined, type I
• Distal X-linked AMC
• Infantile X-linked SMA
• SMAX2
• Spinal muscular atrophy, infantile X-linked
• Spinal muscular atrophy, X-linked 2
• Spinal muscular atrophy, X-linked lethal infantile
• X-linked arthrogryposis multiplex congenita
• X-linked arthrogryposis type I
• X-linked lethal infantile SMA
• XL-SMA
• XLSMA

Vici syndrome

Vici syndrome is a severe, multisystem genetic disorder beginning early in life that impacts brain development, immune function, the heart, skin, and eyes.

Overview

Vici syndrome is a severe disorder that begins early in life and affects many body systems. It is characterized by abnormalities of the brain, immune system, heart, skin, and eyes. Other organs and tissues are less commonly affected. Most people with Vici syndrome do not survive beyond childhood, though survival times can vary widely.

Symptoms

Vici syndrome presents with a wide range of severe symptoms affecting multiple organs:

• Brain abnormalities: Failure of the tissue connecting the left and right halves of the brain to form normally (agenesis of the corpus callosum), underdevelopment of the pons region of the brain (pontine hypoplasia), and lower levels of myelin (the fatty substance that protects nerve cells). Degeneration of brain tissue over time can also result in an unusually small head size (microcephaly).
• Developmental and muscle issues: Profound developmental delays, weak muscle tone (hypotonia), inability to walk or speak, and potential loss of previously acquired motor skills (such as rolling or sitting).
• Immune deficiency: Impaired immune function leading to recurrent, life-threatening infections, most commonly respiratory infections, as well as gastrointestinal and urinary tract infections.
• Heart conditions: A progressive, potentially life-threatening heart muscle disease (cardiomyopathy) that makes it difficult to pump blood efficiently, as well as congenital heart defects present from birth.
• Skin and hair features: Lighter skin and hair color than family members or others of the same ethnic background (hypopigmentation).
• Eye abnormalities: Clouding of the lenses of the eyes (cataracts) or other eye abnormalities that may reduce vision.
• Other symptoms: Seizures; hearing loss caused by inner ear abnormalities (sensorineural hearing loss); an opening in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate); unusual facial features; abnormal function of the thyroid, liver, or kidneys; and abnormally slow growth and weight gain.

Frequency

Vici syndrome is a rare disorder, though its exact prevalence is unknown. Approximately 100 individuals have been diagnosed with this condition.

Causes

Variants (mutations) in the EPG5 gene cause Vici syndrome. This gene provides instructions for making a protein involved in a cellular process called autophagy. Cells use autophagy to recycle or break down worn-out or unnecessary cell parts, and to use materials efficiently when energy demands are high. The EPG5 protein also aids in the body's immune response to foreign invaders like bacteria and viruses.

Certain variants in the EPG5 gene result in abnormal EPG5 proteins that do not respond properly to foreign invaders, leading to recurrent infections. Additionally, these variants impair the autophagy process. Researchers believe that problems with autophagy disrupt the normal development and survival of cells in the brain and other organs, though the exact mechanism leading to the specific signs and symptoms of Vici syndrome is not fully understood.

Associated Genes

• EPG5

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• Absent corpus callosum cataract immunodeficiency
• Corpus callosum agenesis-cataract-immunodeficiency syndrome
• Dionisi Vici Sabetta Gambarara syndrome
• Dionisi-Vici-Sabetta-Gambarara syndrome
• Immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum