Alzheimer's disease

Alzheimer’s disease is a type of Dementia, accounting for 62% of Dementia cases in the UK. It is a neurodegenerative disorder (affecting the brain and becoming progressively worse with time) found predominantly in elderly people, with the incidence of the disease doubling with every 5 year increase in age above 65 years.  There is also a rare form of the disease known as early onset familial Alzheimer’s disease which is inherited and occurs in people aged between 30 and 60. The disease will present slightly differently in each person with the illness, but is characterised by a decline in brain function, such as memory loss, impaired speech and vision, disorientation, delusions and changes to behaviour and personality.

The brain is made of nerve cells known as neurons, these cells carry electrical impulses and between the neurons there are gaps known as synapses, across which chemicals known as neurotransmitters diffuse, to pass the impulse from one neuron to another, enabling us to respond to both internal and external stimuli. In Alzheimer’s disease, several changes occur within the brain, including the destruction of the neuron and synapses resulting in the atrophy (severe reduction in size due to wasting away) of certain regions of the brain. In the cells of a healthy brain, a fibrous protein known as tau is produced, and is essential for maintaining the size and shape of nerve cells and ensuring effective cell communication. In those with Alzheimer’s an abnormal version of tau is produced, which cannot carry out these functions and accumulates in, what are known as, neurofibrillary tangles, disrupting the communication between cells and causing the disintegration of the microtubules that maintain cell structure, eventually leading to cell death. Additionally, in the brains of people who have Alzheimer’s disease, neuritic plaques form. This is the accumulation of a small protein known as beta amyloid, which is produced when APP (amyloid precursor protein) is broken down. Beta amyloid is broken down healthy people, but not in Alzheimer’s disease, therefore it forms plaques around the nerve cells which are thought to be toxic to the cells, causing changes leading to cell death. The changes in Alzheimer’s first occur in the hippocampus region of the brain which is responsible for forming and storing memories. The changes then spread to the cerebral cortex and the frontal (skilled movements and problem solving), temporal (language and hearing) and parietal (sensory abilities such as pain response) lobes. The region known as the basal nucleus of Meynert undergoes degeneration in Alzheimer’s disease. This region is normally rich in neurons using the neurotransmitter acetylcholine, which is thought to be important in memory, however, this degeneration means that the brain produces less acetylcholine.

Alzheimer’s disease is categorised as either mild (usually involving: forgetfulness; mood swings; speech impairment and withdrawing from social situations), moderate (often with symptoms such as: disorientation and problems with spatial reasoning; problems with eyesight; hallucinations; obsessive behaviour; insomnia; incontinence and frustration or depression resulting from confusion and inability to carry out tasks) or severe (likely to display many of the symptoms listed above in addition to: a complete loss of short and long-term memory; hallucinations causing the person with Alzheimer’s to become distressed, violent and suspicious of those around them; self-neglect; difficulty moving or swallowing and a loss of appetite, due to forgetting when they have begun these tasks). The symptoms of Alzheimer’s may also be seen in individuals who are suffering from strokes, brain tumors, multiple sclerosis, thyroid dysfunction, infectious diseases such as HIV and syphilis, substance abuse or the side effects of some medications; it is important to first eliminate any of these, more-treatable conditions as the cause of the symptoms. As a result, Alzheimer’s diagnosis can take some time. The diagnosis of Alzheimer’s will usually involve neurological examination, potentially followed by CT (using x-rays) or MRI (using a magnetic field and radio waves) scans of the brain. Severe Alzheimer’s can lead to compromised immunity and life threatening infections, so as the disease develops, full-time care is needed to support the person with Alzheimer’s disease. Most people with Alzheimer’s disease die with the illness rather than from it, however, there is a significantly reduced the quality of life for those with the disease.

There is no cure for Alzheimer’s disease, however there are a few drugs which have been shown to alleviate some of the symptoms of the disease. Donepezil, galantimine, rivastigmine and memantine are drugs that are currently prescribed for Alzheimer’s treatment. The first three drugs are acetylcholinesterase inhibitors and prevent the breakdown of the neurotransmitter acetylcholine, in an attempt to maintain the levels of this chemical and communication between nerve cells, however they can have the side effects of nausea, diarrhoea and fatigue. Memantine blocks the chemical glutamate which is released in excessive amounts in Alzheimer’s disease and can damage the brain cells. It is also important to treat the psychiatric problems that may present alongside the disease, and incorporate memory aiding activities into day-to-day life such as labelling cupboards, making timetables and diaries and keeping useful addresses and telephone numbers to hand.

The reasons for the brain deterioration in Alzheimer’s are not entirely known, however there are several factors which may increase the risk of developing the disease. Incidence of Alzheimer’s disease is significantly correlated with increasing age, however, it is also thought that lifestyle factors such as keeping mentally and physically active can reduce the risk of Alzheimer’s whereas high blood pressure, high blood cholesterol and smoking increase the risk. Severe head trauma, whiplash injuries and repetitive head injuries such as from boxing can lead to an increased risk of developing Alzheimer’s in later life. People with Down Syndrome who live over the age of 50 are at an increased risk of developing Alzheimer’s, they have an extra copy of Chromosome 21, so have extra copies of the gene producing the protein RCAN1 therefore the protein is produced in excess and can cause neuronal death. The overexpression of this gene can also be caused by stroke, high blood pressure and high levels of beta amyloid.

The influence of inheritance on developing late-onset Alzheimer’s is not very significant, however, recently several genes have been identified as playing a role in the biochemical changes that occur in Alzheimer’s. One particular gene involved in Alzheimer’s is the gene apoE that codes for the protein apolipoprotein E, which carries fat molecules in the brain and are thought to be involved in the breakdown of beta amyloid. This gene has three different alleles (different versions of the same gene), apoE2, apoE3 and apoE4.  The proteins coded for by the genes apoE2 and apoE3 are large protein molecules that effectively transport fats and so can breakdown the plaques, but by apoE4, the protein is a small molecule which is easily degraded so cannot carry out these functions. In some populations, though not all, if a person has one or more copy of the apoE4 allele, they have a greater chance of developing late onset Alzheimer’s, those who are heterozygous (have 1 copy of the apoE4 allele and 1 copy of another allele) have a three times greater risk and homozygotes (who have 2 copies of the apoE4) have a ten times greater risk of developing the condition.

Recent research has identified 11 new genes linked to Alzheimer’s. The study comparing the genetic information of Alzheimer’s patients and healthy volunteers (as controls) has shown that at least 20 genes are involved in late-onset Alzheimer’s, as are significantly more common in those with the disease. The findings are useful as they can provide further information on the biological pathways involved in the disease, and although at the moment there are no preventative drugs against Alzheimer’s disease, if they were developed, this information could be used to screen and identify those at risk in the population. The findings suggest that changes in the inflammatory response, immune system and neuronal communication all affect the progression of the disease.                

Additionally, there has been research into a pill to combat degenerative brain diseases and neuronal death due to the accumulation of protein. This particular study looked at prion (a protein) diseases such as CJD however the biological causes of these diseases are similar to those involved in Alzheimer’s. The study showed that over the 5 week study, mice remained free of symptoms such as memory loss and impaired reflexes, as well as living longer than untreated animals. Although the same effects may not be true for Alzheimer’s in humans and drugs suitable for human trials are unlikely to be developed for many years, this study offers hope into the development of a cure for Alzheimer’s disease in the future.

http://www.nhs.uk/Conditions/Alzheimers-disease/Pages/Introduction.aspx

http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=100

http://www.theguardian.com/science/2013/oct/27/alzheimers-study-new-genes-implicated

http://www.theguardian.com/science/2013/oct/10/study-gives-hope-alzheimers-pill
 

Breast Cancer and Breast Screening

Breast cancer is the unregulated division and growth, due to genetic aberrations in the cells that make up either the ducts (which carry milk to the nipple) or lobules (glands which produce milk) of the breast. This results in the formation of carcinomas in situ (pre-cancerous lesions which remain within the compartment of their respective tissues), developing into invasive carcinomas (which can grow into neighbouring tissues) and potentially undergo metastasis and travel to other organs to form tumours via lymphatic system (or the bloodstream). The development of metastatic tumours means that there are fewer normal cells in the vital organs (such as lung, liver, brain) to carry out critical functions, hence can be fatal. Poorly differentiated breast cancers (the ones whose cells have the most different organisation to those in normal breast tissue), larger tumours and those which have spread to the lymph nodes and are able to metastasise have a worse prognosis. Some breast cells have cell surface protein receptors to which hormones bind and these may be found on cancerous cells. Importantly the presence of oestrogen (ER+), progesterone (PR+) and ERBB2 (HER2+) receptors mean that the cancer cells are dependent on these hormones for their growth, and so these receptors can be a target for treatment of the cancer, improving the prognosis. If we can prevent the supply of these hormones to the tumour, by blocking the receptors, so preventing the hormones from binding a producing a response in the cell, we can potentially destroy the tumour without harming other body cells. Those without any of these receptors present are known as triple-negative. Around 50,000 people are diagnosed with, and around 12,000 die from, breast cancer every year, the majority of those affected by the disease are women (usually postmenopausal), although it can also affect men.

Although 90% of breast lumps are benign (not cancer), one of the most common symptoms of breast cancer is a lump or thickened tissue in the breast (or potentially in the axillary lymph nodes, felt in the armpit). Other symptoms include any changes to the size, shape or the skin of the breast, discharge from the nipple or painful breasts or armpits. People with breast cancer symptoms then discuss them with their GP who can refer them for screening. The NHS also runs a screening programme where women aged 50 to 70 (the most at risk group) are invited for digital mammography. Screening involves either a mammogram or breast ultrasound to produce an image of the breast indicating any tumours. For younger women with denser breasts, ultrasound scans are more effective for indicating tumours. Biopsies are used to see if the lump is cancerous; either a few cells are removed either by using a vacuum to aspirate though a small needle without removing any tissue, or a sample of tissue is removed through a large needle. MRI scans can also be used to further identify the extent of the disease of the breast and to identify the area to be removed in surgery. Tests can also be carried out to check any metastasis to other vital organs (using CT scans or chest X-rays) or to identify the hormone receptor status of the tumour cells removed in biopsy.

The breast cancer screening programme has come under fire recently. A review published in the Lancet medical journal, showed that screening can lead to overdiagnosis, as each patient has a 1% chance of being overdiagnosed if they go for screening. Overdiagnosis is the screening which identifies a cancerous growth, but one which would not have been harmful. This means that patiuents have to unnecessairly undergo treatments (which can have dangerous side effects). There are also risks of false positives where women with no breat cancer at all are told that they have the disease, which leads to the anxiety of being diagnosed with cancer.

Screening is also associated with an increased breast cancer risk as X-rays (a type of ionising radiation) can cause genetic changes in cells. However, screening saves the lives of 1,307 people with breast cancer every year, by correctly idntifying cancer early enough for treatment to be effective. Women are encouraged by the NHS and cancer charities to still attend screening, despite controversy, but are now provided with more details about the risks involved.

Breast cancers are defined by their stage grade and receptor status. The stage of the tumour tells us its size and how far it has spread. TNM staging gives us staging bases on T, tumour size, N, whether the axaillary lymph nodes are affected and M, whether the tumour has metastised. Ductal carcinoma in situ is stage 0; if  the tumour measures less than 2cm and the lymph nodes in the armpit are not affected (also no metastasis) it is in stage 1; Stage 2 is when either the tumour measures between 2cm and 5cm or the lymph nodes in the armpit are affected, or both, with no sign that the cancer has spread elsewhere in the body; if there are still no signs of metastasis, but the tumour measures larger than 2cm and the lymph nodes in the axilla are affected, it is stage 3 (the tumour might be attached to structures in the breast, such as skin or surrounding tissue); Stage 4 describes tumours of any size where the cancer has spread to other parts of the body (metastasis). The grade of the cancer describes the appearance of the individual cancer cells that make up the tumour. If the cells are slow growing, even if they look abnormal, they are G1 (low grade); If the cells have poorer differentiation (and so look more abnormal) than G1 cells we describe them as G2 (medium grade); G3 (high grade) cells look very abnormal and proliferate quickly. 

Cancer develops due to changes to the genetic information in cells, mutations of oncogenes or tumour suppressor genes, which mean that there are changes to the proteins created within cells, which allows tumours to develop. These mutations are somatic which means they happen as the person is alive, rather than being present in the genetic information from conception (although some inherited alleles (versions of gene) are more likely to mutate than others). In cancer, cells are able to evade apoptosis (organised cell death) and anti-growth signals, or sustain their own growth and angiogenesis (formation of a blood supply to the tumour). An example of changes in cancer cells is a mutation causing the activation of the telomerase enzyme, which allows unlimited replication of the cell, as telomeres do not shorten, so the cell can undergo unlimited replications. In breast cancer, commonly inherited mutations include BRCA1, BRCA2, TP53 and PTEN which increase the risk of the disease. These are all tumour suppressor genes that when mutated may no longer be able to prevent excessive cell division and proliferation.

Currently breast cancer can be treated by: surgery to remove the tumour (breast-conserving surgey) or the entire breast (mastectomy) and in some cases the lymph nodes from the under arm (axilla); radiotherapy to destroy cancerous cells with targeted radiation (often used after other treatments to remove any remaining cancer cells); chemotherapy a treatment program which targets rapidly diving cells (such as cancer cells but also often affecting other cells in the body such as blood cells and hair follicles); Hormone therapy to target ER+ cancer cells with drugs to block oestrogen (such as Tamoxifen, aromatase inhibitors or goserelin) and biological therapy for HER2+ cancers through treatment with drugs such as the monoclonal antibody trastuzumab (Herceptin) in addition to chemotherapy. Cancer diagnosis is difficult to deal with and families are often offered counselling to learn more about the illness. Additionally breast removal surgery can be distressing for many women, as can the hair loss associated with chemotherapy, support is offered by charity groups.

Nice (the National Institute for Health and Care Excellence) have recently approved the Oncotype DX test to identify whether breast cancer will benefit from chemotherapy treatment. This will reduce unnecessary treatment as well as the stress and side-effects associated. The test  is used after surgery to see how likely a tumour is to recur (and if therefore chemotherapy needed) by looking at the activity of certain genes in the tumour. The test works best for those with ER+ cancer but HER2- cancers (without the ERBB2 receptors).

Radiotherapy can lead to skin irritation or lymphoedema (fluid build up due to the lymph nodes being blocked). Radiotherapy sessions only take a few minutes at a time, but are intensive for 3 to 5 days a week for 1 to 2 months. Chemotherapy drugs are usually administered intravenously (though in some cases they may be given in tablet form). Chemotherapy sessions usually last between 4 and 8 months, with sessions every 10-20 days. The main risks with chemotherapy is the risk of infection due to the effect on white blood cells which provide the immune response in the body, however other side effects include loss of appetite, nausea, tiredness and hair loss.

Hormone therapies are used in conjuncture with chemotherapy, or as an alternative to other treatments (which are too risky due to the general health of the person with breast cancer) or before surgery to shrink the tumour so that it is easier to remove. Hormone therapies can cause side effects like those associated with menopause such as hot flushes, tiredness, aching joints and weight gain. Tamoxifen and aromatase inhibitors are taken daily in tablet form, whereas goserelin is taken as an injection once a month. Tamoxifen prevents oestrogen binding to receptors; aromatase inhibitors prevented the production of oestrogen in women who have gone through menopause, for whom oestrogen is produced by aromatase; goserelin is an ovarian suppressor which prevents the production of oestrogen temporarily by the ovaries in pre-menopausal women. Ovarian ablation is a surgical or radiotherapeutic technique for permanent prevention of oestrogen production by the ovaries by inducing early menopause. Monoclonal antibodies work by binding to the HER2+ receptor protein, so indicating the HER2+ cancer cells which can then be destroyed. This treatment must be administered in hospitals via and intravenous drip; sessions take one hour and may be as regularly as once a week. Some side effects of trastuzumab include heart problems (so regular heart function tests are needed) and allergic reactions to the drug causing nausea. By identifying more genetic mutations in cancer cells we may find more ways in which we can treat patients, using targeted biological therapies, specific to the dependencies of their tumour.

http://www.nhs.uk/Conditions/Cancer-of-the-breast-female/Pages/Introduction.aspx

http://www.breakthrough.org.uk/

http://www.bbc.co.uk/news/health-20121043

Down's Syndrome

Down’s syndrome is a chromosomal disorder, caused by an error in cell division. People with Down’s syndrome have an extra copy of all or part of chromosome 21 (the smallest human chromosome) in all or some of their body’s cells. Usually cells contain 46 chromosomes (23 from each parent); chromosomes are separate blocks of DNA that are made up of many genes. The chromosomal makeup of the body’s cells is known as the karyotype.

There are 3 types of Down’s syndrome: Trisomy 21, Translocation and mosaicism. 94% of people with Down’s syndrome have trisomy 21, where every cell in their body has a third copy of chromosome 21 (88% of cases originate due to changes in maternal karyotype). Before or during conception, random misdivision of genetic material in either the sperm or egg may cause an extra chromosome in the baby, known as nondisjunction. Scientists do not know what causes this nondisjunction, and there are no known factors which prevent or induce its occurance. However, maternal age has been linked to an increased likelihood of this misdivision occurring in egg cells (for babies born of mothers aged 25, 1 in 1250 will have the condition, whereas for babies born of mothers aged 45, 1 in 30 have Down’s syndrome). 4% of Down’s syndrome is due to translocation, where part of chromosome 21 breaks off during cell division and attached to another chromosome (usually 14) in the cell, known as Robertsonian translocation. Some people with altered genes may not have any symptoms of Down’s syndrome, but instead be carriers. The chance of passing on the condition for male carriers is 1 in 35, and female carriers is 1 in 8, but the majority of people have translocation Down syndrome due to changes at their own conception, not inherited from previous generations. Mosaicism is the least common type of Down’s syndrome (affecting only 2%). In this condition, some of the body’s cells have extra copies of chromosome 21 and others do not, therefore, people with the condition usually have fewer Down’s syndrome symptoms. Down’s syndrome is usually diagnosed at birth, but antenatal screening at the end of the first trimester can also predict whether babies may have Down’s syndrome.

People with Down’s syndrome are generally born with a lower than average birth weight, and as they grow up, may have hypotonia (low muscle tone). Additionally, physical characteristics such as a single crease across the palms, skin folds around the eyes and a flat nasal bridge are more likely in people with Down’s syndrome. Infants with Down’s syndrome may have delayed development in sitting up and walking due to floppiness cause by hypotonia, but this can be helped by stimulation from a young age and physiotherapy to increase the range of movement. Also speech therapy may be needed to help children to learn to speak and some will experience learning difficulties that may require specialist education, though degree of impairment varies greatly between people with the condition. Some children with Down’s syndrome (around 10%) may also have ADHD (attention deficit hyperactivity disorder) or autistic spectrum disorders.

Hearing and/or  vision problems affect 50% of those with Down’s syndrome. Glue ear (build up of fluid in the middle ear) and ear infections are common; difficulties hearing sometimes makes it harder for children to learn or interact with their peers. People with Down’s syndrome are more likely to develop a squint, lazy eye (inability of one eye to focus), eye infections (such as conjunctivitis) or cataracts (clouding of the lens of the eye).  Skin conditions such as dry, flaky skin and thickened skin on the palms of the hands and soles of the feet are not uncommon.

People with Down’s syndrome may have a lowered immunity, and so are susceptible to infection, especially to conditions such as pneumonia. In the past, many people born with Down’s syndrome did not survive childhood, as around 50% have a congenital heart defect, usually a septal defect (a hole in the septum of the heart, which divides the left and right sides) which causes the heart to work harder to pump blood around the body. There is also an increased risk of childhood leukaemia. Intestinal and bowel problems such as constipation, diarrhoea, indigestion and bowel obstruction are common.  Treatment for heart and digestion conditions may require surgery. There has been research into links between Down’s syndrome and dementia (especially the earlier onset of dementia). However the conclusions of studies showed that the proportion of the adult population of those with Down’s syndrome who have dementia is the same as in the adult population without Down’s syndrome.

10% of people with Down’s syndrome have thyroid problems. Often this is hypothyroidism (an underactive thyroid), which results in lack of energy, weight gain, slow reactions and a risk of type 1 diabetes. Related to this, there is a higher than average incidence of obesity amongst those with Down ’s syndrome and Coeliac disease (gluten intolerance) affects around 15% of those with Down’s syndrome, so advice from a dietician may be needed. Rarely, people with Down’s syndrome may suffer from hyperthyroidism (over production of thyroid hormone) leading to hyperactivity and difficulties breathing. Adults with Down’s syndrome tend to have a lowered fertility rate, and so conceiving children is more difficult, the risk of premature birth or miscarriage is also higher.

The prognosis for those born with Down’s syndrome has greatly improved since the 1980s, when the life expectancy was around 25 years, as now people with Down’s syndrome on average will live into their 60s. This is because of better treatment for the conditions associated with Down’s syndrome. Some people with Down’s syndrome are able to become independent adults, whereas others may require support for the rest of their lives.

Recently, scientists at the University of Massachusetts Medical School, have found the possibility of using gene therapy to silence entire chromosomes. In working with the laboratory grown stem cells of a Down’s syndrome patient, and inserting a gene called XIST, the team were able to silence the extra copy of chromosome 21, correcting the growth patterns of the cells. In the future this could have benefits for babies born with Down’s syndrome and other chromosomal disorders, but at the moment this research is still in its infancy.

http://www.nhs.uk/Conditions/Downs-syndrome/Pages/Introduction.aspx
http://downsyndrome.about.com/od/whatcausesdownsyndrome/a/Causeintro_ro.htm
http://www.bbc.co.uk/news/health-23340924

Three Parent IVF and Mitochondrial Disease

What is Mitochondrial Disease?

Mitochondrial Disease is the name for a group of conditions due to any failure in the mitochondria of the body’s cells, which affects 1 in every 6,500 babies born. Generally the disease affects children under the age of 10 years old, but adult onset types of mitochondrial disease are becoming more common. In people with mitochondrial disease, not enough energy in the form of ATP (chemical energy in the body)is produced by the mitochondria, the body’s cells do not have enough energy to carry out life processes, leading to cell damage and death.

Mitochondria are organelles within the cells of the body (except red blood cells) and are the site of cellular respiration. Respiration is the metabolic process by which glucose, obtained from our food, and oxygen, obtained from the air, are combined to give energy in the form of ATP (with waste products of carbon dioxide and water). Mitochondria contain their own DNA and can replicate independently of the cell. ATP is used to provide energy for metabolism (reactions in the body), and so mitochondria provide 90% of the energy that the body needs to survive. Also, mitochondria are responsible for breaking down, building and recycling molecules; are involved in cell signalling; control cell division, cell growth and programmed cell death(apoptosis). Additionally, mitochondria are involved in specific processes related to the type of tissue cell in which they reside, such as: cholesterol metabolism in the adrenal glands and sex organs (to make steroid hormones such as testosterone and oestrogen); heme synthesis in the bone marrow (to make the protein haemoglobin used to carry oxygen in red blood cells) and detoxifying ammonia in the liver. Therefore, mitochondrial disease may affect the other processes carried out by the mitochondria not simply energy production, and may be tissue-specific (although, generally, 3 or more organs are involved in mitochondrial disease).

Around 3000 genes are involved in building a mitochondrion (37 of which are encoded by genes in mitochondrial DNA, with the other being from the nuclear DNA found in the cell’s nucleus). Mitochondrial DNA is inherited only from the mother as egg cells, but not sperm cells, contribute to the mitochondria of a developing embryo. Mitochondrial disease is a result of mutations (inherited or spontaneous changes) in the genes that code for the proteins used in mitochondria production and function. Mitochondria can be damaged by drugs and infections. Mitochondrial disease may only have visible symptoms once the number of affected mitochondria reaches a threshold level.

What are the types of Mitochondrial Disease and their symptoms?

There are innumerable types of mitochondrial disease because of the vast number of genes that are involved in mitochondrial production, and even identical mutations will not cause the same clinical symptoms (we call these diseases genocopies). It should be noted that conversely different mutations could have the same symptoms (phenocopies). This means that mitochondrial disease is often misdiagnosed.

Mild mitochondrial disease may result in exercise intolerance as suffers cannot respire as effectively to provide the energy needed. People with mitochondrial disease are at a high risk during and following an illness or infection and so must be treated with a course of antibiotics, keep up to date with vaccinations (often advised to be vaccinated against seasonal flu) and may require IV fluids when ill. This is because overcome an illness and stimulating an immune response, which requires a lot of energy, and due to weakened systems, infection can lead to further neurological or organ damage. Muscular dystrophy is often a symptom of mitochondrial diseases. The conditions are degenerative and can often develop into dementia or organ failure.

Some examples of mitochondrial disease include:

MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome) is caused by mitochondrial DNA mutations (often the A3243G mutation)preventing the formation of NADH, therefore preventing aerobic respiration. It can affect either sex, but is inherited solely from the mother. Symptoms of MELAS (including muscle pain or weakness, vomiting, seizures and loss of appetite)often appear in childhood, with stroke-like symptoms (periods of weakness on one side of the body, loss of consciousness, migraine-like headaches, seizures and problems with vision) occurring before the age of 40. Encephalomyopathy refers to th fact that MELAS affects both the brain and muscle tissue. Due to anaerobic respiration (where less oxygen is used) lactic acid can build up in the blood, leading to lactic acidosis, causing vomiting, pain, fatigue, difficulty breathing, loss of bowel control and muscle weakness. People with MELAS may also have involuntary muscle spasms or impaired muscle coordination (ataxia).   

MERRF (Myoclonic epilepsy and ragged-red fibers) is also caused by mutations in mitochondrial DNA preventing the formation of proteins used in the RNA that carries the amino acid lysine, so prevents the building of proteins in the mitochondria which are used in respiration. Myoclonic epilepsy involves brief involuntary muscle twitching that is frequent enough to be disabling. Ragged-red fibers refer to when clumps of diseased mitochondria build up in muscle tissue and appear red when stained with Gömöri trichrome stain (see image). Other symptoms of MERRF include lactic acidosis, hearing loss, short stature and exercise intolerance.

KSS (Kearns-Sayre syndrome) is caused by large deletions of mitochondrial DNA and so usually mutations are caused by environmental factors and are not inherited, although the average onset is below the age of 20. Typically KSS effects the eyesand involves: drooping of the eyelids (ptosis); paralysis of eye muscles (CPEO/chronic progressive external opthalmoparesis); degeneration of the retina (and so inability to see in the dark) and abnormal accumulation of eye pigments (pigmentary retinopathy). Other symptoms include diabetes mellitus, deafness, ataxia and problems with electrical conduction in the heart (heart block) causing palpitations and fainting.

LHON (Leber’s hereditary optic neuropathy) is a caused by a mutation at one of three points in mitochondrial DNA (11778, 3460 or 14484) and so is passed from mother to all of her offspring. The condition is most common in men aged around 20. The condition causes cell damage and death to optic nerve cells. Symptoms include blurriness in one eye, leading to loss of vision in that eye, followed by the same in the other eye, usually within the same year.

MNGIE (Myoneurogenic gastrointestinal encephalopathy) is caused by a mutation in the TYMP gene and often occurs in adults under 50. The mutation prevents the formation of an enzyme used in metabolising (breaking down) parts of nucleic acids (e.g. DNA nucleotides). IN MNGIE pseudo-obstruction of the gut causes peristalsis (contractions of the gastrointestinal tract) to be less efficient, so less food is absorbed. Diarrhoea, constipation, vomiting, GI tract paralysis, weight loss, damage to the peripheral nerves and dysfunctional growth of the white matter of the brain are common symptoms of MNGIE.

Maternally inherited mutations in mitochondrial DNA (ATP6 gene) affect the production of ATP synthetase which is the enzyme used in making ATP, so reduce the energy available to cells, and cause the conditions NARP (Neuropathy, ataxia, retinitis pigmentosa)and Leigh syndrome. In NARP, 70-90% of mitochondria are affected and have the abnormal gene and symptoms include: sensory neuropathy/numbness and pain in the limbs; muscle weakness; problems with balance and co-ordination (ataxia); vision loss due to deterioration of light sensing cells of the retina (retinitis pigmentosa) and learning disabilities or developmental delays. Leigh syndrome occurs when 90-95% of mitochondrial DNA has the mutation of ATP6, but can also be caused by mutations of the nuclear DNA of the cell containing the mitochondria (SURF1 and COX assembly factors). Leigh’s disease usually affects infants (below 2 years old). In Leigh syndrome, loss of mitochondrial function causes lack of energy which occurs in cells of the brain stem (responsible for regulating the central nervous system and the action of the heart and lungs) and basal ganglia (responsible for motor control and learned behaviours). Loss of motor control, seizures, vomiting, heart problems, muscle weakness and lactic acidosis are common symptoms.

How do we currently treat Mitochondrial Disease?

The prognosis for severe manifestations of mitochondrial disease is poor, and most people who develop conditions as children do not survive to adulthood. We do not have a cure for mitochondrial disease, but therapies and treatments for the symptoms can help to extend life, prevent further damage to the body or improve quality of life. Unfortunately in more severe cases, treatment is rarely effective. Physical therapy for motor problems, anti-epilepsy drugs for seizures, insulin injections for diabetes and ophthalmic surgery for vision problems are examples of useful treatments to improve alleviate symptoms. To avoid fatigue and weight loss it may be useful for suffers to have a diet with regular nutrition (for example eating just before going to bed or in the middle of the night) and IV feeding if they become ill. Similarly sufferers should avoid getting too hot or cold, as poor thermoregulation is often associated with the condition. Iron can generate free radicals which can cause mitochondrial damage and DNA mutations so should not be supplemented. Alcohol can speed up the progression of some conditions of the mitochondria and carbon monoxide in cigarette smoke limits oxygen carrying capacity of the blood so leads to anaerobic respiration and potentially lactic acidosis. Supplements such as cofactor Q10 can be effective in improving mitochondria function.

What is three parent IVF and why has the government approved it?

Three parent IVF is an artificial reproductive technique known as ooplasmic transfer  where the nuclear DNA of the mother (a carrier of mitochondrial disease due to mutations in mitochondrial DNA) is inserted into the empty nucleus of a donor egg (with healthy mitochondria) and fertilised with the father’s sperm outside of the body, or the fused nuclei (and so genetic material) of the two parents is inserted into the nuclei of the donor egg immediately after fertilisation. This technique will prevent the inheritance of mutations in mitochondrial DNA which is solely passed on by the mother. Therefore the child will have “three parents” as around 1% of the child’s DNA (that in the mitochondria) will be that of the egg donor.

In 2011, HFEA the Human Fertilisation and Embryology Authority, regulated and assessed trials on animals and early human embryos have shown that the technique is safe. This year, the UK government has supported and drafted regulations for three parent IVF. Obviously any babies born by this technique will require regular health checks to ensure there are no long term issues with the technique for human use. Other ethical issues involve the rights of the donor and if they should remain anonymous, potential psychological effects on the child and whether we have the right to interfere with the phenotype (observable and biochemical characteristics) of a child (e.g. parents should still want the child even if it did have a medical condition) as this could make those living with the condition to feel unwanted/discriminated against. However, it is currently thought that because we are able to prevent the serious conditions I have outlined above, couples should be able have children without worrying about the child having a poor quality of life.

This promising treatment provides hope to prospective mothers who carry mitochondrial disease, but for those currently living with mitochondrial disease, we are yet to find effective treatment.

http://www.nhs.uk/news/2013/06June/Pages/UK-Government-backs-three-parent-IVF.aspx

http://www.umdf.org/site/c.8qKOJ0MvF7LUG/b.7929671/k.BDF0/Home.htm

https://www.gov.uk/government/news/innovative-genetic-treatment-to-prevent-mitochondrial-disease

New Scientist 23^rd March 2013

Type 1 Diabetes

What is diabetes?

Diabetes mellitus is a metabolic disorder where the body cannot control the glucose concentration in the blood. If blood glucose concentration becomes too high, it can cause serious damage to the body’s organs. There are several types of diabetes: type 1 diabetes (also known as insulin-dependent diabetes) occurs when the pancreas does not produce insulin; type 2 diabetes (insulin-resistant diabetes) occurs when not enough insulin is produced or the body’s cells do not react to normal insulin levels; gestational diabetes occurs when pregnant women develop high blood glucose levels (may lead to type 2 diabetes after pregnancy). Type 1 diabetes is responsible for 10% of the diabetes cases in the UK and is more likely to affect young people than any other type of diabetes.

Insulin is a protein hormone produced in the islets of Langerhans (a type of pancreatic cell). Insulin is synthesized specifically by ß cells in the islets of Langerhans and is secreted in response to high blood glucose levels. Insulin causes glucose in the blood to be absorbed by cells in liver, muscle and fat tissues, where it is stored as glycogen, so reduced blood glucose concentration. The hormone also prevents lipolysis (breaking down fat stores for use as an energy source) when blood glucose is high and further increasing blood glucose levels. Insulin also has a role in controlling how many amino acids (broken down proteins) are taken up by body cells. If blood glucose is too low, the pancreas will release the hormone glucagon which causes glycogen to be converted back to glucose, and because insulin is not produced, fat stores will be used as an energy source.

In type 1 diabetes the body’s immune system destroys the ß cells of the pancreas, so prevent insulin synthesis. Type 1 diabetes is said to be an autoimmune disease, because the immune cells (CD4+ and CD8+ T lymphocytes and B lymphocytes which produce autoantibodies) mistake pancreatic cells for harmful/infected cells. There are several causes of this autoimmune destruction, a genetic trigger, infection or trauma.  Genetically, those of European ancestry have a higher risk of having alleles of the IDDM1 gene on chromosome 6 that code for decreased histocompatibility and so causing immune cells to see the body cells as foreign due to the antigens (cell markers) on the cell surface on tissues. In type 1 diabetes, this is thought to be due to the presence of proinsulin, a precursor to insulin on the cell surface. However if an identical twin has type 1 diabetes, their twin will only have the condition 30-50% of the time, and people with no family history of diabetes who migrate to a country with high prevalence develop the disease, suggesting that genetics only increase susceptibility and environmental triggers are needed for the expression of these genes. These triggers could be viral infection of the islets of Langerhans with rubella or Coxsackie virus causing the cells to be destroyed alongside the virus; chemicals such as the rodenticide Vacor (no longer in use in many countries)which destroys pancreatic cells; or drugs such as streptozotocin, an antibiotic used in chemotherapy for pancreatic cancer. Trauma such as pancreatitis (inflammation of the pancreas) or tumours can cause destruction of cells.

What are the symptoms of type 1 diabetes?

Symptoms of type 1 diabetes due to high blood glucose (hyperglycaemia) include drowsiness (as no glucose is moved into the body cells for respiration to produce energy), blurred vision (as the lens of the eye changes shape), polyuria (frequent need to urinate, particularly at night), extreme thirst and a dry mouth. Hyperglycaemia can lead to diabeteic ketoacidosis which can be fatal. This occurs when  the body breaks down muscle and fat as an alternative energy source, causing a build up of acid in the blood causing fever, dry skin and dehydration, rapid deep breathing, unconsciousness, vomiting and abdominal pain. Additionally, if blood glucose levels get too low (i.e. if too much insulin injected or a meal is missed) it is known as hypoglycaemia. Symptoms of hypoglycaemia are hunger, nausea, weakness, sweating, irritability and potentially slurred speech and unconsciousness.

In the long term symptoms such as weight loss and loss of muscle bulk, skin infections and susceptibility to thrush, blurred vision and cramps are indicative of type 1 diabetes. Blurred vision develops due to blocking of the blood vessels in the retina causes changes in shape of the lens and preventing light from fully passing to the retina. If blood sugar levels are not controlled, the chance of developing atherosclerosis (fatty deposits in the endothelial walls of arteries, reducing the size of artery lumen and causing plaques and potentially blood clotting) increases, so heart disease and stroke risks increase. High blood glucose levels can cause damage to the nervous system, this can cause tingling pain in the extremities and limbs or cause diarrhoea or constipation in the digestive system. The nerve damage and loss of blood flow to the feet can mean injuries to the feet go unnoticed and foot ulcers and infection can develop, potentially leading to gangrene and amputation. Also the small blood vessels in the kidneys may become blocked and lead to kidney failure.

Female diabetics in pregnancy must carefully control blood sugar levels in early stages of pregnancy to prevent serious damage to the baby or miscarriage. Diabetes can also lead to a reduced sex drive, in men, nerve damage can lead to erection problems, and women can suffer from vaginal dryness and pain during sex.

People with a type 1 diabetes diagnosis have an approximately three times higher incidence of depression than non-diabetics, neurological changes such as the thinning of the pre-frontal cortical are associated with depression in diabetes and may be caused by long term control of blood sugar. Parents of young people with diabetes have a higher prevalence of psychological distress than parents of those without the condition. Due to fear of hypoglycaemia, some people neglect their self care and physical activity. Eating disorders are more common in female diabetics than female non-diabetics, and in studies, some women were seen to manipulate their insulin dose to promote polyuria and reduce appetite to aid weight loss.

How do we diagnose diabetes?

We can diagnose diabetes with urine and blood tests. Normally urine does not contain glucose, as glucose is reabsorbed by the kidneys after blood is filtered, however this does not occur in diabetics, we can also test for ketones in the urine which may suggest diabetic ketoacidosis. Fasting blood tests are taken and if glucose levels are high, it suggest diabetes. If blood glucose is low you may still have diabetes and so need to have an oral glucose tolerance test, where, after drinking a sugary drink, your blood is tested every 30 minutes for 2 hours. To identify type 1 diabetes in particular, blood is tested for autoantibodies targeting islet cells and insulin.

What treatment is available?

There is no cure for diabetes, but the condition can be kept under control, so that sufferers can have an improved quality of life and a life expectancy within 5 to 8 years of non-diabetics. Treatment of type 1 diabetes requires regular review of diet and medication, as well as checks of the eyes, feet, nerves and kidney function. People with type 1 diabetes should try to eat a healthy and consistent diet, but do not necessarily need to eat a special diet. Diabetics should aim to exercise regularly to help maintain blood glucose levels, but any activities should be discussed as it may affect insulin dose. Children may need to have a care plan put in place at school so that insulin injections can be administered. Women trying to conceive will need support to ensure insulin doses and diet match the needs of both mother and child. Counselling may be needed to overcome needle-phobias to allow for injection of insulin. Smoking increases the risk of cardiovascular diseases such as heart attacks and stoke, so it is advised that diabetics in particular give up smoking. Additionally, diabetics may need to take statins to reduce high cholesterol or blood-thinning medication to prevent stroke. Alcohol should be not drunk in excess or on an empty stomach, as this can lead to either hyperglycaemia or hypoglycaemia. Diabetics should also be regularly vaccinated (i.e. against seasonal flu) as people with diabetes have a higher risk of complications associated with infection due to the increase in blood glucose as a response to many infections. Some people may experience reactions to vaccination such as swelling and a slight fever due to mild disruption in blood glucose.

For people with type 1 diabetes, insulin treatment is needed to keep blood glucose at stable levels. We can produce insulin by genetically engineering bacteria by inserting a gene for human insulin production. Insulin cannot be taken orally as would be digested by the stomach, so is taken by a subcutaneous (into the fat/muscle layer just below the skin) injection, so uses a smaller needle than those used for taking blood. Alternatively, insulin pens can be used so that the correct dose is injected (rather that drawing up dose into syringe), or auto-injectors to surround the injector pen to automatically inject the needle. It is important to relax the area or perhaps numbing it with ice before injection, the site into which you inject should be alternated regularly. the sites for insulin injection are shown above. Insulin must be stored below room temperature (i.e. in a fridge) and not kept for more than 28 days out of the fridge. There are many different types of insulin: rapid-acting analogues can be injected around the time that food is eaten and work for 2 to 5 hours, with peaks at 0 and 3 hours; long-acting analogues provide background insulin and are injected once a day, lasting 24 hours; short-acting insulin is injected half an hour before a meal, it lasts 8 hours, and has peak action between 2 and 6 hours; medium/long-acting insulin again provides background insulin for up to 30 hours. Often a combination of insulin is used, with around 2 to 4 injections a day. Insulin pumps have also been developed, which can be worn for 24 hours, they involve a small device (about the size of a mobile phone) which contains insulin and a piece of tubing and cannula which is inserted under the skin, allowing insulin to flow into the bloodstream, regular monitoring of blood glucose levels using a finger prick test are needed. Insulin pumps can be removed for up to a hour if needed, e.g when taking part in contact sports.

We can control hyperglycaemia by adjusting diet or insulin dose, however if it leads to diabetic ketoacidosis, hospital admittance is needed for intravenous insulin treatment and fluids given by drip to restore normal blood composition. We can treat hypoglycaemia by taking pure glucose tablets, or having a glucagon injection to increase blood glucose, however, often a high sugar food may be all that is needed. Another treatment is islet transplant, where cells are extracted from the pancreas of a dead donor and implanted into the patient. Islet transplant is a minor procedure requiring only local anaesthetic. Islet transplants are offered to people who have had several incidences severe hypoglycaemia. However the treatment is not suitable for those with poor kidney function, the medication to prevent islet cell rejection has some side effects and there is a risk of infection. The transplants lead to improved awareness and responsiveness of the body when blood glucose is low (especially in people who have used insulin therapy for many years and have become unresponsive), less variation in blood glucose levels and so an improved quality of life.

What are the conclusions of current research into the treatment of type 1 diabetes?

Recent research has shown that some pancreatic cells in mice (specifically glucagon producing α cells) can be converted into insulin producing ß cells. It was also found that pancreatic duct cells can be made into α and therefore ß cells, by forcing the activation of a gene called Pax4. This means that the pancreas has an almost endless supply of ß cells to replace those destroyed in type 1 diabetes. This research provides an avenue for the development of new treatments for type 1 diabetes.

Attempts to prevent the autoimmune destruction in type 1 diabetes using immunosuppressant medication has not yielded very promising results, as the drugs prevent the body from fighting infection. This week however, there have been results from the clinical trial of a new vaccine to treat type 1 diabetes. the aim of the vaccine was to suppress the CD8+ lymphocytes which destroy ß islet cells leading to type 1 diabetes. Normally vaccines stimulate an immune response by exposing lymphocytes to foreign antigens (proteins) so that cells which display these proteins can be destroyed. In treating an autoimmune disease, we need to prevent the destruction of cells showing proteins which the immune system does not recognise, such as proinsulin. This was achieved by modifying the gene that codes for proinsulin so that the cells to which the vaccine was delivered could send an anti-inflammatory signal to the CD8+ cells, preventing an immune response. In those trialled, levels of insulin production were either maintained or increased, implying that the ongoing destruction of ß cells was halted by the vaccine. A DNA vaccine has never before been approved for human use, this vaccine could be the first, and similar principles could be used in treating other autoimmune conditions. However, this particular vaccine still requires more attention, as after the 12 week course of the trial, the beneficial effects of the vaccine began to wear off, but as no side effects were observed, this vaccine gives a lot of hope  for the future treatment of this condition. 

http://www.sciencedaily.com/releases/2013/06/130627131832.htm

http://www.sciencedaily.com/releases/2013/06/130626142932.htm

http://www.bbc.co.uk/news/health-23064897

http://www.nhs.uk/Conditions/Diabetes-type1/Pages/Introduction.aspx

http://www.diabetes.org.uk/Type-1-diabetes/

Returning to blogging

Sorry for being absent online for the past few months, I decided to take a break from blogging to focus on my exams. Now I am back to explain and share with you some developments in medicine and healthcare that I have been interested to find out a little more about.

Measles, Mumps and Rubella

What are vaccines?

Vaccines provide long term protection against a disease. Thanks to vaccines, we have been able to eradicate many life threatening diseases from our society. They work by introducing weakened (attenuated) or dead forms a a pathogen, a live form of a milder pathogen or a preparation of the toxins or antibodies of a pathogen. This triggers an immune response and the body produces antibodies (proteins produced by white blood cells) specific to the antigens that coat the pathogen. these antibodies can then neutralise the pathogen by attaching to white blood cells, allowing them to engulf the pathogen by phagocytosis; or bind to many pathogens, preventing them from entering and so infecting body cells. This response also creates memory cells which stay in the blood (as antibodies do not) so that the next time the pathogen is detected the body can mount a faster immune response. Some vaccines require regular boosters (e.g. tetanus boosters every 10 years) in order to maintain the levels of these memory cells in the blood.

Vaccination programmes can either involve ring vaccination, where the inhabitants of the region where a disease outbreak occurs are all vaccinated so that the disease cannot spread and is isolated (this method was used to control the outbreak of Aphthae epizooticae/foot-and-mouth disease in 2001), or herd vaccination, where the majority of the population is vaccinated so enough people are protected and so cannot carry the disease (usually this means over 85% but is dependent on the disease, e.g. measles requires up to 94%).

Measles

Measles is a disease caused by a virus and is highly infectious, it is spread through droplets in coughs and sneezes. Measles is common in children between 1 and 4 years old. Measles is characterised by an itchy and spotty rash starting behind the ears and spreading over the face and then body with a red-brown colour. The rash is often preceded by red -eyes, cough, fever and white spots inside the mouth. Adults are more likely to have severe complications when they develop measles, these can include diarrohea, pneumonia (1 in 20 child measles cases), severe ear infection and deafness, encephalitis (swelling of the brain which can cause seizures), it can also cause miscarriages and low birth-weight babies of infected women.Rarely people with childhood measles can go on to develop subacute sclerosing panencephalitis (or, less of a mouthful, SSPE) around 7 years after infection which is a degenerative disease of the nervous system and leads to changes in personality, muscle spasms and mental deterioration.

Mumps


Mumps is again a viral infection and is spread in the same way as measles, colds and flu. Mumps causes swelling of the parotid (saliva) glands, causing pain and difficulty swallowing. people with mumps also often have headaches, fever and joint pain. Complications of mumps include: if caught around puberty the painful swelling of the testicles in males or the ovaries and/or breasts in females which can lead to fertility problems in the future; deafness; and the swelling of the brain (encephalitis) and/or spinal cord (meningitis) which if untreated, can go on to cause severe neurological damage.

Rubella

Rubella (or German Measles) is a viral infection, spread by droplets, and often has a two week lag period before symptoms manifest, with sufferers becoming infectious, a week after catching the disease. Rubella has a characteristic red skin rash which lasts several days, as well as swollen glands, fever and runny nose.Rubella is particularly dangerous if caught by pregnant women in the first 16 weeks of pregnancy, as can cause birth defects in the developing baby such as cataracts, deafness, heart defects, brain damage and liver and spleen damage, together these problems are known as congenital rubella syndrome (CRS).

The MMR vaccine

In 1988 a vaccine was developed against Measles, mumps and rubella, known as the MMR vaccine. The vaccine contains attenuated forms of the measles mumps and rubella viruses and is given as a single injection into the arm or thigh. It is administed to babies aged between 12 and 13 months and a booster is given before starting primary school in the hope of providing herd immunity to the entire population. The three-in-one injection minimises the risk of children developing any of the illnesses in the time between separate jabs.  Due to the effects of rubella on pregnant women, non vaccinated women hoping to get pregnant are also given the vaccine.The vaccine provide lifelong immunity and thanks to the vaccine, levels of all three disease fell to an all time low.

Side affects of the injection include: after a week of vaccination, a mild form of measles that lasts for 2 or 3 days and usually includes a rash and fever; after a month of vaccination, a mild form of mumps that again lasts around 2 days and includes swollen glands; stiff and swollen joints of adult women who take the vaccine to protect against rubella; very rarely bruise-like spots may appear this is known as idiopathic thrombocytopenic purpura (ITP) which is linked to the rubella vaccine, however, ITP is far more common in people who catch live forms of measles or rubella that from the vaccine, and there is treatment for the disease. Some children have an allergic reaction immediately after the vaccine, however medical staff who give vaccines are trained to deal with this and can ensure quick treatment of the reaction. People who have been vaccinated with MMR are unable to infect others with any of the diseases.

In 1988 a study was published linking the MMR vaccine to autism and bowel disease, these findings based on the study of a sample of 12 children has since been discredited and recent studies have shown that there is no link between the vaccine and the conditions. There was also worry about the fact that a three-in-one vaccine would put too much strain on a child's immune system. Unfortunately, the study put parents in a very difficult situation as the claims were spread by the media and so many were insure whether to vaccinate their children. This has left an estimated 2 million people at risk from the diseases and the current epidemic in Swansea has seen a man dead due to measles.

http://www.nhs.uk/Conditions/vaccinations/Pages/mmr-vaccine.aspx
http://www.cdc.gov/measles/
http://www.cdc.gov/mumps/
http://www.cdc.gov/rubella/
http://news.bbc.co.uk/1/hi/health/1808956.stm