MedGen

The pathogenesis of HIV infection and the progression from infection to AIDS vary significantly between exposed individuals. Infection occurs after the virus, which has macrophage (M)- and T lymphocyte (T)-tropic strains and more than 12 subtypes, survives an array of nonspecific, nongenetic environmental and host factors. [from OMIM]

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. [from GeneReviews]

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. [from GeneReviews]

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. [from GeneReviews]

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. [from GeneReviews]

Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human. [from OMIM]

Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. The phenotype varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s. [from GeneReviews]

DFNA2 nonsyndromic hearing loss is characterized by symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies. At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies; in older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. Although the hearing impairment is often detected during routine hearing assessment of a school-age child, it is likely that hearing is impaired from birth, especially at high frequencies. Most affected persons initially require hearing aids to assist with sound amplification between ages ten and 40 years. By age 70 years, all persons with DFNA2 nonsyndromic hearing loss have severe-to-profound hearing impairment. [from GeneReviews]

Autosomal recessive limb-girdle muscular dystrophy-6 (LGMDR6) is a very rare and severe neuromuscular disorder with onset in most patients in the first decade of life. Generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs is progressive, and patients require walking aids or become wheelchair-bound. Some patients have cardiomyopathy or heart rhythm abnormalities, or require ventilatory support (Alonso-Perez et al., 2022). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600). [from OMIM]

Dronabinol is the main psychoactive component in marijuana. Dronabinol is used in the treatment of chemotherapy-induced nausea and vomiting (CINV) among individuals who have not responded to conventional antiemetic therapy, and to treat anorexia associated with weight loss in individuals with acquired immunodeficiency syndrome (AIDS). Dronabinol is primarily metabolized by CYP2C9, which is responsible for the formation of the major active metabolite (11-hydroxy-delta-9-THC). Individuals who lack CYP2C9 activity (“CYP2C9 poor metabolizers”) have an increased exposure to dronabinol and an increased risk of side effects. Adverse events associated with dronabinol therapy include sedation, physical weakness, facial flushing, and palpitations.nThe FDA-approved drug label for dronabinol recommends monitoring for the increased adverse reactions that could potentially occur in individuals who are known to have genetic variants associated with diminished CYP2C9 function. The label states that published data indicates these individuals may have a 2- to 3-fold higher exposure to dronabinol. [from Medical Genetics Summaries]

Complete LCAT deficiency is a disorder that primarily affects the eyes and kidneys.

In complete LCAT deficiency, the clear front surface of the eyes (the corneas) gradually becomes cloudy. The cloudiness, which generally first appears in early childhood, consists of small grayish dots of cholesterol (opacities) distributed across the corneas. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals; it aids in many functions of the body but can become harmful in excessive amounts. As complete LCAT deficiency progresses, the corneal cloudiness worsens and can lead to severely impaired vision.

People with complete LCAT deficiency often have kidney disease that begins in adolescence or early adulthood. The kidney problems get worse over time and may eventually lead to kidney failure. Individuals with this disorder also usually have a condition known as hemolytic anemia, in which red blood cells are broken down (undergo hemolysis) prematurely, resulting in a shortage of red blood cells (anemia). Anemia can cause pale skin, weakness, fatigue, and more serious complications.

Other features of complete LCAT deficiency that occur in some affected individuals include enlargement of the liver (hepatomegaly), spleen (splenomegaly), or lymph nodes (lymphadenopathy) or an accumulation of fatty deposits on the artery walls (atherosclerosis). [from MedlinePlus Genetics]

A prodromal phase of infection with the human immunodeficiency virus (HIV). Laboratory criteria separating aids-related complex (ARC) from aids include elevated or hyperactive B-cell humoral immune responses, compared to depressed or normal antibody reactivity in aids; follicular or mixed hyperplasia in arc lymph nodes, leading to lymphocyte degeneration and depletion more typical of aids; evolving succession of histopathological lesions such as localization of Kaposi's sarcoma, signaling the transition to the full-blown aids. [from MONDO]

An overwhelming, irrational, and persistent fear of contracting Acquired Immune Deficiency Syndrome. [from NCI]

Inflammation of arteries in the central nervous system that occurs in patients with acquired immunodeficiency syndrome or aids-related opportunistic infections. [from MONDO]

Familial candidiasis is an inherited tendency to develop infections caused by a type of fungus called Candida. Affected individuals typically have infections of the skin, the nails, and the moist lining of body cavities (mucous membranes). These infections are recurrent and persistent, which means they come back repeatedly and can last a long time. This pattern of infection is called chronic mucocutaneous candidiasis.

Candida is commonly present on the skin and on the mucous membranes, and in most people usually causes no health problems. However, certain medications (such as antibiotics and corticosteroids) and other factors can lead to occasional overgrowth of Candida (candidiasis) in the mouth (where it is known as thrush) or in the vagina. These episodes, commonly called yeast infections, usually last only a short time before being cleared by a healthy immune system.

Most people with familial candidiasis have chronic or recurrent yeast infections that begin in early childhood. Skin infections lead to a rash with crusty, thickened patches; when these patches occur on the scalp, they can cause loss of hair in the affected area (scarring alopecia). Candidiasis of the nails can result in thick, cracked, and discolored nails and swelling and redness of the surrounding skin. Thrush and gastrointestinal symptoms such as bloating, constipation, or diarrhea are common in affected individuals. Women with familial candidiasis can develop frequent vaginal yeast infections, and infants can have yeast infections on the skin that cause persistent diaper rash.

Depending on the genetic change involved in this condition, some affected individuals are at risk for developing systemic candidiasis, a more severe condition in which the infection spreads through the bloodstream to various organs including the brain and the meninges, which are the membranes covering the brain and spinal cord. Systemic candidiasis can be life-threatening.

Chronic or recurrent yeast infections can occur in people without familial candidiasis. Some individuals experience recurrent candidiasis as part of a general susceptibility to infections because their immune systems are impaired by a disease such as acquired immune deficiency syndrome (AIDS) or severe combined immunodeficiency (SCID), medications, or other factors. Other individuals have syndromes such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or autosomal dominant hyper-IgE syndrome (AD-HIES) that include a tendency to develop candidiasis along with other signs and symptoms affecting various organs and systems of the body. [from MedlinePlus Genetics]

Caudal regression syndrome is a disorder that impacts the development of the lower (caudal) part of the spine. The condition can affect many parts of the lower body, including the lower back and limbs, the genitourinary tract, and the gastrointestinal tract.

In people with this disorder, the bones of the lower spine (vertebrae) are misshapen or missing. The end of the spinal cord, the bundle of nerves and cells protected by the vertebrae, may also be malformed or missing. Sometimes, the spinal cord is abnormally connected (tethered) to nearby tissues. People with caudal regression syndrome can also have an abnormal curvature of the spine (lordosis or kyphosis). The spinal abnormalities may affect the size and shape of the chest, which very rarely leads to breathing problems.

Individuals with caudal regression syndrome may have small hip bones. The buttocks tend to be flat and dimpled. The bones of the legs are typically underdeveloped, and the joints in the lower limbs may be unusually stiff and difficult to move. In some affected individuals, the legs are bent with the knees pointing out to the side and the feet tucked underneath the hips (sometimes called a frog leg-like position). These individuals may have webbed skin behind their knees. In other affected individuals, the knees may not bend, and the legs remain in a straight position. Their feet may be inward- and upward-turning (clubfeet) or outward- and upward-turning (calcaneovalgus). Some people with caudal regression syndrome have reduced or excessive sensation in their lower limbs. Sensitivity differs from person to person and from one area of the limb to another.

Mobility in people with caudal regression syndrome is varied. Some individuals with the condition walk independently, and others require mobility aids, such as braces, crutches, walkers, or wheelchairs.

Abnormalities in the genitourinary tract in people with caudal regression syndrome are diverse. Urinary tract problems can result from abnormalities in the lowest part of the spinal cord, which contains the nerves that control bladder function. Damage to these nerves can cause a condition called neurogenic bladder, which makes it difficult to control the flow of urine. In addition, the kidneys may be malformed in people with caudal regression syndrome; defects include a missing kidney (unilateral renal agenesis), kidneys that are fused together (horseshoe kidney), or duplication of the tubes that carry urine from each kidney to the bladder (ureteral duplication). These kidney abnormalities and neurogenic bladder can lead to frequent urinary tract infections and the backflow (reflux) of urine into the kidneys, which damage the kidneys and can cause progressive kidney failure.

Genital abnormalities in people with caudal regression syndrome can include the urethra opening on the underside of the penis (hypospadias) or undescended testes (cryptorchidism). Some affected people may have an abnormal connection between the rectum and vagina (rectovaginal fistula). In severe cases, people with this condition may have underdeveloped genitalia (genital agenesis).

People with caudal regression syndrome may have abnormal twisting (malrotation) of the large intestine, an obstruction of the anal opening (imperforate anus), soft out-pouchings in the lower abdomen (inguinal hernias), or other malformations of the gastrointestinal tract. Affected individuals are often constipated and may have difficulty with bowel control.

 

The upper part of the body can also be affected. Some people with caudal regression syndrome have a heart condition or hearing problems. [from MedlinePlus Genetics]

Charcot-Marie-Tooth disease type 2FF (CMT2FF) is an autosomal dominant progressive axonal sensorimotor peripheral neuropathy characterized by early-childhood onset of difficulties walking or running due to atrophy and weakness of the lower limbs. Most patients have foot and ankle deformities, requiring surgery or walking aids. Some patients lose independent ambulation. There is also prominent involvement of the upper limbs, with weakness and atrophy of the forearm, wrist, and intrinsic hand muscles. Proximal muscle function is preserved. Affected individuals have variable distal sensory impairment. Most patients have hyporeflexia, although brisk reflexes, suggesting upper motor involvement, have been described in 1 family. Sural nerve biopsy showed abnormal myelination (Rebelo et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210). [from OMIM]

Pneumonia caused by cytomegalovirus. Most humans are exposed to cytomegalovirus. Healthy individuals do not develop signs and symptoms of infection. Patients with weakened immune system (e.g., AIDS patients, cancer patients who are being treated with chemotherapy, and patients who have received bone marrow or solid organ transplants) develop signs and symptoms of infection. They include cough, shortness of breath, fatigue, malaise, fever, muscle and joint pain, and excessive sweating. [from NCI]

Infections with species in the genus pneumocystis, a fungus causing interstitial plasma cell pneumonia (pneumonia, pneumocystis) and other infections in humans and other mammals. Immunocompromised patients, especially those with aids, are particularly susceptible to these infections. Extrapulmonary sites are rare but seen occasionally. [from MONDO]