Pancreatic Cancer – Important Facts

The pancreas is a gland, located behind the stomach, which produces digestive juices and hormones that regulate blood sugar. Pancreatic cancer is the twelfth most common cancer in the world (along with kidney cancer), with 338,000 new cases diagnosed in 2012. The early stages of this cancer do not usually produce symptoms, so the disease is generally advanced when it is diagnosed. The estimated 5-year prevalence of people in the world living with pancreatic cancer is 4.1 per 100,000. This cancer is almost always fatal, and is the seventh most common cause of death from cancer. About 55 per cent of pancreatic cancer cases occurred in more developed countries, with the highest incidence of pancreatic cancer being in Northern America and Europe; and the lowest incidence in Africa and Asia(1).

Adenocarcinoma is the most frequent type of pancreatic cancer; slower-growing endocrine tumors account for only a small fraction of the total burden of disease. As for nearly all cancers, incidence rates of pancreatic cancer vary among countries, with approximate 5- to 7-fold differences between countries with the lowest and highest incidence; rates reported from African countries are low because of insufficient data(3).

In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and an estimated 40,560 people will die of this disease(2). The global annual incidence rate for pancreas cancer is about 8/100,000 persons(3).

Genetics of Pancreatic Cancer

Pancreatic cancer has been associated with a number of environmental exposures and factors. One such factor is smoking. Established results show that smoking contributes to atleast 20-30% of all pancreatic cancers. Passive smoking also can increase the risk of pancreatic cancer, since environmental tobacco smoke (ETS) contains the same toxins like nicotine, carbon monoxide, ammonia and benzene. Other factors associated with pancreatic cancer are alcohol consumption, diet, obesity, diabetes mellitus, blood type and exposure to certain types of drugs like medication.

A genetic predisposition to the disease is a major risk factor for pancreatic cancer. Activation of the oncogene KRAS, with simultaneous inactivation of the tumor suppressor genes p53, DPC4, p16 and BRCA2 have been associated with the onset of pancreatic cancer. 90% of all cases of pancreatic cancer have p16 mutations, 70% have p53 mutations, and 55% have DPC4 mutations (4).

Around 10% of pancreatic cancers are hereditary, many of which occur as part of rare medical syndromes such as familial breast cancer, Peutz-Jeghers syndrome, familial melanoma, hereditary colon cancer, hereditary pancreatitis, Ataxia telangiectasia and familial pancreatic cancer(5).

MedGenome’s Solutions

MedGenome, a provider of clinical genomics solutions for personalized healthcare, offers comprehensive genetic diagnostic solutions for early detection of pancreatic cancer. The solutions provided range from single gene testing to testing a panel of genes (oncogenes and tumor suppressor genes) implicated in the onset of the disease.

Our Hereditary Cancer panel covers all the major genes linked to pancreatic cancer like KRAS, TP53 and STK11. Early detection of cancer is the most important step in ensuring a favorable prognosis, and timely surgical intervention can reduce the risk of developing cancer by up to 85%.


  3. Yadav, Dhiraj, and Albert B. Lowenfels. “The epidemiology of pancreatitis and pancreatic cancer.”Gastroenterology6 (2013): 1252-1261.


Gene Therapy: a promising potential treatment modality for LCA

Leber congenital amaurosis (LCA) is a congenital retinal disorder that primarily affects the retina. It occurs in 2 to 3 among 100,000 new born and accounts for 10-18% of all inherited blindness or severe visual impairment in children that can alleviate or worsen over a period of time. It is characterized by nystagmus, hyperopia, keratoconus, photophobia, cataract, and glaucoma, and Franceschetti’s oculo-digital sign, behaviour associated with pressing, rubbing or poking of eyes with fingers or knuckles resulting in deep-set eyes and keratoconus. 1 2 Certain genetic subtypes of LCA are also known to cause early onset of renal failure.


With more than 13 identified types of LCA, each type can be differentiated by their impairment pattern, eye abnormalities, and genetic cause. Mutation in more than 25 genes3 that are required for normal development and function of retina can result in the disease and early visual impairment. The genes may be associated with either the development of photoreceptor cells, involved in phototransduction or normal functioning of cilia. While mutations in genes RPE65, CRB1, GUCY2D, and CEP290 are known to contribute majorly, mutations in other genes are also known to cause LCA. Below is the table showing genes and its proportion of contribution in LCA.4


Gene Occurrence
RPE65 3%-16%
GUCY2D 6%-21%
AIPL1 4%-8%
LCA5 ~1%-2%
CRX ~3%
CEP290 ≤20%
RDH12 ~4%
KCNJ13, and
Not certain
IMPDH1 Rare cause of dominant LCA


Situated on chromosome 1’s short arm (p), RPE65 gene encodes a vital enzyme in the retinal pigment epithelium (RPE) needed for regeneration of 11-cis-retinol during the visual cycle. Absence of the enzyme in biallelic mutation of the gene results in the accumulation of toxic precursors that damage the epithelial cells, and loss of photoreceptor cells and vision.


LCA follows autosomal recessive pattern of inheritance and can be diagnosed by Electroretinography (ERG), a technique measuring electrical activity of retina. Children with LCA show lower or absence of the activity. With no surgical or medical therapy available currently, LCA is regarded as an incurable disorder and is mainly managed through symptomatic and supportive. Additionally, refractive error correction, utilization of low-vision aids is also known to benefit affected individuals. However, with several clinical trials underway at institutions like Moorfields Eye Hospital at the University College of London, Universities of Pennsylvania and Florida, and Children’s Hospital of Philadelphia showing positive results of gene therapy for LCA2 caused RPE65 mutation is showing up as a potential treatment option.5


Detection of RPE65 mutations is done using molecular genetic testing using sequencing technologies with clinical symptoms and signs providing vital information about the genes to test for and their order.6 Identifying the genetic cause of an inherited disease, genetic diagnostics helps by confirming the clinical diagnosis, availing appropriate therapeutic methods, and enables clinicians to determine the prognosis and progression of the disorder.7


Gene therapies treat disease by inactivating or replacing defective gene or by introducing a novel gene. Viruses, especially Adeno-associated viruses (AAV) are commonly used for introduction of genes due to their simple structure and biology. Belonging to parvovirus family, AAV need co-infection on other viruses such as adenovirus for replication. Although less immunogenic on comparison chances of triggering an immune response are present. Thus, delivering appropriate dosage without eliciting an immune response that could be dangerous to patient or render the therapy ineffective is a challenge. Among the 12 identified serotypes, AAV1 to AAV 12, AAV2, AAV4, and AAV5 are exclusive for retinal disorders, AAV2 being more common.


Small size of eye allows for small amounts of vector usage and immunological advantage offered by the blood-ocular barrier in eye make it ideal for gene therapy. Various studies are being conducted to check the effectiveness of the therapy in retinal diseases caused by RPE65 variants using AAV vectors for introducing normal copy of the gene subretinaly. Situated on chromosome 1’s short arm (p), RPE65 gene encodes a vital enzyme in the retinal pigment epithelium (RPE) needed for regeneration of 11-cis-retinol during the visual cycle. Absence of the enzyme in biallelic mutation of the gene results in the accumulation of toxic precursors that damage the epithelial cells, and loss of photoreceptor cells and vision.
Gene therapy gained further impetus as a potential treatment in 2017 with U.S. Food and Drug Administration (FDA) approving Luxturna (voretigene neparvovec-rzyl) by Spark Therapeutics, Inc for treating eye disorders caused by RPE65 mutations. Using recombinant AAV vector, Luxturna helps in restoring the normal vision in children and adults by delivering a normal copy of the gene directly to retinal cells that allows for the expression of a protein responsible for converting light to an electrical signal in the retina.8 A phase 3 study conducted on 31 subjects showed that patients who received Luxturna demonstrated significant improvement in effectively finishing the obstacle path even at low illumination in contrast to control group.


In order to analyse the efficacy and safety of unilateral and subretinal injections of AV2 and 4 Le Meur, et al, Molecular Therapy, carried out a study on 9 subjects having RPE65 gene mutation associated LCA. Visual activity and general and ocular tolerance in nine subjects were assessed for a year after administering of the vectors in either low or heavy dosages. In an ancillary study which included six of the above subjects assessment was followed up for 2 to 3.5 years. At the end all of them showed good tolerance for the vector; and visual field improvement and stabilization, enhanced visual acuity in subjects with nystagmus, and cortical activation along with visual field and pathways was observed during Functional magnetic resonance imaging (fMRI) evaluation.9


India also is slowly catching up on gene therapy with currently 10 centres across India concentrating on genetic therapies for various disorders ranging from head and neck cancer, haemophilia, leukaemia, cervical cancer to eye disorders.10Narayana Nethralaya, an eye hospital in Bengaluru, has set up a Centre for Regenerative Medicine, Genetics and Gene Therapy that will be focused on providing genetic care to patients, especially those having LCA.11 12 Government of India is also encouraging the gene therapy research in India by providing financial assistance through organizations like Department of Science and Technology (DST), Department of Biotechnology (DBT), and Indian Council of Medical Research (ICMR), etc. 9


Gene therapy is potential treatment modality that holds promise of curing a disease at the root cause than just alleviating the symptoms. It could be an effective treatment option of future if more researches and clinical studies are conducted to analyse the safety and efficacy of the therapy and regulatory authorities to develop policies in streamlining the process. 10


Reference :

Pompe Disease

Pompe disease is a rare (estimated at 1 in every 40,000 births), inherited and often fatal disorder that disables the heart and skeletal muscles.  It is caused by mutations in a gene that makes an enzyme called acid alpha-glucosidase (GAA).  Normally, the body uses GAA to break down glycogen, a stored form of sugar used for energy.  The enzyme performs its function in intracellular compartments called lysosomes. Lysosomes are known to function as cellular clearinghouses; they ingest multiple substances including glycogen, which is converted by the GAA into glucose, a sugar that fuels muscles. In Pompe disease, mutations in the GAA gene reduce or completely eliminate this essential enzyme.  Excessive amounts of lysosomal glycogen accumulate everywhere in the body, but the cells of the heart and skeletal muscles are the most seriously affected. The severity of the disease and the age of onset are related to the degree of enzyme deficiency. [1]


Types of Pompe Disease :


Early onset (or the infantile form) is the result of complete or near complete deficiency of GAA.  Symptoms begin in the first months of life, with feeding problems, poor weight gain, muscle weakness, floppiness, and head lag. Respiratory difficulties are often complicated by lung infections.  The heart is grossly enlarged. Many infants with pompe disease also have enlarged tongues.  Most babies die from cardiac or respiratory complications before their first birthday. [1]


Late onset (or juvenile/adult) Pompe disease is the result of a partial deficiency of GAA. The onset can be as early as the first decade of childhood or as late as the sixth decade of adulthood. The primary symptom is muscle weakness progressing to respiratory weakness and death from respiratory failure after a course lasting several years.  The heart is usually not involved. A diagnosis of pompe disease can be confirmed by screening for the common genetic mutations or measuring the level of GAA enzyme activity in a blood sample. Once pompe disease is diagnosed, testing of all family members and a consultation with a professional geneticist are recommended. Carriers are most reliably identified via genetic mutation analysis. [1]


Genetic Changes :


Mutations in the GAA gene cause Pompe disease. The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (also known as acid maltase). This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. The enzyme normally breaks down glycogen into a simpler sugar called glucose, which is the main energy source for most cells.

Mutations in the GAA gene prevent acid alpha-glucosidase from breaking down glycogen effectively, which allows this sugar to build up to toxic levels in lysosomes. This build up damages organs and tissues throughout the body, particularly the muscles, leading to the progressive signs and symptoms of Pompe disease.[2]

Flow Chart: [4]


Treatment :

The discovery of the GAA gene has led to rapid progress in understanding the biological mechanisms and properties of the GAA enzyme.  As a result, an enzyme replacement therapy has been developed that has shown, in clinical trials with infantile-onset patients, to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation.  A drug called alglucosidase alfa (Myozyme©), has received FDA approval for the treatment of infants and children with Pompe disease.  Another algluosidase alfa drug, Lumizyme©, has been approved for late-onset (non-infantile) Pompe disease.[1]


Sign & Symptoms :

Pompe disease is a genetic disorder that is always present at birth for those who are affected. However, symptoms may show up at any time from infancy through adulthood. Pompe disease is a single disease, but it affects people differently.Historically, Pompe disease had been described by physicians as either early-onset or late-onset, depending on when the patient’s signs and symptoms first appear. However, Pompe disease may be best understood

as a spectrum. When symptoms occur during the first few months of life, Pompe disease progresses very rapidly and is almost always fatal by the age of 1 year, usually due to heart failure. When symptoms occur after infancy, Pompe disease progresses more variably but can cause great difficulties as muscles throughout the body become weaker and weaker. The muscles most often affected are those used for breathing and mobility (the ability to move around).[5]



Pompe Disease in Infants :

Pompe disease in infants is a life-threatening condition that affects all of the major body organs. Without disease-specific treatment, the disease progresses rapidly. The infant may quickly become gravely ill. Without treatment, infants with Pompe disease are not likely to survive past the age of 1 year. The chart below lists the major symptoms. [5]


Pompe Disease in Children and Adults :


Pompe disease in children and adults tends to progress more variably than in infants. Symptoms and severity can vary widely from one person to another. Major breathing problems, such as respiratory failure, can shorten the life span of people with Pompe disease. However, many are able to adapt to the challenges that the disease presents and continue with their lives. The chart below describes the major symptoms. [5]



Diagnosis :


Diagnosing Pompe disease can be challenging because many of the symptoms are similar to those of other diseases. In addition, symptoms often develop slowly and may not present themselves at the same time. It may be easier to diagnose infants with Pompe disease because the rapid progression and more pronounced symptoms may prompt healthcare providers to perform more extensive testing. [5]


Tests that confirm the diagnosis :


A number of tests may be done to help diagnose Pompe disease and determine the extent of muscle weakness or how far the disease has progressed. However, an enzyme assay is commonly used to confirm a diagnosis of Pompe disease. This biochemical test measures the activity of acid alpha-glucosidase enzyme in a small sample of skin, muscle, or blood. The enzyme assay may be performed using different samples, which include:
⦁ Dried blood spot Lymphocyte or leukocyte (blood)
⦁ Cultured skin fibroblasts
⦁ Muscle
A diagnosis of Pompe disease is confirmed if the test shows there is less than normal or no enzyme activity. [5]
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Duchenne Muscular Dystrophy(DMD)

Duchenne muscular dystrophy (DMD) is a progressive form of muscular dystrophy that occurs primarily in males, though in rare cases may affect females. DMD causes progressive weakness and loss (atrophy) of skeletal and heart muscles. [1] It is a recessive X-/a

Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. [2]

Cause :

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene. The DMD gene provides instructions for making a protein called dystrophin. Dystophin is primarily made in the muscle cells of the heart and skeletal muscle. The main job of dystrophin in muscle cells is to help stabilize and protect muscle fibers. [1]

When dystrophin is missing, the muscle cells become damaged more easily. In response to the damage, inflammation occurs, which only worsens the process. Over time, the muscle cells without dystrophin weaken and die, leading to the muscle weakness and heart problems seen in DMD. The non-progressive memory and learning problems, as well as social behavioral problems, in some boys with DMD are most likely linked to loss of dystrophin in the neurons of the hippocampus and other parts of the brain where dystrophin is normally produced in small amounts, but at this point it is not known why this occurs and why only some people with DMD have these problems. [1]

Different genetic changes in the DMD gene can cause a spectrum of disorders known as dystrophinopathies. The dystrophinopathies can range from very mild symptoms to the more severe symptoms seen in people with DMD. Other dystrophinopathies include Becker muscular dystrophy (BMD) and DMD-associated dilated cardiomyopathy (DCM). [1]

Dystrophin in muscle fibers


Inheritance :

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In many cases, an affected male inherits the mutation from his mother, who carries one altered copy of the DMD gene. The remainder of cases probably result from new mutations in the gene in affected males and are not inherited.

In X-linked recessive inheritance, a female with one mutated copy of the gene in each cell is called a carrier. She can pass on the altered gene but usually does not experience signs and symptoms of the disorder. Occasionally, however, females who carry a DMD gene mutation may have muscle weakness and cramping. These symptoms are typically milder than the severe muscle weakness and atrophy seen in affected males. Females who carry a DMD gene mutation also have an increased risk of developing heart abnormalities including cardiomyopathy. [3]

Symptoms :

Symptoms of Duchenne muscular dystrophy (DMD) are usually noticed in boys between 1 to 6 years of age. There is a steady decline in muscle strength between the ages of 6 and 11 years. By age 10, braces may be needed for walking. By age 13, most boys with DMD are using a wheelchair full-time. The signs and symptoms include:

⦁ Taking longer to learn to sit, stand, or walk on own, which is known as delayed motor development. The average age for walking in boys with DMD is 18 months.
⦁ Having a waddling walk and difficulty climbing stairs or running.
⦁ Difficulty getting up from the floor. Children may walk their hands up their legs to stand which is known as the Gower maneuver.
⦁ Enlarged calf muscles due to the calf muscle cells being replaced by fat and connective tissue(pseudohypertrophy). This may also cause calf pain.
⦁ Muscle weakness first affecting the muscles of the hips, pelvic area, thighs and shoulders, and later the skeletal (voluntary) muscles in the arms, legs and trunk.
⦁ Tight or rigid joints (also known as contractures) may develop as muscle loss progresses. If not treated, these will become severe, causing discomfort and restricting mobility and flexibility. Contractures can affect the knees, hips, feet, elbows, wrists and fingers.
⦁ Scoliosis may develop within several years of full-time wheelchair use.
⦁ By the early teens, the respiratory and heart muscles are also affected.
⦁ Breathing problems due to weakness of the diaphragm and the other muscles around the lungs. Skeletal changes, such as scoliosis, may also increase breathing problems. Breathing problems may become life-threatening.
⦁ Progressive enlargement of the heart (cardiomyopathy) that stops the heart from pumping blood efficiently and becomes life-threatening in many cases.
⦁ Learning and memory issues (cognitive impairment) may occur in some cases, but do not worsen as DMD progresses.
⦁ Communication may be more difficult for some.
⦁ Social behavior may be affected, as well as the ability to read facial cues. [1]

Diagnosis :

A child’s doctor may suspect Duchenne muscular dystrophy (DMD) in young boys who have the signs and symptoms of DMD, including progressive muscle weakness. Family history is also important. Blood tests can be used to check for increased levels of certain special proteins called muscle enzymes in the blood which can leak from damaged muscles. Most commonly, the blood level of the enzyme creatine phosphokinase (CPK or CK) is checked, but a doctor may also check the blood levels of transaminases such as aspartate transaminase and alanine transaminase. Finding a change in the DMD gene that can cause DMD through genetic testing confirms the diagnosis of DMD.

Testing for DMD may include :  

  • Blood test which measures the levels of serum creatine phosphokinase (CK or CPK). Very high CK levels indicate muscle damage is causing the muscle weakness, rather than nerve damage.
  • Molecular genetic testing (usually blood cells are used) to see whether there is a change or mutation in the DMD gene that can cause DMD or one of the related dystrophinopathies.
  • Electromyography can be used to distinguish conditions that only impact the muscles (myotonic) from those that involve that brain and muscles (neurogenic). [1]

Treatment :

There is no known cure for Duchenne muscular dystrophy (DMD) but research is ongoing. The goal of treatment is to control the symptoms of DMD and related complications caused by severe progressive muscle weakness and loss in order to maximize the quality of life. An enlarged, weakened heart (dilated cardiomyopathy) may be treated with medications, but in severe cases a heart transplant may be necessary. Assistive devices for breathing difficulties may be needed, especially at night and as the disease progresses.

Gentle exercise is encouraged for people with DMD. Physical inactivity (such as bed rest) can worsen the muscle disease, but so can overexertion. Physical therapy may be helpful to maintain muscle strength and function. Orthopedic devices (such as braces and wheelchairs) may improve the ability to move and take care of oneself.

Steroids (corticosteroids) may improve the strength and function of muscles in people with DMD, including lung function. Steroid options include:
⦁ Prednisone is a steroid that has been shown to extend the ability to walk by 2 to 5 years. However, the possible side effects of prednisone include weight gain, high blood pressure, behavior changes, and delayed growth.
Deflazacort (another form of prednisone), is used in Europe and believed to have fewer side effects and was recently approved in the United States by the FDA.

Oxandrolone, a medication used in a research study, also has similar benefits to prednisone, but with fewer side effects. [3]

Rehabilitation: Physical therapy, occupational therapy, speech therapy and other recreational therapies play a very important role in helping the patient to go about his daily activities and increasing their own independency. The main aim of these therapies is to maintain the muscle extensibility and prevent joint contractures that lead to deformities.

Rehabilitative improve quality of life of the patients and prevent secondary complications like contractures and deformity. [4]

Gene Therapy: The aim of the Gene Therapy is precisely to introduce these genes into the patients to normalize the gene expression and protein production. Although it might seem like an easy task, in reality it is quiet daunting due to the complexity of human genes and gene expression.

Several novel strategies for replacing or repairing the defective gene are in development, with early encouraging results from animal models. In most of the gene therapies a normal gene is inserted into the genome to replace the abnormal gene causing the disease. This can be done using viral vectors, Antisense- Induced Exon Skipping or Read through Stop Codon Strategies. However, the high cost and lack of human clinical trials, makes gene therapy an apprehensive approach.

All the treatment options that are available so far provide only symptomatic treatment but fail to act at a cellular level. They fail to regenerate the wasted muscles or reverse the pathology of the disease.

Also, Muscular Dystrophy is a genetic disorder and hence no treatment can repair the core changes in the defective genetic structure. [4]

Case Study 1:

Credit: NeurogenGen Brain & Spine Institute by Dr. Nandini Gokulchandran and Dr. Alok Sharma

The patient who is 5 years old child residing in Kanchrapara, Kolkata. The patient is a known case of Duchenne’s Muscular Dystrophy (DMD). Since birth, there were small movements on a bed which patient could not perform but not really noticed by his parents. His parents first noticed an abnormality in their child when he was 3 years old. It all started with difficulty in climbing stairs and not being able to pull himself upright from a sitting or sleeping position, running slowly etc. When he was around 4 years old he was diagnosed with Duchene Muscular Dystrophy on the basis of clinical investigations.

At NeuroGen on examination following problems were noted in Patient:
⦁ Partially dependent in all ADLs (All Day Living Activities)
⦁ Difficulty in climbing stairs
⦁ Difficulty in running and walking
⦁ Couldn’t comfortably pull himself upright from seating or sleeping position.
⦁ Abnormal thickness and tightening in calf muscles
⦁ Gait was abnormal, he used to bend is stomach front and used to walk by bending on each side.
⦁ Lower limb – strongest muscles of our body the hip muscles and inner thigh muscles were affected.
⦁ Poor breathing capacity
⦁ Walking balance was fair
⦁ Poor stability and mobility of trunk muscles like abdominals and back extensors.
⦁ Performing hand functions was difficult.
⦁ Difficulty in bed mobility
⦁ standing balance was poor
⦁ Speech was affected, he stammers a lot.
⦁ Can’t do cycling or one leg standing
⦁ Stamina to do exercise is less, gets tired early.
⦁ He used to fall for once or twice every day.
⦁ Occurrence of bed wetting occasionally
He underwent Stem Cell Transplantation and advised to continue a certain diet chart along with medications. He is doing 4-5 hours of therapy in a day. Within two months after discharge, He has shown tremendous improvements and has reached a near around 70% improvement stage. On following up with a patient condition on the telephone, we have found below improvements:
⦁ Patient has now started cycling with his friends which he was unable to do earlier.
⦁ Standing and walking balance has improved – now he attempts to do one leg standing which was not possible before at all.
⦁ He can run properly now and play with his friends.
⦁ Qualitative improvements are noted in terms of shifting himself on his own. He has to put lesser efforts now for doing bed mobility activities like rolling and getting up from sleeping position.
⦁ His speech has improved, he stammers less now and hence speech has become almost normal.
⦁ Upper limb activity like wearing his own clothes and brushing teeth etc has become better than before.
⦁ Gait and posture has improved, he sits with more erect posture now and walks with better foot clearance.
⦁ Calf muscle hypertrophy has reduced; calves are softer now.
⦁ Stamina has improved – earlier he used to so only 1-2hrous or therapy but now he can do 4-5hours of therapy sessions every day and can now perform any activity for longer duration.
⦁ Falls have reduced greatly, after stem cell therapy since December 2015, he has fallen only twice. It has almost stopped.
⦁ Bed wetting has completely stopped.

Case Study 2:
Credit: Rupam Sinha, Soumyabrata Sarkar, Tanya Khaitan and  Soumyajit Dutta
Department of Oral Medicine and Radiology, Haldia Institute of Dental Sciences and Research, Haldia, West Bengal, India
J Family Med Prim Care. 2017 Jul-Sep; 6(3): 654–656.

A 12-year-old male patient with a chief complaint of the painful decayed tooth in the lower right jaw region.

The medical history of repeated falls, fatigue, muscle weakness, and inability to climb stairs. There was no history of muscular pain and cranial nerve involvement. His intelligence quotient was claimed to be in the normal range. Patient’s family history revealed that one of his maternal uncles died of the same illness at a young age.

On general physical examination, the child had an obese appearance and presented with difficulty in standing, walking, getting up from sitting position and climbing stairs, proximal weakness, calf hypertrophy, hamstring muscle contracture, and positive Gower’s sign.

Figure: Proximal muscle weakness of upper and lower limbs and calf hypertrophy

There was no thinning and twitching of muscles, muscle tone, and cranial nerve examination was also found to be normal. Intraoral examination revealed anterior open bite, left posterior cross bite, enlarged tongue, crowding in lower anteriors, decayed 46, and poor oral hygiene status.

The patient was subjected to radiological and laboratory investigations. Panoramic radiography revealed no abnormality except for grossly carious 46 indicative of chronic periapical abscess. Serological analysis showed creatine kinase (CK) level to be elevated to 7342 U/L, lactate dehydrogenase to 595 μg/dl, and alanine transaminase level to 124 U/L. On electromyographic examination, interference pattern analysis revealed myopathic pattern in the right vastus lateralis suggestive of primary muscle disease. Deltoid muscle biopsy revealed positivity for alpha, beta, gamma, delta-sarcoglycan and negativity for DYS1, DY2, and DYS3. Based on the history, clinical examination and investigations, a diagnosis of DMD were established.

References :

Cystic Fibrosis

Cystic Fibrosis (CF) is a chronic, genetic disease that affects the secretory glands, which are responsible for the production of fluids like mucus and sweat. Due to abnormal function of these glands, patients excessively produce a thick and sticky mucus that affects the respiratory, digestive and reproductive systems. It is particularly problematic in the lungs since the mucus accumulates and block the airways, leading to breathing difficulties.[1]

Cystic fibrosis is a common genetic disease within the white population in the United States. The disease occurs in 1 in 2,500 to 3,500 white newborns. Cystic fibrosis is less common in other ethnic groups, affecting about 1 in 17,000 African Americans and 1 in 31,000 Asian Americans. [2]
Most people with cystic fibrosis also have digestive problems. Some affected babies have meconium ileus, a blockage of the intestine that occurs shortly after birth. Other digestive problems result from a buildup of thick, sticky mucus in the pancreas. In people with cystic fibrosis, mucus blocks the ducts of the pancreas, reducing the production of insulin and preventing digestive enzymes from reaching the intestines to aid digestion. Problems with digestion can lead to diarrhea, malnutrition, poor growth, and weight loss. In adolescence or adulthood, a shortage of insulin can cause a form of diabetes known as cystic fibrosis-related diabetes mellitus (CFRDM). [2]



Genetic Changes :

Mutations in the CFTR gene cause cystic fibrosis. The CFTR gene provides instructions for making a channel that transports negatively charged particles called chloride ions into and out of cells. Chloride is a component of sodium chloride, a common salt found in sweat. Chloride also has important functions in cells; for example, the flow of chloride ions helps control the movement of water in tissues, which is necessary for the production of thin, freely flowing mucus.

Mutations in the CFTR gene disrupt the function of the chloride channels, preventing them from regulating the flow of chloride ions and water across cell membranes. As a result, cells that line the passageways of the lungs, pancreas, and other organs produce mucus that is unusually thick and sticky. This mucus clogs the airways and various ducts, causing the characteristic signs and symptoms of cystic fibrosis.

Other genetic and environmental factors likely influence the severity of the condition. For example, mutations in genes other than CFTR might help explain why some people with cystic fibrosis are more severely affected than others. Most of these genetic changes have not been identified, however. [2]

Cystic Fibrosis Statistics Worldwide :

Cystic fibrosis can be developed by people from both genders, as well as all races and ethnic groups. However, the incidence of CF varies across the globe. Cystic fibrosis is particularly common among Caucasians of Northern European descent and among Latinos and American Indians, especially the Pueblo and Zuni. The incidence of cystic fibrosis in the European Union one in 2000-3000 newborns, but there are also discrepancies among the different countries. On the contrary, the disease is severely underdiagnosed in Asia, and research on the topic suggests that the prevalence of CF is rare. [1]

The increase in CF patients’ life expectancy is a worldwide tendency, with a steadily growth in the number of adults who suffer from the disease. However, this also carry negative implications. Adult CF patients tend to experience additional health challenges including CF-related diabetes and osteoporosis. In addition, over 95% of men with CF are sterile. In addition to the increase in life expectancy, research also demonstrates that there has been a decrease in the incidence of the disease worldwide. [1]
According to the Cystic Fibrosis Foundation Patient Registry, in the United

States :
⦁ More than 30,000 people are living with cystic fibrosis (more than 70,000 worldwide).
⦁ Approximately 1,000 new cases of CF are diagnosed each year.
⦁ More than 75 percent of people with CF are diagnosed by age 2.
⦁ More than half of the CF population is age 18 or older. [3]
In Europe, the rate of cystic fibrosis is between 1:2000 and 1:3000 births. In southern Africa, the carrier frequency is 1 in 42, with a calculated incidence of 1 in 7056 births. The incidence in Latin America ranges from 1:3900 to 1:8500. Estimates for the Middle East are between 1:2560 and 1:15,876. [4]
Cystic fibrosis is rare among Asians. In India, the prevalence is estimated at around 1:40 000 to 1:100 000 births. In Japan, the estimated incidence is 1:100 000 to 1:350 000. [4]

Estimated Burden of Cystic fibrosis in India :

Total estimated live births in India during year 2012 were 27,271,000. The number of children born every year with CF may be about 10908 presuming incidence to be about 1 in 2500 live birth; 2727 with a presumed incidence of 1 in 10000; and 681 with a presumed incidence of 1 in 40000. Most of these children may be dying due to severe pneumonia or malnutrition as the diagnosis may not be made due to ignorance or non-availability of diagnostic tests.

The children with CF in India are diagnosed late, but the clinical features are similar to the patients from rest of the world. Indian patients differ from their counterparts from developed world in being frequently malnourished, having clinical evidence of fat soluble vitamin deficiencies and more chances of being colonized with Pseudomonas. Diagnostic facilities in India are scarce. Mutation profile is different with a lower prevalence of ΔF508. Management of CF in India is difficult due to inadequate trained manpower, lack of financial support, limited availability and high cost of pharmacologic agents. The determinants of early death in Indian children with CF include: severe malnutrition, colonization with Pseudomonas at the time of diagnosis, more than four episodes of lower respiratory infection per year and age of onset of symptoms before 2 months of age. [5]

Clinical Presentations in Indian Cystic fibrosis Cases :

The Indian CF patients mainly present with respiratory and gastrointestinal problems associated with malnutrition. Among these varied clinical symptoms, pulmonary involvement has been observed to be the most predominant and severe CF manifestation.

Although majority of CF cases present during infancy and childhood, a number of cases have been diagnosed in the adulthood. The cases presenting pancreatic abnormalities especially were observed, to possess a higher age group, indicating that the damage of pancreas inutero occurs progressively; and the patients can present with symptomatic pancreatic abnormalities as the initial manifestations of CF in adulthood. [6]

Diagnosis :

The diagnosis of cystic fibrosis requires a combination of clinical features suggestive of the disease with biochemical or genetic markers of CFTR dysfunction. (Table 1)

In a child with a high pretest probability of CF, the diagnosis is confirmed by sweat chloride estimation by pilocarpine iontophoresis method. A sweat chloride concentration of > 60 mmol/L is almost always diagnostic of CF, as a falsely elevated sweat chloride in the absence of CF is rare, although reported in a number of unusual clinical conditions; they can usually be readily distinguished from CF. Non-classic or atypical CF (1-2% of CF population), defines patients with a CF phenotype in at least one organ system and a normal or borderline sweat chloride level. In practice, the most common cause of incorrect sweat chloride results is laboratory error; therefore, it is recommended to be done only at CFF accredited care centers. But in countries like India where such facilities are not available, it should be carried out in experienced laboratories and repeated 2-3 times. [5]

Symptoms :

The type and severity of CF symptoms can differ widely from person to person. The most common symptoms are:
⦁ Very salty-tasting skin
⦁ Persistent coughing, at times with phlegm
⦁ Frequent lung infections, such as pneumonia or bronchitis
⦁ Wheezing or shortness of breath
⦁ Poor growth or poor weight gain in spite of a good appetite
⦁ Frequent greasy, bulky stools or difficulty in bowel movements
⦁ Small, fleshy growths in the nose, called nasal polyps
⦁ Chronic sinus infections
⦁ Clubbing or enlargement of the fingertips and toes
⦁ Rectal prolapse (when the rectum sticks out through the anus)
Male infertility[5]

Cystic Fibrosis Medications :

Cystic fibrosis is a life-threatening, genetic disease that affects patients’ ability to breathe and is marked by persistent lung infections. While it currently has no cure, a number of treatments, therapeutics, and supplements exist to help cystic fibrosis patients maintain their health and well-being. These include medications approved for the disease, but treatment plans are unique and tailored to each patient’s specific health characteristics and needs. Cystic fibrosis medications range from CFTR modulators and enzyme supplements, to mucolytics, antibiotics, and vitamins. [7]

Enzymes to Treat Cystic Fibrosis :

According to the Cystic Fibrosis Foundation (CFF), 87 percent of people with cystic fibrosis need to take enzymes. These supplements come in the form of oral capsules that work in the intestines to help patients absorb nutrients from their food. Each capsule has small beads with digestive enzymes, and is covered with a special enteric coating to allow the beads to dissolve in the small intestine. It is important that patients take the right amount of enzymes, just before a meal, and should check with the dietitian on their CF care team for the exact amount of enzymes to take. Enzymes help patients digest carbohydrates, proteins and fats; gain and maintain a healthy weight; and absorb essential nutrients, such as vitamins and minerals. Enzymes for patients with cystic fibrosis include:
Pancrelipase (Cotazym, Cotazym-S, Creon, Dygase, Ku-Zyme, Ku-Zyme HP, Kutrase, Lapase, Lipram, Lipram UL, Palcaps 10, Pancrease MT, Pancreaze, Pancrecarb MS, Pangestyme CN 10, Pangestyme EC, Panocaps, Panocaps MT 16, Panokase, Pertzye, Ultrase, Viokace, Viokase, Zenpep)
⦁ Pancreatin (Hi-Vegi-Lip, Pan-2400, Pancreatin 4X) [7]

Mucolytics for Patients with Cystic Fibrosis :

Mucolytics are in a category of cystic fibrosis medications designed to help thin mucus in the lungs so patients can cough and expel mucus more easily. These inhaled medications “cut up” the DNA strands outside the cell that are responsible for making CF mucus thick and sticky. The DNA strands are formed in the white blood cells and are able to fight lung infections. By moving the mucus out of the lungs, the damage caused by chronic lung infections is delayed or reduced. The class of mucolytic medications include:
Dornase alfa (Pulmozyme)
⦁ Hypertonic saline[7]

Antibiotics to Help Cystic Fibrosis Patients :

Lung infections are particularly common in cystic fibrosis, and antibiotics are used to fight or control infection-causing bacteria. There are oral antibiotics (liquids, tablets or capsules to be swallowed), intravenous (IV) antibiotics (liquid medicine administered directly into the blood through a catheter), and inhaled antibiotics (an aerosol or mist inhaled directly to the airways). The choice of antibiotic drug, dosage, and duration of treatment depend on the patient and the infection, but the options include:

⦁ Tobramycin inhalation solution (TOBI, Bethkis)
⦁ Aztreonam for inhalation solution (Cayston, Azactam)
⦁ Tobramycin inhalation powder (TOBI Podhaler)
⦁ Azithromycin (Zithromax, Zmax)
⦁ Amikin (Amikacin)
⦁ Gentamicin (Garamycin[7]

Vitamins to Ease Cystic Fibrosis Symptoms :

Vitamins can help the bodies of patients with cystic fibrosis to grow, function better, and fight infections. While vitamin A is used to improve vision, bone and tooth formation, cell function, and immunity, vitamin D helps to build and maintain strong bones and teeth. Vitamin E is particularly important as it is an antioxidant that protects compounds in the body from combining with oxygen, keeping red blood cells healthy and helping to fight infections. In addition, vitamin K helps the blood to clot and helps maintain the health of the bones. Some vitamins of note include:
⦁ Alpha E
⦁ Amino-Opti-E
⦁ Aqua Gem-EAqua-E
⦁ Aquasol E
⦁ Aquavite-E
⦁ Centrum Singles-Vitamin E
⦁ E Pherol
⦁ E-400 Clear
⦁ E-600
⦁ E-Gems
⦁ Nutr-E-Sol
⦁ Vita-Plus E Natural [7]

References :

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