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 cblG is the result of quantitative methionine synthase deficiency, whereby this enzyme is required for the metabolization of homocysteine. Individuals suffering from methionine synthase deficiency have megaloblastic anemia, which is why the disease is also referred to as homocystinuria with megaloblastic anemia type cblG (HMAG). Patients also present diffuse encephalopathy and developmental delays.
HMAG patients appear normal at birth. Most of them are soon presented to the pediatrician, showing failure to thrive, developmental delays, and neurological symptoms. Symptom onset may, however, be delayed until adulthood in isolated cases . Furthermore, HMAG may follow a mild, non-progressive course during childhood and adolescence, but induce a neurological deterioration in adulthood .
The spectrum of neurological deficits is broad and ranges from cognitive impairment to ataxia and other movement disorders, anomalies of muscle tone, apnea, and decreased consciousness  . Psychiatric conditions and behavioral disorders are not usually observed in HMAG patients but are frequently described in those suffering from related disorders . HMAG 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  .
Renal involvement resulting in thrombotic microangiopathy and hemolytic uremic syndrome has been reported in two cases only  . Cardiovascular complications are frequently observed in patients suffering from remethylation disorders and have also been described in HMAG patients. Indeed, one of those patients who developed hemolytic uremic syndrome also suffered from progressive pulmonary hypertension .
Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging . HMAG may also be associated with hydrocephalus . Rarely, affected individuals are microcephalic . 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 HMAG 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 HMAG diagnosis, but are more cumbersome and don't provide any information as to the specific mutation in the MTR gene. Still, such assays have to be carried out if mutations cannot be identified despite strong suspicion . Concerning the results of enzyme activity assessments, the following may be expected:
Guidelines for the diagnosis and management of cobalamin-related remethylation disorders including HMAG 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 HMAG complications. Ophthalmological complications of HMAG don't usually respond to treatment and progressive visual impairment is common despite compliance with therapeutic regimens . Treatment failure seems to be more common in HMAG patients than in those suffering from homocystinuria without methylmalonic aciduria type cblE although this fact could not yet be explained .
HMAG is related to mutations in the MTR gene. This gene is located on the long arm of chromosome 1 and encodes for methionine synthase, a cobalamine-dependent enzyme catalyzing the conversion of homocysteine to methionine. Despite the rarity of the disease, more than a dozen MTR mutations have been reported to date, the most common one being missense mutation c.3518C>T. This mutation may account for more than half of all cases . Still, genotype-phenotype correlations have neither been established for missense mutation c.3518C>T nor for other, generally private MTR mutations .
HMAG is a rare disease. About two dozen patients have been described to date  . Both males and females may be affected by HMAG. First symptoms usually manifest in infancy, but may be observed as early as the neonatal period or be delayed until adulthood .
Under physiological conditions, methionine synthase catalyzes the conversion of homocysteine to methionine. 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 HMAG 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 fulfills non-enzymatic functions. If this was the case, the dysregulation of the respective processes would constitute another pathogenetic mechanism in HMAG and related disorders.
The prenatal diagnosis of HMAG is feasible. Mutations in the MTR 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 MTR 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 HMAG .
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 HMAG is diagnosed .
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 cbIG or HMAG, this form of homocystinuria without methylmalonic aciduria is the result of mutations in the MTR gene. The MTR gene encodes for methionine synthase, an enzyme required for the remethylation of homocysteine to methionine. Thus, HMAG-related functional methionine synthase deficiency results from quantitative methionine synthase deficiency.
Because cobalamin functions as a cofactor for methionine synthase, HMAG 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 cblG carry mutations in a gene named MTR. 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 MTR 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.