Homocystinuria due to methylene tetrahydrofolate reductase deficiency (H-MTHFR) is the most common inborn error of cobalamin metabolism. Metabolic anomalies due to H-MTHFR mainly affect the central nervous system. The clinical presentation of H-MTHFR varies considerably and ranges from neonatal-onset disease with a fatal outcome to milder H-MTHFR manifesting in adulthood. It mainly depends on the residual activity of methylene tetrahydrofolate reductase. Treatment with high doses of betaine may prevent a patient's neurocognitive decline and should be started as early as possible. Still, betaine-based therapy may not avoid the progression and/or appearance of all symptoms related to H-MTHFR.
H-MTHFR patients appear normal at birth. However, first symptoms may present within 24 hours after birth. In other cases, children remain asymptomatic for prolonged periods of time or clinical disease doesn't become apparent until adulthood: The lower the residual activity of methylene tetrahydrofolate reductase is, the earlier symptom onset occurs.
- Parents presenting their babies to the pediatrician often claim feeding difficulties and failure to thrive. Muscular hypotonia is another hallmark of early-onset H-MTHFR and is usually associated with apnea and lethargy. Affected individuals may be microcephalic. H-MTHFR patients may experience seizures. Rarely, visual impairment due to optic atrophy is detected in ophthalmological examinations. Nystagmus has also been described .
- Late-onset H-MTHFR is characterized by neurological symptoms ranging from cognitive impairment to ataxia, spasticity, and other movement disorders, by psychiatric conditions and behavioral disorders  . Peripheral neuropathies may be identified .
Although cardiovascular complications are frequently observed in patients suffering from other disorders of cobalamin metabolism, they are uncommon in individuals affected by H-MTHFR. Still, they are not unheard of: Thrombosis of the pulmonary artery has been described as the cause of death in at least one case, and venous thrombosis has been reported in another patient . Renal involvement resulting in thrombotic microangiopathy and hemolytic uremic syndrome has only been observed in a subgroup of patients expressing a thermolabile variant of methylene tetrahydrofolate reductase . These patients don't usually suffer from clinical H-MTHFR.
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If left untreated, H-MTHFR follows a slowly progressive course and results in increasingly severe developmental delays, mental retardation, and possibly death. [symptoma.com]
The combination of ocular findings and phenotypic features suggested homocystinuria as the underlying metabolic cause for her developmental delay. [ncbi.nlm.nih.gov]
Clinical description Homocystinuria without methylmalonic aciduria manifests mainly in early childhood with failure to thrive, megaloblastic anemia, developmental delay, hypotonia, seizures and cerebral atrophy with white matter abnormalities. [orpha.net]
At least 40 rare MTHFR gene variants have been found in people with decreased or no working enzyme. 0000708 Gait disturbance Abnormal gait Abnormal walk Impaired gait Last updated: 4/14/2015 Homocystinuria due to MTHFR deficiency is inherited in an autosomal [rarediseases.info.nih.gov]
Obsessions ( n 1), dysarthria ( n 1), myoclonus ( n 1, with PME), paresthesia ( n 1), episodic diplopia ( n 1), reduced visual acuity ( n 1), urinary and fecal incontinence ( n 1), anorexia with progressive withdrawal ( n 1), tremor ( n 1), UL dysmetria [ojrd.biomedcentral.com]
disorder, encephalopathy, atypical psychosis (with visual hallucinations, cognitive disorder, drowsiness), and young onset thrombosis. [ojrd.biomedcentral.com]
Patient n 10 presented generalized tonic-clonic seizures at 19 years-old which were successfully treated by phenytoin, without preventing the onset of leg weakness 2 months after his first seizures. [ojrd.biomedcentral.com]
[…] sided weakness UMN signs 19/19 (100%) Spasticity 14/17 (82%) Peripheral Neuropathy 10/14 (71%) Ataxia 7/20 (35%) Epilepsy 12/24 (50%) GTCS 5/9 (55%), 1 with myoclonus in a context of PME (same patient presenting as JME) Absence 1/9 (11%) Focal seizures [ojrd.biomedcentral.com]
Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging . H-MTHFR may also be associated with hydrocephalus . 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:
- Hyperhomocysteinemia, hypomethioninemia, and homocystinuria are common findings in blood chemistry and point at a remethylation disorder. Furthermore, blood samples obtained from H-MTHFR patients usually contain low or low-to-normal levels of S-adenosylmethionine, while the concentrations of S-adenosylhomocysteine and cystathionine are often elevated. Concentrations of methylmalonic acid are within physiological ranges. Of note, these laboratory findings don't usually correlate with the severity of the disease .
- Contrary to other types of homocystinuria without methylmalonic aciduria, no hematologic abnormalities are to be expected in H-MTHFR patients . Although transient anomalies like macrocytosis, macro-, normo-, or microcytic anemia, leukopenia, and thrombocytopenia have been observed in isolated cases, data are insufficient to establish a causal relation with H-MTHFR .
Still, these results don't allow for a reliable diagnosis of H-MTHFR, with the main differential diagnosis being classical homocystinuria . Both genetic studies and enzyme activity measurements are required to confirm the tentative diagnosis and to determine the residual activity of methylene tetrahydrofolate reductase. It is important to note that the residual enzyme activity cannot be reliably predicted based on the underlying mutation in the MTHFR gene . Furthermore, numerous polymorphisms in the MTHFR gene have been described and related to common disorders and conditions other than H-MTHFR, which further reduces the informative value of questionable genetic findings . With regard to enzyme activity measurements, methylene tetrahydrofolate reductase is preferentially assessed in cultured skin fibroblasts and in the forward direction .
Since causal treatment is not available, betaine supplementation is the mainstay of H-MTHFR therapy. An early initiation of treatment is associated with a better prognosis because it may prevent the neurocognitive decline of H-MTHFR patients . H-MTHFR patients should initially receive 100-250 mg betaine per day and kg body weight but that dose may be reduced to 5-20 g betaine per day in adult patients  . Patients may also benefit from methionine supplementation. Beyond that, folinic acid and 5-methyltetrahydrofolate supplementation may be considered but data regarding the efficacy of this measure are scarce . Folic acid shouldn't be administered to those suffering from H-MTHFR its application may aggravate the deficiency of 5-methyltetrahydrofolate in the central nervous system . 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 .
Cobalamin supplementation is frequently started as soon as suspicion of a remethylation disorder arises. This is a standard procedure carried out to prevent irreversible damage to the central nervous system. However, cobalamin injections may be ceased as soon as the diagnosis of H-MTHFR is confirmed .
If left untreated, H-MTHFR follows a slowly progressive course and results in increasingly severe developmental delays, mental retardation, and possibly death . Furthermore, central nervous system damage due to H-MTHFR-related metabolic anomalies is irreversible and late treatment doesn't suffice to overcome any underdevelopment experienced so far. The timely initiation of high-dose betaine therapy is thus the most important prognostic factor . Ideally, treatment is started before symptom onset occurs. This way, significant reductions in H-MTHFR-related morbidity and mortality as well as near-to-normal psychomotor development can be achieved  . It should be noted, though, that therapy may not alleviate all biochemical abnormalities and clinical symptoms  .
H-MTHFR is related to mutations in the MTHFR gene. This gene is located on the short arm of chromosome 1 and encodes for methylene tetrahydrofolate reductase, an enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter is required for the transmethylation of homocysteine to methionine, so methylene tetrahydrofolate reductase provides one of the substrates needed in the remethylation pathway. To date, more than 100 mutations in the MTHFR gene have been described, with most of them being missense mutations. The vast majority of mutations related to H-MTHFR are private mutations that have only been identified in single families. There are six mutations only that have been confirmed in more than five families. While pathogenic MTHFR mutations may abolish methylene tetrahydrofolate reductase activity, residual enzyme activity may be detected in carriers of other genetic variants. Residual enzyme activity is the main predictor of the severity of the disease and the time of symptom onset: Whereas early-onset H-MTHFR is associated with methylene tetrahydrofolate reductase activity <5%, patients with adult-onset H-MTHFR have a mean residual enzyme activity of about 15% . In this context, it should be noted that intrafamilial variation of the clinical phenotype has been described and that residual enzyme activity cannot be predicted based on the results of genetic studies . In general, genotype-phenotype correlations have not yet been established.
In a study carried out to assess the efficacy of an alternative approach to newborn screenings for H-MTHFR and related remethylation disorders, Tortorelli and colleagues identified two H-MTHFR patients among 400,000 neonates. Thus, the incidence of H-MTHFR may approximate 1 in 200,000 live births . To date, about 200 cases have been described in literature. Both males and females may be affected by H-MTHFR .
Methylene tetrahydrofolate reductase is an enzyme that catalyzes the physiologically irreversible reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate . On the other hand, methionine synthase catalyzes the conversion of homocysteine to methionine, the key reaction in the remethylation pathway. And because methionine synthase activity depends on the availability of 5-methyltetrahydrofolate, methylene tetrahydrofolate reductase deficiency interferes with homocysteine elimination and methionine synthesis.
H-MTHFR 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 H-MTHFR 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 . In fact, lack of cerebral methylation has been proposed as a major pathophysiological mechanism in H-MTHFR .
It could not yet be clarified whether methylene tetrahydrofolate reductase fulfills non-enzymatic functions. If this was the case, the dysregulation of the respective processes would constitute another pathogenetic mechanism in H-MTHFR and related disorders.
Literature clearly supports the notion that an early diagnosis and timely initiation of treatment are the most important prognostic factors . In this context, the implementation of newborn screenings for H-MTHFR and other disorders of cobalamin metabolism has been suggested  . It is not yet routinely done, though, unless a neonate has a positive family history of such diseases. Affected families may also opt for genetic counseling and prenatal diagnosis if the parents' genotype has previously been determined. The first prenatal diagnosis of H-MTHFR has been realized in 1985 . Today, there's a broad spectrum of prenatal diagnostic tools comprising measurements of metabolite concentrations in cell-free amniotic fluid, enzyme activity measurements in cultured amniotic cells, the assessment of the incorporation of propionate and methyltetrahydrofolate into macromolecule, and genetic analyses.
Despite its low incidence, H-MTHFR is the most common disorder of cobalamin metabolism  . The disease is inherited in an autosomal recessive manner and is caused by mutations in the MTHFR gene, which encodes for methylene tetrahydrofolate reductase. Pathogenic MTHFR mutations result in functional methionine synthase deficiency and inadequate remethylation because methylene tetrahydrofolate reductase provides one of the substrates required for methionine synthase activity. Methylmalonyl metabolism isn't disturbed in H-MTHFR patients. Thus, they present with hyperhomocysteinemia, hypomethioninemia, and normal levels of methylmalonic acid, which constitute the classic symptom triad of remethylation disorders. Depending on the severity of methylene tetrahydrofolate reductase deficiency and consecutive metabolic anomalies, H-MTHFR may be associated with lethal metabolic decompensation in the neonatal period or mild clinical disease becoming apparent in adulthood. Intermediate variants of H-MTHFR have been described. Symptoms due to central nervous system disease dominate the clinical picture.
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. These differences originate from distinct gene defects, but they aren't necessarily reflected in the clinical presentation. Quite the contrary, mutations in a single gene may give rise to a broad spectrum of symptoms. This does also apply to mutations in the MTHFR gene, causative of homocystinuria due to methylene tetrahydrofolate reductase deficiency (H-MTHFR). MTHFR mutations may merely reduce the activity of methylene tetrahydrofolate reductase, an enzyme involved in cobalamin and amino acid metabolism, or may entirely abolish it:
- Patients with low residual enzyme activity usually present in the neonatal period or infancy with failure to thrive, muscular hypotonia, and lethargy. Their parents often claim feeding difficulties.
- On the other hand, high residual enzyme activity may delay symptom onset until adulthood. Affected individuals typically suffer from cognitive impairment, ataxia, spasticity, and other movement disorders, psychiatric conditions and behavioral disorders.
If left untreated, the disease follows a progressive course and results in increasingly severe developmental delays and disability. The mainstay of H-MTHFR treatment is betaine supplementation, which is required on a daily basis throughout life. Betaine therapy improves the patients' prognosis because it prevents their cognitive decline. Still, it may not be able to alleviate all symptoms associated with H-MTHFR.
An early diagnosis is a prerequisite for the timely initiation of H-MTHFR treatment. H-MTHFR diagnosis is mainly based on genetic studies and enzyme activity measurements, which may be carried out before birth. Parents with a known family history of H-MTHFR and related disorders are recommended to seek genetic counseling and opt for the prenatal diagnosis of the disease.
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