Cockayne syndrome

• CS Type I, the "classic" form, is characterized by normal fetal growth with the onset of abnormalities in the first two years of life. Vision and hearing gradually decline. The central and peripheral nervous systems progressively degenerate until death in the first or second decade of life as a result of serious neurological degradation. Cortical atrophy is less severe in CS Type I. • CS Type II is present from birth (congenital) and is much more severe than CS Type 1. Typically patients with this early-onset form of the disorder show more severe brain damage, including reduced myelination of white matter, and more widespread calcifications, including in the cortex and basal ganglia. ==Causes==

If hyperoxia or excess oxygen occurs in the body, the cellular metabolism produces several highly reactive forms of oxygen called free radicals. This can cause oxidative damage to cellular components including the DNA. In normal cells, our body repairs the damaged sections. In the case of this disease, due to subtle defects in transcription, children's genetic machinery for synthesizing proteins needed by the body does not operate at normal capacity. Over time, went this theory, results in developmental failure and death. Every minute, the body pumps 10 to 20 liters of oxygen through the blood, carrying it to billions of cells in our bodies. In its normal molecular form, oxygen is harmless. However, cellular metabolism involving oxygen can generate several highly reactive free radicals. These free radicals can cause oxidative damage to cellular components including the DNA. In an average human cell, several thousand lesions occur in the DNA every day. Many of these lesions result from oxidative damage. Each lesion—a damaged section of DNA—must be snipped out and the DNA repaired to preserve its normal function. Unrepaired DNA can lose its ability to code for proteins. Mutations also can result. These mutations can activate oncogenes or silence tumor suppressor genes. According to research, oxidative damage to active genes is not preferentially repaired, and in the most severe cases, the repair is slowed throughout the whole genome. The resulting accumulation of oxidative damage could impair the normal functions of the DNA and may even result in triggering a program of cell death (apoptosis). The children with this disease do not repair the active genes where oxidative damage occurs. Normally, oxidative damage repair is faster in the active genes (which make up less than five percent of the genome) than in inactive regions of the DNA. The resulting accumulation of oxidative damage could impair the normal functions of the DNA and may even result in triggering a program of cell death (apoptosis).{{cite web |url=https://www.lecturio.com/concepts/cell-injury-and-death/ | title=Cell Injury and Death ==Genetics==

pattern of inheritance.|230x230px|alt=|frameless Cockayne syndrome is classified genetically as follows: • Mutations in the ERCC8 (also known as CSA) gene or the ERCC6 (also known as CSB) gene are the cause of Cockayne syndrome type A and type B. Mutations in the ERCC6 gene mutation makes up ~70% of cases. The proteins made by these genes are involved in repairing damaged DNA via the transcription-coupled repair mechanism, particularly the DNA in active genes. DNA damage is caused by ultraviolet rays from sunlight, radiation, or free radicals in the body. A normal cell can repair DNA damage before it accumulates. If either the ERCC6 or the ERCC8 gene is altered (as in Cockayne Syndrome), DNA damage encountered during transcription isn't repaired, causing RNA polymerase to stall at that location, interfering with gene expression. As the unrepaired DNA damage accumulates, progressively more active gene expression is impeded, leading to malfunctioning cells or cell death, which likely contributes to the signs of Cockayne Syndrome such as premature aging and neuronal hypomyelination. ==Mechanism==

In contrast to cells with normal repair capability, CSA and CSB deficient cells are unable to preferentially repair cyclobutane pyrimidine dimers induced by the action of ultraviolet (UV) light on the template strand of actively transcribed genes. This deficiency reflects the loss of ability to perform the DNA repair process known as transcription coupled nucleotide excision repair (TC-NER). CSB protein is also normally recruited to DNA damaged sites, and its recruitment is most rapid and robust as follows: interstrand crosslinks > double-strand breaks > monoadducts > oxidative damage. The accumulation of CSB protein at sites of DNA double-strand breaks occurs in a transcription dependent manner and facilitates homologous recombinational repair of the breaks. During the G0/G1 phase of the cell cycle, DNA damage can trigger a CSB-dependent recombinational repair process that uses an RNA (rather than DNA) template. The premature aging features of CS are likely due, at least in part, to the deficiencies in DNA repair (see DNA damage theory of aging). ==Diagnosis==

People with this syndrome have smaller than normal head sizes (microcephaly), are of short stature (dwarfism), their eyes appear sunken, and they have an "aged" look. They often have long limbs with joint contractures (inability to relax the muscle at a joint), a hunched back (kyphosis), and they may be very thin (cachetic), due to a loss of subcutaneous fat. Their small chin, large ears, and pointy, thin nose often give an aged appearance. Laboratory studies are mainly useful to eliminate other disorders. For example, skeletal radiography, endocrinologic tests, and chromosomal breakage studies can help in excluding disorders included in the differential diagnosis. Imaging studies Brain CT scanning in Cockayne syndrome patients may reveal calcifications and cortical atrophy. Other tests Prenatal evaluation is possible. Amniotic fluid cell culturing is used to demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation. Neurology Imaging studies reveal a widespread absence of the myelin sheaths of the neurons in the white matter of the brain and general atrophy of the cortex. Calcifications have also been found in the putamen, an area of the forebrain that regulates movements and aids in some forms of learning, along with the cortex. Additionally, atrophy of the central area of the cerebellum found in patients with Cockayne syndrome could also result in the lack of muscle control, particularly involuntary, and poor posture typically seen. ==Treatment==

There is no cure for this syndrome, although patients can be symptomatically treated. Treatment usually involves physical therapy and minor surgeries to the affected organs, such as cataract removal. Optimal nutrition can also help. Genetic counseling for the parents is recommended, as the disorder has a 25% chance of being passed to any future children, and prenatal testing is also a possibility. Currently, there are two ongoing projects focused on the development of gene therapy for Cockayne syndrome. The first project, led by the Viljem Julijan Association for Children with Rare Diseases, aims to develop gene therapy specifically for Cockayne syndrome type B. The second project, led by the Riaan Research Initiative, is dedicated to the development of gene therapy for Cockayne syndrome type A. ==Prognosis==

The prognosis for those with Cockayne syndrome is poor, as death typically occurs by the age of 12. The prognosis for Cockayne syndrome varies by disease type. There are three types of Cockayne syndrome according to the severity and onset of the symptoms. However, the differences between the types are not always clear-cut, and some researchers believe the signs and symptoms reflect a spectrum instead of distinct types: Cockayne syndrome Type A (CSA) is marked by normal development until a child is 1 or 2 years old, at which point growth slows and developmental delays are noticed. Symptoms are not apparent until they are 1 year. Life expectancy for type A is approximately 10 to 20 years. These symptoms are seen in CS type 1 children. Cockayne syndrome type B (CSB), also known as "cerebro-oculo-facio-skeletal (COFS) syndrome" (or "Pena-Shokeir syndrome type B"), is the most severe subtype. Symptoms are present at birth and normal brain development stops after birth. The average lifespan for children with type B is up to 7 years of age. These symptoms are seen in CS type 2 children. Cockayne syndrome type C (CSC) appears later in childhood with milder symptoms than the other types and a slower progression of the disorder. People with this type of Cockayne syndrome live into adulthood, with an average lifespan of 40 to 50 years. These symptoms are seen in CS type 3. ==Epidemiology==

Cockayne syndrome is rare worldwide. No racial predilection is reported for Cockayne syndrome. No sexual predilection is described for Cockayne syndrome; the male-to-female ratio is equal. Cockayne syndrome I (CS-A) manifests in childhood. Cockayne syndrome II (CS-B) manifests at birth or in infancy, and it has a worse prognosis. ==Recent research==

The recent research on Jan 2018 mentions different CS features that are seen globally with similarities and differences: CS has an incidence of 1 in 250,000 live births, and a prevalence of approximately 1 per 2.5 million, which is remarkably consistent across various regions globally: ==See also==