How Does Disease Happen?

The science behind sickness!

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Down Syndrome

1. In a nutshell Down Syndrome is a type of genetic disease, and is an example of an aneuploid condition. Down Syndrome typically results from an individual possessing an extra copy of chromosome 21 (trisomy 21). Clinical manifestations of Down Syndrome include abnormal facial features, cardiac defects, developmental delay and premature onset of significant cognitive decline. In the United States, Down Syndrome is thought to occur in around 1 in 700 live births; the risk of Down Syndrome increases exponentially with rising maternal age.

2. What causes it? Molecular analysis has revealed that around 95% of individuals with Down Syndrome have an extra copy of chromosome 21. How the extra gene dosage contributes to the clinical features of Down Syndrome is poorly understood. Studies have revealed that approximately 75% of cases of trisomy 21 are caused by an additional maternal chromosome, and that a minority of Down Syndrome cases (~5%) are due to what is termed a robertsonian translocation. A translocation of this sort occurs when the long arm of chromosome 21 translocates to another acrocentric chromosome. 

Figure 1. Trisomy 21 karyotype. Note the extra copy of chromosome 21. (Courtesy: National Human Genome Research Institute - Human Genome Project, Public Domain, https://commons.wikimedia.org/w/index.php?curid=889304) 3. What are the symptoms? The range of phenotypic expression in Down Syndrome is extremely wide, and it is rare for any two individuals with the condition to exhibit the same set of clinical manifestations. Readily visible features of Down Syndrome include a flat facial profile, oblique palpberal fissures, and epicanthic folds. Congenital heart defects occur in approximately 50% of individuals with Down Syndrome. A leading cause of mental retardation, up to 80% of Down Syndrome patients have an IQ between 25 to 50. Alzheimer's-like neuropathic changes occur in virtually all affected individuals after the age of 40. Additionally, Down Syndrome patients have been observed to have defects in both cellular and humoral immune function, making them more susceptible to serious forms of infectious disease. 

Figure 2. The clinical features and karyotypes of selected autosomal trisomies. (Kumar, 2020).   4. What’s going on? The karyotype and clinical features of trisomy 21 have been known for decades. Despite this, the exact relationship between genotype and phenotype in Down Syndrome remains poorly understood. In trisomy 21, molecular analysis can show which gamete contributed the extra copy of chromosome 21. As there are no overt clinical differences between these types of trisomy 21 individuals, gametic imprinting is thought to play an insignificant role in the pathogenesis of Down Syndrome. A small subset of patients have 46 chromosomes, and Down Syndrome in these individuals is thought to occur due to robertsonian translocations that typically affect chromosomes 14 or 22; this type of genetic derangement is not associated with advanced maternal age, but can result in genetically unbalanced gamete cells - increasing the risk of recurrence. Karyotypic mosacism is observed in approximately 1% of Down Syndrome individuals and can occur both prezygotically and postzygotically. It is worth mentioning that mosaic individuals may have only mild phenotypic changes and a near normal IQ. 

5. How is it treated? Prenatal screening can be used to identify the condition before birth. Sometimes, the condition is suspected based on the appearance of the neonate, molecular analysis is used to confirm the clinical suspicion in these cases. In terms of management, early childhood intervention strategies, proper education and work-related training can improve the quality of life for individuals affected by Down Syndrome. Screening programs have improved the detection of congenital heart defects, and most serious cardiac malformations can be treated surgically. Hearing aids and speech therapy may benefit some individuals. The improved management of Down Syndrome has meant an increase in the longevity of affected individuals. The median age of death is now approximately 47 years, up from 25 years in 1983. 

Figure 3. Enlarged NT and absent nasal bone in an eleven week old fetus with Down Syndrome. (This Photo was taken by Wolfgang Moroder)  6. That’s interesting... Based on human and animal studies, the critical genetic loci involved in the pathogenesis of Down Syndrome is thought to involve genes that are involved in the normal function of the mitochondrial energy pathway, central nervous system development and folate metabolism. 

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I have ambitious plans for developing this blog and ideas that go beyond posting on tumblr. To achieve these goals I need a little bit of help. Anything at all is very much appreciated!

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CERN congratulates CNAO on a world’s first proton treatment of a cardiac pathology

The CNAO (Centro Nazionale di Adroterapia Oncologica) hadrontherapy centre in Pavia, Italy, hit the headlines in January, when for the first time in the world, a patient with ventricular arrhythmia was treated with proton beams. Ventricular arrhythmia is an abnormality of the heart’s rhythm and can prevent oxygen-rich blood from circulating around the body. In this particular case, the patient was suffering from frequent cardiac arrests. Hadrontherapy centres such as CNAO routinely use proton beams to treat cancer, exploiting the beams’ property of depositing energy very precisely in the tumour region, while not damaging surrounding healthy tissue. For this cardiac patient, who had not responded to any drugs or traditional interventions, doctors decided to bombard the part of the heart responsible for causing the irregular heartbeats with a proton beam. The procedure was a success and the 73-year-old patient is recovering well. CERN and CNAO have a long-standing collaboration, which dates back to the design phase of the treatment centre. In the early 1990s, under the impulsion of Ugo Amaldi, CERN hosted and contributed to the Proton-Ion Medical Machine Study (PIMMS), which aimed to combine efforts and expertise in order to optimise a design for a cancer therapy synchrotron. The PIMMS concept was made publicly available and, after further enhancement by Amaldi’s TERA foundation, evolved into the final CNAO accelerator, with seminal contributions from INFN; the MedAustron centre in Wiener Neustadt, Austria, was then based on the CNAO design. CERN continues to collaborate with CNAO and MedAustron by sharing its expertise in accelerator and magnet technologies. CNAO is one of only six centres in the world able to perform hadrontherapy with both proton and carbon ions and has treated more than 2700 cancer patients since opening in 2011. Perhaps this is just the start of using hadrontherapy outside of the field of oncology. It is another perfect example of how tools developed by particle physicists, to pursue their scientific goals, can have beneficial (sometimes even unexpected) applications well outside the walls of CERN and other basic research laboratories. As CNAO keeps expanding its therapeutic reach, for example through the addition of a new dedicated proton therapy system, and CERN starts its NIMMS (Next Ion Medical Machine Study) programme to develop technologies for ion therapy, one can expect numerous synergies and collaborations in the years to come.

An article from a couple of months ago...And a brief interruption to the current post topic of genetic disease,...But, I felt compelled to share this as I found it such a fascinating read! 

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Many soft-drinks, rich in artificial sweetners like aspartame, now display a warning for PKU sufferers that the product contains phenylalanine. 

[fuckyeahmedicalstuff]

Diffusion-weighted imaging of white matter abnormalities in patients with Phenylketonuria.

Case 1: a 27-year-old man was screened at birth and was found to have a borderline phenylalanine level.

A–C, FLAIR (A), trace diffusion-weighted (B), and ADCav (C) images show extensive white matter abnormalities with restricted diffusion. 

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Phenylketonuria (PKU)

1. In a nutshell Phenylketonuria or PKU is an inborn disorder of metabolism. The name of the condition denotes the presence of elevated levels of phenylpyruvate and phenylacetate in the urine. These two compounds are ketone bodies and accumulate when blood levels of phenylalanine rise above the normal reference range (0.06mmol/L - 0.1mmol/L). Hyperphenylalaninemia in PKU is a consequence of deleterious mutations in a gene that codes for the enzyme phenylalanine hydroxylase; this enzyme converts phenylalanine to the amino acid tyrosine. PKU detrimentally affects the developing brain and can cause irreversible mental retardation if it goes untreated. Screening of neonates is commonplace and necessary to avoid the potentially catastrophic clinical consequences of this condition.

Fig 1. The heel-prick test is routinely used to identify PKU in the neonate. 2. What causes it? PKU is a genetic disease, most commonly inherited in an autosomal recessive manner. Deleterious mutations in a single gene, the PAH gene, result in a deficiency of the enzyme phenylalanine hydroxylase. 

3. What are the symptoms? Untreated PKU can result in growth retardation, seizures, moderate-to-severe mental retardation, hypopigmentation and eczema. Cases where the treatment of PKU is only partial or ceased prematurely can cause a significant decline in IQ and increased incidences of behavioural and learning disabilities. 

4. What’s going on? Under normal circumstances the catabolism of phenylalanine is dependent on the enzyme phenylalanine hydroxylase. Through the action of this enzyme, phenylalanine is then converted to tyrosine. Tyrosine is an important non-essential amino acid that is a biosynthetic precursor for melanin and neurotransmitter development. In PKU, harmful mutations in the PAH gene (>600 have been described) result in the decreased production of phenylalanine hydroxylase which causes the substrate, phenylalanine, to accumulate. Tyrosine becomes an essential amino acid in PKU individuals as they can no longer synthesise it through dietary phenylalanine catabolism. Hyperphenylalaninemia affects the developing brain by disrupting energy production, protein synthesis and neurotransmitter homeostasis. Hypopigmentation in PKU is likely due to the inhibition of dopaquinone synthesis in melanocytes. Approximately 1% of PKU patients will also have defects in tetrahydrobiopterin (BH4) metabolism. This situation adds insult to injury as proper tetrahydrobiopterin metabolism is crucial for the formation of both phenylalanine hydroxylase and tryptophan and tyrosine hydroxylase. Thus, individuals with deranged tetrahydrobiopterin metabolism suffer from PKU and a lack of important serotenergic and catecholaminergic neurotransmitters. This further compounds and complicates the clinical picture and results in severe neurologic dysfunction.

Fig 2. Schematic diagram showing the metabolic fates of phenylalanine. (McPhee and Hammer, 2019).  5. How is it treated? Dietary restriction of phenylalanine is initiated once the condition is detected. It is necessary to continue dietary restriction of phenylalanine indefinitely, as even mild hyperphenylalaninemia can have detrimental effects on cognition and overall CNS health. Additionally, hyperphenylalaninemia, in the context of PKU, can also deprive the brain of adequate levels of other, important amino acids and supplementation is therefore recommended. 

6. That’s interesting... As women with PKU reach child-bearing age, fetal hyperphenylalaninemia due to in uterine exposure becomes a possibility. This can occur irrespective of the fetal genotype; neonates affected by this situation display microcephaly, congenital heart defects and profound developmental delay. Rigorous control of maternal phenylalanine prior to conception and up to birthing is essential in minimising the risk of significant fetal abnormalities in maternal PKU.

[hydrolases]

Chromosome packing and mitosis.

[biomedicool]

Oncogenes

An oncogene is a gene which, in the right circumstances, can transform a cell into a tumour cell. 

Exogenous - originating outside the body, include viral oncogenes which may be introduced into cells by tumour viruses Endogenous  - genes that are normally present in the cell but have been altered to produce the oncogene - this alteration can be called activating.

Proto-oncogenes - “dominant” (only one allele necessary),  genes that normally help cells grow. When a proto-oncogene mutates, or there are too many copies of it, it becomes permanently activated and the cell grows out of control –> tumour.

Tumour suppressor genes - “recessive”,  normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (apoptosis). These are like the brakes of a car; when inactivated, cells grow out of control –> tumour. 

The functions of oncogenes can be altered by:

point mutations 

amplifications

gene rearrangements/translocations

deletions of part or all of the chromosome

altered expression*

*Altered expression/epigenetics 

Occurs without any mutational event - no change in the nucleotide sequence, therefore would not be picked up in DNA sequences. E.g. changes in the methylation patterns of the promoter region of the gene leads to an altered expression in the transcription of the mRNA and its translation.

[howdoesithappen]

Osteogenesis Imperfecta (OI)

1. In a nutshell Osteogenesis imperfecta (OI) is a term used to define a heterogeneous group of genetic disorders that are broadly characterised by extreme bone fragility. OI is typically inherited in an autosomal dominant manner, and involves mutations in genes that code for collagen. Collagen is the major extracellular protein in the body and adequate amounts are essential for the proper development of bone and tissue. In OI, mutations in the genes that code for collagen lead to either an insufficient amount or improper handling of the protein, which ultimately results in the clinical signs and symptoms of the condition. Individuals with OI will present with recurrent bone fractures; they are often very short in stature and may also present with spinal deformity, sclera discolouration and conductive hearing loss. Presentation and prognosis vary considerably and are somewhat dependent on the specific OI phenotype. There is no cure for OI; management of the condition generally relies on medications that will improve bone strength, pain relief, physiotherapy and, in some cases, surgery to strengthen and support long bones and to correct and deformity. 

Figure 1. Blue scleras are considered a “classic” finding in osteogenesis imperfecta but are not present in every case presentation of the condition. 2. What causes it? OI is a genetic condition that is typically caused by deleterious mutations in genes that code for type-1 collagen. In the “classic” form of the disease ~90% of cases result from pathogenic variants of the COL1A1 or COL1A2 gene. Less commonly. loss-of-function mutations in proteins that are required for the proper folding, processing and secretion of collagen result in OI. In rare cases, the condition is inherited in an autosomal recessive manner. 

3. What are the symptoms? The genetic profile and clinical manifestations of OI help clinicians to categorise the disease. Four clinical sub-types of OI have been identified: mild, perinatal lethal, progressive deforming and deforming with normal scleras. In mild OI, patients are typically short in stature, exhibit postnatal fractures, have few or no deformities, blue scleras and suffer premature hearing loss. In perinatal lethal type OI, there are severe postnatal fractures, abnormal bone formation, severe deformities, blue scleras and connective tissue fragility. Progressive deforming OI features include prenatal fractures, deformities that are usually present at birth, very short stature, blue scleras and hearing loss; patients may also be nonambulatory. Finally, in deforming with normal scleras OI, patients will dental abnormalities and normal or grey scleras in addition to postnatal fractures, mild to moderate deformities and premature hearing loss. 

Table 1. Osteogenesis imperfecta subtypes. (McPhee and Hammer, 2019). 4. What’s going on? Collagen is an essential extracellular protein that facilitates tissue and bone development. Type-1 collagen is a major player in bone development and OI results from the insufficient production or absence of this type of collagen. The molecular genetics of OI are complex, but, generally speaking, the fundamental problem that results in a common OI phenotype is the decreased synthesis of type-1 collagen. This is as a consequence of a loss-of-function mutation in the COL1A1 gene. Under normal conditions, this gene contributes to the proper architecture of the type-1 collagen molecule; in the context of type-1 OI, the loss-of-function mutation leads to the production of non-functional mRNA and decreased, deranged protein synthesis. 

5. How is it treated? There is no cure for OI and the management of the condition is usually supportive. Bisphonate drugs can be prescribed to strengthen bone and prevent fractures. Maintaining a healthy lifestyle is recommended. Physiotherapy is considered an important treatment modality and some patients may benefit from surgery to further support bones or treat deformities. Bone infections are a possibility in OI, and are treated with antibiotics and antiseptics. Most people with OI have mild disease and the prognosis is generally favourable. 

6. That’s interesting... Immunotherapy is a novel and dynamic area of modern medicine that has the potential to treat a wide array of diseases. Denosumab is an emerging agent in the treatment of osteogenesis imperfecta. This immunotherapeutic drug prevents osteoclast formation which inhibits bone resorption. It is thought that denosumab may help prevent fractures in OI patients, although more research is needed in this area.

[biomedicool]

Chromosomes

Chromosomes are thread-like structures located inside the nucleus of animal and plant cells. Each chromosome is made of protein and a single molecule of deoxyribonucleic acid (DNA). Passed from parents to offspring, DNA contains the specific instructions that make each type of living creature unique.

Humans have 23 pairs of chromosomes, for a total of 46 chromosomes.

The unique structure of chromosomes keeps DNA tightly wrapped around spool-like proteins, called histones. Without such packaging, DNA molecules would be too long to fit inside cells. 

Cells must constantly divide to produce new cells to replace old, worn-out cells. 

During cell division, it is essential that DNA remains intact and evenly distributed among cells - chromosomes ensure this.

Changes in the number or structure of chromosomes in new cells may lead to serious problems/cancer.

Centromeres

Centromeres help to keep chromosomes properly aligned during cell division. As chromosomes are copied in preparation for production of a new cell, the centromere serves as an attachment site for the two halves of each replicated chromosome, known as sister chromatids.

Telomeres

Telomeres are repetitive stretches of DNA located at the ends of linear chromosomes. 

They protect the ends of chromosomes - similar to the way the tips of shoelaces keep them from unravelling.

In many types of cells, telomeres lose a bit of their DNA every time a cell divides. 

When all of the telomere DNA is gone, the cell cannot replicate and dies.

Telomeres also play a role in cancer. The chromosomes of malignant cells usually do not lose their telomeres, helping to fuel the uncontrolled growth..

How are chromosomes inherited?

In humans and most other complex organisms, one copy of each chromosome is inherited from the female parent and the other from the male parent. This explains why children inherit some of their traits from their mother and others from their father.

The pattern of inheritance is different for the small circular chromosome found in mitochondria. Only egg cells - and not sperm cells - keep their mitochondria during fertilization. So, mitochondrial DNA is always inherited from the female parent. In humans, a few conditions, including some forms of hearing impairment and diabetes, have been associated with DNA found in the mitochondria.

[howdoesithappen]

Super post for anybody interested in molecular biology!

[biotechnlgy]

[howdoesithappen]

Maple syrup urine disease: mechanisms and management

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in ...

A comprehensive paper on MSUD. 

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Maple Syrup Urine Disease (MSUD)

1. In a nutshell Maple syrup urine disease (MSUD) is an inborn disorder of metabolism. MSUD is a genetic condition, inherited in an autosomal dominant manner. Genetic mutations affect the branched-chain alpha-ketoacid dehydrogenase complex (BCKAD), and cause errors in BCCA catabolism. Clinical severity varies, but MSUD classically presents in the neonate with developmental delay, failure to thrive, feeding difficulty and a maple syrup odour in the ear wax and urine. If untreated, irreversible neurological damage and metabolic decompensation can occur with catastrophic consequences. Treatment of MSUD involves dietary restriction of BCAA’s and close monitoring of metabolic status. Prognosis is favourable if the condition is detected and treated early. Thus, newborn screening for MSUD is relatively common. 2. What causes it? MSUD is a genetic disorder; the condition is inherited in an autosomal recessive manner, this means that both parents of an affected individual are unaffected carriers. Autosomal recessive disorders may not occur in every familial generation. In MSUD, genetic mutations affecting the BCKAD (BCKDHA, BCKDHB, DBT and DLD) drive the underlying pathophysiology and clinical symptomatology. 

3. What are the symptoms? There a several clinical phenotypes of MSUD. The disease is named after the characteristic odour present in the urine and cerumen of the neonate; In the classic presentation of the disease this may be accompanied by poor feeding. irritability and lethargy. Neurological damage and developmental delay are serious consequences of unaddressed MSUD. 

4. What’s going on? The BCKAD is necessary in order for the proper catabolism or “breaking-down” of BCAA’s. BCAA’s are found ubiquitously in protein-rich foodstuffs and play important roles in protein synthesis, glucose metabolism and cellular signalling. Under normal conditions, the BCKAD converts the BCAA’s leucine, isoleucine and valine into alpha-ketoacids by the enzyme branched-chain aminotransferase. The BCKAD then initiates the oxidative decarboxylation of these alpha-ketoacids into the active compounds: acetoacetate, acetyl-CoA and succinyl-CoA. Accumulation of BCAA’s due to pathogenic defects in the BCKAD cause MSUD and result in the development of the many signs and symptoms of the condition.

Figure. Overview of BCAA catabolic pathway. Abbreviations: KIC, α-ketoisocaproic acid; KIV, α-ketoisovaleric acid; KMV, α-keto-β-methylvaleric acid; Glu, glutamate; BCAAs, branched-chain amino acids; BCKAD, branched-chain α-ketoacid dehydrogenase. 5. How is it treated? Early detection of MSUD is key as the prognosis is generally very favourable if the condition is treated early. Tandem mass spectrometry has helped in achieving a timely diagnosis. Dietary restriction of BCAA’s is effective in ameliorating the harmful clinical consequences of MSUD. 

6. That’s interesting... In a neurological context, the proper catabolism of BCAA’s is essential for the proper synthesis of glutamate. Glutamate is a neurotransmitter that plays a role in brain development and cognitive functions such as learning and memory formation. It is thought that the disordered BCAA metabolism in MSUD leads to improper synthesis of glutamate. leading to the development of some of the neurological symptoms of this disease. 

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Further reading

If you’d like to read more about the urinary system and renal disease, or if you’re just interested in learning where I source information from, here is a short reading list:

Azer, S., 2012. Core Clinical Cases In Basic Biomedical Science. London, GBR: CRC Press.

Marieb, E. and Hoehn, K., 2018. Human Anatomy & Physiology.

McPhee, S. and Hammer, G., 2019. Pathophysiology Of Disease. New York: McGraw-Hill Education Medical. 

Sahu, S., 2019. Basics of Nephrotic Syndrome. International Journal of Trend in Scientific Research and Development, Volume-3(Issue-2), pp.591-602.

I must say, Pathophysiology Of Disease is an excellent resource. I’d recommend this text to second and final year biomedicine students; it will be invaluable to you when you start looking a case studies and selected diseases in greater detail.

[howdoesithappen]

Asterixis (”Flapping Tremor”) in the setting of kidney disease

Asterixis can occur as a neuromuscular manifestation of advanced kidney disease. According to Hammer and McPhee (2019), asterixis is defined as “involuntary hand flapping when the arms are extended and wrists held back to “stop traffic.”” This condition results from altered nerve conduction in metabolic encephalopathy, which can result from many conditions apart from advanced kidney disease. 

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Proteinuria

Normally, the kidneys will retain proteins and distinguish them from waste products to be excreted in urine. Thus, proteinuria is a medical term used to describe the presence of excessive levels of protein in the urine. Transient increases in the levels of protein found in the urine may result from: 

Infection.

Prolonged, vigorous exertion.

Medication.

Pregnancy.

Diet.

Hypothermia/ exposure.

Psychosocial reasons.

If proteinuria is greatly increased or persistent in nature, it may mean that there is chronic kidney disease. Proteinuria generally results from damage to the renal filtration mechanism.  Nephrotic syndrome (NS) is characterised by massive protein loss in the urine. Albumin is an important protein, present in the blood, that is responsible for transport processes and in maintaining the oncotic pressure within the intravascular space. In other words, albumin prevents excess fluid from “leaking” out of the vessels and into the interstitial space. In the context of nephrotic syndrome, significant oedema or fluid retention develops primarily because of the loss of vast amounts of albumin in the urine. The oedema is often so severe that patients may not be able to fit their feet into their shoes. Oedema may also be overt and generalised - a condition known as anascara. 

Figure 1. Protein structure of albumin. Albumin makes up around 40-60% of blood protein content.

[medbeyondwords]

Hemodialysis

It is used for patients with end-stage renal disease (ESRD). It removes metabolic wastes and excess body water.

Dialyzers are composed of a capsule which hollow parallel membrane plates suspended in dialysate. The plates function as a semipermeable membrane across which blood and dialysate flow. By crossing this membrane, solutes and water move between a patient’s body and the dialyzer.

DIALYZERS

Hollow-fiber: These are the most common dialyzers. A porous, capillary-like fibers carrying blood serve as the dialyzer membrane.

Parallel-plate: No longer in common use. These are flat sheets of membrane material arranged in parallel. Blood and dialysate follow in parallel.

The hemodialysis machine must include a blood pump to move blood between patient and the dialyzer, a delivery system to transport dialysis solution, and monitoring devices such as pressure monitors.

Synthetic tubing designated as the “arterial” line carries blood from the arteriovenous access to the dialyze. And a “venous” line simultaneously carries dialyzed blood back to the patient.

UpToDate

[howdoesithappen]

Great post explaining renal dialysis!