Direct sequencing of FAH gene in Pakistani tyrosinemia type 1 families reveals a novel mutation
-
Sadaqat Ijaz
,
Muhammad Imran
Abstract
Background: Hereditary tyrosinemia type 1 (HT1) is a rare inborn error of tyrosine catabolism with a worldwide prevalence of one out of 100,000 live births. HT1 is clinically characterized by hepatic and renal dysfunction resulting from the deficiency of fumarylacetoacetate hydrolase (FAH) enzyme, caused by recessive mutations in the FAH gene. We present here the first report on identification of FAH mutations in HT1 patients from Pakistan with a novel one.
Methods: Three Pakistani families, each having one child affected with HT1, were enrolled over a period of 1.5 years. Two of the affected children had died as they were presented late with acute form. All regions of the FAH gene spanning exons and splicing sites were amplified by polymerase chain reaction (PCR) and mutation analysis was carried out by direct sequencing. Results of sequencing were confirmed by restriction fragment length polymorphism (PCR-RFLP) analysis.
Results: Three different FAH mutations, one in each family, were found to co-segregate with the disease phenotype. Two of these FAH mutations have been known (c.192G>T and c.1062+5G>A [IVS12+5G>A]), while c.67T>C (p.Ser23Pro) was a novel mutation. The novel variant was not detected in any of 120 chromosomes from normal ethnically matched individuals.
Conclusions: Most of the HT1 patients die before they present to hospitals in Pakistan, as is indicated by enrollment of only three families in 1.5 years. Most of those with late clinical presentation do not survive due to delayed diagnosis followed by untimely treatment. This tragic condition advocates the establishment of expanded newborn screening program for HT1 within Pakistan.
Acknowledgments
The authors would like to thank the families for participating in the study.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Reserach funding: Higher Education Commission, Pakistan provided the funding; SRGP#932.
Employment or leadership: None declared.
Honorarium: None declared.
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©2016 by De Gruyter
Articles in the same Issue
- Frontmatter
- Review
- Role of nutrition in preventing insulin resistance in children
- Original Articles
- Reduced frequency and severity of ketoacidosis at diagnosis of childhood type 1 diabetes in Northwest Saudi Arabia
- Differences in parental involvement in the care of children and adolescents with type 1 diabetes mellitus on multiple daily insulin injections versus continuous subcutaneous insulin infusion
- Value of the intrarenal arterial resistivity indices and different renal biomarkers for early identification of diabetic nephropathy in type 1 diabetic patients
- Remission of congenital hyperinsulinism following conservative treatment: an exploratory study in patients with KATP channel mutations
- Relationship between visceral obesity and plasma fibrinogen in obese children
- Diagnostic approach in children with unusual symptoms of acquired hypothyroidism. When to look for pituitary hyperplasia?
- The shortened combined clonidine and arginine test for growth hormone deficiency is practical and specific: a diagnostic accuracy study
- Bone maturation along the spectrum from normal weight to obesity: a complex interplay of sex, growth factors and weight gain
- Outcomes analysis of radioactive iodine and total thyroidectomy for pediatric Graves’ disease
- Direct sequencing of FAH gene in Pakistani tyrosinemia type 1 families reveals a novel mutation
- Odontoiatric perspectives and osteonecrosis of the jaw as a possible adverse effect of bisphosphonates therapy in fibrous dysplasia and McCune-Albright syndrome
- The relation of urinary bisphenol A with kisspeptin in girls diagnosed with central precocious puberty and premature thelarche
- Pattern of teen menstruation among secondary school girls in south east Nigeria
- Should children with isolated premature adrenarche be routinely evaluated for non-classical congenital adrenal hyperplasia?
- Anxiety, depression and self-esteem levels in obese children: a case-control study
- Case Reports
- Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2
- Isolated methylmalonic acidemia with unusual presentation mimicking diabetic ketoacidosis
- A first case report of UDP-galactose-4′-epimerase deficiency in China: genotype and phenotype
- A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA)
- Letter to the Editor
- Partial biotinidase deficiency: identification of a single novel mutation (p.H314R) in a Greek newborn
Articles in the same Issue
- Frontmatter
- Review
- Role of nutrition in preventing insulin resistance in children
- Original Articles
- Reduced frequency and severity of ketoacidosis at diagnosis of childhood type 1 diabetes in Northwest Saudi Arabia
- Differences in parental involvement in the care of children and adolescents with type 1 diabetes mellitus on multiple daily insulin injections versus continuous subcutaneous insulin infusion
- Value of the intrarenal arterial resistivity indices and different renal biomarkers for early identification of diabetic nephropathy in type 1 diabetic patients
- Remission of congenital hyperinsulinism following conservative treatment: an exploratory study in patients with KATP channel mutations
- Relationship between visceral obesity and plasma fibrinogen in obese children
- Diagnostic approach in children with unusual symptoms of acquired hypothyroidism. When to look for pituitary hyperplasia?
- The shortened combined clonidine and arginine test for growth hormone deficiency is practical and specific: a diagnostic accuracy study
- Bone maturation along the spectrum from normal weight to obesity: a complex interplay of sex, growth factors and weight gain
- Outcomes analysis of radioactive iodine and total thyroidectomy for pediatric Graves’ disease
- Direct sequencing of FAH gene in Pakistani tyrosinemia type 1 families reveals a novel mutation
- Odontoiatric perspectives and osteonecrosis of the jaw as a possible adverse effect of bisphosphonates therapy in fibrous dysplasia and McCune-Albright syndrome
- The relation of urinary bisphenol A with kisspeptin in girls diagnosed with central precocious puberty and premature thelarche
- Pattern of teen menstruation among secondary school girls in south east Nigeria
- Should children with isolated premature adrenarche be routinely evaluated for non-classical congenital adrenal hyperplasia?
- Anxiety, depression and self-esteem levels in obese children: a case-control study
- Case Reports
- Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2
- Isolated methylmalonic acidemia with unusual presentation mimicking diabetic ketoacidosis
- A first case report of UDP-galactose-4′-epimerase deficiency in China: genotype and phenotype
- A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA)
- Letter to the Editor
- Partial biotinidase deficiency: identification of a single novel mutation (p.H314R) in a Greek newborn
