MedGen

Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in the first week of life, most often on day two to three of life, and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant to improve quality of life. Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits. [from GeneReviews]

Homocystinuria caused by cystathionine ß-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ? or only one ? of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis. [from GeneReviews]

The phenotypic spectrum of SERAC1 deficiency comprises MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome), juvenile-onset complicated hereditary spastic paraplegia (in 1 consanguineous family), and adult-onset generalized dystonia (in 1 adult male). MEGD(H)EL syndrome is characterized in neonates by hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. During the first year of life feeding problems, failure to thrive, and/or truncal hypotonia become evident; many infants experience (transient) liver involvement ranging from undulating transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. By age two years progressive deafness, dystonia, and spasticity prevent further psychomotor development and/or result in loss of acquired skills. Affected children are completely dependent on care for all activities of daily living; speech is absent. [from GeneReviews]

Congenital melanocytic nevus syndrome is characterized by pigmentary skin defects apparent at birth. Most individuals have 1 or more large or giant lesions greater than 20 cm and up to over 60 cm in diameter, which may cover up to 80% of total body area. These lesions may or may not be hairy. Smaller 'satellite' pigmented lesions numbering in the hundreds may also be present all over the body. Congenital melanocytic nevi (CMN) can be associated with malignant melanoma (see CMM1, 155600), but the risk appears to be low, ranging from 1 to 2% for all individuals, but rising to 10 to 15% in those with very large nevi (greater than 40 cm). A small subset of patients with CMNS have abnormalities of the central nervous system, known as 'neurocutaneous melanosis' or 'neuromelanosis' (249400), which may be symptomatic. Patients with CMNS also tend to have a characteristic facial appearance, including wide or prominent forehead, periorbital fullness, small short nose with narrow nasal bridge, round face, full cheeks, prominent premaxilla, and everted lower lip (summary by Kinsler et al., 2008; Kinsler et al., 2012). Spitz nevi are benign melanocytic melanomas composed of epithelioid or spindle cell melanocytes. They usually present as solitary skin tumors but can occur in multiple patterns, having agminated, dermatomal, and disseminated forms (summary by Sarin et al., 2013). Nevus spilus, also known as speckled lentiginous nevus, is a congenital hyperpigmented patch that progressively evolves, with affected individuals developing dark macules and papules during childhood and adolescence. Over time, nevus spilus may give rise to common lentigines, melanocytic nevi, Spitz nevi, and melanomas (summary by Sarin et al., 2014). [from OMIM]

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]

Trastuzumab is a monoclonal antibody used in the treatment of breast and gastric/gastroesophageal cancer. It targets an epidermal growth factor receptor encoded by the ERBB2 gene, which is commonly referred to as the HER2 gene. Multiple biosimilar products to Herceptin are now available: Kanjinti, Trazimera, Ontruzant, Herzuma and Ogivri. The ERBB2 gene is overexpressed in 15–20% of breast cancers and 15–20% of gastric and esophageal cancers. Overall, “HER2 positive” tumors are associated with a faster rate of growth and—in some cases—a poorer prognosis in absence of anti-HER2 therapy. The use of trastuzumab in treatment regimens improves outcomes, with limited adverse effects that include cardiac toxicity. The FDA-approved drug label states that trastuzumab should only be used to treat individuals with tumors that have either HER2 protein overexpression or ERBB2 gene amplification, as determined by an accurate and validated FDA-approved assay, specific for the type of tumor tested (breast or gastric). The FDA-approved drug label for all trastuzumab biosimilars describes only the use of trastuzumab in adjuvant treatment of breast cancer, though its efficacy in neoadjuvant care for breast cancer and esophageal adenocarcinoma has also been documented. The most recent update (2018) of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines continues to state that all newly diagnosed individuals with breast cancer must have an HER2 test performed. Individuals who then develop metastatic disease must have an HER2 test performed in a metastatic site, if tissue sample is available. [from Medical Genetics Summaries]

Hydroxychloroquine, which is closely related to chloroquine, can be used for the prevention and treatment of some forms of malaria and rheumatic conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Malaria is an infection caused by the Plasmodium parasite, transmitted via mosquito bites. Hydroxychloroquine sulfate is indicated for the prevention and treatment of uncomplicated malaria due to sensitive strains of Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. vivax), Plasmodium malariae (P. malariae), Plasmodium ovale (P. ovale), and Plasmodium knowlesi (P. knowlesi) by both the US Centers for Disease Control (CDC) and World Health Organization (WHO). Resistance to chloroquine and hydroxychloroquine has been reported in Plasmodium species, thus hydroxychloroquine therapy is not recommended if the infection arose in a region with known resistance. Most P. falciparum infections are resistant to the 4-aminoquinolines (chloroquine and hydroxychloroquine), and as such these drugs are no longer used widely for these infections. Hydroxychloroquine must be co-administered with an 8-aminoquinoline compound for the radical cure of P. vivax or P. ovale infection to eliminate the hypnozoite forms of these parasites. Additionally, hydroxychloroquine is indicated for the treatment of many rheumatoid conditions in adults, including chronic discoid lupus erythematosus, systemic lupus erythematosus, as well as acute and chronic rheumatoid arthritis. Hydroxychloroquine has also been used in an off-label capacity for the management of Sjögren syndrome. Hydroxychloroquine accumulates in cellular acidic compartments such as the parasitic food vacuole and mammalian lysosomes, leading to alkalinization of these structures. Among antimalarial medications, hydroxychloroquine is less likely than other medicines to cause hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals; however, the U.S. FDA-approved drug label states there is still a risk of acute hemolytic anemia (AHA). In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) performed a systematic review of the available clinical literature and found low-to-no risk of AHA for individuals with G6PD deficiency who take hydroxychloroquine. 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). Regardless of G6PD phenotype, chronic use of hydroxychloroquine can cause irreversible retinal damage and regular visual exams are recommended by the FDA. [from Medical Genetics Summaries]

Propafenone is an antiarrhythmic medication. It is used to prevent the reoccurrence of atrial fibrillation in patients with episodic atrial fibrillation who do not have underlying structural heart disease (propafenone may provoke proarrhythmic events in patients with structural heart disease). Propafenone belongs to class IC of antiarrhythmic agents and acts on cardiac sodium channels to inhibit action potentials. In general, because of the lack of evidence that antiarrhythmic agents improve survival, they should only be used to treat arrhythmias that are thought to be life-threatening. Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 enzymes. Approximately 6% of Caucasians in the US lack CYP2D6 activity, and are known as “CYP2D6 poor metabolizers”. Standard doses of propafenone will lead to higher plasma drug concentrations in poor metabolizers, compared to normal metabolizers. In addition, drugs that inhibit CYP2D6, CYP3A4, and CYP1A2 may also increase propafenone levels, which may lead to cardiac arrhythmia episodes. The FDA-approved drug label for propafenone states that the recommended dosing regimen of propafenone is the same for all patients (CYP2D6 poor metabolizers and normal metabolizers). However, the label also cautions that the simultaneous use of propafenone with both a CYP2D6 inhibitor (or in patients with CYP2D6 deficiency) and a CYP3A4 inhibitor should be avoided, because of the increased risk of causing arrhythmias and other adverse events. A guideline from The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Pharmacists Association (KNMP) provides dosing recommendations for propafenone, based on CYP2D6 genotype. For CYP2D6 poor metabolizers, the guideline recommends reducing the initial dose of propafenone by 70%, ECG monitoring, and monitoring plasma concentrations. For intermediate and ultrarapid metabolizers, the guideline states there is insufficient data to allow for a calculation of dose adjustment. Therefore, it is recommended to adjust the dose in response to plasma concentration and to monitor with ECG, or select an alternative drug (e.g., sotalol, disopyramide, quinidine, amiodarone). [from Medical Genetics Summaries]

Sofosbuvir is an antiviral agent used in the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is FDA-approved to treat patients infected with HCV genotypes 1, 2, 3, and 4, as part of a combination antiviral treatment regimen. HCV genotype 1 is the most prevalent worldwide and HCV genotype 3 is the next most prevalent. Sofosbuvir may also be used as part of the treatment regimen of HCV genotypes 5 or 6. About 180 million people worldwide are infected with chronic hepatitis C, which is a major cause of chronic liver disease, cirrhosis, and liver cancer. Viral eradication is suboptimal with peginterferon plus ribavirin-based therapy, with only about half of patients with HCV genotype 1 infection achieving a sustained virological response (SVR) after 24 weeks. A SVR is defined as undetectable HCV RNA by the end of treatment or at a specific number of weeks after the initiation of treatment, e.g., undetectable HCV RNA at 12 weeks is annotated (SVR12). Direct-acting antivirals (DAAs), such as sofosbuvir, were developed to improve viral eradication rates. They target HCV-encoded proteins involved in viral replication and infection. Sofosbuvir, the first and thus far only DAA, targets NS5B polymerase, the viral enzyme required for HCV RNA replication. Sofosbuvir may be used in combination with peginterferon. The genetic variant rs12979860, located in the INFL4 gene, is a strong predictor of response to peginterferon-based therapies. The variant is a C to T change—individuals with the favorable "C/C" genotype have about a 2-fold higher likelihood of achieving SVR compared to individuals with CT or TT genotypes. (Note, because the association of rs12979860 with treatment response was reported several years before the discovery of IFNL4, the variant is commonly, but mistakenly, referred to as IL28B, which is the previous name for the IFNL3 gene.) For specific treatment regimens that include sofosbuvir, although the IFNL4 variant still influences treatment outcomes, the SVR remains relatively high for all IFNL4 genotypes. For example in the NEUTRINO study, which is referred to in the FDA-approved drug label for sofosbuvir, the SVR12 rate was 99% in individuals with baseline C/C alleles and 87% in individuals with baseline non-C/C alleles. The individuals in this study had HCV genotype 1 or 4 infection, and were receiving sofosbuvir plus peginterferon plus ribavirin therapy. The drug label for sofosbuvir also discusses viral resistance. In cell culture, the amino acid substitution S282T in the viral NS5B polymerase is associated with reduced susceptibility to sofosbuvir. During the ELECTRON trial, this substitution was transiently detected in one individual who relapsed during sofosbuvir monotherapy. However, the clinical significance of such substitutions remains unknown. [from Medical Genetics Summaries]

Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.

The signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.

Hair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.

In vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels. [from MedlinePlus Genetics]

Researchers have identified several types of porphyria, which are distinguished by their genetic cause and their signs and symptoms. Some types of porphyria, called cutaneous porphyrias, primarily affect the skin. Areas of skin exposed to the sun become fragile and blistered, which can lead to infection, scarring, changes in skin coloring (pigmentation), and increased hair growth. Cutaneous porphyrias include congenital erythropoietic porphyria, erythropoietic protoporphyria, hepatoerythropoietic porphyria, and porphyria cutanea tarda.

Environmental factors can strongly influence the occurrence and severity of signs and symptoms of porphyria. Alcohol, smoking, certain drugs, hormones, other illnesses, stress, and dieting or periods without food (fasting) can all trigger the signs and symptoms of some forms of the disorder. Additionally, exposure to sunlight worsens the skin damage in people with cutaneous porphyrias.

The porphyrias can also be split into erythropoietic and hepatic types, depending on where damaging compounds called porphyrins and porphyrin precursors first build up in the body. In erythropoietic porphyrias, these compounds originate in the bone marrow. Erythropoietic porphyrias include erythropoietic protoporphyria and congenital erythropoietic porphyria. Health problems associated with erythropoietic porphyrias include a low number of red blood cells (anemia) and enlargement of the spleen (splenomegaly). The other types of porphyrias are considered hepatic porphyrias. In these disorders, porphyrins and porphyrin precursors originate primarily in the liver, leading to abnormal liver function and an increased risk of developing liver cancer.

Other types of porphyria, called acute porphyrias, primarily affect the nervous system. These disorders are described as "acute" because their signs and symptoms appear quickly and usually last a short time. Episodes of acute porphyria can cause abdominal pain, vomiting, constipation, and diarrhea. During an episode, a person may also experience muscle weakness, seizures, fever, and mental changes such as anxiety and hallucinations. These signs and symptoms can be life-threatening, especially if the muscles that control breathing become paralyzed. Acute porphyrias include acute intermittent porphyria and ALAD deficiency porphyria. Two other forms of porphyria, hereditary coproporphyria and variegate porphyria, can have both acute and cutaneous symptoms.

Porphyria is a group of disorders caused by abnormalities in the chemical steps that lead to heme production. Heme is a vital molecule for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver. Heme is a component of several iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). [from MedlinePlus Genetics]

This term applies for all abnormalities of the big toe, also called hallux. [from HPO]