X-Linked Disorders and Female Carriers

  • Female carriers of x-linked diseases have to deal with difficult reproductive decisions -- as illustrated in the video below, each child they bear has a 50% chance of inheriting the defective gene. In addition, they often suffer from anxiety and/or depression, particularly if a father, brother or son is affected by or died from the x-linked disorder they carry (in fact many females only learn they are carriers after a male relative becomes sick or dies). If that were not enough, female carriers face an uncertain future themselves, as recent studies have demonstrated that with many of the x-linked  recessive diseases (many of which are not truly 'recessive'), females are not, as traditionally thought, "just carriers" -- rather, they too, are at risk for developing physical symptoms, which in some cases may be severe and disabling. Often, female carriers and their doctors do not know what symptoms to look for or fail to make the connection between the symptoms and the female's carrier status, resulting in a lack of treatment and unnecessary suffering.  Much more research is needed when it comes to female carriers of x-linked diseases. In the meantime, carriers need to take charge of their own health and learn as much as possible about their own risk for developing physical symptoms so that they are not subject to years of tolerating problems that could have been treated.  Some of the more prevalent x-linked "recessive" disorders and their manifestations in female carriers are discussed below.   


X-Linked Recessive Inheritance Explained

This short video clip published by UCD Medicine depicts the x-linked recessive inheritance pattern, wherein males typically develop symptoms of the disorder in question, and females are referred to as carriers. Contrary to the commonly held belief that females merely pass on x-linked disorders, however, in fact, many female carriers do develop physical symptoms--the extent and severity of which varies depending on the particular x-linked disorder, as set forth below.

Specific X-Linked Recessive Disorders

Hemophilia A & B

  • Hemophilia A (factor VII deficiency) affects 1 in 5,000 males; Hemophilia B (factor IX deficiency) affects in in 25,000. These bleeding disorders, which affect males of all races, colors, & ethnicities, range from mild to severe. Although hemophilia has been known for thousands of years, it is only recently that health care professionals have recognized that up to 60% of female carriers also have bleeding problems (e.g., heavy, prolonged menstrual bleeding, abnormal bleeding following trauma, childbirth or surgery) that can greatly affect their quality of life.

X-Linked Retinitis Pigmentosa

  • X-linked retinitis pigmentosa (XLRP)  is an inherited disorder which can cause significant vision loss, and sometimes complete blindness, in males, usually in the fourth decade of life. While females were long thought to be unaffected carriers, recent studies have shown that up to 40% of females develop mild to moderate visual abnormalities as a result of XLRP as well. A small percentage of XLRP carriers (around 2.5%) are legally blind.

Duchenne & Becker Muscular Dystrophy

  • These are genetic, muscle-wasting conditions caused by the complete (Duchenne) or partial (Becker) lack of a protein called dystrophin. While they usually only affect boys, up to 10% of females can be affected as "manifesting carriers." Most manifesting carriers experience mild problems with muscle weakness in their legs--sometimes spreading to the shoulders and arms. Rarely, carriers may develop a muscular dystrophy that is nearly severe as boys. Carriers may also have problems with their heart (cardiomyopathy) which can be treated if recognized early.

X-Linked Alport Syndrome

  • X-linked Alport Syndrome is caused by a mutation in the type IV collagen genes.  While males with XLAS are usually more severely affected than females, approximately 30% of female carriers develop kidney insufficiency later in life. Some carriers may also experience hearing loss. Both males and females who begin treatment early can delay the progression of the disease.

Adrenoleukodystrophy

  • ALD affects the white matter of the brain and most commonly affects boys and men, often resulting in serious neurological impairment or death. Female carriers were long thought to be unaffected or only very mildly affected. Research has shown, however, that more than 80% of females develop symptoms that very in severity from mild weakness and spasticity in the lower limbs, to incapacitating sphincter disturbances, and cerebral neurological regression. 

Chronic Granulomatous Disease

  • Many medical professionals are unfamiliar with this rare genetic condition, in which recent studies have shown that many female carriers experience symptoms such as painful mouth ulcers, lupus-like skin issues with recurring abscesses, inflammation of the lymph glands, gastrointestinal problems, fatigue, anxiety, and increased susceptibility to life-threatening infections. While many carriers are unaffected, most develop one or more of these symptoms.

X-Linked Ichthyosis

  • XLI occurs in approximately 1 in 6,000 births and It results in a build up of dark scales on the skin, which covers a portion of the body. Like the other x-linked recessive disorders XLI occurs most often in males, however, some female carriers may report dry skin problems, shadows of scales on the skin, and/or asymptomatic cloudy spots on the corneas. During pregnancy, the enzyme defect in female carriers can cause a decrease in production of maternal estriol in late pregnancy, which may affect labor and delivery; therefore, all pregnant XLI carriers should be carefully monitored. 

Lowe Syndrome

  • Boys with Lowe syndrome have cataracts that are present at birth, poor muscle tone with delayed motor development, kidney problems, and intellectual disabilities ranging from mild to severe. Half have seizures by age six, and some have behavioral problems. Other signs may include short stature, dental cysts, soft bones, skeletal changes, scoliosis and degenerative joint disease. While female carriers do not develop the same symptoms as males, almost  every carrier over age 10 will show characteristic changes in the lenses of her eyes. Some females will develop significant cataracts in their early 30's sufficient to require surgery.

Hunter Syndrome (MPSII)

  • MPS II is caused by a deficiency in the activity of the enzyme iduronate 2-sulfatase. Its manifestations, which occure predominently in males, are widely variable and include short stature, coarse facies, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease and profound neurological involvement leading to developmental delays. Female carriers are rarely symptomatic, with the most frequent symptomology being bone anomalies, respiratory and ear problems, abnormalities of the teeth, and live anomalies.

X-Linked Myotubular Myopathy

  • XLMTM is a rare genetic neuromuscular disease thought to be present in 1 in every 50,000 births, which results in various symptoms including mild to moderate muscle weakness and diminished muscle tone which often results in an inability to walk, as well as respiratory problems and feeding difficulties due to weakness of the muscles involved in breathing and swallowing. While the disorder primarily affects males, some female carriers do develop mild symptoms of the disease. Rarely, female carriers develop severe symptoms.

Pelizaeus-Merzbacher Diseases

  • One of the group of leukodystrophies that affect the growth of the myelin sheath, PMD most often follows an x-linked recessive inheritance pattern. Males are usually affected in infancy, and may display rapid, involuntary eye movements and low muscle tone, delaying or completed impairing their motor abilities. They may also experience tremors and involuntary movements with spasticity in the arms and legs, and a deterioration in mental function. While most female carriers are asymptomatic, at least 20% develop transient neurological symptoms similar to boys, from which they may recover.

Choroideremia

  • Choroideremia is a rare disorder of sight which primarily affects males and may cause an extensive loss of all of the retinal layers in the eyes.  Affected individuals typically initially experience difficultly seeing in the dark, which eventually leads to a loss of peripheral vision, then tunnel vision, sometimes progressing to total blindness. While many female carriers are asymptomatic, some carriers do develop mild symptoms later in their lives, including difficultly seeing in the dark and sensitivity to glare.

X-Linked Hypohidrotic Ectodermal Dysplasia

  • X-linked Hypohidrotic Ectodermal Dysplasia is an inherited condition that affects the development of the skin, nails, hair and teeth, and which causes a reduced, and potentially life-threatening, inability to sweat. Prognosis is good, if the disease is recognized in childhood and measures are taken toward temperature regulation. Approximately 50% of females  who carry this disease have symptoms which warrant intervention, including the absence and/or malformation of teeth, sparse hair, and/or reduced sweating. 

X-Linked Hydrocephalus

  • X-linked Hydrocephalus (L1 Syndrome) occurs in approximately 1 in 30,000 births, and is characterized by  characterized by hydrocephalus of varying degrees of severity, intellectual deficiencies, seizures, spasticity of the lower extremities, and adducted thumbs.  Most female carriers do not develop symptoms. Those who do typically have less severe symptoms than males, such as adducted thumbs or mild intellectual deficits/ 

Fragile X Syndrome

  • Fragile X Syndrome has a unique mode of inheritance and can not be characterized as either truly dominant or recessive. Many females with the full mutation have significant symptoms (though typically less severe than males), including intellectual disabilities, social difficulties, and heightened levels of impulsivity.  Ten percent of these females meet the criteria for a diagnosis of autisim. 1 in 151 females  are premutation carriers, approximately 8-25% of whom may experience numbness, dizziness  fainting, irregular menstrual cycles, infertility and premature ovarian failure.  

Norrie Disease

  • Norrie Disease is a disorder of the retaina of the eyes that leads to blindness in males at birth or shortly thereafter.  More than 1/2 of males with Norrie Disease have development delays in motor skills and approximately 1/3  develop progressive hearing loss. While most female carriers do not develop symptoms, some do develop mild hearing loss and retinal problems.

Ornithine Transcarbamylase Deficiency

  • U Ornithine transcarbamylase (OTC) deficiency, a subtype of Urea Cycle Disorder, is an X-linked genetic disorder of the urea cycle that leads to elevated levels of ammonia in the blood. The ammonia can reach toxic levels and cause confusion, refusal to eat, lethargy, vomiting, and swelling in the brain. While OTC is fully expressed in males only, 20% of female carriers are symptomatic. Female carriers may be prone to headaches following protein intake, and may develop milder symptoms of the disorder.

Kennedy's Disease (SBMA)

  • Spinal Bulbar Muscular Atrophy (a/k/a Kennedy's Disease) is a progressive muscle disorder which usually affects 1 in 40,000 males in their mid-twenties through early forties. The disease gradually erodes the muscles and motor neurons in the body. There is no treatment or cure for this disorder. Some females carriers experience physical symptoms such as hand tremors, weakness in the legs and difficulty swallowing.

FG Syndrome

  • FG Syndrome is an x-linked recessive disease which is not well understood. "FG" represents the surname initials of the first individuals diagnosed with the disease.  Males with this disorder are more severely affected than females and frequently have a wide range of physical abnormalities and conditions, including intellectual disabilities, cardiac problems, chronic constipation, weak muscle tone, difficult eating habits, seizure disorders, speech delay, respiratory conditions, a wide and high forehead, small ears, chronic ear infections, and more. Some individuals with FG Syndrome actually fall into the category of intellectually gifted - it has been hypothesized, for example, that "Rain Man" actually had FG Syndrome rather than autism. It has recently been recognized that females may be affected with symptoms of FG, however, because there have been so few studies involving females, the nature and extent of the condition in females is difficult to pinpoint at the current time.

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