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Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin precursors and porphyrin species. Afflicted patients present with a myriad of symptoms causing a diagnostic odyssey. Symptoms often overlap with those of common diseases and may be overlooked unless there is heightened clinical suspicion. We are reporting clinical features and diagnostic challenges in four pediatric patients having variegate porphyria, congenital erythropoietic porphyria, acute intermittent porphyria, and erythropoietic protoporphyria (EPP), who presented with diverse multisystem manifestations. This case series illustrates a logical analysis of symptoms and judicious selection of investigations and the role of genotyping in successfully diagnosing porphyrias. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 3-month-old infant with progressing breathlessness, fever and feeding difficulty among other conditions. Examinations showed skeletal abnormalities, enlarged kidneys, and pulmonary hypertension, and the infant had a suggested diagnosis of skeletal ciliopathies like short rib thoracic dysplasia (SRTD). The patient was given supplemental oxygen and oral nifedipine and sildenafil among other treatments and was discharged after 33 days on nasal oxygen.

We report three brothers with Allgrove syndrome. All three had evidence of adrenal insufficiency and deficient tear production, though neither of them had achalasia, the third component of the disorder at the time of this report. Neurological abnormalities were present in the index case. The younger siblings were neurologically normal. The familial association of achalasia, alacrimia and adrenal insufficiency, rather than being fortuitous, is a distinct clinical entity. [ABSTRACT FROM AUTHOR]

Reported below is the association of unusual hand malformations and congenital cardiac anomalies, possibly a variant of Heart--Hand syndrome IV in a 10 year old male. In addition to these malformations, he also had genitourinary defects. The differential diagnosis of polydactyly with cardiac defects is discussed along with a review of relevant literature. [ABSTRACT FROM AUTHOR]

Background: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India., Results: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study., Conclusion: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases., (© 2024. The Author(s).)

Red cell pyruvate kinase (PK) deficiency is a genetic disorder affecting the enzyme PK in red blood cells. A deficiency in PK leads to hemolytic anemia. Hypertriglyceridemia means elevated levels of triglycerides in the blood. The hypertriglyceridemia disorder can be primary or secondary to an underlying disease. Hypertriglyceridemia with β-thalassemia major is a known association and is called hypertriglyceridemia-thalassemia syndrome. A four-month-old male child was found to have milky serum. On investigation, there was severe anemia, with triglycerides at 1197 mg/dL and high lactate dehydrogenase (LDH). The child had severe pallor, mild icterus, a dysmorphic face, and splenohepatomegaly. Ophthalmic examination showed lipemia retinitis. The child was treated with medium-chain fatty acid formula feed. Regular blood transfusions, folic acid supplements, and avoidance of salicylate group drugs were advised. The child improved and is doing well. Thus, early diagnosis and treatment can change the prognosis and help maintain a near-normal life for affected infants., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hinge et al.)

Background: Current clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India., Results: 903 smMIPs were designed to target exon and exon-intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood., Conclusion: We developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm., (© 2024. The Author(s).)

A girl in the early adolescent age group presented with multisystem manifestations in the form of periodic fever, recurrent abdominal pain, hypertension, seizure, skin lesions over the chest and gangrene over the left ring and middle fingertips. Her condition had remained undiagnosed for 11 years. On evaluation, she had features of polyarteritis nodosa (PAN) (multiple aneurysms, symmetric sensorimotor peripheral neuropathy, superficial ulcers, digital necrosis, myalgia, hypertension and proteinuria). As childhood PAN is a phenocopy of adenosine deaminase 2 with a different management strategy, whole-exome sequencing was performed, which revealed a pathogenic variant in ADA2 gene. The child was treated with TNF alpha inhibitors and showed improvement in the Paediatric Vasculitis Activity Score. The paper highlights the gratifying consequences of correct diagnosis with disease-specific therapy that ended the diagnostic odyssey, providing relief to the patient from debilitating symptoms and to the family from the financial burden of continued out-of-pocket health expenditure., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To estimate the economic burden of patients diagnosed with Gaucher disease at a public hospital from a societal perspective., Methods: Data from 30 Gaucher patients visiting the Genetic Clinic of the Department of Pediatrics at the study site in Mumbai was analyzed between January 2019 and January 2021. A cost of illness analysis was undertaken to estimate direct, indirect and intangible costs. Costs in treated and treatment naive groups were compared., Results: The total cost (direct and indirect) for 30 patients was ₹25,45,74,743/- (3440199.2 USD). Majority of this cost (99.8%) was due to direct costs of which medications [Enzyme replacement therapy (ERT) and Substrate reduction therapy (SRT)] constituted 98.8%. The notional cost was ₹1,43,94,695. Total costs of 14 treated patients were ₹25,29,67,279 and 16 treatment naive patients were ₹16,15,064 with a ratio of 157:1. Direct costs and cost of school absenteeism were significantly higher in the treated subgroup. Overall, direct, total costs and costs of school absenteeism were significantly associated with age and disease duration., Conclusions: The economic burden of Gaucher disease is a staggering amount. This is an underestimate, as the expenses are highly subsidized in a public health facility. The highest contributor to cost component was direct costs, especially medication costs. Against the backdrop of the National Policy for Rare Diseases, resource allocation towards Gaucher disease should consider short term measures for judicious funding or reimbursement of disease-specific therapy and long-term cost-effective measures for promoting preventive strategies as the most practically feasible solution to reduce this economic burden., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

CHST3-related chondrodysplasia with congenital joint dislocations (CDCJD, #MIM 143095), is a rare genetic skeletal disorder caused by biallelic loss of function variants in CHST3. CHST3 is critical for the sulfation of chondroitin sulfate. This study delineates the clinical presentation of nine individuals featuring the key symptoms of CDCJD; congenital joint (knee and elbow) dislocations, short trunk short stature progressive vertebral anomalies, and metacarpal shortening. Additional manifestations include irregular distal femoral epiphysis, supernumerary carpal ossification centers, bifid humerus, club foot, and cardiac abnormalities. Sanger sequencing was carried out to investigate molecular etiology in eight patients and exome sequencing in one. Genetic testing revealed five homozygous variants in CHST3 (four were novel and one was previously reported). All these variants are located on sulfotransferase domain of CHST3 protein and were classified as pathogenic/ likely pathogenic. We thus report on nine individuals with CHST3-related chondrodysplasia with congenital joint dislocations from India and suggest monitoring the health of cardiac valves in this condition., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background Treating beta-thalassaemia major may entail high costs with considerable out-of-pocket expenditure. Therefore, determination and valuation of the economic costs of a common haemoglobinopathy such as beta-thalassaemia major in India may provide insights to evolve policies for reduction or elimination of the disease. We estimated economic burden of beta-thalassaemia major in Mumbai in terms of cost to the family and the healthcare system. Methods This single-centre, prospective, cross-sectional, non-interventional study included children <12 years of age treated at the thalassaemia day care centre of a public hospital in Mumbai. The demographic data and treatment-related information was recorded. Cost of illness was studied from a societal perspective by the prevalence-based approach. Direct (medical and non-medical), indirect (loss of wages and loss of school days) and intangible costs (closed-ended iterative bidding) were calculated for each patient by interview. Results The total annual cost of treating 130 children with beta-thalassaemia major in Mumbai was ₹86 72 412 (US$ 127 535) or ₹66 710 (US$ 981) per patient per year and ₹12 82 30 412 (US$ 1 885 741) including intangible costs. Direct costs contributed to 94% of the cost of illness with chelation therapy (23%) and blood investigations (21%) being major contributors. Direct and indirect costs correlated significantly with duration of blood transfusion (p<0.05 and p=0.006, respectively), whereas indirect costs correlated with socioeconomic status (rho=0.25). Conclusion The majority (94%) of costs incurred by families for treatment of beta-thalassaemia major are direct costs, especially expenses for chelation and blood investigations. Even at subsidized rates, financial burden to the families from lower socioeconomic strata is likely to be considerable as these are out-of-pocket expenses. In consideration of the economic impact of treating beta-thalassaemia major in individual families, the healthcare system and society, it is prudent to promote and pursue long-term and short-term measures with urgent emphasis on prevention as a public health activity at the national level in India.

Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by rhizomelic short-limbed skeletal dysplasia. The primary clinical and radiographic features include disproportionate dwarfism, joint laxity and hyperextensibility, exaggerated lumbar lordosis, and late ossification of the epiphyses. Identification of disease-causing variants in heterozygous state in COMP establishes the molecular diagnosis of PSACH. We examined 11 families with clinical features suggestive of PSACH. In nine families, we used Sanger sequencing of exons 8-19 of COMP (NM&#95;000095.2) and in two families exome sequencing was used for confirming the diagnosis. We identified 10 de novo variants, including five known variants (c.925G>A, c.976G>A, c.1201G>T, c.1417&#95;1419del, and c.1511G>A) and five variants (c.874T>C, c.1201G>C, c.1309G>A, c.1416&#95;1421delCGACAA, and c.1445A>T) which are not reported outside Indian ethnicity. We hereby report the largest series of individuals with molecular diagnosis of PSACH from India and reiterate the well-known genotype-phenotype corelation in PSACH., (© 2021 Wiley Periodicals LLC.)

Pathogenic variations in SMPD1 lead to acid sphingomyelinase deficiency (ASMD), that is, Niemann-Pick disease (NPD) type A and B (NPA, NPB), which is a recessive lysosomal storage disease. The knowledge of variant spectrum in Indian patients is crucial for early and accurate NPD diagnosis and genetic counseling of families. In this study, we recruited 40 unrelated pediatric patients manifesting symptoms of ASMD and subnormal ASM enzyme activity. Variations in SMPD1 were studied using Sanger sequencing for all exons, followed by interpretation of variants based on American College of Medical Genetics and Genomics & Association for Molecular Pathology (ACMG/AMP) criteria. We identified 18 previously unreported variants and 21 known variants, including missense, nonsense, deletions, duplications, and splice site variations with disease-causing potential. Eight missense variants were functionally characterized using in silico molecular dynamic simulation and in vitro transient transfection in HEK293T cells, followed by ASM enzyme assay, immunoblot, and immunofluorescence studies. All the variants showed reduced ASM activity in transfected cells confirming their disease-causing potential. The study provides data for efficient prenatal diagnosis and genetic counseling of families with NPD type A and B., (© 2021 Wiley Periodicals LLC.)

Glutaric acidemia type 1 (GA-1, OMIM 231670) is an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-coenzyme A (CoA) dehydrogenase with most children presenting in infancy with encephalopathy, dystonia, and macrocephaly. In this article, we presented the clinical characteristics, molecular profile, and outcomes in 29 unrelated families with affected children (30 cases total). The mean age at onset of illness was 10 months (±14.58), whereas the mean age at referral for molecular diagnosis was 29.44 months (±28.11). Patients were residents of nine different states of India. Clinical presentation varied from acute encephalitis followed by neuroregression and chronic/insidious developmental delay. Neurological sequelae varied from asymptomatic (no sequelae, 2 patients) to moderate (5 patients) and severe (23 patients) sequelae. All patients underwent blood tandem mass spectrometry (TMS on dried blood spots) and/or urine gas chromatography mass spectrometry (GCMS). Neuroimaging demonstrated batwing appearance in 95% cases. Sanger's sequencing of GCDH , covering all exons and exon-intron boundaries, was performed for all patients. Variants identified include 15 novel coding variants: p.Met100Thr, p.Gly107Ser, p.Leu179Val, p.Pro217Ser, p. Phe236Leufs*107, p.Ser255Pro, p.Met266Leufs*2, p.Gln330Ter, p.Thr344Ile, p.Leu345Pro, p.Lys377Arg, p.Leu424Pro, p.Asn373Lys, p.Lys377Arg, p.Asn392Metfs*9, and nine known genetic variants such as p.Arg128Gln, p.Leu179Arg, p.Trp225Ter, p.Met339Val, p.Gly354Ser, p.Arg402Gln, p.Arg402Trp, p.His403Tyr, and p.Ala433Val (Ensembl transcript ID: ENST00000222214). Using in silico analysis, genetic variants were shown to be affecting the residues responsible for homotetramer formation of the glutaryl-CoA dehydrogenase protein. Treatment included oral carnitine, riboflavin, protein-restricted diet, lysine-deficient special formulae, and management of acute crises with intravenous glucose and hydration. However, the mortality (9/30, 27.58%) and morbidity was high in our cohort with only two patients affording the diet. Our study is the largest multicentric, genetic variant-proven series of glutaric aciduria type 1 from India till date., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Diagnosis of rare disorders requires heightened clinical acumen. When such disorders present with atypical or novel features, it adds to the diagnostic challenge. A 9-month-old female infant who had received a diagnosis of neonatal hepatitis due to cytomegalovirus infection at 2 months of age presented to our institute with developmental delay, fever, vomiting, feeding difficulty, breathlessness and features of elevated intracranial pressure due to hydrocephalus. Key examination findings with cholestatic jaundice as an early manifestation led to suspicion of type 4 Farber disease. Observation of hydrocephalus, hypertension, bilateral pinguecula and Erlenmeyer flask deformity of the femur were unusual findings for Farber disease. The child had few features (pinguecula, Erlenmeyer flask deformity and hydrocephalus) overlapping with Gaucher disease. Alternatively, prosaposin deficiency (Farber disease type 7) was another differential diagnosis. Diagnosis of Farber disease was confirmed by detection of foamy macrophages on skin biopsy and two homozygous missense variants in ASAH1 gene., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

We evaluated the clinical histories, motor and pulmonary functions, cardiac phenotypes and GAA genotypes of an Indian cohort of twenty patients with late onset Pompe disease (LOPD) in this multi-centre study. A mean age at onset of symptoms and diagnosis of 9.9 ± 9.7 years and 15.8 ± 12.1 years respectively was identified. All patients had lower extremity limb-girdle muscle weakness. Seven required ventilatory support and seven used mobility assists. Of the four who used both assists, two received ventilatory support prior to wheelchair use. Cardiac involvement was seen in eight patients with various combinations of left ventricular hypertrophy, tricuspid regurgitation, cardiomyopathy, dilated ventricles with biventricular dysfunction and aortic regurgitation. Amongst 20 biochemically diagnosed patients (low residual GAA enzyme activity) GAA genotypes of 19 patients identified homozygous variants in eight and compound heterozygous in 11: 27 missense, 3 nonsense, 2 initiator codon, 3 splice site and one deletion. Nine variants in 7 patients were novel. The leaky Caucasian, splice site LOPD variant, c.-32-13T>G mutation was absent. This first study from India provides an insight into a more severe LOPD phenotype with earlier disease onset at 9.9 years compared to 33.3 years in Caucasian patients, and cardiac involvement more than previously reported. The need for improvement in awareness and diagnosis of LOPD in India is highlighted., Competing Interests: Declaration of Competing Interest Access to ERT (alglucosidase alfa) is provided under the Indian Charitable Access Program (INCAP) of Sanofi Genzyme for patients of authors RDP, NG, SN, SJ, MK, MM, MB and ICV. The association is purely academic, and no financial compensation is provided. The authors are also committee members of the INCAP and/or CAP programs. The authors declare no other conflicts of interest. PSK is a member of the IMAB (India Medical Advisory Board) and an advisor within the INCAP. PSK has received research/grant support from Sanofi Genzyme, Valerion Therapeutics, and Amicus Therapeutics. PSK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics and Asklepios Biopharmaceutical, Inc. (AskBio). PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies. PSK has equity in Asklepios Biopharmaceutical, Inc. (AskBio), which is developing gene therapy for Pompe disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The present study examined referral pattern and diagnostic practices for mucopolysaccharidosis (MPS) in India in 40 patients with a confirmed diagnosis. Time lag between age of onset of symptoms and consultation with primary physician ranged from 0 to 84 months, between consultation with primary physician and visit to genetic clinic of 0 to 128 months, from visit to genetic clinic and diagnosis of 1 to 111 months, and that between onset of symptoms and diagnosis 1 to 154 months. Major causes for delayed diagnosis were symptoms overlooked by physician (54%), late consultation by care giver (48.6%), late onset of symptoms (43.2%), and resource crunch (32.4%). Diagnosis at referral other than MPS was noted in 45%. Thus, diagnostic delay for MPS is common due to health seeking practices of parents, as well as physicians' clinical practices. Overcoming these barriers would necessitate strengthening awareness and educational activities for physicians and lay public., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Objectives: To evaluate the clinical and molecular spectrum, and factors affecting clinical outcome of patients in India diagnosed with infantile-onset Pompe disease (IOPD)., Study Design: In this multicenter, cross-sectional study, we evaluated the records of 77 patients with IOPD to analyze their clinical course, outcomes, and factors influencing the outcomes., Results: Of the 77 patients with IOPD, phenotype data were available in 59; 46 (78%) had the classic phenotype. Overall, 58 of 77 (75%) and 19 of 77 (25%) patients were symptomatic before and after age 6 months, respectively. Alpha-glucosidase gene variant analysis available for 48 patients (96 alleles) showed missense variants in 49 alleles. Cross-reactive immunologic material (CRIM) status could be determined or predicted in 44 of 48 patients. In total, 32 of 44 patients (72%) were CRIM-positive, and 12 of 44 patients (27%) were CRIM-negative. Thirty-nine cases received enzyme-replacement therapy (ERT), alglucosidase alfa, and 38 patients never received ERT. Median age at initiation of ERT was 6.5 months. Response to ERT was better in babies who had CRIM-positive, non-classic IOPD., Conclusions: This study highlights the clinical spectrum of IOPD in India and provides an insight on various factors, such as undernutrition, feeding difficulties, and recurrent respiratory infection, as possible factors influencing clinical outcomes in these patients. The study also reiterates the importance of raising awareness among clinicians about the need for early diagnosis and timely treatment of IOPD., (Copyright © 2019 Elsevier Inc. All rights reserved.)