Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 395; DO: 9263;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | Homocystinuria due to MTHFR deficiency | 236250 | Autosomal recessive | 3 | MTHFR | 607093 |
A number sign (#) is used with this entry because homocystinuria due to methylenetetrahydrofolate reductase deficiency is caused by homozygous or compound heterozygous mutation in the MTHFR gene (607093) on chromosome 1p36.
Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. In the classic form, both thermostable and thermolabile enzyme variants have been identified (Rosenblatt et al., 1992).
Freeman et al. (1972) studied a 15-year-old mildly retarded black female with a 2-year history of progressive withdrawal, hallucinations, delusions, and catatonia unresponsive to psychotherapy. Homocystinuria without elevation of plasma methionine was found. Psychotic symptoms gradually disappeared with administration of pyridoxine and folic acid. A sister had the same chemical findings but no symptoms. Cystathionine synthetase and the enzymes methylating homocysteine were normal in liver and fibroblasts. A decrease was shown in methylenetetrahydrofolate reductase, the enzyme synthesizing N(5)-methyltetrahydrofolate. Preliminary results of enzymatic studies in Freeman's case were reported by Mudd et al. (1972).
Shih et al. (1972) described the case of a 16-year-old boy with proximal muscle weakness, waddling gait, and episodes of flinging movements of the upper limbs. Folic acid reduced the homocystinuria. Flavin adenine dinucleotide, which had no effect in Freeman's cases, reduced the homocystinuria. Thus, the patient studied by Shih et al. (1972) may have had an allelic disorder.
Narisawa et al. (1977) described 2 cases of homocysteinuria that differed from the 4 earlier reported ones in that progression to death occurred in 1 year. Clinical features included fits of apnea, seizures, and coma. They suggested that this is an infantile form of the disorder.
In a sibship of 6, Visy et al. (1991) found 3 sibs with homocysteinemia and homocystinuria due to MTHFR deficiency. All 3 came to medical attention because of severe recurrent thrombotic strokes in adulthood, at ages 23, 24, and 20 years. All 3 had mild mental retardation with IQs in the 80s. Two of the sibs died within a year of clinical onset.
Haworth et al. (1993) reported the cases of 2 brothers with MTHFR deficiency. One brother remained asymptomatic at age 37 years. The younger brother developed limb weakness, incoordination, paresthesiae, and memory lapses at age 15 years; by his early twenties, he was wheelchair-bound. Both had homocystinuria, homocysteinemia, and low plasma levels of methionine. In cultured skin fibroblasts of both patients, MTHFR activities were less than 10% of control values, and residual enzyme activities were markedly reduced on heating. The parents had intermediate enzyme activities, and the reductase in the father (who had unexplained paraparesis and homocysteinemia), but not in the mother, was also thermolabile. With oral folate and betaine therapy, the biochemical abnormality was improved but not totally corrected.
Cappuccio et al. (2014) reported 2 sibs and a first cousin with MTHFR deficiency presenting as early infantile epileptic encephalopathy. All showed poor sucking, hypotonia, microcephaly, and lethargy in the newborn period. The most severely affected patient had onset of intractable seizures at age 1 month and died at age 7 months. Brain MRI showed cerebral atrophy with abnormal sulcation and gyral patterns in the frontobasal areas. The 2 other children developed intractable seizures associated with hypsarrhythmia at 10 and 18 months of age, respectively. The seizures were at first difficult to control, but both patients eventually became seizure-free with topiramate. Both had developmental delay of varying degrees. The patient with onset of seizures at age 18 months could walk independently at age 5 years but was unable to speak, whereas the other child showed severe psychomotor retardation and was unable to sit or stand at age 2. Brain imaging of both patients showed diffuse white matter hyperintensities, hypoplasia of the cerebellum and brainstem, and thinning of the corpus callosum. Laboratory studies showed increased plasma homocysteine and decreased methionine, consistent with MTHFR deficiency, and genetic analysis identified compound heterozygous mutations in the MTHFR gene. Treatment with folinic acid and betaine resulted in only a slight improvement in muscle tone. Cappuccio et al. (2014) noted the phenotypic variability in these patients with the same genotype, and suggested that the neurotoxicity in MTHFR deficiency may be augmented by homocysteine-derived metabolites, although it may also be multifactorial.
Thermolabile Variant
Kang et al. (1991) found a form of MTHFR deficiency that is characterized by the absence of neurologic abnormalities, an enzyme activity of about 50% of normal, and distinctive thermolability of the MTHFR enzyme under specific conditions of heat inactivation. Studies in 10 families were consistent with autosomal recessive inheritance of the thermolabile trait. A plot of percent residual activity after heat inactivation against a specific enzyme activity as determined in lymphocytes separated affected individuals from unaffected. Frosst et al. (1995) identified a C-to-T substitution at nucleotide 677 (607093.0003) of the MTHFR gene that converts an alanine to a valine residue and is responsible for the synthesis of a thermolabile form of MTHFR.
Kang et al. (1991) concluded that thermolabile MTHFR is positively associated with the development of coronary artery disease. In 17% of cardiac patients and only 5% of controls, thermolabile MTHFR was found. The average age of onset of clinical coronary artery disease in patients with thermolabile MTHFR was 57.3 years; the mean total plasma homocysteine concentration in patients with thermolabile MTHFR was 13.19, a significantly different value from the normal mean of 8.50 nmol/ml. Engbersen et al. (1995) studied thermolability of MTHFR in control subjects and in vascular patients with mild hyperhomocysteinemia or normohomocysteinemia. They concluded that abnormal homocysteine metabolism could be attributed to thermolabile MTHFR in 28% of hyperhomocysteinemic patients with premature vascular disease.
Adams et al. (1996) studied 532 subjects (310 myocardial infarction patients and 222 population-based controls) and found no difference in either MTHFR genotype distribution (p = 0.57) or allele frequencies (p = 0.68) between cases and controls. They concluded that the thermolabile variant of MTHFR is not a major risk factor for myocardial infarction and is unlikely to explain a significant proportion of the reported association of hyperhomocysteinemia with coronary artery disease.
Among 16 obligate heterozygotes with thermolabile MTHFR deficiency, Kang et al. (1991) found 4 subjects who had less than 25% of normal mean MTHFR specific activity in lymphocyte extracts. The biochemical features in these 4 subjects were distinguishable from homozygotes for the thermolabile MTHFR, whose specific activity was approximately 50% of the normal mean, and from heterozygotes for severe MTHFR deficiency, in whom the enzyme is thermostable and has a specific activity of about 50% of the normal mean. Kang et al. (1991) proposed that these 4 subjects represent genetic compounds of the allele for the severe mutation and the allele for the thermolabile mutation of the MTHFR gene. Subjects with this genetic compound constitution appear to be more susceptible to the development of intermediate hyperhomocysteinemia despite normal folate and B12 levels. Nonetheless, hyperhomocysteinemia due to this compound heterozygosity is correctable by oral folic acid therapy.
Jakubowski et al. (2008) found that patients with homocystinuria due to MTHFR deficiency or CBS deficiency (236200) had increased plasma levels of N-homocysteine (Hcy)-linked proteins, including the prothrombotic N-Hcy-fibrinogen (see 134820). N-Hcy-proteins are detrimental because they contribute to both thrombogenesis and immune activation. The authors suggested that increased levels of N-Hcy-fibrinogen may explain the increased susceptibility to thrombogenesis in these individuals.
Prenatal Diagnosis
Christensen and Brandt (1985) made a prenatal diagnosis of MTHFR deficiency.
Over a 4-year period, Strauss et al. (2007) collected clinical and biochemical data from 5 Amish children who were homozygous for the MTHFR 1129C-T mutation (607093.0011). The 4 oldest patients had irreversible brain damage before diagnosis. The youngest child, diagnosed and started on betaine therapy as a newborn, was healthy at the age of 3 years. In all affected children, treatment with betaine increased plasma S-adenosylmethionine, improved markers of tissue methyltransferase activity, and resulted in a 3-fold increase of calculated brain methionine uptake. Betaine therapy did not normalize plasma total homocysteine, nor did it correct cerebral 5-methyltetrahydrofolate deficiency. They concluded that when the 5-methyltetrahydrofolate content of brain tissue is low, dietary betaine sufficient to increase brain methionine uptake may compensate for impaired cerebral methionine recycling. To support the metabolic requirements of rapid brain growth effectively, Strauss et al. (2007) suggested that a large dose of betaine should be started early in life.
The patient who was diagnosed prenatally with MTHFR deficiency by Christensen and Brandt (1985) was treated from neonatal life with betaine, folic acid, and cobalamin and was reported to be physically and neurologically healthy at the age of 21 years (Skovby, 2007).
By RT-PCR of RNA from MTHFR-deficient patients, followed by single-strand conformation polymorphism (SSCP) analysis, Goyette et al. (1994) identified 3 substitutions in the MTHFR gene: 2 missense mutations (in residues conserved in the enzyme and bacteria) and 1 nonsense mutation. The nonsense mutation (607093.0001) and 1 of the missense mutations (thr to met) were identified in severe early-onset patients; the second missense mutation (arg to gln; 607093.0002) was identified in 2 patients with a thermolabile enzyme and late-onset neurologic disease. Goyette et al. (1995) described 7 additional mutations.
Frosst et al. (1995) identified a C-to-T substitution at nucleotide 677 (607093.0003) of the MTHFR gene that converts an alanine to a valine residue and is responsible for the synthesis of a thermolabile form of the disorder.
Goyette et al. (1996) reported an additional 5 mutations causing severe MTHFR deficiency. They also reported results of analysis of the enzyme thermolability in 22 patients with MTHFR deficiency. Six of the 22 patients had 4 mutations in the MTHFR gene--2 rare mutations causing severe deficiency and 2 mutations for the common ala-to-val mutation associated with enzyme thermolability.
Rozen (1996) tabulated 9 point mutations that had been identified in cases of severe MTHFR deficiency.
Sibani et al. (2000) stated that 18 rare mutations had been reported in patients with MTHR deficiency. In addition, 2 well-known polymorphisms had been found to cause mild enzyme deficiency. They reported 6 novel mutations, bringing the total to 24. They stated that each of 22 patients were compound heterozygotes for 2 separate mutations.
Coronary Artery Disease
Morita et al. (1997) studied 362 Japanese male patients with angiographically confirmed coronary artery disease and 778 controls. They reported a significantly higher frequency of the 677C-T allele (607093.0003) in the disease group. Van Bockxmeer et al. (1997) did not, however, find such a relationship in their study of 555 white Western Australians with angiographically documented coronary artery disease and 143 unrelated controls. Schwartz et al. (1997) studied allele frequencies of the MTHFR 677C-T polymorphism in 69 non-Hispanic white female survivors of myocardial infarction and 338 controls. They found a similar distribution of alleles in both groups.
Neural Tube Defects
Papapetrou et al. (1996) followed up on 3 studies in Dutch, Irish, and U.S. populations that found homozygosity for the 677C-T mutation at higher frequency in offspring with neural tube defects (NTD; see 601634) than in control populations. They compared the frequency of the 677T homozygotes in 199 normal controls with that in 41 British NTD cases and their parents (36 mothers, 26 fathers). The data showed no evidence for an association between the 677T allele and the occurrence of NTDs. Papapetrou et al. (1996) commented that discrepancies between the findings of the studies may involve population differences in the frequency of the MTHFR thermolabile allele. Papapetrou et al. (1996) advocated the use of 'within family' genetic studies, which are not affected by population differences in allele frequency, to test allele association and provide matched controls. Ou et al. (1996) studied 41 fibroblast cultures from NTD-affected fetuses and compared their genotypes for the 677C-T allele with 109 controls and found that the allele was associated with a 7.2 fold increased risk for NTDs. A metaanalysis by van der Put et al. (1997) appeared to confirm the 677C-T mutation as a genetic risk factor for neural tube defects. On the other hand, Mornet et al. (1997) found the same distribution of the 677C-T mutation in prenatally diagnosed neural tube defect cases as in controls and concluded that it cannot be regarded as a genetic risk factor for neural tube defects.
Cleft Lip/Palate
Martinelli et al. (2001) investigated 64 patients with cleft lip with or without cleft palate (CL/P) and their parents for the 677C-T MTHFR mutation. No linkage disequilibrium was found using the transmission disequilibrium test. However, a higher mutation frequency was noted in mothers of patients with CL/P compared to controls. The odds ratios for mothers having the CT or TT genotype, compared to the normal CC genotype, were 2.75 (95% CI 1.30 to 5.57) and 2.51 (1.00 to 6.14), respectively. The authors suggested that this study indicates an effect of the maternal rather than the embryonic genotype.
Cancer
Skibola et al. (1999) undertook a population-based case-control study of adult acute leukemia to evaluate the possibility that carriers of variant alleles for MTHFR677 (607093.0003) and/or MTHFR1298 (607093.0004) may have a protective advantage against leukemia. The hypothesis was based on the fact that reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by MTHFR. Diminution in the activity of the MTHFR enzyme increases the pool of methyleneTHF at the expense of the pool of methylTHF. Enhanced availability of methyleneTHF in the DNA synthesis pathway reduces misincorporation of uracil into DNA, which might otherwise result in double-strand breaks during uracil excision repair processes. Previous studies had shown that individuals with adequate folate status who are homozygous for the MTHFR677 mutation had a reduced incidence of colorectal cancer. Because colorectal carcinomas and leukemias are derived from rapidly proliferating tissues that might have the greatest requirement for DNA synthesis, they might be expected to be affected similarly by the metabolic fate of folic acid. Skibola et al. (1999) found that the 677TT genotype was lower among 71 acute lymphocytic leukemia (ALL) cases compared with 114 controls, conferring a 4.3-fold decreased risk of ALL. They observed a 3-fold reduction in risk of ALL in individuals with the MTHFR 1298AC polymorphism and a 14-fold decreased risk of ALL in those with the MTHFR 1298CC variant allele. In acute myeloid leukemia (AML), no significant difference in MTHFR677 and -1298 genotype frequencies was observed between 237 cases and 377 controls. The findings suggested that folate inadequacy may play a key role in the development of ALL, but not in the development of AML.
Wiemels et al. (2001) reported associations of MTHFR polymorphisms in 3 subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL (159555) rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. They genotyped 253 pediatric leukemia patients and 200 healthy newborn controls for the MTHFR polymorphisms 677C-T and 1298A-C. A significant association for carriers of 677C-T was demonstrated for leukemias with MLL translocations when compared with controls (adjusted odds ratio, 0.36; 95% CI, 0.15-0.85). This protective effect was not evident for 1298A-C alleles (odds ratio, 1.14). In contrast, CC homozygotes at nucleotide 1298 and TT homozygotes at nucleotide 677 showed protective effect in hyperdiploid leukemias. No significant associations were evident for either polymorphism with TEL-AML1 leukemias.
Goyette and Rozen (2000) presented evidence that the 677C-T polymorphism influences the severity of the homocystinuria caused by mutations elsewhere in the MTHFR gene. Specifically, a mutation in combination with the Val allele was associated with greater clinical severity, and, by study of doubly mutant constructs in a bacterial expression system, they demonstrated that several mutations showed further decrease in enzyme activity when present in cis with the Val allele.
Yamada et al. (2001) studied the functional properties of MTHFR carrying one or the other or both of 2 common polymorphisms, 677C-T (A222V) and 1298A-C (E429A). By using a baculovirus expression system, recombinant human MTHFR was expressed at high levels and purified to homogeneity in quantities suitable for biochemical characterization. The E429A protein had biochemical properties that were indistinguishable from the wildtype enzyme. The A222V protein, however, had an enhanced propensity to dissociate into monomers and to lose its flavin adenine dinucleotide (FAD) cofactor on dilution; the resulting loss of activity is slowed in the presence of methyltetrahydrofolate or adenosylmethionine. Scott (2001) noted that the approach used by Yamada et al. (2001) may be useful in determining the significance of other specific polymorphisms in disease. Scott (2001) pointed out that van der Put et al. (1998) had concluded that the combination of being heterozygous for both A222V and E429A results in additional risk of neural tube defects. The biochemical studies of Yamada et al. (2001) demonstrated no additive effect when both amino acids were altered, suggesting that the claim that the double variant increases risk needs to be reevaluated.
Spontaneous Abortion
Zetterberg et al. (2002) examined the distribution of 677C-T and 1298A-C in 80 fetal tissue samples from spontaneous abortions occurring between the sixth and twentieth week of pregnancy, compared to 125 healthy blood donors (both cases and controls were from Crete, Greece). Only 1 of the 80 spontaneously aborted embryos had the wildtype combined genotype 677CC/1298AA as compared to 19 of 125 controls (p = 0.001). A significant odds ratio of 14.2 (95% CI, 1.78-113) for spontaneous abortion was obtained when comparing the prevalence of at least 1 MTHFR mutation in abortions and controls (p = 0.001). Zetterberg et al. (2002) concluded from the data, that the effect of 1 or more MTHFR mutated alleles may be detrimental during embryogenesis when the folate requirement is high, and emphasized the potential protective role of periconceptional folic acid supplementation.
To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, Chen et al. (2001) generated Mthfr knockout mice. Plasma total homocysteine levels in heterozygous and homozygous knockout mice were 1.6- and 10-fold higher than those in wildtype littermates, respectively. Both heterozygous and homozygous knockouts had either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appeared normal, whereas the homozygotes were smaller and showed developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia (603174) in these mice.
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