MedGen

Tyrosinase-positive oculocutaneous albinism (OCA, type II; OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Although affected infants may appear at birth to have OCA type I, or complete absence of melanin pigment, most patients with OCA type II acquire small amounts of pigment with age. Individuals with OCA type II have the characteristic visual anomalies associated with albinism, including decreased acuity and nystagmus, which are usually less severe than in OCA type I (Lee et al., 1994; King et al., 2001). OCA type II has a highly variable phenotype. The hair of affected individuals may turn darker with age, and pigmented nevi or freckles may be seen. African and African American individuals may have yellow hair and blue-gray or hazel irides. One phenotypic variant, 'brown OCA,' has been described in African and African American populations and is characterized by light brown hair and skin color and gray to tan irides. The hair and irides may turn darker with time and the skin may tan with sun exposure; the ocular features of albinism are present in all variants (King et al., 2001). In addition, previous reports of so-called 'autosomal recessive ocular albinism,' (see, e.g., Witkop et al., 1978 and O'Donnell et al., 1978) with little or no obvious skin involvement, are now considered most likely to be part of the phenotypic spectrum of OCA1 or OCA2 (Lee et al., 1994; King et al., 2001). [from OMIM]

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. [from GeneReviews]

Genetic Heterogeneity of Variation in Skin/Hair/Eye Pigmentation Multiple genes influence normal human skin, hair, and/or eye pigmentation. Pigmentation phenotypes influenced by variation in the OCA2 gene are termed SHEP1. The SHEP2 association (266300) is determined by variation at the MC1R locus (155555) and describes a phenotype predominantly characterized by red hair and fair skin. SHEP3 (601800) encompasses pigment variation influenced by the TYR gene (606933); SHEP4 (113750), that influenced by the SLC24A5 gene (609802). Variation in the SLC45A2 (606202) and SLC24A4 (609840) genes result in the phenotypic associations SHEP5 (227240) and SHEP6 (210750), respectively. Sequence variation thought to affect expression of KITLG (184745) results in the SHEP7 (611664) phenotypic association. SHEP8 (611724) is associated with variation in the IRF4 gene (601900). Polymorphism in the 3-prime untranslated region of the ASIP gene (600201) influences the SHEP9 association (611742). The SHEP10 association (612267) comprises variation in the TPCN2 gene (612163), and SHEP11 (612271) is associated with polymorphism near the TYRP1 gene (115501). [from OMIM]

Properdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (Janeway et al., 2001). [from OMIM]

The presence of tall, peaked P waves in EKG lead II. [from HPO]

V-shaped cut (notch) in the middle of the P wave. [from HPO]

Malaria, a major cause of child mortality worldwide, is caused by mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the 4 species that infect humans, P. falciparum causes the most severe forms of malaria and is the major cause of death and disease. Although less fatal, P. malariae, P. ovale, and, in particular, P. vivax infections are major causes of morbidity. The parasite cycle involves a first stage in liver cells and a subsequent stage at erythrocytes, when malaria symptoms occur. A wide spectrum of phenotypes are observed, from asymptomatic infection to mild disease, including fever and mild anemia, to severe disease, including cerebral malaria, profound anemia, and respiratory distress. Genetic factors influence the response to infection, as well as disease progression and severity. Malaria is the strongest known selective pressure in the recent history of the human genome, and it is the evolutionary driving force behind sickle-cell disease (603903), thalassemia (see 141800), glucose-6-phosphatase deficiency (300908), and other erythrocyte defects that together constitute the most common mendelian diseases of humans (Kwiatkowski, 2005; Campino et al., 2006). [from OMIM]

P wave below instead of above the baseline. P-wave inversion in the inferior leads may indicate a non-sinus origin of the P waves. [from HPO]

Any anomaly of the P wave of the EKG, which results from atrial depolarization. The P wave occurs when the sinoatrial node creates an action potential that depolarizes the atria. [from HPO]

A broad (120 ms or longer in duration) and bifid P-wave in EKG lead II. [from HPO]

EEM syndrome (EEMS) denotes a disorder characterized by ectodermal dysplasia, ectrodactyly, and macular dystrophy. The ectodermal dysplasia consists of hypotrichosis affecting scalp hair, eyebrows, and eyelashes, with partial anodontia. Different degrees of absence deformities as well as syndactyly have been described, the hands often being more severely affected than the feet. The retinal lesion appears as a central geographic atrophy of the retinal pigment epithelium and choriocapillary layer of the macular area with coarse hyperpigmentations and sparing of the larger choroidal vessels (summary by Kjaer et al., 2005). [from OMIM]

A blood group related both to the ABO and P systems that includes several different antigens found in most people on erythrocytes, in milk, and in saliva. The antibodies react only at low temperatures. [from MeSH]

Congenital hypotrichosis with juvenile macular dystrophy (HJMD) is an autosomal recessive disorder characterized by hair loss followed by progressive macular degeneration and early blindness. Scalp hair is lost during the first months of life, with onset of retinal degeneration and vision loss a few years to 2 decades later (summary by Sprecher et al., 2001 and Indelman et al., 2002). [from OMIM]

HSD10 mitochondrial disease (HSD10MD) most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (summary by Rauschenberger et al., 2010; Zschocke, 2012). In a review of this disorder, Zschocke (2012) noted that although it was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity (see PATHOGENESIS). [from OMIM]

Increased time for the PR interval (beginning of the P wave to the beginning of the QRS complex). [from HPO]

An atrial arrhythmia characterized by disorganized atrial activity without discrete P waves on the surface EKG, but instead by an undulating baseline or more sharply circumscribed atrial deflections of varying amplitude an frequency ranging from 350 to 600 per minute. [from HPO]

Chloroquine is used for the treatment of uncomplicated malaria and extra-intestinal amebiasis. Malaria is caused by infection of Plasmodium parasites. Chloroquine is active against the erythrocytic forms of susceptible strains of Plasmodium falciparum (P. falciparum), Plasmodium malariae (P. malariae), Plasmodium ovale (P. ovale), and Plasmodium Vivax (P. vivax). Chloroquine is not active against the gametocytes and the exoerythrocytic forms including the hypnozoite stage (P. vivax and P. ovale) of the Plasmodium parasites. Additionally, resistance to chloroquine and hydroxychloroquine has been reported in Plasmodium species, thus chloroquine therapy is not indicated if the infection arose in a region with known resistance. Chloroquine is used in first-line treatment of P. vivax malaria with primaquine. Studies have indicated chloroquine is effective against the trophozoites of Entamoeba histolytica (E. histolytica), which causes amebic dysentery, or amebiasis. Chloroquine also has off-label uses for treatment of rheumatic diseases and has been investigated as a potential antiviral therapy as well as an adjuvant chemotherapy for several types of cancer. Chloroquine accumulates in cellular acidic compartments such as the parasitic food vacuole and mammalian lysosomes, leading to alkalinization of these structures. This change in pH can impair the action of enzymes responsible for the formation of hemozoin by the parasite from ingestion of the host’s hemoglobin; this reaction occurs in the parasitic vacuole. Thus, chloroquine targets the blood-stage of the malaria parasites but cannot eliminate dormant hypnozoites and must be administered with a drug that targets the dormant parasitic form. Chloroquine, developed in the 1940s, has been superseded as the first-line recommended antimalarial therapy by both the US Centers for Disease Control (CDC) and World Health Organization (WHO), with the exceptions of during the first trimester of pregnancy or for malarial prophylaxis of a pregnant individual who is also deficient for glucose-6-phosphate dehydrogenase (G6PD). Among antimalarial medications, chloroquine is less likely than other medicines to cause hemolysis in G6PD-deficient individuals; however, the FDA-approved drug label states there is still a risk of hemolysis. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) performed a systematic review of the available clinical literature and found low-to-no risk of acute hemolytic anemia for individuals with G6PD deficiency who take hydroxychloroquine or chloroquine. It should be noted that G6PD deficiency has a range of severity; CPIC advises caution for all medications when used by an individual with a severe G6PD deficiency with chronic non-spherocytic hemolytic anemia (CNSHA). [from Medical Genetics Summaries]

Tafenoquine is an antimalarial agent that was approved by the FDA in 2018 for preventing malaria (brand name Arakoda, 100 mg tablets), and for the radical cure of malaria (brand name Krintafel, 150 mg tablets) caused by Plasmodium vivax (P. vivax). Malaria is caused by the Plasmodium parasite, which infects mosquitos and is spread to humans when an infected mosquito bites a person. In 2018 the World Health Organization (WHO) estimated 228 million cases of malaria occurred worldwide. There are several clinical patterns of malaria that are caused by different species of the parasite. In P. vivax malaria, the parasite can lie dormant in the liver as hypnozoites, until it emerges weeks or months later, to cause a relapse of malaria. In combination with an antimalarial active against the blood stage parasites, tafenoquine provides a radical cure of P. vivax by targeting its dormant liver stage, thus preventing malaria relapse. Tafenoquine is the second drug of its kind (with hypnozoiticidal activity) to be approved by the FDA. The first was primaquine, approved in 1952. Because of its longer half-life, tafenoquine can be dosed less frequently than primaquine, which may improve compliance. For example, when used for the radical cure of P. vivax malaria, tafenoquine is taken as a single 300 mg dose (in uncomplicated cases, in persons aged 16 years and older). In contrast, primaquine radical cure is recommended to be given daily over 14 days, or higher doses over 7 days. Tafenoquine, like primaquine, should not be used in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. In the case of tafenoquine, an individual with <70% of normal G6PD activity is considered deficient and should not take the drug. Worldwide, approximately 400 million people have a deficiency of the G6PD enzyme, but most are asymptomatic and do not know they are at risk. A lack of G6PD in red blood cells makes the cells susceptible to damage by oxidative stress. Usually, only low levels of oxidative stress occur naturally, and so the condition is undetected. However, certain drugs, which include tafenoquine and primaquine, are oxidizing agents. In people with G6PD deficiency, these drugs cause irreparable oxidative damage to the red blood cells, which are then rapidly destroyed (hemolysis). This can lead to a potentially life-threatening deficiency of mature red blood cells (hemolytic anemia). The FDA-approved drug label for tafenoquine states that testing for G6PD must be performed before starting tafenoquine therapy, and that all individuals should be monitored for signs of hemolysis. In addition, because of the risk of tafenoquine causing fetal harm in a woman pregnant with a fetus with G6PD deficiency, pregnancy testing is highly recommended in women of reproductive age. Consequently, tafenoquine therapy is contraindicated in adults when the G6PD status is either unknown, intermediate or deficient, namely, enzyme activity lower than 70%, in pregnancy, and in breastfeeding mothers when the infant’s G6PD status is either unknown or deficient. To date, no safety studies have been reported in children. [from Medical Genetics Summaries]

Glaucomas are a group of common neurodegenerative diseases of the optic nerve and retinal ganglion cells, characterized by progressive cupping of the optic nerve head with resultant visual field loss. Elevated intraocular pressure (IOP) is a strong risk factor for glaucoma; however, glaucoma can occur at any IOP. The most common form of glaucoma in the US is primary open-angle glaucoma (POAG; see 137760). POAG that occurs with an IOP below an arbitrary threshold of 21 mm Hg is often termed 'normal tension glaucoma' (summary by Fingert et al., 2011). For a discussion of genetic heterogeneity of primary open angle glaucoma, see 137760. [from OMIM]