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Congenital Methemoglobinemia

Congenital methemoglobinemia is a rare autosomal recessive disorder due to the deficiency of NADH-cytochrome b5 reductase. The hallmark finding of this disease is cyanosis in the absence of cardiopulmonary etiology. The type I form is benign while type II is life-threatening and features severe neurological and developmental delay.


Presentation

Congenital methemoglobinemia is a genetic disease resulting from the deficiency of NADH-cytochrome b5 reductase due to mutations on chromosome 22 [1] [2]. This enzyme is responsible for converting methemoglobin to hemoglobin. There are 2 forms of congenital methemoglobinemia, known as type I and type II [3]. Patients with type I lack the soluble form of this important enzyme in erythrocytes whereas those with type II are deficient in the membrane-bound form of the enzyme in somatic cells [4]. The first type is benign while the second is associated with significant morbidity and mortality [3].

Patients with congenital methemoglobinemia present with cyanosis often at birth. Another hallmark feature of this disease is that the cyanosis is not corrected with the administration of supplemental oxygen [1].

The cyanosis in type I is not accompanied by other symptoms. However, type II is characterized by severe neurological manifestations such as impaired psychomotor skills, dystonia, encephalopathy, progressive microcephaly, strabismus, and growth retardation [5]. Other features may include refractory epilepsy, skeletal deformities, and behavior abnormalities [5].

Methemoglobinemia is associated with methemoglobin levels greater than 1%. Symptoms are correlated to methemoglobin concentration. For example, a methemoglobin level greater than 35% is associated with tachycardia, tachypnea, headache, dizziness, nausea, emesis, and fatigue whereas a concentration above 55% is reflected by lethargy, arrhythmia, acidosis, and loss of consciousness. Fatality is connected to levels exceeding 70% [1] [6].

Physical Exam

Patients with this disease exhibit an overall slate-blue appearance and a discoloration of their mucus membranes and the blood. Mental status changes, cardiac arrhythmias, skeletal deformities, and other manifestations may be present as well. Also, corneal epitheliopathy has been noted in a handful cases [7].

Fatigue
  • For example, a methemoglobin level greater than 35% is associated with tachycardia, tachypnea, headache, dizziness, nausea, emesis, and fatigue whereas a concentration above 55% is reflected by lethargy, arrhythmia, acidosis, and loss of consciousness[symptoma.com]
  • Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, and blue-colored skin.[icd9data.com]
  • In rare cases, methemoglobinemia beta-globin type can cause headaches, weakness and fatigue. Symptoms may appear at the age of 6 months.[ivami.com]
  • Reduction — When a chemical element or compound gains an electron. methemoglobinemia [ met-he″mo-glo″bĭ-ne me-ah ] the presence of excessive methemoglobin in the blood, resulting in cyanosis and headache, dizziness, fatigue, ataxia, dyspnea, tachycardia[medical-dictionary.thefreedictionary.com]
Feeding Difficulties
  • Abnormal facial muscle movements can interfere with swallowing, which can lead to feeding difficulties and further slow growth.[ghr.nlm.nih.gov]
Aspiration
  • Etiology of cyanosis was not clarified exactly but was readily but erroneously attributed to uncontrolled, repetitive convulsions and aspiration of excessive oral secretions.[ncbi.nlm.nih.gov]
Nausea
  • For example, a methemoglobin level greater than 35% is associated with tachycardia, tachypnea, headache, dizziness, nausea, emesis, and fatigue whereas a concentration above 55% is reflected by lethargy, arrhythmia, acidosis, and loss of consciousness[symptoma.com]
  • Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, and blue-colored skin.[icd9data.com]
  • Patient complained of epigastric discomfort and nausea. She did not have any vomiting, loss of consciousness, or seizures while being transferred to the hospital.[mjmsr.net]
  • Reduction — When a chemical element or compound gains an electron. methemoglobinemia [ met-he″mo-glo″bĭ-ne me-ah ] the presence of excessive methemoglobin in the blood, resulting in cyanosis and headache, dizziness, fatigue, ataxia, dyspnea, tachycardia, nausea[medical-dictionary.thefreedictionary.com]
Joint Deformity
  • deformations, which have never been described in association with this enzyme deficiency.[ncbi.nlm.nih.gov]
Severe Mental Retardation
  • A case of congenital enzymopenic methemoglobinemia associated with severe mental retardation is described.[ncbi.nlm.nih.gov]
  • In type II, cyanosis is associated with severe mental retardation and neurological impairment. The objective of this study is to establish the cause of cyanosis in our cases of congenital methaemoglobinemia.[ncbi.nlm.nih.gov]
  • In the type II form, cyanosis is associated with severe mental retardation and neurologic impairment; the enzymatic defect is systemic, involving both soluble and membrane-bound isoforms.[ncbi.nlm.nih.gov]
  • mental retardation and recessive congenital methemoglobinemia in three Indian patients: compound heterozygous for NADH-cytochrome b5 reductase gene mutations. ( 21328435 ) Kedar P.S....Colah R.B. 2011 26 A rare cause of mental motor retardation: recessive[malacards.org]
  • mental retardation and recessive congenital methemoglobinemia in three Indian patients: compound heterozygous for NADH-cytochrome b5 reductase gene mutations. ( 21328435 ) Kedar P.S....Colah R.B. 2011 22 A rare cause of mental motor retardation: recessive[malacards.org]
Impulsivity
  • Myelin insulates nerve cells and promotes the rapid transmission of nerve impulses. This reduced ability to form myelin (hypomyelination) leads to a loss of nerve cells, particularly in the brain.[ghr.nlm.nih.gov]
Phenylketonuria
  • At the time, I did not think this particularly important but took it for granted that diseases such as alkaptonuria and phenylketonuria resulted from a specific hereditable enzyme defect, claiming only that this was the first case to involve a redox enzyme[bloodjournal.org]
Headache
  • For example, a methemoglobin level greater than 35% is associated with tachycardia, tachypnea, headache, dizziness, nausea, emesis, and fatigue whereas a concentration above 55% is reflected by lethargy, arrhythmia, acidosis, and loss of consciousness[symptoma.com]
  • […] the value of MetHb shown by co-oximeter. [7], [8] Treatment protocol of methemoglobinemia consists of removal of the inducing agents, administration of high-flow O 2 and co-oximetric analysis. [8] In cases of significant clinical symptoms (dizziness, headache[joacp.org]
  • Symptoms may include headache, dizziness, fatigue, shortness of breath, nausea, vomiting, rapid heartbeat, loss of muscle coordination, and blue-colored skin.[icd9data.com]
  • In rare cases, methemoglobinemia beta-globin type can cause headaches, weakness and fatigue. Symptoms may appear at the age of 6 months.[ivami.com]
  • With levels above 25% the following symptoms may be present: Cyanosis unaffected by oxygen administration Blood that is dark or chocolate in color that will not change to red in the presence of oxygen Headache Weakness Confusion Chest pain When methemoglobin[medical-dictionary.thefreedictionary.com]
Dystonia
  • This report presents two siblings with central cyanosis, growth retardation, mental retardation, microcephaly, dystonia and hypertonia diagnosed as RCM type II.[ncbi.nlm.nih.gov]
  • However, type II is characterized by severe neurological manifestations such as impaired psychomotor skills, dystonia, encephalopathy, progressive microcephaly, strabismus, and growth retardation.[symptoma.com]
  • After a few months of apparently normal development, children with type II develop severe brain dysfunction (encephalopathy), uncontrolled muscle tensing (dystonia), and involuntary limb movements (choreoathetosis); also, the size of their head remains[ghr.nlm.nih.gov]
Unable to Walk
  • They can sit unassisted and grip objects but have impaired motor skills that leave them unable to walk. In type II, growth is often slowed.[ghr.nlm.nih.gov]

Workup

Neonates with cyanosis should undergo a complete workup consisting of the patient, maternal, and family history, as well as a complete physical exam and the appropriate studies.

In patients with congenital methemoglobinemia, the arterial blood gas (ABG) values and pulse oximetry readings are typically normal [8]. Even severe cases of this disease may exhibit normal Pao2 and pulse oximetry [9]. Of importance, these patients exhibit a"saturation gap," which refers to the discrepancy between the oxygen saturation on the pulse oximetry and the value derived from the ABG.

To determine the presence of hemoglobin M, hemoglobin electrophoresis and gene sequencing are key tests [8]. When methemoglobinemia is established, specific enzyme assays are useful to help diagnose this disease [8].

Co-oximetry, if available, will diagnose methemoglobinemia as it measures and differentiates methemoglobin from other types of hemoglobin.

Note that brown colored blood is a characteristic feature of methemoglobinemia. The color will remain brown upon exposure to oxygen, which makes for a simple test.

To exclude hemolysis, the workup should include a complete blood count (CBC), reticulocyte count, liver and renal function tests as well as the levels of lactate dehydrogenase (LDH), bilirubin, haptoglobin, and electrolytes. Moreover, Heinz body preparation and peripheral smear examination must be performed.

Imaging

Brain magnetic resonance imaging (MRI) and computed tomography (CT) in patients with type II reveal cortical and subcortical atrophy [5] [10] [11].

Note that cardiopulmonary disease should be excluded with echocardiography and chest imaging.

Treatment

  • These findings are encouraging for symptomatic improvement with regular prophylactic MB treatment but represent a single case report, which must be interpreted with caution.[ncbi.nlm.nih.gov]
  • The pathophysiology, etiology, clinical manifestations, anesthetic considerations, and treatment options of methemoglobinemia are discussed.[ncbi.nlm.nih.gov]
  • Treatment with ascorbic acid relieved the cyanosis and returned methemoglobin levels to normal.[ncbi.nlm.nih.gov]
  • The second edition concludes with current and developing approaches to treatment, incorporating new agents for iron chelation, methods to induce fetal hemoglobin production, novel treatment approaches, stem cell transplantation, and progress in gene therapy[books.google.com]
  • The etiology, pathophysiology, classification, diagnosis, clinical manifestations, anesthetic considerations, treatment options, and postoperative management are also discussed.[ncbi.nlm.nih.gov]

Prognosis

  • N/A What should you tell the patient and the family about prognosis? Toxic exposures to methemoglobin, if weathered without permanent cardiovascular or central nervous system damage, have an excellent prognosis.[cancertherapyadvisor.com]
  • Prognosis If found early, acquired methemoglobinemia can be easily treated with no side effects. After treatment with methylene blue the patient can expect a full recovery. Congenital methemoglobinemia is typically benign and should be observed.[encyclopedia.com]
  • […] who do not respond to methylene blue therapy Hyperbaric oxygen therapy where the patient breathes pure oxygen in a pressurized room IV rehydration to replenish electrolyte loss Other medications which include ascorbic acid, riboflavin Dietary control Prognosis[medindia.net]
  • Prognosis - Hemoglobinemia People with Type 1 methemoglobinemia and hemoglobin M disease usually do well. Type 2 methemoglobinemia is much more serious, and usually causes death within the first few years of life.[checkorphan.org]

Etiology

  • The pathophysiology, etiology, clinical manifestations, anesthetic considerations, and treatment options of methemoglobinemia are discussed.[ncbi.nlm.nih.gov]
  • The etiology, pathophysiology, classification, diagnosis, clinical manifestations, anesthetic considerations, treatment options, and postoperative management are also discussed.[ncbi.nlm.nih.gov]
  • Etiology of cyanosis was not clarified exactly but was readily but erroneously attributed to uncontrolled, repetitive convulsions and aspiration of excessive oral secretions.[ncbi.nlm.nih.gov]
  • The hallmark finding of this disease is cyanosis in the absence of cardiopulmonary etiology. The type I form is benign while type II is life-threatening and features severe neurological and developmental delay.[symptoma.com]
  • Methemoglobinemia is a syndrome with multiple etiologies and its diagnosis should be considered in the cases not responding to oxygen therapy.[joacp.org]

Epidemiology

  • : common etiology Cetacaine Epidemiology : common etiology Lidocaine (see Lidocaine , [[Lidocaine]]) Epidemiology : common etiology Prilocaine Epidemiology : common etiology Nitrites and Nitrates (see Nitrites and Nitrates , [[Nitrites and Nitrates]][mdnxs.com]
  • Epidemiology Toxic methemoglobinemia, resulting from exposure to oxidant chemicals or drugs, is the most common cause of methemoglobinemia among children older than 6 months of age.[unboundmedicine.com]
  • Epidemiology [ edit ] Methemoglobinemia mostly affects infants under 6 months of age (particularly those under 4 months) due to low hepatic production of methemoglobin reductase. [13] [14] The most at-risk populations are those with private water sources[en.wikipedia.org]
Sex distribution
Age distribution

Pathophysiology

  • The pathophysiology, etiology, clinical manifestations, anesthetic considerations, and treatment options of methemoglobinemia are discussed.[ncbi.nlm.nih.gov]
  • The etiology, pathophysiology, classification, diagnosis, clinical manifestations, anesthetic considerations, treatment options, and postoperative management are also discussed.[ncbi.nlm.nih.gov]
  • Pathophysiology of common hemoglobin disorders is discussed next in an entirely new section devoted to vascular biology, the erythrocyte membrane, nitric oxide biology, and hemolysis.[books.google.com]
  • In 1986, Jaffe 13 proposed a clinical-biochemical classification scheme based on important differences in the pathophysiology of the disorder.[pediatrics.aappublications.org]
  • With the knowledge of these pathophysiological entities and limitations of conventional monitoring equipments, the anestheiologist can be sensitized to diagnose and conduct appropriate treatment. Financial support and sponsorship Nil.[joacp.org]

Prevention

  • Cyanosis caused by abnormal forms of hemoglobin can also be life-threatening, and early recognition is mandatory to prevent unnecessary investigations and delay in management.[ncbi.nlm.nih.gov]
  • Rapidly find the answers you need with separate sections on diseases and disorders, differential diagnosis, clinical algorithms, laboratory results, and clinical preventive services, plus an at-a-glance format that uses cross-references, outlines, bullets[books.google.com]
  • Prevention - Hemoglobinemia Genetic counseling is recommended for couples with a family history of methemoglobinemia who are considering having children. Diagnosis - Hemoglobinemia Methemoglobinemia can be diagnosed with a blood test.[checkorphan.org]
  • […] inactive physiologically, but will be activated by methylene blue. 1 It is recommended that patients with congenital methemoglobinemia should be adequately oxygenated before, during and after recovery from anesthesia, in order to avoid hypoxemia and prevent[anesthesiology.pubs.asahq.org]
  • A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood 1995; 86:3598-3603. ‎[books.google.ro]

References

Article

  1. Rehman HU. Methemoglobinemia. West J Med. 2001;175(3):193-196.
  2. Manabe J, Arya R, Sumimoto H, et al. Two novel mutations in the reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase gene of a patient with generalized type, hereditary methemoglobinemia. Blood. 1996;88(8):3208-3215.
  3. Kuş A, Berk D, Hoşten T. The Role of Preoperative Evaluation for Congenital Methemoglobinemia. Turk J Anaesthesiol Reanim. 2014;42(4):223-226.
  4. Gibson QH. The reduction of methemoglobin in red blood cells and studies on the cause of idiopathic methemoglobinemia. Biochem J. 1948;42: 13-23.
  5. Ewenczyk C, Leroux A, Roubergue A, et al. Recessive hereditary methaemoglobinaemia, type II: delineation of the clinical spectrum. Brain. 2008;131(3): 760-761.
  6. Maurtua MA, Emmerling L, Ebrahim Z. Anesthetic management
    of a patient with congenital methemoglobinemia. J Clin
    Anesth. 2004;16(6):455-457.
  7. Chaurasia S, Ramappa M, Bhargava A. Corneal epitheliopathy in congenital methemoglobinemia. Cornea. 2014;33(4):422-424.
  8. Da-Silva SS, Sajan IS, Underwood JP 3rd. Congenital methemoglobinemia: a rare cause of cyanosis in the newborn--a case report. Pediatrics. 2003;112(2):e158-161.
  9. Ralston AC, Webb RK, Runciman WB. Potential errors in pulse oximetry. Anesthesia. 1991;46(4):291– 295.
  10. Aalfs CM, Salieb-Beugelaar GB, Wanders RJ, Mannens MM, Wijburg FA. A case of methemoglobinemia type II due to NADH-cytochrome b5 reductase deficiency: determination of the molecular basis. Hum Mutat. 2000;16(1):18-22.
  11. Toelle SP, Boltshauser E, Mossner E, Zurbriggen K, Eber S. Severe neurological impairment in hereditary methaemoglobinaemia type 2. Eur J Pediatr. 2004;163(4-5):207-209.

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Last updated: 2019-07-11 20:18