ABSTRACT
Inborn errors of cobalamin (Cbl) metabolism affect its absorption, transport, as well as its intracellular metabolism. Hereditary juvenile megaloblastic anaemia due to cobalamin deficiency, results from defects in Cbl absorption. There is a lack of vitamin B12 in congenital pernicious anaemia due to intrinsic factor deficiency and megaloblastic anaemia 1 due to selective intestinal malabsorption of vitamin B12 or Imerslund-Gräsbeck syndrome. Differential diagnosis can't be accomplished only by clinical and biochemical findings. We present a patient from Spain with a megaloblastic anaemia due to intrinsic factor deficiency (IFD). The patient is a compound heterozygous in GIF gene for a splice site mutation inherited from his mother and a missense change inherited from his father. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions.
Subject(s)
Microfilament Proteins/genetics , Point Mutation/genetics , Vesicular Transport Proteins/genetics , Vitamin B 12 Deficiency/genetics , Child, Preschool , Humans , Male , SyndromeABSTRACT
Los errores congénitos del metabolismo de la cobalamina afectan a su absorción, transporte o metabolismo intracelular. La anemia megaloblástica hereditaria juvenil por déficit de vitamina B12 está causada por una malabsorción de cobalamina. En la anemia perniciosa congénita por déficit de factor intrínseco, y en la anemia megaloblástica 1 por malabsorción de vitamina B12, causada por un defecto en el receptor vitamina B12/factor intrínseco o síndrome de Imerslund-Gräsbeck, existe un déficit de vitamina B12. El diagnóstico diferencial entre estas dos entidades no puede ser completado únicamente mediante la clínica y los datos de laboratorio. Presentamos un paciente español con anemia megaloblástica hereditaria juvenil por déficit de factor intrínseco, heterocigoto compuesto para dos mutaciones distintas en el gen GIF. La identificación de mutaciones causantes de la enfermedad en genes específicos ha mejorado nuestra capacidad de diagnóstico y tratamiento de estas situaciones (AU)
Inborn errors of cobalamin (Cbl) metabolism affect its absorption, transport, as well as its intracellular metabolism. Hereditary juvenile megaloblastic anaemia due to cobalamin deficiency, results from defects in Cbl absorption. There is a lack of vitamin B12 in congenital pernicious anaemia due to intrinsic factor deficiency and megaloblastic anaemia 1 due to selective intestinal malabsorption of vitamin B12 or Imerslund-Gräsbeck syndrome. Differential diagnosis can't be accomplished only by clinical and biochemical findings. We present a patient from Spain with a megaloblastic anaemia due to intrinsic factor deficiency (IFD). The patient is a compound heterozygous in GIF gene for a splice site mutation inherited from his mother and a missense change inherited from his father. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions (AU)
Subject(s)
Humans , Male , Child , Vitamin B 12 Deficiency/complications , Vitamin B 12 Deficiency/diagnosis , Vitamin B 12 Deficiency/genetics , Mutation/genetics , Mutation/physiology , Diagnosis, Differential , Anemia, Megaloblastic/complications , Schilling Test/methods , Vitamin B 12 Deficiency/physiopathology , Anorexia/complications , Pallor/complications , Fatigue/complications , Biopsy/methods , Schilling Test/trends , Schilling TestABSTRACT
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Subject(s)
Aged , Male , Humans , Erythropoietin , Multiple Sclerosis , Anemia , Pressure UlcerABSTRACT
BACKGROUND: Identification of RBC pyruvate-kinase (PK) gene mutations by polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) followed by PK gene sequencing in positive cases has been assessed and the results obtained with a preliminary study of 15 unrelated patients of Spanish origin are presented. PATIENTS AND METHODS: Patients have been classified into two different groups: group 1, propositus (15 cases), and group 2, relatives of the patients included in group 1 (10 males and 5 females). In group 1, a PCR was followed by SSCP and sequencing, and in group 2, the PCR was followed by digestion with specific restriction endonucleases (PCR-ER). RESULTS: Group 1: from 15 patients included in the study 2 were identified as homozygous, 4 as heterozygous and 9 as compound heterozygous. In this group, were identify 26 affected alleles with 11 different mutations: T1456 10 alleles (38.6%), T721 3 alleles (11.6%), A1010, C514, C1015 and T1223 2 alleles (7.7%), and C1070, A1291, T1508, A1595 y T1675 one allele. Relatives from 8 out of 15 patients from group 1 showed the following pattern: homozygous (one case), heterozygous (10 cases), compound heterozygous (2 cases) and normal (2 cases). CONCLUSIONS: SSCP procedure followed by direct gene sequencing in positive cases is fast and simple enough to allow the identification of PK deficient variants, avoiding the need of biochemical characterisation of semipurified deficient enzyme, which is more cumbersome and time consuming. In addition, the PCR-ER method is a very useful tool for screening of the most frequent molecular variants, as well as, for the detection of the carrier condition of this enzymopathy (family studies).
Subject(s)
Anemia, Hemolytic/genetics , Erythropoiesis/genetics , Pyruvate Kinase/deficiency , Pyruvate Kinase/metabolism , Amino Acids/genetics , Anemia, Hemolytic/enzymology , Chronic Disease , Female , Genotype , Hematology , Humans , Male , Nucleotides/genetics , Point Mutation/genetics , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Sequence Analysis, DNA , Societies, Medical , SpainSubject(s)
Cataract/congenital , Cataract/genetics , Ferritins/blood , Adult , Female , Humans , Male , Spain , SyndromeABSTRACT
The PK-LR gene has been studied in 12 unrelated patients with red cell pyruvate kinase deficiency and hereditary nonspherocytic haemolytic anaemia (CNSHA). The entire codifying region of the R-type PK gene and the flanking intronic regions were analysed by single-stranded conformation polymorphism (SSCP) followed by direct sequencing of abnormal DNA. 10 different mutations were identified in 22/24 alleles at risk. Eight of these were missense mutations that caused the following single amino acid changes: G514C (172Glu-Gln), G1010A (337Arg-Gln), G1015C (339Asp-Gln), T1070C (357Ile-Thr), C1223T (408Thr-Ile), G1291A (431Ala-Thr), C1456T (486Arg-Trp) and G1595A (532Arg-Gln). Two were nonsense mutations: G721T (241Glu-Stop) and C1675T (559Arg-Stop). 7/22 alleles demonstrated the same C1456 --> T mutation. The study of the polymorphic site at nucleotide (nt) 1705 performed in all cases disclosed a 1705 C/C mutation in 10 and a 1705 A/C mutation in three. This is the first report on the presence of several different L-type PK gene mutations within Spanish population. Furthermore, from the PK gene mutations found, six were unique and not previously described (1015C, 1070C, 1223T, 1291A, 1595A and 1675T) and one (C1456T) seems to be predominant in Spain. Interestingly, no case with the 1529A mutation commonly found in Northern European populations was present here.