World Rare Disease Day
Eminent Author, Medical Biochemist and Scientist, Technical Education consultant.
AGD Biomedicals (Pvt) LTD. Andheri East, Mumbai.
Timely interventional strategies backed by routine and advanced IVD laboratory tests based on DOT-BLOT hybridization molecular techniques can identify genetic traits related to rare diseases and prevent births of babies born with rare diseases(1)(Refer to case studies). In spite of their low prevalence, rare diseases can have a significant impact on the lives of the affected individuals and their families(2,5). Hereditary disorders related to hemoglobin belong to rare diseases and can be diagnosed accurately by complete hemogram test (CBC), confirmed by fifth generation POCT Hb tests, methods based on HPLC and electrophoresis techniques(1, 3, 4, 6, 7)(Refer to case studies). Despite progress in recent years, effective or safe treatment is not available for most of the rare diseases. Early diagnosis is critical for rare diseases, since it can prevent further complications and provide patients with access to appropriate supportive treatment regimen(6,7). Rare diseases place a major economic burden on any country(5). Hence, provision for the financial capacity of families to support expensive treatment should be an important aspect in the public health policy development for rare diseases(5).
Q1. What are rare diseases, give various examples and present status of related therapy?
Q2. What are the examples of hereditary disorders of hemoglobin?
ANS: Examples of hereditary hemoglobin disorders:
(A) Thalassemias: Hemoglobin synthesis disorders: α-Thalassemia, β-thalassemia.
(B) Hemoglobinopathies: Hemoglobin structural disorders: Sickle-cell anemia, sideroblastic anemia, hereditary spherocytosis, hereditary elliptocytosis, etc.
Q3. What is the prevalence of β-thalassemia and sickle cell anemia in India?
ANS:
(A) The March of Dimes Global Report on Birth Defects has estimated that the prevalence of hemoglobinopathies in India is 1.2 per 1000 live births. It has been suggested that there would be 32,400 babies with a serious hemoglobin disorder born each year based on 27 million births per year in India(2). About 10,000 to 12,000 thalassemia children are born annually in India. Very few thalassemia babies are optimally managed(4, 5).
(B) The average prevalence of sickle cell disease (SCD) among tribal groups is around 8.61% while non-tribal populations show a lower rate of 4.81%. India contributes to 14.5 % of the global burden of SCD(3).
Q4. What are the routine IVD laboratory tests useful to detect hereditary disorders of hemoglobin?
ANS: The routine IVD laboratory tests: Complete hemogram (CBC) (Refer to case studies), POCT Hb meter test, Dithionate test.
Q5. What is the importance of microscopic examination of stained blood smear in the detection of hereditary disorders of hemoglobin?
ANS:
- Presence of occasional target cells and poikilocytes may indicate thalassemia trait(1).
- Presence of occasional target cells, sickle cells, siderocytes, elliptocytes and macrocytes may indicate hemoglobin structural disorders(1).
Refer to case studies
Q6. What are the latest innovations in IVD laboratory tests that could significantly impact the diagnosis of hereditary disorders of hemoglobin?
ANS: Blood Hemoglobin fractionation by HPLC or cellulose-acetate electrophoresis, and Dot-Blot hybridization techniques can diagnose genetic trait related to hemoglobin disorders or a disease(1).
CASE STUDY 1
A 17 year year-old-male college student’s blood was routinely examined in a clinical laboratory, since, he complained of episodes of severe exhaustion after participating in athletic games. His complete hemogram report was as follows:
Complete Hemogram
| PARAMETER | VALUE | REFERENCE RANGE (NORMAL RANGE) |
| Hemoglobin | 12.8 g/dl | 13–18 g/dl |
| Total erythrocyte count | 3.6 X 1012/l | 5.0 ± 0.5 X 1012 /l |
| Total leukocyte count | 6.3 X 109/l | 7.0 ± 3.0 X 109 /l |
| Differential leukocyte count | ||
| Neutrophils | 62% | 40-75% |
| Lymphocytes | 34% | 20-45% |
| Eosinophils | 2% | 1-4 % |
| Monocytes | 2% | 2-8 % |
| Stained peripheral blood smear Microscopic observations: | ||
| Hypochromia | + | Normal cells |
| Microcytosis | + | Normal cells |
| Anisocytosis | + | Normal cells |
| PCV | 37% | 36–48% |
| MCV | 78.5 fL | 82–92 fL |
| MCH | 27 pg | 27–32 pg |
| MCHC | 32% | 32–36% |
| RDW- CV | 16.8 | 12–14 |
| Platelet count | 157 X 109/l | 150–400 X 109 /l |
| Stained blood smear examination : Presence of occasional target cells and poikilocytes | ||
Note :
Due to low hemoglobin, presence of target cells and poikilocytes, following additional test was advised:
HbA2 (Hemoglobin A2) determination (HPLC method):
4.8% (Normal: 1.3- 3.5%) – Significant increase in HbA2
Diagnosis
Patient was a case of thalassemia minor trait.
Note
Only by routine CBC test, supportive Hb HPLC and by accurate evaluation of the reports, it was possible to detect thalassemia trait. Counselling is necessary in such case so that in future marriage with a partner having thalassemia trait could be avoided. There are 50% chances of a child with thalassemia major, if both the parents belong to thalassemia trait. It is necessary to avoid birth of a thalassemia major child.
CASE STUDY 2
A 12 year year-old-girl’s blood was routinely examined in a clinical laboratory since she complained of occasional pain in the joints, chest, back, legs and shortness of breath, severe exhaustion following normal exercises. Her complete hemogram report was as follows:
Complete Hemogram
| PARAMETER | VALUE | REFERENCE RANGE (NORMAL RANGE) |
| Hemoglobin | 10.7 g/dl | 12–16 g/dl |
| Total erythrocyte count | 3.1 X 1012/l | 4.0 ± 0.5 X 1012 /l |
| Total leukocyte count | 7.3 X 109/l | 7.0 ± 3.0 X 109 /l |
| Differential leukocyte count | ||
| Neutrophils | 73% | 40-75% |
| Lymphocytes | 24% | 20-45% |
| Eosinophils | 1% | 1-4 % |
| Monocytes | 2% | 2-8 % |
Stained peripheral blood smear Microscopic observations: | ||
| Hypochromia | + | Normal cells |
| Microcytosis | ++ | Normal cells |
| Anisocytosis | ++ | Normal cells |
| PCV | 34% | 36–48% |
| MCV | 80.5 fL | 82–92 fL |
| MCH | 28 pg | 27–32 pg |
| MCHC | 33% | 32–36% |
| RDW- CV | 18.1 | 12–14 |
| Platelet count | 187 X 109/l | 150–400 X 109 /l |
| Stained blood smear examination : Presence of occasional sickle cells, target cells and poikilocytes | ||
Note :
Due to low hemoglobin, PCV, and presence of sickle cells, target cells and poikilocytes, following additional tests were advised:
(1) Screening for sickle cells by sodium metabisulfite and dithionate test: Positive
(2) Fractionation of Hb by HPLC: Presence of HbS: 44%, HBA: 57%, HbF: 2%
(3) Dot-Blot molecular diagnostic test for genetic screening: Sickle cell trait detected
Diagnosis
Patient was a case of sickle cell anemia trait.
Note
By routine CBC test, Hb HPLC and Dot-Blot hybridization tests, it was possible to detect sickle cell trait. Counselling is necessary in such case so that in future marriage with a partner having sickle cell anemia train could be avoided. There are 50% chances of a child with sickle cell disease, if both the parents belong to sickle cell anemia trait. It is necessary to avoid birth of a sickle cell disease child.
Q7. How does timely detection of rare disease through IVD impact patient outcomes and overall healthcare costs?
ANS: The economic burden of rare diseases in India is significant. Patients suffer from high treatment costs, lengthy diagnostic procedures, and substantial non-medical expenses and specialized care procedures. These factors place a major financial strain on individuals and families. Particularly in a resource-constrained setting in India; the cost of treatment for some rare diseases can reach more than 1 crore rupees annually for a child, with a requirement for lifelong treatment(5).
Q8. What are the Interventional strategies to prevent rare diseases related to hemoglobin?
ANS: Interventions to reduce the burden of genetic diseases related to hemoglobin include prenatal screening, preventing the birth of an affected child, public education, and mandatory screening of school children.
References
(1) Godkar PB, Godkar DP. Text book of Medical laboratory technology (4th edition, 2024), Bhlani Publishers, Mumbai. India.
(2) Jayesh Sheth, et al. Burden of rare genetic disorders in India: twenty-two years’ experience of a tertiary centre. Orphanet Journal of Rare Diseases volume 19, Article number: 295 (2024)
(3) Priyanka Rao,Elstin Anbu Raj, Senthilkumar Natesan. Prevalence of Sickle cell disease, Sickle cell trait and HBS-beta-thalassemia in India: A systematic review and Meta-analysis. Clinical Epidemiology and Global Health. Volume 28, July–August 2024, 101678.
(4) Roshan Colah, Khushnooma Italia, Ajit Gorakshakar. Burden of thalassemia in India: The road map for control. Pediatric Hematology Oncology Journal. Volume 2, Issue 4, December 2017, Pages 79-84.
(5) March of dimes global report on birth defects, the hidden toll of dying and disabled children Arnold Christianson Division of Human Genetics, National Health Laboratory Service and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2000, South Africa. email: arnold.christianson@nhls.ac.za Christopher P. Howson Global Programs, March of Dimes Foundation, White Plains, New York 10605, USA email: chowson@marchofdimes.com
(6) CDC (2019-02-08). “Hemoglobinopathies Research”. Centers for Disease Control and Prevention. Retrieved 2019-05-05.
(7) Weatherall, D. J.; Clegg, J. B. (2001). “Inherited haemoglobin disorders: An increasing global health problem”. Bulletin of the World Health Organization. 79 (8): 704–712. PMC 2566499. PMID 11545326.
