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  .
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:
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:
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.