Fragile X-associated primary ovarian insufficiency (FXPOI) is a condition that affects women and is characterized by reduced function of the ovaries. The ovaries are the female reproductive organs in which egg cells are produced. As a form of primary ovarian insufficiency, FXPOI can cause irregular menstrual cycles, early menopause, an inability to have children (infertility), and elevated levels of a hormone known as follicle stimulating hormone (FSH). FSH is produced in both males and females and helps regulate the development of reproductive cells (eggs in females and sperm in males). In females, the level of FSH rises and falls, but overall it increases as a woman ages. In younger women, elevated levels may indicate early menopause and fertility problems.\n\nThe severity of FXPOI is variable. The most severely affected women have overt POI (formerly called premature ovarian failure). These women have irregular or absent menstrual periods and elevated FSH levels before age 40. Overt POI often causes infertility. Other women have occult POI; they have normal menstrual periods but reduced fertility, and they may have elevated levels of FSH (in which case, it is called biochemical POI). The reduction in ovarian function caused by FXPOI results in low levels of the hormone estrogen, which leads to many of the common signs and symptoms of menopause, such as hot flashes, insomnia, and thinning of the bones (osteoporosis). Women with FXPOI undergo menopause an average of 5 years earlier than women without the condition. [from MedlinePlus Genetics]

HFE hemochromatosis is characterized by inappropriately high absorption of iron by the small intestinal mucosa. The phenotypic spectrum of HFE hemochromatosis includes: Persons with clinical HFE hemochromatosis, in whom manifestations of end-organ damage secondary to iron overload are present; Individuals with biochemical HFE hemochromatosis, in whom transferrin-iron saturation is increased and the only evidence of iron overload is increased serum ferritin concentration; and Non-expressing p.Cys282Tyr homozygotes, in whom neither clinical manifestations of HFE hemochromatosis nor iron overload are present. Clinical HFE hemochromatosis is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and anterior pituitary gland. In untreated individuals, early symptoms include: abdominal pain, weakness, lethargy, weight loss, arthralgias, diabetes mellitus; and increased risk of cirrhosis when the serum ferritin is higher than 1,000 ng/mL. Other findings may include progressive increase in skin pigmentation, congestive heart failure, and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE hemochromatosis is more common in men than women. [from GeneReviews]

Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE). Deep vein thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that heterozygosity for the Leiden variant has at most a modest effect on risk for recurrent thrombosis after initial treatment of a first VTE. It is unlikely that factor V Leiden thrombophilia (i.e., heterozygosity or homozygosity for the Leiden variant) is a major factor contributing to pregnancy loss and other adverse pregnancy outcomes (preeclampsia, fetal growth restriction, and placental abruption). The clinical expression of factor V Leiden thrombophilia is influenced by the following: The number of Leiden variants (heterozygotes have a slightly increased risk for venous thrombosis; homozygotes have a much greater thrombotic risk). Coexisting genetic thrombophilic disorders, which have a supra-additive effect on overall thrombotic risk. Acquired thrombophilic disorders: antiphospholipid antibody (APLA) syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors. Circumstantial risk factors including but not limited to pregnancy, central venous catheters, travel, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), obesity, leg injury, and advancing age. [from GeneReviews]

Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years (mean age at onset: 10-15 yrs). FRDA is typically associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy, up to 30% have diabetes mellitus, and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes. [from GeneReviews]

Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. Ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs. Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course. [from GeneReviews]

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. [from GeneReviews]

Spinal and bulbar muscular atrophy (SBMA) is a gradually progressive neuromuscular disorder in which degeneration of lower motor neurons results in muscle weakness, muscle atrophy, and fasciculations. SBMA occurs only in males. Affected individuals often show gynecomastia, testicular atrophy, and reduced fertility as a result of mild androgen insensitivity. [from GeneReviews]

SCA8 is a slowly progressive ataxia with onset typically in the third to fifth decade but with a range from before age one year to after age 60 years. Common initial manifestations are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Over the disease course other findings can include eye movement abnormalities (nystagmus, abnormal pursuit and abnormal saccades, and, rarely, ophthalmoplegia); upper motor neuron involvement; extrapyramidal signs; brain stem signs (dysphagia and poor cough reflex); sensory neuropathy; and cognitive impairment (e.g., executive dysfunction, psychomotor slowing and other features of cerebellar cognitive-affective disorder in some). Life span is typically not shortened. [from GeneReviews]

A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. It is said to be the third leading cause of death in the United States. Gunel and Lifton (1996) noted that about 20% of strokes are hemorrhagic, resulting in bleeding into the brain. Ischemic strokes, resulting from vascular occlusion, account for the majority of strokes. Bersano et al. (2008) reviewed genetic polymorphisms that have been implicated in the development of stroke. Candidate genes include those involved in hemostasis (see, e.g., F5; 612309), the renin-angiotensin-aldosterone system (see, e.g., ACE; 106180), homocysteine (see, e.g., MTHFR; 607093), and lipoprotein metabolism (see, e.g., APOE; 107741). See also hemorrhagic stroke, or intracerebral hemorrhage (ICH; 614519). [from OMIM]

Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death. Anticipation in this nucleotide repeat disorder may be so dramatic that within a family a child with infantile or early-childhood onset may be diagnosed with what is thought to be an unrelated neurodegenerative disorder years before a parent or grandparent with a CAG repeat expansion becomes symptomatic. In adolescent-onset SCA7, the initial manifestation is typically impaired vision, followed by cerebellar ataxia. In those with adult onset, progressive cerebellar ataxia usually precedes the onset of visual manifestations. While the rate of progression varies in these two age groups, the eventual result for almost all affected individuals is loss of vision, severe dysarthria and dysphagia, and a bedridden state with loss of motor control. [from GeneReviews]

Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration. [from GeneReviews]

Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late-adult onset have been reported. Those with onset after age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy. [from GeneReviews]

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive disorder of ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children and ataxia, choreoathetosis, and dementia or character changes in adults. Onset ranges from before age one year to age 72 years; mean age of onset is 31.5 years. The clinical presentation varies depending on the age of onset. The cardinal features in adults are ataxia, choreoathetosis, and dementia. Cardinal features in children are progressive intellectual deterioration, behavioral changes, myoclonus, and epilepsy. [from GeneReviews]

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (including fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The risk of developing an associated cancer varies depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant. [from GeneReviews]

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The age of onset ranges from 19 to 73 years; mean age of onset is between 43 and 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved. [from GeneReviews]

Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and dysphagia due to selective involvement of the muscles of the eyelids and pharynx, respectively. For the vast majority of individuals with typical OPMD, the mean age of onset of ptosis is usually 48 years and of dysphagia 50 years; in 5%-10% of individuals with severe OPMD, onset of ptosis and dysphagia occur before age 45 years and is associated with lower limb girdle weakness starting around age 60 years. Swallowing difficulties, which determine prognosis, increase the risk for potentially life-threatening aspiration pneumonia and poor nutrition. Other manifestations as the disease progresses can include limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, and proximal limb girdle weakness predominantly in lower limbs. Some individuals with severe involvement will eventually need a wheelchair. Neuropsychological tests have shown altered scores in executive functions in some. [from GeneReviews]

The development of two genetically distinct EMBRYOS in a single UTERUS at the same time, from two separate OVA fertilized by two separate SPERMATOZOA. [from MeSH]

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by progressive cerebellar ataxia and variable findings including pyramidal signs, a dystonic-rigid extrapyramidal syndrome, significant peripheral amyotrophy and generalized areflexia, progressive external ophthalmoplegia, action-induced facial and lingual fasciculations, and bulging eyes. Neurologic findings tend to evolve as the disorder progresses. [from GeneReviews]

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. [from GeneReviews]