Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects
CHARGE Syndrome
By: C. J. Fields
What is CHARGE syndrome?CHARGE syndrome is an identified (genetic) pattern of birth defects which occurs in about one in every 9 -10,000 births worldwide. CHARGE is a variegated syndrome, that is characterized by extensive medical and physical difficulties that differ from child to child. The majority of CHARGE syndrome births are not indicated by family history or any other similar conditions in the family. Babies with CHARGE syndrome are often born with life-threatening birth defects, including heart abnormalities and respiratory issues. "CHARGE" originally came from the first letter of some of the most common features observed in theses children:
A mutation of the CHD7 gene is the suspected cause of CHARGE syndrome. Gene testing is very expensive and isn't always reliable - only about 2/3 of people with CHARGE test positively for the CHD7 gene mutation. Therefore, the diagnosis of CHARGE syndrome is clinical, and is based on a variety of medical features seen in the child. Evaluations for CHARGE syndrome should be made by a geneticist that specializes in CHARGE. A diagnosis can be made using a combination of Major and Minor features. "Major features are characteristics that are quite common in CHARGE syndrome but relatively rare in other conditions, and are, for the most part, diagnosable in the newborn period."
"Minor features are characteristics which are also common in CHARGE, but not quite as helpful in distinguishing CHARGE from other syndromes." (The CHARGE Syndrome Foundation, 2013)
Major Features of CHARGE Syndrome Feature Includes Frequency Coloboma of the eye Coloboma (sort of like a cleft) of the iris, retina, choroid, macula or disc (not the eyelid); microphthalmos (small eye) or anophthalmos (missing eye): CAUSES VISION LOSS 80% - 90% Choanal atresia or stenosis The choanae are the passages that go from the back of the nose to the throat. They can be narrow (stenosis) or blocked (atresia). It can be unilateral (one-sided) or bilateral (both sides), bony or membranous. 50% - 60% Cranial nerve abnormality I - Missing or decreased sense of smell, IX/X - Swallowing difficulties, aspiration, VII - Facial palsy (one side or both) 90% - 100%, 70% - 90%, 40% CHARGE outer ear Short, wide ear with little or no lobe, "snipped off" helix (outer fold), prominent antihelix (inner fold) which is discontinuous with tragus, triangular concha, decreased cartilage (floppy), often stick out, usually asymmetric. > 50% CHARGE middle ear Malformed bones of the middle ear (ossicles): CAUSES CONDUCTIVE HEARING LOSS Common CHARGE inner ear Malformed cochlea (Mondini defect); small or absent semicircular canals: CAUSE HEARING LOSS AND BALANCE PROBLEMS 90% Minor Features of CHARGE Syndrome Feature Includes Frequency Heart defects Can be any type, but many are complex, such as tetralogy of Fallot 75% Cleft lip +/- cleft palate Cleft lip with or without cleft palate, cleft palate, submucous cleft palate 20% TE fistula Esophageal atresia, Trancheo-esophageal fistula (TEF), H-shaped TEF 15% - 20% Kidney abnormalities Small kidney, missing kidney, misplaced kidney, reflux 40% Genital abnormalities Males: small penis, undescended testes. Females: small labia, small or missing uterus. Both: lack of puberty without hormone intervention 50%, 25%, 90% Growth deficiency Growth hormone deficiency, Other short stature 15%, 70% Typical CHARGE Face Square face with broad prominent forehead, arched eyebrows, large eyes, occasional ptosis (droopy lids), prominent nasal bridge with square root, thick nostrils, prominent nasal columella (between the nostrils), flat midface, small mouth, occasional small chin, larger chin with age. Facial asymmetry even without facial palsy. Varies Palm crease Hockey-stick palmar crease 50% CHARGE Behavior Perseverative behavior in younger individuals, obsessive compulsive behavior (OCD) in older individuals > 50%* None of the above features are necessary for a CHARGE diagnosis. These features may vary from severe to absent in children with CHARGE.
Medical Management and SurgeriesSurgical treatment is necessary in children with CHARGE syndrome to correct congenital anomalies. Example surgical interventions include: Tracheostomy - which is done to stabilize the air passage; Myringotomy and tymphonostomy tubes which is done to treat otitis media; Gastrostomay and fundoplication in cases of feeding difficulty, and cochlear implantation. In addition to available surgeries, appropriate medical management of CHARGE syndrome is necessary.
Resources:Genetic Causes Of Adult-Onset Disorders
A diverse and deadly list of afflictions can be categorized as late-onset disorders, including numerous cancers, Alzheimer's disease (AD), and schizophrenia, to name but a few. While some mutations that contribute to these disorders are present at birth, many more of these mutations arise from intrinsic failures of the genomic replication mechanisms within cells. Some of these failures can be traced to mutagens in the environment. In addition to causing mutations, mutagens can also trigger the expression of genes already present in the genome that are otherwise dormant. Together, this combination of accumulated harmful mutations and inappropriately activated genes can eventually manifest in pathology.
To explore this idea further, consider the example of cancer. While many people are born with genes that increase their chances of developing certain cancers, these people never manifest the disease unless specific mutations occur during the course of their lifetime. For instance, mutations in the HPC1 gene on chromosome 1 have been linked to the development of prostate cancer. Although an individual with this mutation can develop a nonmalignant polyp at a fairly young age, prostate cancer will not metastasize to the man's other organs unless a number of other tumor suppressor genes are also partially or completely disabled. Dozens of such genes have been identified to date, and researchers know that the expression of some of these genes is environmentally induced. Moreover, researchers have also noted that mutation events continue to occur after the disease phenotype has manifested, and these events are often responsible for the development of treatment resistance.
In contrast, due to the involvement of multiple genes and large variation in the severity of disease phenotype, very little is known about many of the more complex late-onset diseases, such as Alzheimer's disease and schizophrenia. AD is the most common cause of dementia in the elderly, and it is characterized physically by the presence of amyloid plaques in the patient's brain and neurofibrillary tangles in his or her nervous tissue. Surprisingly, these plaques and tangles have also been found (to a lesser extent) in the healthy aging population, so it remains unclear whether they cause the neurological symptoms of AD or are merely side effects. Recently, variation in the APOE gene, which is involved in fat metabolism, has been implicated in the formation of amyloid plaques. In healthy individuals, APOE signals the production of apolipoprotein E, which breaks down excess lipids throughout the body. This is not the case in individuals with Alzheimer's, although the exact mechanisms behind disease progression—including the role of APOE variation—are still a mystery. To further complicate matters, additional gene mutations may also have a major effect in AD. For example, approximately 5% of all AD cases are caused by autosomal dominant mutations in APP, PS1, or PS2 genes, and these cases tend to manifest before 60 years of age. In contrast, cases of AD that manifest after 60 years of age have been associated with a number of chromosomal regions, clearly suggesting the condition is a polygenic trait.
Similarly elusive are the genes involved in the onset of schizophrenia. In a commonly used method, researchers are trying to map these genes by considering their functional products. Several theories exist as to the biochemical causes of schizophrenia; the two main hypotheses involve glutamate and dopamine neurotransmitter systems (Stefansson et al., 2002), but they are unfortunately exclusive of one another. Nonetheless, most scientists agree that there is a significant genetic component in schizophrenia. Indeed, genome-wide scans employed in the search for gene variants contributing to the disease have identified multiple loci, adding schizophrenia to the growing list of major late-onset disorders whose patterns are complex and poorly understood.
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