Rare Diseases

A rare disease is a medical condition that affects a small number of people compared to the general population. These diseases are often complex, challenging to diagnose, and have limited treatment options. Rare diseases can be genetic, autoimmune, infectious, or caused by environmental factors. Examples of rare diseases include Huntington's disease, cystic fibrosis, muscular dystrophy, and rare forms of cancer. Due to their rarity, research and funding for rare diseases are often limited, making it difficult for patients to access proper care and support. However, advocacy groups and medical researchers are working tirelessly to raise awareness, improve diagnosis methods, and develop new treatments for rare diseases. By promoting collaboration and understanding, we can strive towards better outcomes and quality of life for individuals affected by rare diseases.

RARE DISEASES-ISSUES AND CHALLENGES

The field of rare diseases is complex and heterogeneous. The landscape of rare diseases is constantly changing, as there are new rare diseases and conditions being identified and reported regularly in medical literature. Apart from a few rare diseases, where significant progress has been made, the field is still at a nascent stage. For a long time, doctors, researchers and policy makers were unaware of rare diseases and until very recently there was no real research or public health policy concerning issues related to the field. This poses formidable challenges in development of a comprehensive policy on rare diseases. Nevertheless, it is important to take steps, in the short as well as long term, with the objective of tackling rare diseases in a holistic and comprehensive manner.

THE INDIAN SCENARIO

Data on how many people suffer from different diseases that are considered rare globally, is lacking in India. The cases identified so far have been diagnosed at tertiary hospitals. The lack of epidemiological data on incidence and prevalence of rare diseases impedes understanding of the extent of the burden of rare diseases and development of a definition. It also hampers efforts to arrive at correct estimation of the number of persons suffering from these diseases and describe their associated morbidity and mortality. In such a scenario, the economic burden of most rare diseases is unknown and cannot be adequately estimated from the existing

data sets.
Although extremely challenging, considering the complexity of various diseases and the difficulty in diagnosis, there is a clear need to undertake systematic epidemiological studies to ascertain the number of people suffering from rare diseases in India.
So far only limited number of diseases has been recorded in India from tertiary care hospitals that are globally considered as rare diseases though ambit may encompass from 7000 to 8000 disorders. The commonly reported diseases include Primary immunodeficiency disorders, Lysosomal storage disorders (Gaucher’s disease, Mucopolysaccharidoses, Pompe disease, fabry disease etc.) small molecule inborn errors of metabolism (Maple Syrup urine disease, organic acidemias etc.), Cystic Fibrosis, osteogenesis imperfecta, certain forms of muscular dystrophies and spinal muscular atrophy, etc.

DEFINITION AND DISEASES COVERED

There is no universal or standard definition of rare disease. A disease that occurs infrequently is generally considered a rare disease, and it has been defined by different countries in terms of prevalence – either in absolute terms or in terms of prevalence per 10,000 population. A country defines a rare disease most appropriate in the context of its own population, health care system and resources.

As mentioned above, India faces the limitation of lack of epidemiological data to be able to define rare diseases in terms of prevalence or prevalence rate, which has been used by other countries. To overcome this, a hospital based National Registry for Rare Diseases has been initiated by ICMR by involving centers across the country that are involved in diagnosis and management of Rare Diseases. This will yield much needed epidemiological data for rare diseases. In the absence of epidemiological data on diseases considered as rare in other countries, it is not possible to prescribe threshold prevalence rates to define a disease condition as rare.

Till the time such data is available and the country arrives at a definition of a rare disease based on prevalence data, the term rare diseases, for the purpose of this policy, shall construe the following groups of disorders identified and categorized by experts based on their clinical experience:

Group 1: Disorders amenable to one-time curative treatment:

a) Disorders amenable to treatment with Hematopoietic Stem Cell Transplantation (HSCT) –

Such Lysosomal Storage Disorders (LSDs) for which Enzyme Replacement Therapy (ERT) is presently not available and severe form of Mucopolysaccharoidosis (MPS) type I within first 2 years of age.
Adrenoleukodystrophy (early stages), before the onset of hard neurological signs.
Immune deficiency disorders like Severe Combined Immunodeficiency (SCID), Chronic Granulomatous disease, Wiskot Aldrich Syndrome etc.
Osteopetrosis
Fanconi Anemia

b) Disorders amenable to organ transplantation

Liver Transplantation -Metabolic Liver diseases:
Tyrosinemia,
Glycogen storage disorders (GSD) I, III and IV due to poor metabolic control, multiple liver adenomas, or high risk for Hepatocellualr carcinoma or evidence of substantial cirrhosis or liver dysfunction or progressive liver failure,
MSUD (Maple Syrup Urine Disease),
Urea cycle disorders,e. Organic acidemias.
Renal Transplantation-
Fabry disease
Autosomal recessive Polycystic Kidney Disease (ARPKD),
Autosomal dominant Polycystic Kidney Disease (ADPKD) etc.
Patients requiring combined liver and kidney transplants can also be considered if the same ceiling of funds is maintained. (Rarely Methyl Malonicaciduria may require combined liver & Kidney transplant) etc.

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)
ii) Non-PKU hyperphenylalaninemia conditions
iii) Maple Syrup Urine Disease (MSUD)
iv) Tyrosinemia type 1 and 2
v) Homocystinuria
vi) Urea Cycle Enzyme defects
vii) Glutaric Aciduria type 1 and 2
viii) Methyl Malonic Acidemia
ix) Propionic Acidemia
x) Isovaleric Acidemia
xi) Leucine sensitive hypoglycemia
xii) Galactosemia
xiii) Glucose galactose malabsorbtion
xiv) Severe Food protein allergy

b) Disorders that are amenable to other forms of therapy (hormone/ specific drugs)

i) NTBC for Tyrosinemia Type 1
ii) Osteogenes isImperfecta – Bisphosphonates therapy
iii) Growth Hormone therapy for proven GH deficiency, Prader Willi Syndrome, Turner syndrome and Noonan syndrome.
iv) Cystic Fibrosis- Pancreatic enzyme supplement
v) Primary Immune deficiency disorders -Intravenous immunoglobulin and sub cutaneous therapy (IVIG) replacement eg. X-linked agammablobulinemia etc.
vi) Sodium Benzoate, arginine, citrulline, phenylacetate (Urea Cycle disorders), carbaglu, Megavitamin therapy (Organic acidemias, mitochondrial disorders)
vii) Others - Hemin (Panhematin) for Acute Intermittent Porphyria, High dose Hydroxocobalamin injections (30mg/ml formulation – not available in India and hence expensive if imported)
viii) Large neutral aminoacids, mitochondrial cocktail therapy, Sapropterin 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})
2. Hurler Syndrome [Mucopolysaccharisosis (MPS) Type I] (attenuated forms)
3. Hunter syndrome (MPS II) (attenuated form)
4. Pompe Disease (Both infantile & late onsetdiagnosed early before development of complications)
5. Fabry Disease diagnosed before significant end organ damage.
6. MPS IVA before development of disease complications.
7. MPS VI before development of disease complications.
8. DNAase for Cystic Fibrosis.

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)
2. Duchenne Muscular Dystrophy (Antesensce oligoneucletides, PTC)
3. Spinal Muscular Atrophy (Antisense oligonucleotides both intravenous & oral & gene therapy)
4. Wolman Disease
5. Hypophosphatasia
6. Neuronal ceroid lipofuschinosis
6.3. The list of diseases under Group 1, Group 2 and Group 3 are not exhaustive and will be reviewed periodically based on updated scientific data by the Technical Committee.

PREVENTION AND CONTROL

Prevention & Control of Rare Diseases:

Capacity building of health professionals
The Central Government will work with the State governments to build capacity of health professionals at various levels. The content of such capacity building would be based on the roles of various health professionals. The Centres of Excellence would develop Standard Operating Protocols to be used at various levels of care for patients with rare diseases to improve early diagnosis, better care coordination and quality of life.

Prevention at different levels

Though in the last two decades, due to advancement in technologies, understanding of the pathophysiological mechanisms of rare genetic disorders has somewhat improved, yet the treatment modalities are few and the available therapies may not lead to “cure’. More importantly, these are exorbitantly costly and not universally available & accessible. Accordingly, prevention needs to be the focus for all genetic disorders. The prevention of genetic disorders can be done at multiple levels. For application of these strategies, the first step is to build the capacity of health professionals and increase awareness in the population at large about the prevalence of such diseases and prevention measures. Frontline workers will be adequately capacitated for screening of rare diseases. Adequate IEC material will be designed and made available across multiple levels of the health care pyramid as this forms a basic pillar of tackling the issue of limited awareness.

Primary Prevention: This aims at preventing the occurrence of the disease, i.e., preventing birth of an affected child. Though not always feasible, this strategy yields the highest returns in terms of decreasing the incidence & prevalence of rare disorders in the population in the long run. Some of the strategies can be as follows:
Examples include avoidance of pregnancy in advanced age, or any other rare monogenic disorder by not marrying a carrier, carrier couples not reproducing etc., but these are not feasible options in the real world scenario. So in most situations the feasible preventive strategy is secondary prevention. However, a simple checklist will be made available to primary health care providers in the health and wellness clinics to identify a couple at risk based on disease in a previous sib or family history of that disorder.

Secondary prevention: This strategy focuses on avoiding the birth of affected fetus (prenatal screening and prenatal diagnosis), early detection of the disorders, appropriate medical intervention to ameliorate or minimize the manifestations (newborn screening).

Prenatal screening: The common screening methods presently recommended for all pregnancies include biochemical screening and ultrasonography for chromosomal disorders like Down syndrome etc. and ultrasonography for other structural defects. In the context of rare diseases, objective of the prenatal screening and diagnosis is to identify the high risk mothers for having an affected fetus with a rare disease. These mothers can be identified based on the family history (previous affected child or affected relative with a known or suspected genetic disorder). Based on the suspected disease a targeted screening of the affected child or couple for a specific disorder or a carrier testing for monogenic disorders using next generation sequencing technique can be offered, the latter being presently expensive.

Prenatal diagnosis by invasive testing (e.g., by Chorionic villus sampling and amniocentesis): is possible

for any single-gene disorder if the disease causing variant in the gene/enzyme defect is known and for any chromosomal abnormality. Most common indications are known single gene disorders or chromosomal abnormality in a previous affected child in the family. These tests can also be offered if the married couple is found to be carrier for any single gene disorder and mutations have been identified in the couple. Now a day, prenatal diagnosis for above mentioned disorders are widely available in India at many institutions. The invasive procedures are performed by obstetricians and fetal medicine experts. These procedures, however, carry a small risk of fetal loss which is very low if done by experienced specialists. This has to be explained to the family before the procedure. Cost would primarily depend on the type of the test to be performed on the sample. If the fetus is found to be affected, the couple has the option for termination of pregnancy, the legal age of which in India has been increased to 24 weeks of pregnancy.

Newborn screening(NBS): is the best example of secondary prevention in which the babies are screened within few days of birth before symptoms of the disease manifest and treatment is initiated which prevents morbidity and mortality. In the developed world NBS is being offered for many rare disorders particularly the treatable ones (e.g., LSDs, SCID) apart from the common disorders.

Early postnatal diagnosis and treatment: before development of severe manifestations /complications which are irreversible is also included in secondary prevention for disorders amenable to therapy which would require increasing awareness and better availability of diagnostics. Timely referral of the suspected patients & their families to appropriate facilities that are equipped to make a correct diagnosis and where indicated, initiate treatment is the key. Genetic testing will also be augmented by laboratories under the National Genomics Core funded by the Department of Biotechnology and Institute of Genomics and Integrative Biology (IGIB) & Centre for Cellular and Molecular Biology (CCMB) under CSIR.

Tertiary prevention refers to provision of better care and medical rehabilitation to those rare disease patients who present at an advanced stage of the disease. It encompasses providing best supportive care to the affected patients with various rare disorders including the ones for which no specific treatment is available. This would improve quality of life of affected individuals and families. Supportive care includes developmental assessment and intervention including early stimulation and behavioural intervention, physical therapy and rehabilitation, provision of visual and hearing aids and above all emotional and psychological support to affected individuals and families.

Optimal screening and diagnosis strategy: Considering the competing priorities within available resources, universal screening of all pregnancies and/or all newborns in the country for all rare disorders is not feasible. The policy recommends a screening and diagnostic strategy wherein those pregnant women in whom there is a history of a child born with a rare disease and that rare disease diagnosis has been confirmed, would be offered prenatal screening test(s) through amniocentesis and / or chorionic villi sampling. This strategy is in sync with the policy direction of reducing the incidence of rare diseases in the population. In cases where, the diagnosis could not be established during the prenatal period, it would be imperative to offer to the newborn or the infant as the case may be and would include newborn screening for (a) small molecule Inborn Errors of Metabolism by liquid chromatography – tandem mass spectrometry (LC-MS/MS), (b) diagnosis of SCID by T cell receptor excision circles (TREC) and (c) diagnosis of lysosomal storage disorders (LSDs) by microfluids / LC-MS/ MS. (d) diagnosis of disorders by newer but economical molecular diagnostic platforms.