Need to balance competing priorities of public health in resource constrained settings
Rare diseases place a major economic burden on any Country and especially in resource-constrained settings. The financial capacity to support exorbitant cost of treatment, is an important consideration in public health policy development with reference to treatment for rare diseases. In resource-constrained settings, it is pertinent to balance competing interests of public health for achieving optimal outcome for the resources allocated. As resources are limited and have multiple uses, the policy makers have to make choice of prioritizing certain set of interventions over others- the appropriate choice is then to support those interventions that would provide more number of healthy life years for given sum of money while simultaneously looking at the equity i.e., interventions that benefit poor who cannot afford healthcare are prioritized. Thus, interventions that address health problems of a much larger number of persons by allocating a relatively smaller amount are prioritized over others such as funding treatment of rare diseases where much greater resources will be required for addressing health problems of a far smaller number of persons. Hence, any policy on rare diseases needs to be considered in the context of the available scarce resources and the need for their utmost judicious utilization for maximizing the overall health outcomes for the whole of society measured in terms of increase of healthy life years.
Group 1: Disorders amenable to one-time curative treatment:
a) Disorders amenable to treatment with Hematopoietic Stem Cell Transplantation (HSCT) –
Lysosomal storage diseases are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. There are nearly 50 of these disorders altogether, and they may affect different parts of the body, including the skeleton, brain, skin, heart, and central nervous system. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases.
Aspartylglucosaminuria: Patients appear normal for several months after birth and then present with recurrent infections, diarrhea, and hernias. Later, there may be a gradual coarsening of facial features, an enlarged tongue (macroglossia) and enlargement of the liver (hepatomegaly).
Mucopolysaccharide Storage Diseases (Hurler Disease and variants, Hunter, Sanfilippo Types A,B,C,D, Morquio Types A and B, Maroteaux-Lamy and Sly diseases): The MPS diseases are caused by disturbances in the normal breakdown of complex carbohydrates known as mucopolysaccharides. All of the MPS diseases have certain characteristics in common, which include deformities of the bones and joints that interfere with mobility and often cause osteoarthritis, especially of the large, weight-bearing joints. All of the MPS diseases except Sanfilippo disease interfere with growth, causing short stature.
Chronic granulomatous (gran-u-LOM-uh-tus) disease (CGD) is an inherited disorder that occurs when a type of white blood cell (phagocyte) that usually helps your body fight infections doesn't work properly. As a result, the phagocytes can't protect your body from bacterial and fungal infections.
Symptoms
People with chronic granulomatous disease experience serious bacterial or fungal infection every few years. An infection in the lungs, including pneumonia, is common. People with CGD may develop a serious type of fungal pneumonia after being exposed to dead leaves, mulch or hay.
It's also common for people with CGD to experience infections of the skin, liver, stomach and intestines, brain, and eyes. Signs and symptoms associated with infections include:
Fever
Chest pain when inhaling or exhaling
Swollen and sore lymph glands
A persistent runny nose
Skin irritation that may include a rash, swelling or redness
Swelling and redness in your mouth
Gastrointestinal problems that may include vomiting, diarrhea, stomach pain, bloody stool or a painful pocket of pus near the anus
Wiskott-Aldrich syndrome is characterized by abnormal immune system function (immune deficiency), eczema (an inflammatory skin disorder characterized by abnormal patches of red, irritated skin), and a reduced ability to form blood clots. This condition primarily affects males.
Individuals with Wiskott-Aldrich syndrome have microthrombocytopenia, which is a decrease in the number and size of blood cells involved in clotting (platelets). This platelet abnormality, which is typically present from birth, can lead to easy bruising, bloody diarrhea, or episodes of prolonged bleeding following nose bleeds or minor trauma. Microthrombocytopenia can also lead to small areas of bleeding just under the surface of the skin, resulting in purplish spots called purpura, or variably sized rashes made up of tiny red spots called petechiae. In some cases, particularly if a bleeding episode occurs within the brain, prolonged bleeding can be life-threatening.
Wiskott-Aldrich syndrome is also characterized by abnormal or nonfunctional immune system cells known as white blood cells. Changes in white blood cells lead to an increased risk of several immune and inflammatory disorders in people with Wiskott-Aldrich syndrome. These immune problems vary in severity and include an increased susceptibility to infection from bacteria, viruses, and fungi. People with Wiskott-Aldrich syndrome are at greater risk of developing autoimmune disorders, such as rheumatoid arthritis, vasculitis, or hemolytic anemia. These disorder occur when the immune system malfunctions and attacks the body's own tissues and organs. The chance of developing certain types of cancer, such as cancer of the immune system cells (lymphoma), is also increased in people with Wiskott-Aldrich syndrome.
Wiskott-Aldrich syndrome is often considered to be part of a disease spectrum with two other disorders: X-linked thrombocytopenia and severe congenital neutropenia. These conditions have overlapping signs and symptoms and the same genetic cause.
Osteopetrosis
Osteopetrosis is marked by increased bone density due to a defect in bone reabsorption by cells called osteoclasts. This leads to accumulation of bone with defective architecture, making them brittle and susceptible to fracture. In some cases, this is also accompanied by skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to bone fragility. Early diagnosis is important in the most severe forms of these disorders, as they cause irreversible complications, and may be treated with hematopoietic stem cell transplant.
There are three types of osteopetrosis, classified by their mode of inheritance: autosomal dominant, autosomal recessive, and X-linked recessive. The autosomal dominant form is the most common: usually, patients have mild symptoms that present in late childhood to adulthood. The autosomal recessive form, also called the malignant infantile type, is apparent soon after birth and frequently shortens life expectancy. Finally, the X-linked form of osteopetrosis is extremely rare, with only a few cases reported. There is also an intermediate type of osteopetrosis, comprising both milder autosomal recessive forms and dominant ones with early and severe presentation.
Me and my mother was diagnosed with osteoporosis and some injection was given my orthopedic surgeon Dr. Bireshwar Banerjee at Kolkata Kothari Medical Center.
Females carry 2 X chromosomes and males only one.
When TB spread to my bones I was adviced an MRI by
Dr. Vineesh Mathur
Director - Division of Spine
Institute Of Musculoskeletal Disorders and Orthopaedics at Medanta for an MRI of legs. We didn't have money and it came out in news on TOI Gurgaon. Paras hospital did the MRI free of cost.
Fanconi anaemia (FA)
It is an autosomal recessive disease with progressive loss of all the formed elements of blood (pancytopenia) with generalised dusky or olive brown pigmentation particularly of the lower trunk, flexures and neck, superimposed with scattered rain drop - like depigmented and hyperpigmented macules. Occasionally cafe- au-lait spots are also present. These patients will also have skeletal malformations in the form of aplasia or hypoplasia of the thumbs, metacarpals or radius, hip dislocations or scoliosis, Malformations of kidneys in the form of renal aplasia or horse shoe kidney, ocular abnormalities in the form of strabismus, microphthalmia and hypogonadism may be present. Some of these patients can also have hyperreflexia and mental retardation. These patients will have high incidence of neoplasias particularly nonlymphatic leukemia and hepatomas. The course is often progressively downhill with death from infections, hemorrhages or neoplasia. Initially bone marrow function can be stimulated with corticosteroids and with androgenic steroid - oxymethalone. Histocompatible bone marrow transplantation considerably improved survival period. The condition was first described by swiss paediatrician Guido Fanconi in 1927.
Fanconi anaemia is a rare disorder with incidence of 1 per 3,60,000 live births. The diagnosis of FA is made by typical cutaneous and haematological findings. Cutaneous manifestations include generalised olive-brown pigmentation particularly on the neck, trunk and flexures superimposed with rain drop-like depigmented macules. The present case was having these macules even on both the palms though it was not described previously. Following repeated blood transfusions hyperpigmentation due to iron overload may be present. Haematological manifestations include pancytopenia. Though cafe-au-lait spots were also described, no such spots were seen in the present case. Malformation of the kidneys in the form of aplasia or horse shoe kidney were described. Right kidney was absent in the present case. Though skeletal and opthalmological abnormalities, hypogondism, hyper reflexia, mental retardation, nonlymphatic leukemia, and hepatomas were described, the present case was not having any of these abnormalities. The only condition which will have these cutaneous changes with pancytopenia is dyskeratosis congenita. But early age of onset of hyperpigmentation, absence of palmoplantar hyperkeratosis, and renal involvement in the present case favour the diagnosis Fanconi anaemia.
~ Case Report
2002:68:1;46-47
PMID: 17656871
Fanconi anaemia
D Masthan Saheb
Department of Dermatology, Govt. General Hospital, Kurnool - 518 002, Andhra Pradesh, India
Correspondence Address:
D Masthan Saheb
Department of Dermatology, Govt. General Hospital, Kurnool - 518 002, Andhra Pradesh
India
Chromosome instability is a characteristic cytogenetic feature of a number of genetically determined human disorders collectively known as chromosome breakage syndromes. These disorders include Fanconi’s anemia (FA), Bloom’s syndrome (BS) and Ataxia telangiectasia (AT). In each of these, chromosome instability exists in the form of increased frequencies of breaks and inter-changes occurring either spontaneously or following treatment with various DNA-damaging agents(1,2).
Although hypersensitivity to MMC and DEB in mitogen-stimulated peripheral blood lymphocyte cultures is accepted as a diagnostic criterion in FA, interpretation is difficult in mosaic patients(3). In the present study, 4 patients showed mixed populations of lymphocytes with hypersensitivity and normal sensitivity to MMC. Such a mosaicism has been reported earlier in 25-30% of FA patients(3,7). Aplastic anemia in the remaining 10 of the 24 patients with relatively no or slight induced chromosomal breakage could be due to other bone marrow failure syndromes or nutritional deficiencies. There is need to further evaluate these patients at the molecular level to screen for FA-like gene mutations(8).
All the 14 Fanconi Anemia patients presented with hematologic abnormalities (pancytopenia and bone marrow aplasia) while only 6 patients (42%) had congenital anomalies (hypopigmentation of skin, skeletal anomalies, the most common being hypo-pigmentation of skin and clinodactyly). Eight patients also had bleeding manifestations mainly from nose and gums. MMC-stress test not only identified patients with congenital anomalies but also 8 patients (58%) who lacked any congenital malformations. Giampietro, et al.(9) reported 25-30% of FA patients without any congenital malformations all of which were diagnosed only after onset of hematologic abnormalities. A similar delay in diagnosis was observed in the present study that could be attributed to the lack of awareness among parents or referring physicians.
In the present study, induced chromosomal breakage studies could diagnose Fanconi Anemia in 5 patients with history of affected siblings. Although these patients were diagnosed after the onset of aplastic anemia, MMC-stress test can be used to detect such patients even in the pre-anemic phase. This would help in avoiding drugs that are usually administered in acquired or ‘idiopathic’ aplastic anemia. Further, screening parents of FA patients can help detect ‘silent’ cases(9-11).
A delay in diagnosis of FA can have serious consequences for patients and their families. An earlier diagnosis in FA patients (i.e., before onset of hematological abnormalities) could provide more time to find a suitable HLA compatible donor for bone marrow transplantation. Further, at-risk families (with an affected child) should be identified early and offered genetic counseling and prenatal diagnosis, as FA is an autosomal recessive disorder with a recurrence risk of 25%(5,10). Such a delay in identification of FA patients and at-risk families can be avoided by performing MMC-stress test in patients with macrocytosis and decreased platelet count as observed during screen- ing of complete blood count with differentials(11,12).
~ Indian Pediatrics Rashmi Talwar†, V. P. Choudhry*, Kiran Kucheria
From the Departments of Anatomy and Hematology*, All India Institute of Medical Sciences, New Delhi 110 029, India.
†Senior Research Fellow of CSIR.
Correspondence to: Dr. Kiran Kucheria, Professor & Head, Department of Anatomy, All India Institute of Medical Sciences, New Delhi-110029, India.
Email: kkucheria@hotmail.com
Manuscript received: January 27, 2003, Initial review completed: March 24, 2003; Revision accepted:July 30, 2003.
b) Disorders amenable to organ transplantation
Tyrosinemia
What is tyrosinemia?
Tyrosinemia is an inborn error or metabolism i.e., a genetic error in the breakdown of an amino acid called tyrosine. Due to the error in breakdown, tyrosine and certain by-products accumulate in the body and cause the various disease manifestations.
What is the defect in tyrosinemia?
Tyrosinemia can be due to a defect in various enzymes involved in tyrosine breakdown. However, the type called tyrosinemia type 1 or hepatorenal tyrosinemia is the only one that affects the liver.
It is caused by the deficiency of an enzyme called fumerylacetoacetate hydrolase (FAH). This defect is genetic and is inherited from parents; hence may run in families.
How common is this disease?
It is a rare disorder, with an estimated prevalence of 1:1,00,000 in the world. The prevalence in India is not known, and perhaps goes undiagnosed.
What are the manifestations of this disease?
This disease usually presents in infancy i.e. in children less than 1 year of age and even as early as the newborn period, but can affect adults also.
The disease mainly affects liver, nerves and kidneys. It is many times precipitated by events like fever or some other infection.
Most commonly, the children present with liver problems and acute liver failure like
fever,
irritability
vomiting,
jaundice,
bleeding from skin leading to bluish spots on the skin,
black stool(malena).
The child may have a peculiar odour of a boiled cabbage.
Doctor examining the child will find an enlarged liver, fluid in abdomen, low sugars and increased liver function tests specially liver enzymes.
Often after the acute episode is managed, certain problems persists like low weight gain, poor growth of the child, liver may remain enlarged and there may be some tests of liver which maybe persistently abnormal, especially those that indicate the tendency of the blood to clot slowly.
A shrunken liver (cirrhosis) may also be found. One of the grievous outcomes of this disease is the tendency to develop liver cancer or hepatocellular carcinoma.
Glycogen storage disorders (GSD) I, III and IV
Glycogen Storage Disease Type I
glycogen storage disease type IA
glycogen storage disease type IB
General Discussion
Glycogen storage diseases are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body. Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Glycogen storage disease type I (GSDI) is characterized by accumulation of excessive glycogen and fat in the liver and kidneys that can result in an enlarged liver and kidneys and growth retardation leading to short stature. GSDI is associated with abnormalities (mutations) in the G6PC gene (GSDIA) or SLC37A4 gene (GSDIB). These mutations result in enzyme deficiencies that block glycogen breakdown in affected organs causing excess amounts of glycogen and fat accumulation in the body tissues and low levels of circulating glucose in the blood. The enzyme deficiency also results in an imbalance or excessive accumulation of other metabolites, especially lactates, uric acid and fats like lipids and triglycerides.
Glycogen Storage Disease II (Pompe Disease): Pompe disease has an infantile form and a delayed onset form. The delayed onset form may be further broken down into a childhood form and a juvenile/adult form. Patients with the infantile form are the most severely affected. Although these infants usually appear normal at birth, the disease presents within the first two to three months with rapidly progressive muscle weakness, diminished muscle tone (hypotonia) and a type of heart disease known as hypertrophic cardiomyopathy. Feeding problems and respiratory difficulties are common. The childhood form presents during infancy or early childhood. Motor milestones may be delayed and some symptoms may resemble muscular dystrophy. The cardiac enlargement that is often present in the infantile form is seldom seen in the childhood form. The juvenile/adult form presents between the first and seventh decades as a slowly progressive muscle weakness or with symptoms of respiratory insufficiency. There is no cardiac involvement with this form.
What are Glycogen Storage Diseases (GSDs)?
GSDs are inherited genetic metabolic diseases. The underlying problem in all the GSDs is the use and storage of glycogen.
A person who has a metabolic disorder has a difficult time breaking down certain foods and creating energy. Metabolic disease is most frequently caused by an absence or deficiency in an enzyme(or protein). An enzyme can act to help the body break down food into energy.
A person with a GSD has an absence or deficiency of one of the enzymes responsible for making or breaking down glycogen in the body. The enzyme deficiency causes either abnormal tissue concentrations of glycogen (too much or too little) or incorrectly or abnormally formed glycogen
What are symptoms of GSD?
Depending upon the deficient enzyme each GSD has different clinical features. Some GSDs also have heterogeneous symptoms. GSDs can affect the liver only, the muscles only, or both the liver and the muscles. Other systems that may be involved include blood cells (red blood cells, white blood cells, and platelets), heart, and kidneys amongst others.
What are types of GSDs and their symptoms?
The main types of GSDs are categorized by number and name and those affecting the liver include:
Type I Von Gierke disease, defect in glucose-6-phosphatase)-most common type of GSD; accounts for 90% of all GSD cases
Type III Cori’s disease, debrancher enzyme deficiency)
Type IV Andersen’s disease, brancher enzyme deficiency)
Type VI Hers’ disease, liver phosphorylase deficiency)
Type IX Liver glycogen phosphorylase kinase)
Type 0 Glycogen synthase deficiency
Type XI Fanconi Bickel Syndrome
Discussion about Maple syrup urine disease
Management of MSUD involves use of specialized diet with restricted branched chain amino acids. However, amino acid profile needs to be checked frequently to ensure that branched chain amino acid levels are within normal levels. Elevated levels of branched chain amino acids can result in encephalopathy, seizures and developmental delay.
The neonate, described herein, developed isoleucine deficiency and presented with skin lesions similar to acrodermatitis enteropathica. These skin lesions have also been described during treatment of organic acidemias (methyl malonic acidemia, glutaric aciduria and propionic acidemia) [3,4] and amino-acidopathies (maple syrup urine disease) [5,8] due to iatrogenic deficiency of isoleucine. It has been called acrodermatitis acidemica [3-9] or acrodermatitis dysmetabolica [9]. Similar lesions have also been described in biotin deficiency and free fatty acid deficiency [10]. The neonate described here had the clinical profile and response to treatment similar to the cases with isoleucine deficiency described previously.
Special formulae with restricted branched chain amino acids is essential for managing neonates with MSUD. However, when used alone even for a short time, neonates can quickly develop branched chain amino acid deficiency as highlighted in this case report. Expressed breast milk (EBM) supplementation is an effective way to avoid and treat deficiency of branched chain amino acid in the neonatal period and early infancy in these babies as was seen in the neonate described herein. The amount of EBM to be added needs to be adjusted depending on the clinical response and repeated amino acid profile testing. The other options to prevent deficiency of branched chain amino acids include supplementation with specific amino acids, use of infant formula and low dose protein supplementation. It is also necessary to frequently monitor amino acid profiles in the growing infants to optimize their dietary intake, growth and ensure normal levels of branched chain amino acids.
Contributors: BR: carried out the literature review and drafted the manuscript; BR, MK and HS: were responsible for the diagnosis and management; AE: was involved in antenatal genetic diagnosis and prenatal counselling.
Urea Cycle Disorders (UCD) are a group of inborn errors of metabolism seen frequently in tertiary care intensive care units (ICUs) in view of the hyperammonemic encephalopathy which is the most common presenting feature. The overall incidence of UCD varies from 1:8000 to 1:44,000 birth,. A more recent study from 3 countries in Europe reported an estimated cumulative incidence of 1 in 51,946 for UCDs . Incidence of UCD is not known in India. All types of UCDs have been recognized.
Urea cycle disorders in India: clinical course, biochemical and genetic investigations, and prenatal testing
Organic acidemias are common in Indian children. Unfortunately they are
detected late, only after the symptoms have appeared. Most of the times, the diagnostic facilities
are not available immediately and the cost of diet and medicines is beyond reach of most of the
Indian patients. In such a situation the mortality is unacceptably high and those who survive have
high rate of neurological affection and other complications.
Dr. Anil B. Japan
metabolicdisorders.com
Fabry disease (FD) is a treatable X linked lysosomal storage disorder with a wide phenotypic spectrum. There is a scarcity of published data on the burden of FD in India. This study evaluates the clinical and molecular spectrum of Indian patients with FD. In this multicentric study involving 10 tertiary referral centers in India, we analyzed the clinical course and genotype of 54 patients from 37 families. Family screening identified 19 new patients (35%) from 12 index cases. Then, 33 GLA gene variants were identified in 49/54 (90.7%) which included 11 novel and 22 known pathogenic variants. Of the 54 patients in our cohort, 40 patients had “classical” and 10 patients had a “nonclassical” presentation. The symptoms and signs included kidney dysfunction in 38/54 (70.3%), neuropathic pain in 34/54 (62.9%), left ventricular hypertrophy in 22/49 (44.8%) and stroke in 5/54 (9.2%). Female heterozygotes were 10/54 (18.5%) of whom 2 were index cases. There was a significant delay in reaching the diagnosis of 11.7 years. Enzyme replacement therapy was initiated in 28/54 (51.8%) patients with significant improvement of neuropathic pain and gastrointestinal symptoms. This study highlights the clinical presentation and mutational spectrum of FD in India and suggests that family screening and screening of high‐risk groups (hypertrophic cardiomyopathy, idiopathic chronic renal failure and cryptogenic stroke) could be the most cost‐effective strategies for early identification of FD.
~Fabry disease in India: A multicenter study of the clinical and mutation spectrum in 54 patients
Sheela Nampoothiri Dhanya Yesodharan Amrita Bhattacherjee Hisham Ahamed Ratna Dua Puri Neerja Gupta Madhulika Kabra … See all authors
First published: 15 August 2020
https://doi.org/10.1002/jmd2.12156
Communicating Editor:: Robert J Desnick
Dr Uma Ramaswami is the senior author.
Funding information: Indian Council of Medical Research, Grant/Award Number: GIA/31(vi)/2014‐DHR; Sanofi Genzyme India
Wiley online library
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary form of kidney disease. Clinical data on this multisystem disorder are scarce from developing countries. We conducted a prospective observational study of the clinical profile of ADPKD patients at a single center over a period of six years. A total of 208 patients were studied. Majority were male (60.6%) and the mean age was 45.8 ± 14.5 years.
~Autosomal dominant polycystic kidney disease: Study of clinical characteristics in an Indian population
Sanjay Vikrant1, Anupam Parashar2
1 Department of Nephrology, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
2 Department of Community Medicine, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
Autosomal dominant polycystic kidney disease: Study of clinical characteristics in an Indian population
Sanjay Vikrant1, Anupam Parashar2
1 Department of Nephrology, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
2 Department of Community Medicine, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
Also says about Autosomal dominant Polycystic Kidney Disease
I didn't get total funds during my VHL liver transplant
I had a liver transplant owing to several tumours in the liver which could not be taken out individually causing excruciating pain due to frequent haemorrhages in 2008. The largest lesion caused splaying of the portal vein around the lesion. Hepatic veins were compressed and displaced by the segment 4&8 mass lesion. I had two episodes of bleeding in the hemangioblastomas and required hospitalisation.
A non-fdg avid lung nodule was found in the right lower lobe.
When my father approached secretary of the health minister in 2010 he was told to get the treatment done and they'd reimburse.
A retired person with meagre pension how can he maintain after the transplant? We are still homeless people living in rented houses. Shortly after he died.
Group 2: Diseases requiring long term / lifelong treatment having relatively lower cost of treatment and benefit has been documented in literature and annual or more frequent surveillance is required:
a) Disorders managed with special dietary formulae or Food for special medical purposes (FSMP)
i) Phenylketonuria (PKU) --Phenylketonuria (PKU) is a rare genetic condition that causes an amino acid called phenylalanine to build up in the body. Amino acids are the building blocks of protein. Phenylalanine is found in all proteins and some artificial sweeteners.
Phenylalanine hydroxylase is an enzyme your body uses to convert phenylalanine into tyrosine, which your body needs to create neurotransmitters such as epinephrine, norepinephrine, and dopamine. PKU is caused by a defect in the gene that helps create phenylalanine hydroxylase. When this enzyme is missing, your body can’t break down phenylalanine. This causes a buildup of phenylalanine in your body.
Ayurvedic herbs used and their active components
• Wood betony: The principal chemical components present in this plant are Tannins, Betulinic acid, oleonilic acid, rosamarinic acid, rutin, urosolic acid, stachydrine and glycosides.
• Nettle: The principal chemical components present in this plant are histamine, formic acid, acetylcholine, serotonin and vitamins.
• Plantago ovate: The principal chemical components present in this plant are xylose, arabinose, alanine, valine, glutamic acid, glycine, cysteine, lysine, leucine, tyrosine and xylose.
• Turmeric: The principal chemical components present in this plant are curcumin and camphene.
• Dandelion: The principal chemical components present in this plant are taraxacin, laevulin, resin and inulin.
The main objective of this study is to establish a novel ligand as drug for the PKU from the phytocompounds of the above mentioned ayurvedic herbs.
When your baby is old enough to eat solid foods, you need to avoid letting them eat foods high in protein. These foods include:
egg, cheese, nuts, milk, beans, chicken, pork,fish
ii) Non-PKU hyperphenylalaninemia conditions
Based on the serum phenylalanine levels under free diet patients with hyperphenylalaninemia are classified as “classical” (>1200μmol/L), “mild” (600-1200 μmol/L), or“nonphenylketonuria (PKU)-hyperphenylalaninemia” (<600μmol/L). Recent studies revealed intellectual, neurologic, and neuropsychologic deficits as well as abnormalities of cerebral white matter(magnetic resonance imaging, MRI) in patients with early and adequately treated PKU. In addition deficits in IQ were reported for a group of 4-y-old patients with untreated mild PKU and non-PKU hyperphenylalaninemia (serum phenylalanine levels below 900 μmol/L). As a consequence, a lifelong diet with serum phyenylalanine levels below 400 μmol/L was recommended even for those patients with serum phenylalanine levels remaining consistently between 400 and 600 μmol/L. Generally patients with non-PKU hyperphenylalaninemia were not treated, as a normal outcome was suspected, but the clinical development of patients with non-PKU hyperphenylalaninemia was not so far studied systematically. We assessed 28 untreated patients with non-PKU hyperphenylalaninemia (age: mean = 21.8, SD = 4.2 y) for IQ, school and job career, clinical-neurologic development, fine motor performances, selective and sustained attention, as well as for frontal lobe-dependent“executive functions.” In addition, cranial MRI was obtained in 10 of these patients. Compared with healthy control subjects, matched for age, sex, and socioeconomic status, the patients reached normal results in all clinical and psychometric tests. Cranial MRI revealed no abnormalities. Additionally, no significant correlations between serum phenylalanine levels and test results were obtained. In the absence of any demonstrative effect, treatment is unlikely to be of significant effect in patients with non-PKU hyperphenylalaninemia.
iii) Maple Syrup Urine Disease (MSUD)
iv) Tyrosinemia type 1 and 2
v) Homocystinuria
Homocystinuria refers to the excretion of homocystine in the urine. It results from either a nutritional deficiency or an inherited defect in the enzymes involved in the remethylation and transsulfuration pathways of methionine metabolism.
In the present study, we report the clinical and biochemical profiles and the spectrum of CBS gene variations in North Indian children presenting with classical homocystinuria.
~In the present study, we report the clinical and biochemical profiles and the spectrum of CBS gene variations in North Indian children presenting with classical homocystinuria.
vi) Urea Cycle Enzyme defects
Urea cycle disorders (UCDs) are inherited metabolic disorders that present with hyperammonemia, and cause significant mortality and morbidity in infants and children. These disorders are not well reported in the Indian population, due to lack of a thorough study of the clinical and molecular profile.
vii) Glutaric Aciduria type 1 and 2
Our study identified the spectrum of variants prevailing in the CBS gene responsible for classical homocystinuria from India. To the best of our knowledge, this is the first study to provide a genetic characterization of homocystinuria in India. Due to the wide genotypic heterogeneity found in our cases and the compound heterozygosity in nearly half of the cases, we could not establish genotype–phenotype correlations from individual patients. Myopia and ectopia lentis were observed as the most consistent clinical findings. Biochemical and genetic analysis has allowed us to diagnose classical homocystinuria accurately correctly. This study also reports the first case of the rare ABCD4 defect of cobalamin metabolism from India. Future studies should focus on new therapeutic targets based on the type of genetic variations.
Long-term treatment will include:
A low protein, high-calorie diet
Medications to remove nitrogen
Supplements of amino acids
Drinking plenty of water
viii) Methyl Malonic Acidemia
Organic acidemias are a heterogeneous group of inherited metabolic disorders due to defects in the catabolism of branched-chain amino acids, lysine and disorders that result in accumulation of lactic acid and dicarboxylic acids(1). Individually, these inborn errors of metabolism are rare and infrequently reported worldwide. Their prevalence is probably underestimated since a substantial proportion of cases remain undiagnosed or mis-diagnosed(2). Of 366 patients with inborn errors of metabolism diagnosed over a period of 20 years at the Hôspital des Enfants-Malades, organic acidemias accounted for 27% of the cases, hyperlacticacidemias (including respiratory chain disorders) in 12% and fatty acid oxidation defects in 8.3%. In this series methylmalonic acidemia was the commonest organic acidemia followed by propionic acidemia(3). In another, lactic acidemias were the commonest disorders (18%), followed by propionic acidemia (9.2%), methylmalonic acidemia (8.8%) and multiple carboxylase deficiency (6.6%)(3). Apart from solitary cases of propionic acidemia, biotinidase deficiency, fatty acid oxidation defects and Leighs disease a Medline search over the past 10 years did not disclose other reports from India(4,5). This can be attributed to the lack of awareness of the wide spectrum of manifestations and lack of diagnostic facilities. This study aims to provide an overview of the clinical features and types of organic acidemias diagnosed at a tertiary care center in Mumbai.
Methylmalonic acidemia is treated primarily with a low-protein, high-calorie diet, certain medications, antibiotics and in some cases, organ transplantation. Medication treatment consists cobalamin (vitamin B12) given as an injection, carnitine, and antibiotics.
Brief Reports
Indian Pediatrics 2001; 38: 518-524
Clinical Features of Organic Acidemias: Experience at a Tertiary Care Center in Mumbai
Mamta N. Muranjan
Pratima Kondurkar
From the Genetics Division, Department of Pediatrics, K.E.M. Hospital, Parel, Mumbai 400 012, India.
Correspondence to: Dr. M.N. Muranjan, 3rd Floor, 16-B, Naushir Bharucha Marg, Tardeo, Mumbai 400 007, India.
ix) Propionic Acidemia
Propionic acidemia is a rare metabolic disorder. It is characterized by deficiency of propionyl-CoA carboxylase, an enzyme involved in the breakdown (catabolism) of the chemical "building blocks" (amino acids) of proteins. Symptoms most commonly become apparent during the first weeks of life and may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, listlessness (lethargy), dehydration and seizures. Without appropriate treatment, coma and death may result. Rarely, the condition may become apparent later in life and may be associated with less severe symptoms and findings. Propionic acidemia is inherited in an autosomal recessive pattern. Individuals with this condition have to follow a specific diet including a low protein intake and specific food formulas (medical foods). Liver transplant is a surgical option that can help decrease the frequency of acute metabolic episodes (decompensation).
x) Isovaleric Acidemia
Isovaleric acidemia is a hereditary metabolic disorder, caused by a change (mutation) in the gene encoding the enzyme isovaleryl-CoA dehydrogenase, resulting in deficient or absent activity. This enzyme is responsible for helping break down leucine, an amino acid, and its deficiency leads to a buildup of chemicals in the blood that cause symptoms. The disorder can present with acute intermittent attacks in infancy or later in childhood. The acute attacks are characterized by vomiting, refusal to eat, listlessness, abnormal lab values, and a sweaty foot odor. Chronic symptoms include failure to thrive and developmental delay. Management for this disease includes a low protein diet with leucine restriction, avoiding triggers of acute attacks, and supplementation with carnitine and/or glycine. Though there is no cure, but as patients age, acute attacks become less frequent.
xi) Leucine sensitive hypoglycemia
The concept of leucine sensitive hypoglycemia, introduced by Cochrane in 1960, has been largely superseded by the recognition of congenital hyperinsulinism and its association, in some infants, with exaggarated insulin responses to amino acid secretogogues.
A dietary regimen, which has been found useful in the management of leucine-sensitive juvenile hypoglycemia, is described. Hypoglycemia is avoided by a combination of leucine restriction and postprandial carbohydrate feedings. Leucine restriction is achieved primarily through limitation of dietary protein, but sufficient protein is supplied to fulfill the minimum requirement. Through the use of this regimen it was possible to achieve satisfactory symptomatic control without the use of corticosteroids.
xii) Galactosemia
Infants with galactosemia can show symptoms in the first few days of life if they eat formula or breast milk that contains lactose. The symptoms may be due to a serious blood infection with the bacteria E coli.
Symptoms of galactosemia are:
Convulsions
Irritability
Lethargy
Poor feeding -- baby refuses to eat formula containing milk
Poor weight gain
Yellow skin and whites of the eyes (jaundice)
Vomiting
Treatment
Collapse Section
Treatment has been expanded.
People with this condition must avoid all milk, products that contain milk (including dry milk), and other foods that contain galactose, for life. Read product labels to make sure you or your child with the condition are not eating foods that contain galactose.
Infants can be fed:
Soy formula
Another lactose-free formula
Meat-based formula or Nutramigen (a protein hydrolysate formula)
Calcium supplements are recommended.
xiii) Glucose galactose malabsorbtion
Glucose-galactose malabsorption is a condition in which the body cannot take in (absorb) the sugars glucose and galactose, which primarily results in severe diarrhea. Beginning in infancy, severe diarrhea results in weight loss and dehydration that can be life-threatening. Small amounts of the simple sugar glucose in the urine (mild glucosuria) may occur in this disorder. Rarely, affected infants develop kidney stones due to deposits of calcium in the kidneys (nephrocalcinosis).
The signs and symptoms of glucose-galactose malabsorption appear early in life when affected infants are fed breast milk or regular infant formulas. These foods contain glucose, galactose, and another sugar called lactose that gets broken down into these two sugars. When these sugar-containing foods are ingested by affected individuals, it leads to diarrhea and other health problems. If foods that contain glucose, galactose, and lactose are removed from the diet, the diarrhea stops.
xiv) Severe Food protein allergy
Overview
Food Protein Induced Enterocolitis Syndrome (FPIES) is a type of non-IgE mediated food allergy that can present with severe vomiting, diarrhea and dehydration. Like other food allergies, FPIES reactions are triggered by eating a particular food. The most common triggers include cow milk, soy and grains (rice, barley, oats). The most severe forms of FPIES can lead to drop in energy, change in body temperature and low blood pressure leading to hospitalization. FPIES is frequently misdiagnosed early on as a potential severe blood infection or repeated infections of a gastrointestinal virus. Unlike most food allergies there is no blood or skin testing available for diagnosis. The primary treatment is strict avoidance of the triggering food. Most children outgrow FPIES by age 3 or 4.
GET RELIEF
Find an allergist
Symptoms
FPIES symptoms begin early in life, typically occurring after the introduction of milk- or soy-based formulas. Early on, infants tend to have poor growth and might be diagnosed with failure to thrive. Older infants can present with solid food FPIES, typically when an infant starts eating rice, oats, barley and other similar foods. This generally occurs after 4 months of age.
Unlike other food-allergic reactions that can trigger an allergic response throughout the body, the symptoms of FPIES typically are confined to the gastrointestinal system. Symptoms include:
Severe vomiting
Diarrhea (sometimes bloody)
Weight loss
Dehydration
Lack of energy
Failure to thrive
Vomiting and diarrhea may not occur until several hours after the offending food is consumed, so a link between the symptom and the food may not be immediately apparent.
If you suspect that your child has symptoms of FPIES, see an allergist for diagnosis and treatment.
Common FPIES Triggers
Soy and dairy products, particularly infant formula
Some cereal grains, such as rice and oats
Chicken, turkey and fish
Food allergy is an adverse immunological response to proteins in food and must be differentiated from food intolerance, which is a general non-specific term for any adverse reactions to particular constituents of food. Cow’s milk protein allergy (CMPA) is an immune- mediated reaction to various proteins in cow’s milk. It is the most common food protein allergy in infants and children. The reaction may be IgE-mediated, non-IgE mediated or mixed. CMPA may have cutaneous, respiratory and/or gastrointestinal manifestations.
In India, awareness among pediatricians is low leading to misdiagnosis or concurrence with parents that the child has allergy. This results in wrong dietary advice and unnecessary use of expensive formulas. The prevalence of CMPA peaks in infancy (1.5 -3 %) and falls to less than 1% at 6 years of age. About 10 to 15% of children who have CMPA are also allergic to soy and the risk of cross- allergy is higher if symptoms begin below 6 months of age. There are no epidemiologic studies on the prevalence of food allergy including CMPA in Indian children. Among hospital-based studies, CMPA was reported as a cause of malabsorption syndrome in 6% children of all ages and 13% of children below 2 years with chronic diarrhea. CMPA was the cause in 35% children below 3 years of age presenting with chronic diarrhea in another study .
b) Disorders that are amenable to other forms of therapy (hormone/ specific drugs)
i) NTBC (Nitisinone) for Tyrosinemia Type 1 --₹ 50,000/ Vial-manufacturer -Roche- on demand
ii) Osteogenesis Imperfecta – $100- $200 for Bisphosphonates therapy
iii) Growth Hormone therapy for proven GH deficiency, Prader Willi Syndrome and Turner syndrome, Noonan syndrome. -cost for a 20 kg child would be Rs 200,000 per year.
iv) Cystic Fibrosis- Pancreatic enzyme supplement -The cost of enzyme replacement treatment was US$ 6881,63 ± 2334,04/year; US$ 6778,19 ± 2339,26/year in the tumor group; US$ 7096,78 ± 2356,17/year in pancreatitis group.
v) Primary Immune deficiency disorders -Intravenous immunoglobulin -Bharglob 16.5% Inj. 2ml Serum 200 International and sub cutaneous therapy (IVIG) --$5736 per first 3 years of therapy replacement eg. etc.
vi) Sodium Benzoate( ₹ 300.00) , arginine (₹ 1,699.00), citrulline (₹ 2,500.00), phenylacetate --₹ 1,000/ Kilogram (Urea Cycle disorders), carbaglu (Rs 80000/kg), Megavitamin therapy--Rs 8000- Rs 18000, says Dr. Mittal(Organic acidemias, mitochondrial disorders)
vii) Others - Hemin --costs British pound sterling 1125 for 4 x 10 ampoules.(Panhematin-313 mg is around $7,558) for Acute Intermittent Porphyria, High dose Hydroxocobalamin injections- 5.35 Euro(30mg/ml formulation – not available in India and hence expensive if imported)
viii) Large neutral aminoacids( ₹ 1,189.00), mitochondrial cocktail therapy ($1,000 per month), Sapropterin (Rs 4000/bottle) and other such molecules of proven clinical management in a subset of disorders
Group 3: Diseases for which definitive treatment is available but challenges are to make optimal patient selection for benefit, very high cost and lifelong therapy.
3a) Based on the literature sufficient evidence for good long-term outcomes exists for the following disorders
1. Gaucher Disease (Type I & III {without significant neurological impairment})
Gaucher disease is categorized as a lysosomal storage disorder (LSD)
Enzyme replacement therapy for Gaucher’s disease, which is available in India, costs about Rs. 40 lakh to Rs. 1 crore a year, depending upon the weight of the child.
2. Hurler Syndrome [Mucopolysaccharisosis (MPS) Type I] (attenuated forms)
MPS I is member of a group of hereditary metabolic diseases known as the mucopolysaccharidoses which, in turn, are part of a larger group of diseases known as lysosomal storage disorders (LSDs) - 46 lakhs approximate annual cost per 10 kg child
3. Hunter syndrome (MPS II) (attenuated form)- 1 crore approximate annual cost per 10 pkg child
4. Pompe Disease (Both infantile & late onset diagnosed early before development of complications) This disorder belongs to a group of diseases known as lysosomal storage disorders. 49 lakhs approximate annual cost per 10 kg child
5. Fabry Disease diagnosed before significant end organ damage. Cost of ERT- 20 lakhs approximate annual cost per 10 kg child(This disorder belongs to a group of diseases known as lysosomal storage disorders.)
6. MPS IVA before development of disease complications.- 1.3crores approximate annual cost per 10 pkg child
7. MPS VI before development of disease complications.- 1.1 crores approximate annual cost per 10 pkg child
All of the above rare diseases are part of the lysosomal storage disorders and detected in early childhood
8. DNAase for Cystic Fibrosis.
Editorial
Indian Pediatrics 2002; 39:813-818
Cystic Fibrosis: Indian Experience
Cystic fibrosis (CF) is the most common life limiting recessive genetic disorder in Caucasians with an incidence of approximately 1 in 2500 children born in the United Kingdom(1). It is less common in African Americans (1 in 15000) and in Asian Americans (1:31000). It also affects other ethnic groups such as black population with an incidence of 1 in 17,000 and the native American population with an approximate incidence of 1 in 80,000 (2,3).
Cystic fibrosis was thought to be extremely rare in India. However published reports, reviews and comments indicate that CF is probably far more common in people of Indian origin than previously thought but is under diagnosed or missed in the majority of cases . The precise incidence of CF among Indians is unknown. The incidence in migrant Indian populations in the USA has been estimated to be 1 in 40000(8), and in the UK between 1 in 10000 to 12000 . As a result of the widespread belief that CF does not occur in Indians, the disease is rarely suspected and even if it is suspected the diagnosis is rarely confirmed due to the poor availability of facilities for diagnosis. The median age of diagnosis among Indian Americans is 12 months compared with 6 months among Caucasian American children and reflects a low index of suspicion for the disease even among Indians in western countries. Recent reports suggest that genetic and clinical profile of Indian children with CF may be different. These reports suggest that the diagnosis of CF is delayed in Indian children which may result in severe malnutrition by the time the condition is eventually diagnosed — one of the bad prognostic indicators for survival.
~
.A. S. Ahuja.
Consultant Pediatrician
Royal Albert Edward Infirmary Wigan, Lancs., UK
S. K. Kabra ,
Additional Professor,
Department of Pediatrics,
All India Institute of Medical Sciences,
New Delhi.
E-mail: skkabra@hotmail.com
Indian pediatrics
Treatment
First and perhaps the most critical part in the management of CF is to explain the diagnosis to the family. Detailed counseling regarding the nature of the disease, inheritance with risk for recurrence in subsequent pregnancies, and need for regular follow up should be emphasized. The holistic management of a child with cystic fibrosis consists of pancreatic enzyme replacement, supplementation of fat soluble vitamins, salt supplementation, airway clearance, antibiotics and supportive care with help of a multi-disciplinary team consisting of physician, physiotherapist, dietician, microbiologist, psychologist and social scientist.
3b) For the following disorders for which the cost of treatment is very high and either long term follow up literature is awaited or has been done on small number of patients
1. Cystic Fibrosis (Potentiators)
Recent advances in the understandings in CF pathophysiology have not yet resulted in dramatic improvements in clinical care, but there is great hope for the future that therapies targeting the basic defect will normalize life of those born with CFTR mutations. Gene therapy attempting to replace the abnormal gene using a viral or liposomal vector is being actively investigated but does not appear to be a therapeutic option for the near future. Disease modifying strategies in CF, other than gene therapy, are approaches that target the protein defect, i.e., CFTR modulators. CFTR modulators can be classified into three classes: potentiators, correctors and read-through agents or premature stop codon suppressors . Ivacaftor, a CFTR potentiator, has been shown to improve CF related functioning and well being and it is currently approved by US-FDA for use in children with CF > 2 years of age with 10 selected mutations. It is not effective in homozygous ΔF508 mutation. Lumacaftor is a CFTR corrector recently being approved for use in combination with Ivacaftor (Orkambi) in patients 12 years and older with homozygous ΔF508 mutation . Among the read through agents, the most promising current drug Ataluren has shown to improve chloride transport in CF patients with non sense mutation.
2. Duchenne Muscular Dystrophy (Antesensce oligoneucletides, PTC)
Antisense oligonucleotides (AONs) hold great promise for therapeutic splice-switching correction in many genetic diseases and in particular for Duchenne muscular dystrophy (DMD), where AONs can be used to reframe the dystrophin transcript and give rise to a partially deleted but yet functional dystrophin protein.
PTC currently has two approved medicines for treating Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene in ambulatory patients aged 2 years and older: TranslarnaTM (ataluren) and EmflazaTM (deflazacort)
TREATMENT
There is no exact cure of cystic fibrosis, but treatment can be done to relieve its symptoms
Medications including antibiotics, mucus-thinning drugs, bronchodilators, and oral pancreatic enzymes
Chest physical therapy to make it easier for people to cough up
Pulmonary rehabilitation to improve your lung function and overall well-being
Surgical procedures include nasal polyp removal, oxygen therapy, endoscopy, lung transplant, feeding tube, bowel surgery etc
~ Max Hospital, Saket
3. Spinal Muscular Atrophy (Antisense oligonucleotides both intravenous & oral & gene therapy)
“Evrysdi is the first drug for this disease that can be taken orally, providing an important treatment option for patients with SMA, following the approval of the first treatment for this devastating disease less than four years ago,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research.
The current price for Spinraza is $750,000 (Rs 5crores) for the first year and $375,000 (Rs 3 crores) for every year after for the life of the patient. It is approved for all forms of SMA, types 0 through 5.It contains nusinersen, an antisense oligonucleotide whose main function is to repair the damaged SMN2 gene.
~
4. Wolman Disease
Wolman disease is a type of lysosomal acid lipase (LAL) deficiency; a rare genetic disorder characterized by complete absence of an enzyme known as lysosomal acid lipase (LIPA or LAL). This enzyme is required to breakdown (metabolize) certain fats (lipids) in the body.
5. Hypophosphatasia
Hypophosphatasia (HPP) is an inborn error of metabolism with highly variable clinical severity caused by loss-of-function mutations in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP).
There is no Food and Drug Administration-approved treatment for HPP. Dr. Tebben notes: "In the perinatal and infantile forms, therapy has largely been supportive. Vitamin B-6 may be helpful for seizures in patients with infantile HPP. Recently, recombinant tissue nonspecific alkaline phosphatase modified to target and anchor to bone has been developed and tested in infants and children with severe HPP. Improved biochemical, radiographic and clinical parameters were observed. Long-term outcomes are yet to be reported. The utility of treatment in less severely affected individuals is unknown."
6. Neuronal ceroid lipofuschinosis
Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins.
Here I may say “Von Hippel-Lindau disease is a rare genetic condition for which there is no systemic treatment option available and is associated with a high risk of cancer development in multiple organs. In fact, up to 70% of patients with VHL develop renal cell carcinoma during their lifetime,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release.
MK-6482 is a selective inhibitor of HIF-2α, which is a protein that can accumulate in patients when VHL is inactivated. Without regulation, this accumulation can cause the stimulation of several oncogenes associated with cellular proliferation, angiogenesis, and tumour growth.
Can this orphan drug be imported for me?
https://www.drugs.com/cdi/sirolimus-oral-solution.html
I have a severe swallowing problem and instead of swallowing the sirolimus tablet I crush it as a powder and take it. Most of the drug remains in the mortar and pestle and I don't get the whole dosage.
It is my immunosuppressive medicine as well as has anti-angiogenic properties and can control my brain tumours and other hemangioblastomas to some extent.
No comments:
Post a Comment