scholarly journals Recessive congenital methemoglobinemia type II: Hypoplastic basal ganglia in two siblings with a novel mutation of the cytochrome b5 reductase gene

2019 ◽  
Vol 32 (2) ◽  
pp. 143-147
Author(s):  
Manal Nicolas-Jilwan
Keyword(s):  
Basal Ganglia ◽  
Missense Mutation ◽  
Movement Disorders ◽  
Imaging Finding ◽  
Novel Mutation ◽  
Cytochrome B5 ◽  
Brain Magnetic Resonance Imaging ◽  
Type Ii ◽  
Caudate Nuclei ◽  
Cytochrome B5 Reductase

Recessive congenital methemoglobinemia type II is a very rare autosomal recessive hematologic disorder due to NADH-cytochrome b5 reductase deficiency, usually caused by full-stop mutations or deletions. This disease classically presents with mild neonatal cyanosis, early onset severe progressive developmental delay, movement disorders, and progressive microcephaly. We report two siblings with recessive congenital methemoglobinemia type II whose evaluation revealed a novel p.Arg92Trp missense mutation of the CYB5R3 gene and a peculiar imaging finding of basal ganglia hypoplasia. Brain magnetic resonance imaging was performed at age 10 months in the older sibling and at age three months in the younger sibling. It revealed similar findings of bilateral small size of the lentiform and caudate nuclei and reduced frontotemporal brain volume. Our patient cases highlight that basal ganglia hypoplasia is an interesting clue to the very rare and frequently unsuspected diagnosis of recessive congenital methemoglobinemia type II, that may explain the associated movement disorders. The novel missense mutation is one of very few identified missense mutations known to cause severe type II recessive congenital methemoglobinemia.

scholarly journals Seven new mutations in the nicotinamide adenine dinucleotide reduced–cytochrome b5 reductase gene leading to methemoglobinemia type I

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 1106-1114 ◽  
Author(s):  
Jan Dekker ◽  
Michel H. M. Eppink ◽  
Rob van Zwieten ◽  
Thea de Rijk ◽  
Angel F. Remacha ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cytochrome B5 ◽  
Enzyme Inactivation ◽  
Amino Acid Substitutions ◽  
Type I ◽  
Type Ii ◽  
3 Dimensional ◽  
Cytochrome B5 Reductase ◽  
Fad Binding

Abstract Cytochrome b5 reductase (b5R) deficiency manifests itself in 2 distinct ways. In methemoglobinemia type I, the patients only suffer from cyanosis, whereas in type II, the patients suffer in addition from severe mental retardation and neurologic impairment. Biochemical data indicate that this may be due to a difference in mutations, causing enzyme instability in type I and complete enzyme deficiency or enzyme inactivation in type II. We have investigated 7 families with methemoglobulinemia type I and found 7 novel mutations in the b5R gene. Six of these mutations predicted amino acid substitutions at sites not involved in reduced nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FAD) binding, as deduced from a 3-dimensional model of human b5R. This model was constructed from comparison with the known 3-dimensional structure of pig b5R. The seventh mutation was a splice site mutation leading to skipping of exon 5 in messenger RNA, present in heterozygous form in a patient together with a missense mutation on the other allele. Eight other amino acid substitutions, previously described to cause methemoglobinemia type I, were also situated in nonessential regions of the enzyme. In contrast, 2 other substitutions, known to cause the type II form of the disease, were found to directly affect the consensus FAD-binding site or indirectly influence NADH binding. Thus, these data support the idea that enzyme inactivation is a cause of the type II disease, whereas enzyme instability may lead to the type I form.

A novel mutation in the NADH-cytochrome b5 reductase gene of a Chinese patient with recessive congenital methemoglobinemia

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3250-3255 ◽  
Author(s):  
Yao Wang ◽  
Yu-Shui Wu ◽  
Pei-Zhen Zheng ◽  
Wen-Xi Yang ◽  
Guo-An Fang ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Novel Mutation ◽  
Cytochrome B5 ◽  
Clinical Manifestations ◽  
Mutant Enzyme ◽  
Chinese Family ◽  
Coding Region ◽  
Cytochrome B5 Reductase ◽  
Nadh Cytochrome

Abstract Recessive congenital methemoglobinemia due to nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) deficiency is classified into 2 clinical types: type 1 (erythrocyte type) and type 2 (generalized type). We found a Chinese family with type 1 recessive congenital methemoglobinemia, the patients from which were diagnosed according to clinical symptoms and b5R enzyme activity in the blood cells. To learn the molecular basis of type 1 recessive congenital methemoglobinemia in this Chinese family, we isolated total RNA from the peripheral leukocytes of the propositus and b5R complementary DNA (cDNA) by reverse transcription– polymerase chain reaction (RT-PCR). The coding region of the b5R cDNA was analyzed by sequencing the cloned PCR products. The results showed that the propositus was homozygous for a G→A transition at codon 203 in exon 7, changing a cysteine to a tyrosine (Cys203Tyr). To characterize the mutant enzyme, both glutathione S-transferase (GST)-fused wild-type b5R and GST-fused mutant Cys203Tyr b5R were expressed in Escherichia coli and affinity purified. The results showed that the catalytic activity of the enzyme was not much affected by this amino acid substitution, but the mutant enzyme exhibited decreased heat stability and increased susceptibility to trypsin. These properties of the mutant enzyme would account for the restricted b5R deficiency and mild clinical manifestations of these type 1 patients. The finding of this novel mutation makes codon 203 the only position within the b5R gene at which more than 1 mutation has been found.

scholarly journals A novel mutation found in the 3' domain of NADH-cytochrome B5 reductase in an African-American family with type I congenital methemoglobinemia

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2993-2999 ◽  
Author(s):  
MM Jenkins ◽  
JT Prchal
Keyword(s):  
African American ◽  
Novel Mutation ◽  
Cytochrome B5 ◽  
Alpha Helix ◽  
Type I ◽  
African American Family ◽  
American Family ◽  
Cytochrome B5 Reductase ◽  
Specific Pcr ◽  
Function Relationship

Congenital methemoglobinemia caused by an erythrocytic deficiency of cytochrome b5 reductase (b5R; type I) in African-American individuals was first reported by this laboratory. The rarity of this observation is possibly due to the difficulty detecting cyanosis that is masked by naturally occurring dark skin pigment. Since previous biochemical studies on the African-American family with variant enzyme b5R- Shreveport showed enzyme instability, we focused on molecular analysis of its transcript. The transcript size was the same as that of a normal control. The nucleotide sequence of both normal and variant transcripts were examined by directly sequencing reverse transcriptase-polymerase chain reaction (RT-PCR) product. The propositus was found to be homozygous for a G to A transition at codon 212 in exon 8, changing a glutamate to a lysine (E212K). In addition, a C to G transversion was found at codon 116 in exon 5, changing a threonine to a serine (T116S). Using allele-specific PCR, we determined that E212K was found only in the propositus and her heterozygous mother. Furthermore, E212K is predicted to disrupt an alpha-helix peptide structure of b5R, suggesting that this is likely the disease-causing mutation. In contrast, T116S was found to be a high-frequency polymorphism specific for the African-American population. The E212K mutation is uniquely present in the 3′ end of the b5R gene (exon 8), which differs from those b5R mutations found among Japanese subjects (exons 3 and 5) and in an Italian subject (exon 4) and, thus, further contributes to our understanding of the structure/function relationship of this housekeeping enzyme.

scholarly journals Congenital methemoglobinemia misdiagnosed as polycythemia vera: Case report and review of literature

2018 ◽  
Vol 10 (1) ◽  
Author(s):  
Dina Sameh Soliman ◽  
Mohamed Yassin
Keyword(s):  
English Literature ◽  
Cytochrome B5 ◽  
Arterial Oxygen Tension ◽  
Arterial Oxygen ◽  
Type I ◽  
Type Ii ◽  
Male Predominance ◽  
Cytochrome B5 Reductase ◽  
Methemoglobin Level ◽  
Arterial Blood

Methemoglobinemia is a rare overlooked differential diagnosis in patients presented with cyanosis and dyspnea unrelated to cardiopulmonary causes. Our patient is 29 year old Indian non-smoker male, his story started 6 months prior to presentation to our center when he had generalized fatigue and discoloration of hands. He presented with persistent polycythemia with elevated hemoglobin level. The patient was misdiagnosed in another center as polycythemia and treated with Imatinib. The diagnosis of PV was revisited and ruled out in view of negative JAK2, normal erythropoietin level and absence of features of panmyelosis. Clinical cyanosis and lowoxygen saturation in the presence of normal arterial oxygen tension was highly suggestive of methemoglobinemia. Arterial blood gas revealed a methemoglobin level of 38% (normal: 0-1.5%). Cytochrome B5 reductase (Methemoglobin reductase B) was deficient at level of <2.6 U/g Hb) (normal: 6.6-13.3), consistent with methemoglobin reductase (cytochrome b5) deficiency and hence the diagnosis of congenital methemoglobinemia was established. The role of Imatinib in provoking methemoglobinemia is questionable and association between Imatinib and methemoglobinemia never described before. In our case, there were no other offending drugs in aggravating the patients’ symptoms and cyanosis. The patient started on Vitamin C 500 mg once daily for which he responded well with less cyanosis and significant reduction of methemoglobin level. Congenital methemoglobinemia is a rare underreported hemoglobin disease and often clinically missed. Upon extensive review of English literature for cases of congenital methemoglobinemia due to deficiency of cytochrome b5 reductase, we found 23 cases diagnosed as type I (including the case reported here). 17 cases (~74%) of type I and 6 cases (27%) of type II. There is male predominance 73% versus 26% in females. Almost half of reported cases 12 cases (52%) are Indian, 2 Japanese, 3 English, 2 Arabic, one case Spanish and one case Italian. For type I, the median calculated age is 31 years with cyanosis and shortness of breath being the most common sign and symptoms. For type II: Six cases were reported in English literature, all in pediatric age group with median calculated age at presentation is 6 years with neurologic manifestations and mental retardation are the most common type II associated symptoms. Due to lack of systematic epidemiological studies, congenital methemoglobinemia is under diagnosed as it is under investigated and usually overlooked especially when presenting in adulthood and in absence of obvious acquired agents.

scholarly journals Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene

Cephalalgia ◽  
2013 ◽  
Vol 34 (3) ◽  
pp. 183-190 ◽  
Author(s):  
Christian Roth ◽  
Tobias Freilinger ◽  
Georgi Kirovski ◽  
Juliane Dunkel ◽  
Yogesh Shah ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Clinical Symptoms ◽  
Novel Mutation ◽  
Epileptic Seizures ◽  
Familial Hemiplegic Migraine ◽  
Type Ii ◽  
Single Patient ◽  
Hemiplegic Migraine ◽  
Atp1a2 Gene

Introduction Familial hemiplegic migraine (FHM) is a rare subtype of migraine with transient hemiplegic aura. Patients and methods We describe three unrelated families with familial hemiplegic migraine type II (FHM2). Retrospectively, information on 47 family members could be obtained, 15 by personal examination and 32 by indirect anamnesis from relatives. Genetic analyses were performed in 13 patients. Results One family had a novel missense mutation in the ATP1A2 gene (c.659C>T, p.Ser220Leu) that segregated with the phenotype in three generations. Two further unrelated families with different ethnic backgrounds (one from Germany and one from Russia) had a missense mutation that has not been described as yet in FHM, but occurred in only a single patient with sporadic hemiplegic migraine (c.2723G>A, p.Arg908Gln). Clinically the patients had severe attacks lasting up to several weeks as well as epileptic seizures. Three patients with a proven mutation in the ATP1A2 gene clinically presented without hemiparesis. Furthermore, there was a possible relation of FHM2 to mental retardation in another two patients. Conclusion Clinical symptoms may last for several weeks in some patients. Patients with FHM2 may also present without hemiplegia. Therefore, the full family history has to be taken into account to establish the diagnosis of FHM.

scholarly journals Two novel mutations in the reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase gene of a patient with generalized type, hereditary methemoglobinemia

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 3208-3215 ◽  
Author(s):  
J Manabe ◽  
R Arya ◽  
H Sumimoto ◽  
T Yubisui ◽  
AJ Bellingham ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Missense Mutation ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cytochrome B5 ◽  
Mutant Enzyme ◽  
Type Ii ◽  
Novel Mutations ◽  
Nadh Cytochrome ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Generalized Type

Hereditary methemoglobinemia due to reduced nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase (b5R) deficiency is classified into two types, an erythrocyte (type I) and a generalized (type II). We investigated the b5R gene of a patient with type II from a white United Kingdom (UK) family and found that the patient was a compound heterozygote for two novel mutations. The first mutation was a C-to-A transversion changing codon 42 (TAC: Tyr) to a stop codon in the one allele. From this mutant allele, the product without the catalytic portion of the enzyme is generated. The second one was a missense mutation at codon 95 (CCC-->CAC) in the other allele with the result that Pro changed to His within the flavin adenine dinucleotide (FAD)-binding domain of the enzyme. To characterize effects of this missense mutation on the enzyme function, we compared glutathione S-transferase (GST)-fused b5R with the GST-fused mutant enzyme with the codon 95 missense mutation (P95H) expressed in Escherichia coll. The mutant enzyme showed less catalytic activity, less thermostability, and a greater susceptibility to trypsin than did the normal counterpart. The absorption spectrum of the mutant enzyme in the visual region differed from that of the wild-type. These results suggest that this amino acid substitution influences both secondary structure and catalytic activity of the enzyme. The compound heterozygosity for the nonsense and the missense mutations apparently caused hereditary methemoglobinemia type II in this patient.

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