MedGen

Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (a-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% a-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, late-onset forms occur in males with greater than 1% a-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; renal failure, associated with ESRD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack. [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]

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes: Severe combined immunodeficiency disease (SCID), often diagnosed by age six months and usually by age 12 months; Less severe "delayed" onset combined immune deficiency (CID), usually diagnosed between age one and ten years; "Late/adult onset" CID, diagnosed in the second to fourth decades; Benign "partial ADA deficiency" (very low or absent ADA activity in erythrocytes but greater ADA activity in nucleated cells), which is compatible with normal immune function. Infants with typical early-onset ADA-deficient SCID have failure to thrive and opportunistic infections associated with marked depletion of T, B, and NK lymphocytes, and an absence of both humoral and cellular immune function. If immune function is not restored, children with ADA-deficient SCID rarely survive beyond age one to two years. Infections in delayed- and late-onset types (commonly, recurrent otitis, sinusitis, and upper respiratory) may initially be less severe than those in individuals with ADA-deficient SCID; however, by the time of diagnosis these individuals often have chronic pulmonary insufficiency and may have autoimmune phenomena (cytopenias, anti-thyroid antibodies), allergies, and elevated serum concentration of IgE. The longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent infection. [from GeneReviews]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

Adenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (summary by Baresova et al., 2012). [from OMIM]

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]

Bipolar disorder is a mental health condition that causes extreme shifts in mood, energy, and behavior. This disorder most often appears in late adolescence or early adulthood, although symptoms can begin at any time of life.

People with bipolar disorder experience both dramatic "highs," called manic episodes, and "lows," called depressive episodes. These episodes can last from hours to weeks, and many people have no symptoms between episodes.

Manic episodes are characterized by increased energy and activity, irritability, restlessness, an inability to sleep, and reckless behavior. Some people with bipolar disorder experience hypomanic episodes, which are similar to but less extreme than manic episodes.

Depressive episodes are marked by low energy and activity, a feeling of hopelessness, and an inability to perform everyday tasks. People with bipolar disorder often have repeated thoughts of death and suicide, and they have a much greater risk of dying by suicide than the general population.

Manic and depressive episodes can include psychotic symptoms, such as false perceptions (hallucinations) or strongly held false beliefs (delusions). Mixed episodes, which have features of manic and depressive episodes at the same time, also occur in some affected individuals.

Bipolar disorder often occurs with other mental health conditions, including anxiety disorders (such as panic attacks), behavioral disorders (such as attention-deficit/hyperactivity disorder), and substance abuse.

Bipolar disorder is classified into several types based on the mood changes that occur. Bipolar I involves manic episodes, which can be accompanied by psychotic symptoms, and hypomanic or depressive episodes. Bipolar II involves hypomanic episodes and depressive episodes. Cyclothymic disorder involves hypomanic episodes and depressive episodes that are typically less severe than those in bipolar I or bipolar II. [from MedlinePlus Genetics]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

Bohring-Opitz syndrome (BOS) is characterized by distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia. The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted. [from GeneReviews]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

Brivaracetam (brand name Briviact) is an antiseizure drug used in the treatment of partial-onset (focal) epilepsy in adults. It is thought to act by binding to a synaptic vesicle glycoprotein, SV2A, and reducing the release of neurotransmitters. Brivaracetam is primarily metabolized by hydrolysis, via amidase enzymes, to an inactive metabolite. To a lesser extent, it is also metabolized by a minor metabolic pathway via CYP2C19-dependent hydroxylation. Individuals who have no CYP2C19 enzyme activity, "CYP2C19 poor metabolizers", will have a greater exposure to standard doses of brivaracetam. Because they are less able to metabolize the drug to its inactive form for excretion, they may have an increased risk of adverse effects. The most common adverse effects of brivaracetam therapy include sedation, fatigue, dizziness, and nausea. The recommended starting dosage for brivaracetam monotherapy or adjunctive therapy is 50 mg twice daily (100 mg per day). Based on how the individual responds, the dose of brivaracetam may be decreased to 25 mg twice daily (50 mg per day) or increased up to 100 mg twice daily (200 mg per day). The FDA-approved drug label for brivaracetam states that patients who are CYPC19 poor metabolizers, or are taking medicines that inhibit CYP2C19, may require a dose reduction. Approximately 2% of Caucasians, 4% of African Americans, and 14% of Chinese are CYP2C19 poor metabolizers. [from Medical Genetics Summaries]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

A type of myelodysplastic syndrome characterized by less than 5% myeloblasts in the bone marrow, but with 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called ringed sideroblasts. [from HPO]

Common variable immune deficiency (CVID) is a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses and often develop recurrent infections, particularly in the lungs, sinuses, and ears. Pneumonia is common in people with CVID. Over time, recurrent infections can lead to chronic lung disease. Affected individuals may also experience infection or inflammation of the gastrointestinal tract, which can cause diarrhea and weight loss. Abnormal accumulation of immune cells causes enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly) in some people with CVID. Immune cells can accumulate in other organs, forming small lumps called granulomas.

Approximately 25 percent of people with CVID have an autoimmune disorder, which occurs when the immune system malfunctions and attacks the body's tissues and organs. The blood cells are most frequently affected by autoimmune attacks in CVID; the most commonly occurring autoimmune disorders are immune thrombocytopenia, which is an abnormal bleeding disorder caused by a decrease in cells involved in blood clotting called platelets, and autoimmune hemolytic anemia, which results in premature destruction of red blood cells. Other autoimmune disorders such as rheumatoid arthritis can occur. Individuals with CVID also have a greater than normal risk of developing certain types of cancer, including a cancer of immune system cells called non-Hodgkin lymphoma and less frequently, stomach (gastric) cancer.

People with CVID may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood; most people with CVID are diagnosed in their twenties or thirties. The life expectancy of individuals with CVID varies depending on the severity and frequency of illnesses they experience. Most people with CVID live into adulthood.

There are many different types of CVID that are distinguished by genetic cause. People with the same type of CVID may have varying signs and symptoms. [from MedlinePlus Genetics]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

Sessile serrated polyposis cancer syndrome (SSPCS) is a rare disorder characterized by the presence of multiple serrated polyps in the colon and an increased personal and familial risk of colorectal cancer. SSPCS is defined by the World Health Organization (WHO) as the presence of at least 5 sessile serrated polyps (also known as 'sessile serrated adenomas,' or SSAs) proximal to the sigmoid colon, with 2 or more that are greater than 10 mm in diameter; or any number of serrated polyps in a person with a first-degree relative with SSPCS; or more than 20 serrated polyps of any size, distributed throughout the colon. SSAs are found in 2% of average-risk individuals undergoing their first screening colonoscopy, and are estimated to be responsible for 20 to 35% of all colon cancers. SSAs exhibit somatic mutations in the BRAF gene (164757), or less commonly in the KRAS gene (190070), early in their development. Individuals with SSPCS have a lifetime risk of colon cancer as high as 54% and may have a strong personal or family history of extracolonic cancers; first-degree relatives have a 32% risk of developing multiple serrated polyps and a 5-fold increased risk of colon cancer. An increased risk of pancreatic cancer has also been observed (summary by Gala et al., 2014). [from OMIM]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [from GeneReviews]

The Headache Classification Committee of the International Headache Society (1988) listed the following criteria for cluster headache (CH): at least 5 attacks of severe unilateral orbital, supraorbital, and/or temporal pain, lasting 15 to 180 minutes, associated with at least 1 of 8 local autonomic signs, and occurring once every other day to 8 per day. Approximately 85% of CH patients have the episodic subtype, in which the headaches occur in cluster periods lasting from 7 days to 1 year and separated by attack-free intervals of 1 month or more. The remainder of patients have the chronic subtype, in which attacks recur for greater than 1 year without remission or with remissions lasting less than 1 month (Lipton et al., 2004). [from OMIM]

Bipolar disorder is classified into several types based on the mood changes that occur. Bipolar I involves manic episodes, which can be accompanied by psychotic symptoms, and hypomanic or depressive episodes. Bipolar II involves hypomanic episodes and depressive episodes. Cyclothymic disorder involves hypomanic episodes and depressive episodes that are typically less severe than those in bipolar I or bipolar II.

Bipolar disorder often occurs with other mental health conditions, including anxiety disorders (such as panic attacks), behavioral disorders (such as attention-deficit/hyperactivity disorder), and substance abuse.

Manic and depressive episodes can include psychotic symptoms, such as false perceptions (hallucinations) or strongly held false beliefs (delusions). Mixed episodes, which have features of manic and depressive episodes at the same time, also occur in some affected individuals.

Depressive episodes are marked by low energy and activity, a feeling of hopelessness, and an inability to perform everyday tasks. People with bipolar disorder often have repeated thoughts of death and suicide, and they have a much greater risk of dying by suicide than the general population.

Manic episodes are characterized by increased energy and activity, irritability, restlessness, an inability to sleep, and reckless behavior. Some people with bipolar disorder experience hypomanic episodes, which are similar to but less extreme than manic episodes.

People with bipolar disorder experience both dramatic "highs," called manic episodes, and "lows," called depressive episodes. These episodes can last from hours to weeks, and many people have no symptoms between episodes.

Bipolar disorder is a mental health condition that causes extreme shifts in mood, energy, and behavior. This disorder most often appears in late adolescence or early adulthood, although symptoms can begin at any time of life. [from MedlinePlus Genetics]