Sumita Danda1, Sony Mohan2, Prabavathi Devaraj2, Atanu K Dutta2, Sheela Nampoothiri3, Dhanya Yesodharan3, Shubha R Phadke4, Anil B Jalan5, K Thangaraj6, Ishwar Chandra Verma7, Debashish Danda8, Isaac Jebaraj9. 1. Department of Medical Genetics, Christian Medical College and Hospital Vellore, OT Block 5th Floor, Vellore, Tamil Nadu, 632004, India. sdanda@cmcvellore.ac.in. 2. Department of Medical Genetics, Christian Medical College and Hospital Vellore, OT Block 5th Floor, Vellore, Tamil Nadu, 632004, India. 3. Amrita Institute of Medical Sciences & Research Centre, Cochin, Kerala, India. 4. Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, UP, India. 5. Navi Mumbai Institute of Research in Mental and Neurological Handicap Navi Mumbai, Navi Mumbai, India. 6. Centre of Cellular and Molecular Biology, Hyderabad, Telangana, India. 7. Institute of Genetics and Genomics, Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India. 8. Department of Clinical Immunology & Rheumatology, Christian Medical College Vellore and Hospital, Vellore, Tamil Nadu, India. 9. Department of Orthopedics, Christian Medical College Vellore and Hospital, Vellore, Tamil Nadu, India.
Abstract
INTRODUCTION: Alkaptonuria (AKU) is a rare metabolic disease. The global incidence is 1:100,000 to 1:250,000. However, identification of a founder mutation in a gypsy population from India prompted us to study the prevalence of AKU in this population and to do molecular typing in referred cases of AKU from the rest of India. OBJECTIVE: To determine the prevalence of AKU in the gypsy population predominantly residing in the seven districts of Tamil Nadu. To determine the molecular characteristic of AKU cases referred to our clinic from various parts of India. METHOD: Urine spot test to detect homogentisic acid followed by quantitative estimation using high-performance liquid chromatography in 499 participants from the gypsy population and confirming the founder mutation in those with high levels by sequencing. Sequence the homogentisate 1,2-dioxygenase (HGD) gene to identify mutations and variants in 29 AKU non-gypsy cases. RESULTS: The founder mutation was detected in homozygous state in 41/499 AKU-affected individuals of the gypsy community giving a high prevalence of 8.4%. Low back pain, knee pain, and eye and ear pigmentation were the most common symptoms and signs respectively. The commonest mutation identified in the non-gypsy AKU cases was p.Ala122Val. CONCLUSION: High prevalence of AKU in the inbred gypsy population at 8.4% was detected confirming the founder effect. Urine screening provided a cost-effective method to detect the disease early. Mutation spectrum is varied in the rest of the Indian population. This study identified maximum number of mutations in exon 6 of the HGD gene. Key Points • High prevalence (8.4%) of alkaptonuria (AKU) in the gypsy population due to founder mutation in the HGD gene. • Inbreeding exemplifies the founder effects of this rare genetic disorder. • Urinary screening is a cost-effective method in this community for early detection of AKU and intervention. • The mutation spectrum causing AKU is diverse in the rest of the Indian population.
INTRODUCTION: Alkaptonuria (AKU) is a rare metabolic disease. The global incidence is 1:100,000 to 1:250,000. However, identification of a founder mutation in a gypsy population from India prompted us to study the prevalence of AKU in this population and to do molecular typing in referred cases of AKU from the rest of India. OBJECTIVE: To determine the prevalence of AKU in the gypsy population predominantly residing in the seven districts of Tamil Nadu. To determine the molecular characteristic of AKU cases referred to our clinic from various parts of India. METHOD: Urine spot test to detect homogentisic acid followed by quantitative estimation using high-performance liquid chromatography in 499 participants from the gypsy population and confirming the founder mutation in those with high levels by sequencing. Sequence the homogentisate 1,2-dioxygenase (HGD) gene to identify mutations and variants in 29 AKU non-gypsy cases. RESULTS: The founder mutation was detected in homozygous state in 41/499 AKU-affected individuals of the gypsy community giving a high prevalence of 8.4%. Low back pain, knee pain, and eye and ear pigmentation were the most common symptoms and signs respectively. The commonest mutation identified in the non-gypsy AKU cases was p.Ala122Val. CONCLUSION: High prevalence of AKU in the inbred gypsy population at 8.4% was detected confirming the founder effect. Urine screening provided a cost-effective method to detect the disease early. Mutation spectrum is varied in the rest of the Indian population. This study identified maximum number of mutations in exon 6 of the HGD gene. Key Points • High prevalence (8.4%) of alkaptonuria (AKU) in the gypsy population due to founder mutation in the HGD gene. • Inbreeding exemplifies the founder effects of this rare genetic disorder. • Urinary screening is a cost-effective method in this community for early detection of AKU and intervention. • The mutation spectrum causing AKU is diverse in the rest of the Indian population.
Entities:
Keywords:
Black bone disease; Genetics; India; Urine screening
Authors: Raida Khalil; Dema Ali; Nesrin Mwafi; Arwa Alsaraireh; Loiy Obeidat; Eman Albsoul; Ibrahim Al Sbou' Journal: Biomed Res Int Date: 2021-03-11 Impact factor: 3.411