pmid: "39788525"
title: "Severe hyperhomocysteinemia due to MTHFR deficiency caused by a new mutation: A case report and literature review."
authors: "Yin Q, Yuan T, Ma J, Tang J, Tan X, Yang L"
journal: "Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences"
pubdate: "2024 Aug 28"
doi: "10.11817/j.issn.1672-7347.2024.240214"
source: "PMC Full Text"

Severe hyperhomocysteinemia due to MTHFR deficiency caused by a new mutation: A case report and literature review.

Autores

Yin Q, Yuan T, Ma J, Tang J, Tan X, Yang L

Periodico

Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences (2024 Aug 28)

Conteudo

Severe hyperhomocysteinemia due to MTHFR deficiency caused by a new mutation: A case report and literature review
Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive genetic disorder caused by mutations in the MTHFR gene, leading to a variety of clinical manifestations. In October 2022, the Second Xiangya Hospital of Central South University admitted a 21-year-old male patient with neuropsychiatric disorders, presenting primarily with cognitive decline, limb tremors, abnormal mental and behavioral symptoms, seizures, and gait disturbances. These symptoms had gradually developed over 5 years, worsening significantly in the past year. The patient’s plasma homocysteine levels were 10 times higher than normal, and brain MRI revealed brain atrophy and significant abnormal signals in the bilateral paraventricular nuclei and heads of the bilateral caudate nuclei. Further genetic testing identified a paternal mutation c.1604G>A (p.R535Q) and a maternal mutation c.227T>G (p.L76R) of the MTHFR gene. After betaine supplementation, the plasma homocysteine levels decreased within a week, and the symptoms improved. The patient was ultimately diagnosed with severe hyperhomocysteinemia due to MTHFR deficiency. The c.227T>G (p.L76R) mutation represents a novel missense mutation in the MTHFR gene associated with MTHFR deficiency, but further research is needed to confirm its potential pathogenicity. Early treatment with betaine can fully reverse the symptoms.
Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disease caused by defects in the MTHFR gene. It is the most common folate metabolism hereditary disease. Hyperhomocysteinemia (HHCY) due to MTHFR deficiency, also known as hyperhomocysteinemia type 2, was first described in 1972, which can lead to severe homocysteinemia, homocystinuria, and progressive neurological dysfunction. This article reports a 21-year-old patient with a rare inborn error in homocysteine (HCY) metabolism, severe HHCY due to late-onset MTHFR deficiency which is a novel mutant strain, predominantly presented with neuropsychiatric disorders, whose biochemical abnormalities and clinical symptoms improved in the short term after betaine treatment. This study aims to provide new evidence for clinical diagnosis and treatment of this rare disease.
Case presentation
A 21-year-old male was admitted to the Second Xiangya Hospital of Central South University in October 2022 presenting with limb tremors and an epileptic seizure. The patient reported experiencing limb tremors 5 years ago, at the age of 16, without any apparent triggers. These episodes lasted for a few seconds and resolved spontaneously. Over the following years, similar symptoms occurred once every 1 to 2 years, but the patient did not seek medical attention or take any medication. At the age of 20, he began to exhibit mental and behavioral abnormalities, including auditory and visual hallucinations. He reported seeing a woman following him who seemed intent on causing harm, but no one else witnessed these events. As a result, he engaged in self-talk and made defensive movements with his hands and feet but did not display suicidal or injurious behavior. In the past year, he experienced weakness, stiffness, and walking instability that gradually worsened. He sought treatment at another hospital in March 2022 where his brain MRI revealed cerebral white matter hyperintensity and brain atrophy; and his spinal MRI showed no significant abnormalities. The day before admission to our hospital, the patient experienced 9 intermittent occurrences of limb tremors lasting a few seconds. Each followed by loss of consciousness, salivation, and dyspnea without convulsions lasting more than 10 minutes before regaining consciousness with no memory of the incident upon waking up. Since the onset of the disease, the patient developed intellectual disabilities from childhood, stopped language development around the age of 3 to 4, and after that, by the end of junior high school, there was a significant decline in academic performance, but there was no significant change in sleep patterns and weight.
The patient’s height is 170 cm and his weight is 48 kg. Vital signs and general examination were within normal limits. The neurological assessment indicated intact consciousness but a suboptimal cognitive state characterized by mutism and diminished executive function, as evidenced by a Mini-Mental State Examination (MMSE) score of 15 and a Montreal Cognitive Assessment (MoCA) score of 16. Cranial nerve function remained unremarkable, while there was noted hypertonia in the limbs and a positive test for paresis in the right lower limb. The patient also exhibited tremors in the flat lifting of the right upper limb, both lower limbs spastic paraplegic gait, active bilateral tendon reflexes, positive bilateral ankle clonus, and positive sucking reflex. A general sensory examination showed no abnormalities.
The results of cranial MRI are showed in Figure 1. The blood count, biochemical analysis, and serologic studies all yielded normal results. Besides, all tests for autoimmunity were negative. However, the patient’s plasma HCY level was significantly elevated at 150.3 μmol/L, which was more than 10 times higher than the normal range (0 to 14 μmol/L), indicating severe HHCY. The patient also had a vitamin B12 level exceeding 2 000 pg/mL (normal range: 187.0 to 883.0 pg/mL), likely due to prior methylcobalamin use before testing. Serum folate levels were within normal limits.
Cranial MRI at admission
A and B: Axial T2-weighted image showing hyperintense lesions around the lateral ventricles on both sides and the head of the bilateral caudate nucleu; C: Coronary T2-FLAIR-weighted image showing hyperintense lesions around the lateral ventricles on both sides; D: Sagittal T1-weighted image showing global cortical atrophy and widened occipital pool. FLAIR: Fluid attenuated inversion recovery.
Further testing including blood amino acid and acylcarnitine profiling, as well as urine organic acid testing, revealed no abnormalities. Both electrocardiogram (ECG) and cardiac ultrasound results were normal. The electroencephalogram (EEG) showed diffuse slow-wave activity in both cerebral hemispheres while brain MRI revealed T2-hyperintense lesions without gadolinium enhancement around the lateral ventricles on both sides and at the head of the bilateral caudate nucleus (Figure 1A and 1B). Global cortical atrophy and widened occipital pool were also observed.
Whole exome sequencing identified a paternal mutation c.1604G>A (p. R535Q) (Figure 2) and a maternal mutation c.227T>G (p.L76R) (Figure 3) of the MTHFR gene, resulting in a new compound heterozygous variant.
Genetic sequencing data of the patient showing a paternal mutation

MTHFR gene chr1: 11852363 NM_005957.5 c.1604G>A, p.R535Q.
Genetic sequencing data of the patient showing a maternal mutation

MTHFR gene chr1: 11862947 NM_005957.5 c.227T>G, p. L76R.
Although the brain MRI features of the patient suggested that the patient may also have early-onset Alzheimer’s disease (EOAD), the patient did not exhibit clinical manifestations of EOAD such as advanced episodic memory and whole exome sequencing did not reveal any mutations in the APP, PS1/2, or APOE genes, which are linked to EOAD. The patient presented with cognitive delay in early childhood, exhibiting poor learning abilities, particularly in arithmetic. Additionally, he displayed deficiencies in memory, comprehension, attention, and other advanced intelligence compared to his peers. In adolescence, he experienced mental and behavioral abnormalities, seizures, gait disorders, limb tremors, and weakness in the lower limbs. These symptoms progressively worsened over 5 years and became aggravated at the age of 21. No other systemic symptoms were observed. The patient’s plasma HCY level was significantly elevated while amino acid and acylcarnitine profiling as well as urine organic acid detection showed normal results for blood genetic metabolic disease.
After excluding common causes for these neurological symptoms, it was determined that the patient had severe HHCY which led to the consideration of an inborn error of HCY metabolism caused by HHCY. Not only did the patient have HHCY but also increased methionine due to cystathionine-β-synthetase (CBS) deficiency (classic homocystinuria). However normal levels of methionine excluded CBS deficiency. Furthermore, the absence of methylmalonic acidemia (MMA) and megaloblastic anemia ruled out Cobalamin deficiency or nutritional vitamin B12 deficiency leading us to suspect MTHFR deficiency.
The patient was administered oral betaine to improve HCY metabolism. After one week of treatment, plasma HCY levels reduced from 150.3 μmol/L to 75.4 μmol/L (normal range: 0 to 14 μmol/L). The patient’s biochemical abnormalities and symptoms improved rapidly after oral betaine administration, leading to their prompt discharge from the hospital in good mental condition with improved speech patterns and communication skills. The score of the MMSE decreased to 5, and the score of the MoCA decreased to 6. The patient was advised to continue taking oral betaine post-discharge while also attending regular follow-up appointments for ongoing care management.
Discussion
This study presents the clinical manifestations, laboratory test results, and genetic findings of a 21-year-old male diagnosed with severe HHCY due to late-onset MTHFR deficiency, who exhibited neuropsychiatric disorders. The patient carried 2 mutations: MTHFR c.1604G>A (p. R535Q) and MTHFR c.227T>G (p. L76R), the latter of which is reported here. The pathogenicity of these 2 gene mutations is currently unclear. This may be a new missense mutation c.227T>G (p. L76R) in the MTHFR gene, along with another missense mutation c.1604G>A (p. R535Q), which together constitute a novel compound heterozygous variant leading to severe HHCY and neurological damage. MTHFR deficiency arises from homozygous or compound heterozygous mutations in the MTHFR gene, which encodes the MTHFR enzyme. The human MTHFR gene is located on chromosome 1p36.22 and comprises 13 exons. In 1994, Goyette, et al. first molecularly characterized mutations associated with congenital defects in folate metabolism, isolating the cDNA of human MTHFR and identifying both a missense mutation and a nonsense mutation in patients with severe early-onset MTHFR deficiency. To date, 120 pathogenic variants of the MTHFR gene have been documented, along with 52 likely pathogenic variants, while 193 variants remain of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation). The most prevalent MTHFR gene variant is the homozygous mutation 677C>T, which substitutes cytosine with thymine at nucleotide 677, leading to a conversion of alanine to valine in the enzyme and a consequent reduction in enzyme activity. In this case, whole-exome sequencing revealed that the patient inherited the paternal mutation MTHFR c.1604G>A (p. R535Q) and the maternal mutation MTHFR c.227T>G (p. L76R). The c.1604G>A mutation has been previously reported in patients with HHCY due to MTHFR deficiency. In contrast, c.227T>G (p. L76R) has not been documented in the literature, and its pathogenicity remains unclear. This mutation represents a novel site in the MTHFR gene, and the patient’s pathogenesis may be attributed to the compound heterozygous mutations at both locus mutations.
The MTHFR enzyme is a crucial regulator of HCY remethylation to methionine, catalyzing the irreversible conversion of 5,10-methylenetetrahydrofolate (CH2THF) to 5-methyltetrahydrofolate (CH3THF), which serves as a methyl donor for HCY remethylation to methionine. Methionine is subsequently metabolized to S-adenosylmethionine (SAM), a universal methyl donor involved in various biosynthetic processes, including DNA methylation, gene regulation, phospholipid synthesis, myelin assembly, polyamine formation, neurotransmitter synthesis, and creatine production. Mutations in the MTHFR gene lead to decreased enzyme activity, resulting in impaired conversion of CH2THF to CH3THF, which limits biosynthetic reactions and contributes to HCY accumulation. Additionally, CH3THF is the primary form of folate found in blood and cerebrospinal fluid, and severe MTHFR deficiency can lead to decreased folate levels in these fluids, resulting in secondary cerebral folate deficiency. In summary, the neurotoxicity associated with MTHFR deficiency is likely multifactorial, with SAM-dependent methylation playing a vital role in myelination, neurotransmitter synthesis, and gene expression. Patients with MTHFR deficiency exhibit reduced levels of CH3THF and lack of S-adenosylhomocysteine (SAH), leading to various neurological deficits. HCY and its metabolites may also contribute to neurotoxicity. HHCY is directly toxic to the vascular endothelium, leading to early atherosclerosis and thrombosis. HHCY is also thought to have a direct epileptic effect.
HCY is an unstructured amino acid formed by methionine (Met). It is present in plasma, with normal levels between 5 and 15 μmol/L, a slightly elevated level between 15 and 30 μmol/L, moderate from 30 to 100 μmol/L and a value>100 μmol/L classified as severe HHCY. Under normal circumstances, HCY has 2 metabolic pathways (Figure 4). On the one hand, it is converted to methionine by the remethylation pathway, this pathway requires the participation of MTHFR and methionine synthase (MTR). On the other hand, HCY is converted to cysteine by the transitional pathway under the action of cystathionine β-synthase (CBS). Finally, it will degrade to hydrogen sulfide (H2S). HCY elevation is caused by hereditary and non-genetic factors. The main hereditary factors are MTHFR deficiency, CBS deficiency, and cobalamin metabolism disorders (several types that can cause HHCY, cblC, D, E, or G). Non-hereditary factors include malnutrition, acquired vitamin B12, folate deficiency, drug-related effects (drugs that interfere with folate circulation, such as antiepileptic drugs and methotrexate), methionine synthase inhibitors (eg, exposure to nitrous oxide), chronic renal failure, smoking, and increasing age. These different etiologies impair any link in the HCY metabolic pathway, ultimately causing HCY to accumulate in the body to form HHCY and homocystinuria. Yet HHCY is associated with inflammation and atherosclerosis and has been considered as an independent risk factor for cardiovascular disease (CVD) and stroke. HCY is considered a sulfur-containing neurotoxin that promotes neuronal apoptosis and heightens neuronal vulnerability to excitotoxicity. Furthermore, elevated levels of H2S, which are metabolites derived from HCY, can trigger harmful effects, including pro-oxidant properties, and induce cytostatic and cytotoxic responses.

Metabolic pathways of homocysteine MTHFR: Methylenetetrahydrofolate reductase.
The clinical manifestations of hyperhomocysteinemia due to MTHFR deficiency range from asymptomatic to severe neurological symptoms. Study including 33 patients reported several clinical manifestations of hyperhomocysteinemia including muscular hypotonia, feeding problems/failure to thrive, developmental delay/mental retardation, and signs of encephalopathy (including lethargy and confusion). It is worth mentioning that some symptoms will improve as time goes on, such as lethargy, encephalopathy, muscular hypotonia, mild apnea, hypoplasia, insanity, microcephaly, epilepsy, etc. But the mental retardation and some neurological symptoms will become more and more serious. Early-onset MTHFR deficiency presenting with neurological symptoms is classified as severe MTHFR deficiency. Patients typically exhibit early-onset MTHFR deficiency in infancy (under 1 year of age), characterized by a higher incidence and more severe manifestations, primarily including feeding problems, dysplasia, hypotonia, lethargy, epilepsy, apnea, microcephaly and often resulting in premature death. Late-onset MTHFR deficiency (occurring after 1 year of age) can manifest in children or adults. However, adult onset is rare, these patients generally experience lower incidence rates and significant individual variability with a lack of specific clinical features. Symptoms may include neurocognitive impairment, gait abnormalities, mental disorders, ataxia or subacute combined degeneration symptoms, peripheral neuropathy, and vascular disease. A minority may remain asymptomatic. The clinical severity correlates with the activity level of the MTHFR enzyme in cultured fibroblasts, and the age at which symptoms first appear (lower enzymatic activity coupled with an earlier onset tends to indicate more severe symptomatology), and is also associated with the type of mutation. The clinical manifestations of HHCY caused by MTHFR deficiency may vary among different populations. A meta analysis reports the MTHFR C677T polymorphism is associated with cognitive impairment in Asian populations, but not in Caucasians. Rai, et al. have found 677 T allele of MTHFR significantly increases epilepsy susceptibility.
Biochemical abnormalities primarily consist of homocystinuria and HHCY, accompanied by low/normal plasma methionine and SAM levels, as well as severe reductions in folic acid levels in both the blood and cerebrospinal fluid. Within the group of genetic homocystinuria conditions, plasma metabolite profile analysis along with urinary methylmalonic acid testing can help identify etiology. The differential diagnosis is shown in Table 1. However, the patient’s blood routine laboratory typically does not show macrocytic anemia, nor does methylmalonic acidemia accompany it.
Inherited metabolic diseases of hyperhomocysteinemia and biochemical features
Disease Enzyme/cofactor HCY Met MMA Megaloblastic anemia/Macrocytosis CBS deficiency CBS ↑ ↑ N Absent MTHFR deficiency MTHFR ↑ N/↓ N Absent Cobalamin deficiency Cobalamin ↑ N/↓ ↑ Present
MTHFR: Methylenetetrahydrofolate reductase; CBS: Cystathionine-β-synthetase; HCY: Homocysteine; Met: Methionine; MMA: Methylmalonic acid; N: None.
In the realm of imaging, a MRI of th e head frequently reveals cerebral atrophy and white matter abnormalities. It is posited that the primary cause of white matter disease and brain atrophy is a defect in myelination, which is attributed to a deficiency of SAM in the brain, stemming from a MTHFR deficiency. Furthermore, neuropathological examination centers on demyelinating conditions in the periventricular or diffuse white matter, while the spinal cord is primarily affected by the dorsal and lateral columns, leading to joint sclerosis of the spinal cord. Enzyme activity in fibroblasts, amniotic fluid cells, and villi cells can detect varying degrees of decreased MTHFR activity, which is helpful in diagnosis. MTHFR genetic testing can further confirm the disease.
Among 24 reviewed late-onset patients with MTHFR deficiency in literature, all developed symptoms in adolescents/adults (the mean age of onset of neurological symptoms was 22.4-year-old, excluding mild learning disabilities reported in 29% of patients), some patients experienced a sub-acute onset of symptoms, sometimes following chronic evolution of symptoms, clinical manifestations included gait disorder (96%, from both central and peripheral etiologies), cognitive decline (74%), epileptic syndromes (50%), encephalopathy (30%), psychotic symptoms (17%), and thrombotic events (21%). Homocysteinemia was increased in all patients and brain MRI showed mostly periventricular white matter changes in 71% of cases, these patients stabilized or improved following metabolic treatment. The primary clinical presentation of the case involved neuropsychiatric disorders. On admission to the hospital at the age of 21, the patient exhibited symptoms such as limb tremors, seizures, cognitive decline, mental and behavioral abnormalities, gait disorder (spastic paraplegic gait), and lower limb weakness. These symptoms began in the patient at the age of 16 and had worsened over the past year. It was found that these neurological symptoms have been reported in varying combinations in different cases of MTHFR deficiency. Based on an MRI examination of the patient’s brain, high signals were found in the white matter around the bilateral ventricles, which is consistent with imaging changes common in patients with delayed MHTFR deficiency. Additionally, brain atrophy is a frequent imaging change seen in MHTFR deficiency. In this case, global cortical atrophy was also evident. What distinguishes this case is the identification of extra imaging in our patient. The brain MRI showed another T2-hyperintense lesion devoid of gadolinium enhancement situated in the heads of the bilateral caudate nuclei, a discovery that has not been recorded in the literature concerning patients with MTHFR deficiency.
The genetic evaluation indicates that our patient exhibits compound heterozygous variants in the MTHFR gene, specifically c.1604G>A (p.R535Q) and c.227T>G (p.L76R). The c.227T>G (p.L76R) variant has not been documented previously. Birnbaum, et al. were the first to describe a novel missense mutation c.1604G>A (p.R535Q) in a 31-year-old male with MTHFR deficiency who developed rapidly progressive tetraparesis, ataxia, and psychosis, becoming bedridden within 8 weeks due to undiagnosed homocystinuria, with initial symptoms manifesting at 28 years (gait disturbances). Neuroimaging via cranial MRI disclosed generalized cerebral atrophy and leukoencephalopathy, while laboratory assessments indicated significantly elevated HCY levels (186 μmol/L). Two missense mutations (c.1070G>A, p.R357H and c.1604G>A, p.R535Q) were identified as contributors to compound heterozygosity. This represents the initial report linking the MTHFR gene variant c.1604G>A (p.R535Q) to MTHFR deficiency. Our patient also possesses the c.1604G>A (p.R535Q) variant, alongside the novel missense mutation c.227T>G (p.L76R) within the MTHFR gene. Although we currently classify its clinical significance as uncertain, based on classical clinical manifestations, biochemical profiles, and imaging findings, we hypothesize that this newly identified mutation may be implicated in MTHFR deficiency. We will continue to follow uphe patient and look forward to further studies to substantiate this association in the future.
MTHFR deficiency must be distinguished from both inherited and non-inherited disorders of HCY metabolism. The hereditary factors primarily differentiate CBS deficiency from disorders related to cobalamin metabolism. CBS deficiency is an uncommon genetic condition, often referred to as classic HHCY. CBS is an enzyme responsible for catalyzing the condensation of HCY and serine to transform HCY into cysteine through the transsulfuration pathway. A disorder of this pathway in individuals with CBS deficiency results in the accumulation of HCY. Severe manifestations typically occur in childhood, including lens subluxation, significant myopia, skeletal issues (most frequently osteoporosis), and neurological impairments, while thromboembolism emerges as the primary symptom in adult-onset cases, which may also present a horse-like appearance. In conjunction with HHCY, biochemical analyses have revealed elevated levels of methionine and normal blood folate levels. The diagnosis of CBS deficiency necessitates measuring cystathionine synthase activity in fibroblasts or plasma and/or conducting mutation analysis of the CBS gene. Newborn screening for CBS deficiency can be conducted by assessing elevated methionine levels, the methionine-to-phenylalanine ratio, and/or HHCY. The management of CBS deficiency involves vitamin B6 supplementation, unrestricted protein intake, along with folic acid supplementation.
Another hereditary condition that must be distinguished from MTHFR deficiency is the metabolism of cobalamin within cells. Cobalamin (vitamin B12) is essential for the enzymatic functions of methyl malonyl-CoA mutase and methionine synthase in human cells. There exists a variety of congenital anomalies related to cobalamin absorption, transport, uptake, and intracellular metabolism. Such congenital defects lead to the accumulation of MMA and HCY in both blood and urine as substrates for the activity of methyl malonyl-CoA mutase and methionine synthase. In patients presenting with elevated levels of methylmalonic acid and/or HCY, congenital defects in cobalamin metabolism should be considered. However, it is pertinent to eliminate dietary cobalamin deficiency before making a definitive diagnosis. Cobalamin C (cblC) deficiency represents the most prevalent intracellular metabolic disorder linked to cobalamin, categorized as an autosomal recessive disorder primarily associated with mutations in the cblC gene (MMACHC OMIM 609831). A limited number of mutations within the adjacent PRDX1 gene contribute to the silencing of MMACHC and subsequent product deficiencies, which in turn results in inadequate production of the cofactor methylcobalamin for methionine synthase, as well as adenosylcobalamin for methyl malonyl-CoA mutase, ultimately causing an increased accumulation of HCY and MMA. The biochemical presentation of this condition includes HHCY, MMA, and reduced plasma methionine levels, while plasma folate and vitamin B12 typically remain within normal ranges. Clinically, this may also present alongside megaloblastic anemia, neutropenia, or pancytopenia. The disorder can be categorized into early-onset and late-onset cblC disease. Early-onset cases exhibit a greater incidence and a poorer prognosis, typically manifesting symptoms within the first year of life, including feeding difficulties, growth retardation, hypotonia, acute encephalopathy, seizures, metabolic acidosis, hydrocephalus, and atypical hemolytic uremic syndrome (aHUS). Numerous infants may experience vision impairment due to retinopathy or optic nerve atrophy. Additionally, some may present with cardiac anomalies and intrauterine growth restriction. In contrast, hemolytic uremic syndrome (HUS) and pulmonary hypertension commonly serve as initial symptoms in children diagnosed with late-onset cblC disease, whereas adolescents may exhibit more pronounced neuropsychiatric manifestations. Neonatal screening facilitates the swift identification of the disease by measuring elevated propionyl carnitine and reduced methionine via mass spectrometry analysis of dried blood spots, with subsequent analysis of MMA and HCY aiding in definitive diagnosis. The primary therapeutic approach involves intramuscular administration of hydroxocobalamin, particularly crucial for late-onset patients, as timely diagnosis and intervention can effectively ameliorate symptoms.
Due to the unavailability of treatment options for MTHFR deficiency, betaine serves as the primary method for alleviating symptoms. The therapeutic efficacy of betaine in this condition is facilitated by betaine-homocysteine-methyltransferase (BHMT), which remethylates HCY to methionine by substituting methyl donors, thereby mitigating homocysteinemia. Research indicates that betaine can prevent neurological decline and enhance clinical outcomes in individuals with MTHFR deficiency. Oral betaine anhydrous (100 to 250 mg/kg/day) exhibits a rapid onset of action, making it the preferred treatment approach, with an emphasis on initiating therapy early. However, considering that betaine methyltransferase is absent in the brain, CH3THF is uniquely capable of traversing the blood-brain barrier, underscoring the significance of folinic acid in the management of MTHFR deficiency.
Methionine supplementation has the potential to enhance clinical outcomes. However, folic acid treatment currently lacks standardized clinical efficacy. Hyland, et al. advise against the use of folic acid due to its potential to exacerbate the deficiency of central nervous system methyltetrahydrofolate. Early initiation of betaine therapy is highly recommended for patients with MTHFC deficiency, as it significantly improves clinical results and mitigates neurological decline associated with MTHFR deficiency. The prenatal diagnosis of severe MTHFR deficiency through biochemical techniques is attainable. In 1983, Wendel, et al. presented a case of prenatal diagnosis utilizing cultured amniotic fluid cells to evaluate MTHFR enzyme activity. Subsequently, in 1986, Shin, et al. established that MTHFR activity can be accurately measured in cultured chorionic villi cells. Given the polymorphisms present in the MTHFR gene, prenatal diagnosis via linkage analysis (gene tracking) emerges as a viable approach. In 2005, More, et al. demonstrated that carriers could be identified through molecular linkage analysis as an adjunct to MTHFR enzyme assessment in prenatal diagnostics, affirming that linkage analysis for severe MTHFR deficiency represents a practical method within prenatal diagnosis, marking the inaugural application of molecular genetic techniques in this context. Furthermore, in 2015, Huemer, et al. explored neonatal screening protocols for MTHFR deficiency and other remethylation deficiencies by analyzing low methionine levels and the methionine/phenylalanine ratio in dried blood spots, supplemented by measuring plasma total HCY as a secondary marker.
In conclusion, the clinical presentations of individuals with MTHFR deficiency exhibit considerable heterogeneity and this condition is classified as rare. This study delineates a case of severe HHCY resulting from late-onset MTHFR deficiency. The patient had MTHFR c.1604 G>A (p. R535Q) and MTHFR c.227T>G (p. L76R). The latter represents a novel mutation reported here, thereby enriching the existing catalog of MTHFR mutations. However, further investigation is required to validate its pathogenic role. Clinicians should be highly skeptical for MTHFR deficiency in patients presenting with unexplained neuropsychiatric symptoms, including cognitive decline, mental health disorders, seizures, and gait abnormalities. For individuals diagnosed with HHCY, prompt identification, timely diagnosis, and early intervention with betaine therapy may reverse biochemical anomalies and mitigate neurological compromise, ultimately enhancing prognostic outcomes.
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Funding Statement
This work was supported by the National Natural Science Foundation (81971696) and the Natural Science Foundation of Hunan Province (2022JJ30861), China.
Conflict of Interest
The authors declare that they have no conflicts of interest to disclose.
AUTHORS’CONTRIBUTIONS
YIN Qing Research design, data collecting, and paper writing; YUAN Tianxiang Data collecting and paper writing; MA Jie and TAN Xuling Data analysis; TANG Jianguang Paper modification; YANG Li Research design and paper revision. The final version of the manuscript has been approved and read by all authors.
Note
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2024081363.pdf
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