Homocystinuria without methylmalonic aciduria is a rare metabolic disorder. There are three types of the disease, all of which are inherited in an autosomal recessive manner and caused by a functional deficiency of methionine synthase. Homocystinuria without methylmalonic aciduria type cblE is the result of quantitative methionine synthase reductase deficiency, whereby methionine synthase reductase is required to recover methionine synthase activity after the oxidation of its cofactor, cob(I)alamin. Individuals suffering from methionine synthase reductase deficiency have megaloblastic anemia, which is why the disease is also referred to as homocystinuria with megaloblastic anemia type cblE (HMAE). Patients also present diffuse encephalopathy and developmental delays.
HMAE patients appear normal at birth but are soon presented to the pediatrician with failure to thrive, developmental delays, and neurological symptoms. Affected individuals may be microcephalic. The spectrum of neurological deficits is broad and ranges from cognitive impairment to movement disorders, anomalies of muscle tone, apnea, and decreased consciousness   . Psychiatric conditions, behavioral disorders, and ataxia are not usually observed in HMAE patients but are frequently described in those suffering from related disorders . HMAE patients may experience seizures, though. Visual impairment due to optic atrophy or retinopathy may be detected in ophthalmological examinations. Nystagmus has also been described . Peripheral neuropathies may be identified. Owing to extensive neurological disease, parents often describe feeding difficulties  .
Kidney damage resulting in hemolytic uremic syndrome has been reported in a single case of HMAE but histological studies indicate that glomerulopathy may not be uncommon  . Cardiovascular complications have not been described in HMAE patients but have been observed in patients suffering from other remethylation disorders and may eventually occur  .
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Owing to extensive neurological disease, parents often describe feeding difficulties. [symptoma.com]
When the condition begins early in life, babies have difficulty gaining weight (failure to thrive), feeding difficulties, and a pale appearance. Babies may also have weak muscle tone (hypotonia) and seizures. [rarediseases.info.nih.gov]
Patients with cblD present with severe learning difficulties, behavioral problems and movement and gait abnormalities and patients with cblF and cblJ present with feeding difficulties, hypotonia, stomatitis, mild facial dysmorphism, cardiac malformations [orpha.net]
The spectrum of neurological deficits is broad and ranges from cognitive impairment to movement disorders, anomalies of muscle tone, apnea, and decreased consciousness. [symptoma.com]
Cataract dental syndrome * Cataract Hutterite type * Cataract hypertrichosis mental retardation * Cataract mental retardation hypogonadism * Cataract microcornea syndrome * Cataract microphthalmia septal defect * Cataract skeletal anomalies * Cataract, alopecia [medicalgeek.com]
[…] polymicrogyria, Aicardi's syndrome, Akesson syndrome, Al gazali aziz salem syndrome, Al gazali sabrinathan nair syndrome, Albers-schonberg disease, Albright's hereditary osteodystrophy, Aldred syndrome, Alexander disease, Allan-herndon-dudley syndrome, Alopecia [ec2-184-73-211-184.compute-1.amazonaws.com]
[…] akt2, al, alacrima, alagille, alar, albers-schonberg, albinism, albinism-deafness, albipunctatus, albright, alcohol, aldolase, aldosterone, aldred, aleukocytosis, alexander, alkaptonuria, alkylating, allergic, alloimmune, alloimmunisation, almeida, alopecia [rapsodyonline.eurordis.org]
Some children exhibit skin rash and alopecia. Affected children exhibit metabolic acidosis, organic aciduria, and mild to moderate hyperammonemia. [dokumen.tips]
This gene is located on the short arm of chromosome 5 and encodes for methionine synthase reductase, an enzyme involved in cobalamin metabolism. Despite the rarity of the disease, at least 19 distinct MTRR mutations have been reported to date. [symptoma.com]
arm, Chromosome 7, partial monosomy 7p, Chromosome 7, trisomy 7p, Chromosome 7, trisomy 7p13 p12 2, Chromosome 7, trisomy 7q, Chromosome 7p deletion syndrome, Chromosome 7p duplication syndrome, Chromosome 7q deletion syndrome, Chromosome 7q duplication [ec2-184-73-211-184.compute-1.amazonaws.com]
arm deletion * Chromosome 4, monosomy 4p14 p16 * Chromosome 4, monosomy 4q * Chromosome 4, monosomy 4q32 * Chromosome 4, monosomy distal 4q * Chromosome 4, partial trisomy distal 4q * Chromosome 4, Trisomy 4p * Chromosome 4, trisomy 4q * Chromosome 4 [medicalgeek.com]
Clinical description Patients usually present in infancy or early childhood with features including lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, hepatomegaly and coma. [malacards.org]
Psychiatric conditions, behavioral disorders, and ataxia are not usually observed in HMAE patients but are frequently described in those suffering from related disorders. HMAE patients may experience seizures, though. [symptoma.com]
disorders Behavioral disturbances Behavioral problems Behavioral/psychiatric abnormalities Behavioural/Psychiatric abnormality Psychiatric disorders Psychiatric disturbances [ more ] 0000708 Gait disturbance Abnormal gait Abnormal walk Impaired gait [rarediseases.info.nih.gov]
Presenting signs are variable depending on which aspect(s) of cobalamin metabolism are affected and can include developmental delay, severe learning difficulties, seizures, movement and gait abnormalities, behavioral problems and signs of megaloblastic [orpha.net]
Behavioral changes Behavioral disorders Behavioral disturbances Behavioral problems Behavioral/psychiatric abnormalities Behavioural/Psychiatric abnormality Psychiatric disorders Psychiatric disturbances [ more ] 0000708 Gait disturbance Abnormal gait [rarediseases.info.nih.gov]
Peripheral neuropathies may be identified. Owing to extensive neurological disease, parents often describe feeding difficulties. [symptoma.com]
Neuropathy (Andermann Syndrome) Alport Syndrome, Autosomal Recessive Antley-Bixler syndrome Argininosuccinic aciduria Arthrogryposis, Mental Retardation, & seizures Aspartylglycosaminuria Ataxia neuropathy spectrum (ANS) Ataxia with vitamin E deficiency [genpathdiagnostics.com]
Folate deficiency: linked to depression Vitamin B12 deficiency: subacute combined degeneration, peripheral neuropathy and dementia Vitamin B6 deficiency: peripheral neuropathy and seizures What are the congenital defects associated with one carbon metabolism [quizlet.com]
neuropathy * Cervical intraepithelial neoplasia * Cervical ribs sprengel anomaly anal atresia urethral obstruction * Cervical vertebral fusion * Cervicooculoacoustic syndrome * Chagas disease * Chalazion * Chancroid * Chandler's syndrome * CHANDS * Chang [medicalgeek.com]
Patients with LCHAD/TFP defi ciencies may also develop pigmentary retinopathy and a peripheral neuropathy, whose pathophysiology remains obscure. [dokumen.tips]
gait Abnormal walk Impaired gait [ more ] 0001288 Hydrocephalus Too much cerebrospinal fluid in the brain 0000238 5%-29% of people have these symptoms Skin rash 0000988 Showing of 17 Last updated: 3/1/2020 Making a diagnosis for a genetic or rare disease [rarediseases.info.nih.gov]
Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging  . HMAE may also be associated with hydrocephalus . All these findings are non-specific, though. Analyses of blood and urine samples have to be carried out and provide essential information as to the underlying metabolic disorder:
- With regard to blood counts, megaloblastic anemia and thrombocytopenia or pancytopenia are to be expected. Despite megaloblastic anemia being a hematological hallmark of HMAE, it is not a constant feature: Zavadakova and colleagues reported normal mean corpuscular volumes in six out of nine patients. Megaloblastic changes were, however, identified in all bone marrow samples examined .
- Hyperhomocysteinemia, hypomethioninemia, and homocystinuria are common findings in blood chemistry and urine analysis and point at a remethylation disorder , with hypomethioninemia possibly being absent . Concentrations of methylmalonic acid are within physiological ranges .
These results don't allow for a reliable diagnosis of HMAE since similar findings may be obtained in patients suffering from much more common disorders like vitamin B12 deficiency and folic acid deficiency, and in those with other hereditary diseases . While serum levels of vitamin B12 and folic acid can be assessed easily, the differential diagnosis of remethylation disorders and other inherited conditions requires genetic studies. Enzyme activity measurements in fibroblasts or lymphocytes constitute an alternative approach to HMAE diagnosis, but are more cumbersome and don't provide any information as to the specific mutation in the MTRR gene  . Still, such assays have to be carried out if mutations cannot be identified despite strong suspicion .
Guidelines for the diagnosis and management of cobalamin-related remethylation disorders including HMAE have recently been published . In general, treatment aims at improving clinical features and normalizing hematological and metabolic values:
- Cobalamin supplementation is the mainstay of therapy. In order to maintain methionine synthase activity, HMAE patients should receive regular intramuscular injections of hydroxycobalamin. While the drug may also be administered via the subcutaneous and intravenous routes, the efficacy of subcutaneous applications seems to be limited and long-term intravenous treatment is inconvenient. Initially, 0.33 mg of hydroxycobalamin should be administered per kg body weight and day. Over the course of the disease, single doses and injection frequencies may be lowered if clinical and laboratory parameters remain stable. In order to prevent irreversible damage to the nervous system, hydroxycobalamin should be administered to all patients presenting symptoms consistent with a remethylation disorder and those who tested positive for hyperhomocysteinemia .
- The administration of folate and betaine has repeatedly been reported to improve disease control   and is thus recommended as an additional therapeutic measure. Both folate and betaine enhance the conversion of homocysteine to methionine and thus contribute to the reduction of hyperhomocysteinemia. Beyond that, carnitine and methionine supplementation may be considered but data regarding the efficacy of this measure are scarce.
- Patients should be recommended to avoid protein restriction and circumstances that may induce a catabolic state. Nitrous oxide shouldn't be utilized in these patients either.
Although cobalamin supplementation is likely to improve neurological parameters like cognitive performance, motor function, and alertness, central nervous system damage is largely irreversible  . Substantial improvements in cerebral atrophy and white matter changes are not to be expected . Therefore, patients who are diagnosed and treated early have a much better prognosis than those who are diagnosed after the manifestation of clinical symptoms. Still, even adequate therapy cannot entirely prevent the development of HMAE complications. Ophthalmological complications of HMAE don't usually respond to treatment and progressive visual impairment is common despite compliance with therapeutic regimens . Also, non-response to therapy with a fatal outcome has also been reported .
HMAE is related to mutations in the MTRR gene. This gene is located on the short arm of chromosome 5 and encodes for methionine synthase reductase, an enzyme involved in cobalamin metabolism. Despite the rarity of the disease, at least 19 distinct MTRR mutations have been reported to date . Both homozygosity and compound heterozygosity may trigger HMAE . With one exception, genotype-phenotype correlations have not yet been established and may be difficult to observe due to the large proportion of private mutations . MTRR mutation c.1361C>T seems to be associated with a milder phenotype, as has been observed in two patients originating from the Iberian peninsula .
HMAE is a rare disease. About two dozen patients have been described to date, most of them being of European origin  . Both males and females may be affected by HMAE. First symptoms may manifest within the neonatal period, within infancy or early childhood . The patients' median age at symptom onset is three months .
HMAE is a rare disorder of cobalamin metabolism. Affected individuals suffer from methionine synthase reductase deficiency. This enzyme catalyzes the reduction of cob(II)alamin to cob(I)alamin, which functions as a cofactor for methionine synthase. The latter is an enzyme unable to fulfill its role in the remethylation pathway if its cofactor remains oxidized. Alternative pathways for the reductive activation of cob(II)alamin and methionine synthase have long since been a matter of discussion since they are known to exist in prokaryotes. In this context, NADPH-dependent reductive activation of methionine synthase has been shown to occur in the presence of cytochrome B5 and novel reductase 1, but this reaction seems to play a minor role in mammals .
Under physiological conditions, methionine synthase catalyzes the conversion of homocysteine to methionine. Functional methionine synthase deficiency is thus associated with increased serum and tissue levels of homocysteine. Homocysteine and its metabolic product homocysteic acid possibly exert neurotoxic effects and cause neurological deficits in HMAE patients. At the same time, methionine concentrations are reduced. Shortage of this essential amino acid may interfere with a variety of biological processes, e.g., the function of rapidly proliferating tissues such as bone marrow or epithelia. Methionine is converted to S-adenosylmethionine, which acts as a methyl group donor. Therefore, deficiencies of methionine result in a lack of S-adenosylmethionine and a decreased methylation capacity .
It could not yet be clarified whether methionine synthase or methionine synthase reductase fulfill non-enzymatic functions. If this was the case, the dysregulation of the respective processes would constitute another pathogenetic mechanism in HMAE and related disorders.
The prenatal diagnosis of HMAE is feasible. Mutations in the MTRR gene can be identified in nucleic acids isolated from chorionic villi or amniotic fluid samples. Targeted genetic analyses require strong suspicion based on the carrier state of both parents. Most reliable results are obtained if the specific MTRR mutations of a child's mother and father are known. If genetic studies cannot be realized or yield inconclusive results, biochemical assays and enzyme activity measurements may be carried out. While an increased concentration of homocysteine in amniotic fluid may indicate a number of remethylation and transsulfuration disorders, decreased activity of methionine synthase reductase in cultured amniotic cells specifically suggests HMAE .
Of note, prenatal therapy via maternal treatment with hydroxycobalamin has yielded promising results in a child affected by homocystinuria with methylmalonic aciduria type cblC and may be considered if HMAE is diagnosed . This same approach has indeed been chosen during the second pregnancy of a woman whose first child was affected by HMAE, but genetic studies have not been carried out to confirm the tentative diagnosis in the second child .
There are three types of homocystinuria without methylmalonic aciduria, namely cblD-variant 1, cblE, and cblG  . All of them are induced by functional methionine synthase deficiency and resemble each other in their clinical presentation, but they differ in how methionine synthase deficiency is caused. With regard to type cbIE or HMAE, this form of homocystinuria without methylmalonic aciduria is the result of mutations in the MTRR gene. The MTRR gene encodes for methionine synthase reductase, an enzyme required for the regeneration of the cofactor of methionine synthase after it has been oxidized. In this state, methionine synthase activity is largely reduced. The cofactor that cannot be regenerated in case of methionine synthase reductase deficiency is cob(II)alamin. Therefore, HMAE may also be classified as an inherited disorder of cobalamin metabolism. The abbreviation cbl stands for cobalamin.
The term "homocystinuria" refers an increased excretion of homocystine in the urine. This condition may be due to distinct metabolic disorders associated with elevated serum concentrations of homocysteine, an intermediate amino acid and precursor of methionine. In patients suffering from inherited conditions that interfere with the conversion of homocysteine to methionine, blood and tissue levels of homocysteine are increased while methionine concentrations are below reference ranges.
There are different types of homocystinuria and they differ with regards to hematological and biochemical anomalies. Besides hyperhomocysteinemia and hypomethioninemia, patients may have increased serum levels of methylmalonic acids, which is why "homocystinuria with methylmalonic aciduria" is differentiated from "homocystinuria without methylmalonic aciduria". These differences originate from distinct gene defects, but they aren't reflected in the clinical presentation. Most patients suffering from homocystinuria present within the neonatal period or infancy: Their parents may claim feeding difficulties and failure to thrive, and affected children show neurological deficits ranging from cognitive impairment to movement disorders, anomalies of muscle tone, apnea, and decreased consciousness. Seizures and visual impairment are also common. If left untreated, these diseases follow a slowly progressive course and may lead to severe disability or death.
Individuals affected by homocystinuria without methylmalonic aciduria type cblE carry mutations in a gene named MTRR. Thus, genetic studies can be carried out to confirm the diagnosis. Genetic studies may even be realized before birth if a child's parents are known to be carriers of MTRR mutations. Children will develop the disease if they inherit pathogenic alleles from their mother and their father. Their prognosis largely depends on their age at the time of diagnosis and the initiation of treatment. The earlier an adequate treatment is started, the better the prognosis of the individual patient. Treatment mainly consists in intramuscular injections of hydroxycobalamin and oral supplementation of betaine and folic acid. Lifelong therapy is required in all cases and despite utmost compliance with therapeutic regimens, it may not be possible to prevent all complications.
- Carrillo N, Adams D, Venditti CP. Disorders of Intracellular Cobalamin Metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
- Fowler B, Schutgens RB, Rosenblatt DS, Smit GP, Lindemans J. Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease). J Inherit Metab Dis. 1997; 20(6):731-741.
- Huemer M, Diodato D, Schwahn B, et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis. 2017; 40(1):21-48.
- Zavadakova P, Fowler B, Zeman J, et al. CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. J Inherit Metab Dis. 2002; 25(6):461-476.
- Palanca D, Garcia-Cazorla A, Ortiz J, et al. cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period. JIMD Rep. 2013; 8:57-62.
- Paul EA, Guttenberg M, Kaplan P, et al. Atypical glomerulopathy associated with the cblE inborn error of vitamin B(1)(2) metabolism. Pediatr Nephrol. 2013; 28(7):1135-1139.
- Zavadáková P, Fowler B, Suormala T, et al. cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. Hum Mutat. 2005; 25(3):239-247.
- Huemer M, Burer C, Ješina P, et al. Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. J Inherit Metab Dis. 2015; 38(5):957-967.
- Ruiz-Mercado M, Vargas MT, de Soto IP, et al. Methionine synthase reductase deficiency (CblE): A report of two patients and a novel mutation. Hematology. 2016; 21(3):193-197.
- Rosenblatt DS, Cooper BA, Pottier A, Lue-Shing H, Matiaszuk N, Grauer K. Altered vitamin B12 metabolism in fibroblasts from a patient with megaloblastic anemia and homocystinuria due to a new defect in methionine biosynthesis. J Clin Invest. 1984; 74(6):2149-2156.
- Vilaseca MA, Vilarinho L, Zavadakova P, et al. CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene. J Inherit Metab Dis. 2003; 26(4):361-369.
- Olteanu H, Banerjee R. Redundancy in the pathway for redox regulation of mammalian methionine synthase: reductive activation by the dual flavoprotein, novel reductase 1. J Biol Chem. 2003; 278(40):38310-38314.
- Trefz FK, Scheible D, Frauendienst-Egger G, et al. Successful intrauterine treatment of a patient with cobalamin C defect. Mol Genet Metab Rep. 2016; 6:55-59.
- Rosenblatt DS, Cooper BA, Schmutz SM, Zaleski WA, Casey RE. Prenatal vitamin B12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease). Lancet. 1985; 1(8438):1127-1129.
- Suormala T, Baumgartner MR, Coelho D, et al. The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem. 2004; 279(41):42742-42749.
- Watkins D, Rosenblatt DS. Genetic heterogeneity among patients with methylcobalamin deficiency. Definition of two complementation groups, cblE and cblG. J Clin Invest. 1988; 81(6):1690-1694.