Iida et al. BMC Neurology (2017) 17:47
DOI 10.1186/s12883-017-0827-0

CASE REPORT

Open Access

Rapidly progressive psychotic symptoms
triggered by infection in a patient with
methylenetetrahydrofolate reductase
deficiency: a case report
Shin Iida1, Masataka Nakamura1* , Shinya Asayama1, Takenobu Kunieda1, Satoshi Kaneko1, Hitoshi Osaka2
and Hirofumi Kusaka1

Abstract
Background: Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn error of metabolism
inherited in autosomal recessive pattern and is associated with a wide spectrum of neurological abnormalities.
Case presentation: We herein describe a 15-year-old boy with MTHFR deficiency who presented with a slowly
progressive decline of school performance and a spastic gait. Rapidly deteriorating psychosis and repetitive seizures
triggered by a febrile infection prompted neurological investigation. He had significantly elevated total plasma
homocysteine and urinary homocystine levels, as well as a decreased plasma methionine level. Brain magnetic
resonance imaging (MRI) revealed leukoencephalopathy. DNA gene sequencing showed c.446_447 del GC ins TT
and c.137G > A, and c.665C > T heterozygous mutations in the MTHFR gene of the patient. Oral administration of
betaine drastically improved his clinical symptoms within a few months. After 8 months of treatment, his total
plasma homocysteine level moderately decreased; and the plasma methionine concentration became normalized.
Furthermore, the white matter lesions on MRI had disappeared.
Conclusion: This patient demonstrates the possibility that MTHFR deficiency should be considered in mentally
retarded adolescents who display an abnormally elevated plasma level of homocysteine in association with
progressive neurological dysfunction and leukoencephalopathy. Febrile infections may be an aggravating factor in
patients with MTHFR deficiency.
Keywords: MTHFR, Betaine, Spastic paraplegia, Psychosis, Leukoencephalopathy

Background
5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disease. The enzyme
MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which serves as a
methyl donor in the remethylation of homocysteine to
methionine (Fig. 1). Therefore, patients with this deficiency show hyperhomocysteinemia, hypomethioninaemia and usually low folate levels. A broad spectrum of
clinical symptoms can appear neonatally, in early or late

childhood, or even in the adult. The infantile presentation
is the most clinically severe and includes hypotonia, seizures, apneas and/or coma. Adolescents or adults may
present with mental retardation, motor and gait disturbance, seizures, psychiatric manifestations, and thrombosis
[1]. We herein report the case of a 15-year-old patient
with MTHFR deficiency presenting with a slowly progressive mental decline and spastic paraplegia, followed by
rapidly progressive psychosis and repetitive seizures triggered by infection that successfully responded to betaine
treatment.

* Correspondence: nakamuma@hirakata.kmu.ac.jp
1
Department of Neurology, Kansai Medical University, 2-5-1, Shinmachi,
Hirakata, Osaka 5731010, Japan
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Iida et al. BMC Neurology (2017) 17:47

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Fig. 1 An overview of methionine and homocysteine metabolism. MTHFR, Methylenetetrahydrofolate reductase; CBS, cystathionine beta-synthase;
BHMT, betaine-homocysteine S-methyltransferase

Case presentation
A 15-year-old Japanese boy was referred to our hospital
for rapidly progressive psychiatric and neurological symptoms. His growth and development had been normal until
the age of 11, when he began to experience academic
difficulties.
At the age of 13 years, he visited a local hospital because
of a 6-month history of slowly progressive difficulty in
walking. Neurological examination revealed a spastic gait
and marked lower limb hyper-reflexia. However, brain and
spinal magnetic resonance imaging (MRI) showed no
abnormalities. His total plasma homocysteine level was
216 nmol/ml (normal, 3.7-12.5 nmol/ml); and serum
folic acid and cobalamine levels were 1.7 ng/ml (normal,
3.6–12.9 ng/ml) and 397 pg/ml (normal, 233–914 pg/ml),
respectively. The plasma concentrations of very-longchain fatty acids were all within normal limits. Based on a
tentative diagnosis of subacute combined degeneration of
the spinal cord secondary to folic acid deficiency, folic
acid (15 mg/day) therapy was started. However, his gait
disturbance gradually worsened.
At the age of 15 years, he began to show deficits in
motivation and effort. One week later, he was immediately
admitted to a hospital because of a high fever and acute
diarrhea with vomiting caused by viral gastroenteritis that
had started the previous evening. After admission, he rapidly developed psychotic symptoms, particularly delusions
and auditory hallucinations. His general condition was improved by rehydration, and he was discharged 3 days
later with a diagnosis of hospital-induced delirium.
However, his psychotic symptoms, such as depression,
delusions, hallucinations, and anorexia, worsened over

the next 2 weeks. Furthermore, he experienced several
episodes of generalized convulsions, for which levetiracetam was prescribed (1000 mg/day). He was repeatedly in
and out of another local hospital because of dehydration
due to a refusal to eat caused by his psychotic state or
convulsions. He was treated with risperidone for a month,
but still suffered from delusions, hallucination, and failure
to eat. A brain MRI showed generalized atrophy and
hyperintensity in the white matter around the posterior
horns of the lateral ventricles on T2-weighted and fluidattenuated inversion recovery (FLAIR) images (Fig. 2a-c).
An electroencephalogram showed a diffusely low-amplitude background activity without epileptic discharge.
The results of a nerve conduction study and biochemical
examination including lysosomal enzymatic activities were
both normal. He became severely apathetic and bedridden
within two months after infectious gastroenteritis.
Therefore, he was transferred to our hospital for further
investigation.
On admission, no abnormal facial appearance or skeletal
anomalies were noted. Neurological examination revealed
a fluctuating level of consciousness with confusion, delusion, and abnormal behavior. Cranial nerves were normal.
Marked spasticity of the lower limbs was noticed, with
hyper-reflexia in both arms and legs. There was also
sustained clonus at the ankles following sudden passive
dorsiflexion of the foot. However, pathological reflexes
(Babinski and Chaddock signs) were negative. Serum folic
acid and cobalamine levels were elevated (more than
20 ng/ml and 1120 pg/ml, respectively). Plasma amino
acid analysis showed an elevated level of total homocysteine (229.9 nmol/ml) and a decreased methionine

Iida et al. BMC Neurology (2017) 17:47

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Fig. 2 a-c Axial and coronal T2 weighted magnetic resonance imaging (MRI) images and axial fluid-attenuated inversion recovery (FLAIR) MRI
image obtained at age 15 reveal a high-intensity area in the white matter around the posterior horns of the lateral ventricles. d-f Axial and coronal T2
weighted MRI images and FLAIR MRI image obtained at age 16 (8 months after betaine treatment) show resolution of the hyper-intensity in
the white matter

level (10.9 nmol/ml; normal, 19.2-32.7 nmol/ml). Cerebrospinal fluid analysis indicated normal values. Gas
chromatographic-mass spectrometric urinary metabolome
analysis revealed a markedly elevated urinary homocystine
level of 19.7 mmol/mol total creatinine (normal, not detected) and undetectable urinary methionine levels (−3.0
standard deviation; SD). His urinary methylmalonic acid
level was normal (−0.3 SD). These results of the amino
acid analyses were highly suggestive of MTHFR deficiency.
Therefore, MTHFR gene sequencing was undertaken; and
the results showed compound heterozygous mutations
c.446_447 del GC ins TT (p.Gly149Val) and c.137G > A
(p.Arg46Gln). In addition, heterozygous c. 665C > T
(p.Ala222Val) polymorphism was noted. Multivitamins
including vitamins B1, B6, and B12 (750 μg/day) as well
as folic acid were administered. Subsequently, oral substitution treatment with betaine was initiated at a dosage of 3 g/day, which was slowly increased to 9 g/day.
Over a few months, consciousness, delusion, and abnormal behavior dramatically improved, and he became
able to sit in a wheelchair. After 8 months of therapy,
the earlier white matter hyperintensities on T2-weighted
and FLAIR images had resolved (Fig. 2d-f). Moreover, his
total plasma homocysteine level had decreased to around
half of its initial value (91.2 nmol/ml); and the plasma methionine level had normalized (20.4 nmol/ml). Thereafter,
low specific activity of MTHFR was observed in skin

fibroblasts cultured from the patient (2.8 nmol/h/mg protein; normal control values in 75 normal subjects, 25.3 ±
8.9 nmol/h/mg protein). MTHFR gene sequencing of his
mother revealed mutation c.137G > A and polymorphism
c. 665C > T, both in the heterozygous state. Following
2 years of clinical follow-up, the patient had no psychiatric
symptoms (apathy, delusion or hallucination) or relapse,
and he became able to stand up and walk with the aid of a
walker.

Discussion
Our patient had two compound missense mutations,
c.446_447 del GC ins TT and c.137G > A, in the heterozygous state in addition to a c. 665C > T functional polymorphism. The tandem missense mutation c.446_447
del GC ins TT had already been described in Japanese
patients with MTHFR deficiency [2–4]. These patients
had a homozygous or heterozygous mutation and displayed
decreased MTHFR activity. The MTHFR gene polymorphism c. 665C > T is also known to be associated with reduced enzyme activity [5]. Genetic analysis of the present
patient’s mother revealed the presence of c.137G > A and c.
665C > T, indicating that pathogenicity of our patient could
have been due to the combined effect of tandem missense
mutation c.446_447 del GC ins TT and common polymorphism c. 665C > T.

Iida et al. BMC Neurology (2017) 17:47

Newborn screening for homocystinuria is based on the
identification of an increased level of plasma methionine.
MTHFR deficiency causes a low methionine level and is
therefore not detected by current screening. Unless clinicians maintain a high index of suspicion and are aware
of varied clinical presentations, this diagnosis is often
missed. The clinical presentation and age at onset of
MTHFR deficiency varies greatly depending on the degree
of enzyme deficiency [6]. Patients with severe MTHFR
deficiency (0-20% residual enzyme activity) in infancy
or adolescence present with developmental delay, severe
mental retardation, motor and gait dysfunction, seizures,
psychiatric disturbances, and other neurological abnormalities. Our patient displayed decreased MTHFR activity
(11% of control activity) and had a clinical pattern and age
at presentation consistent with a severe deficiency.
Previously, rapidly deteriorating psychosis was reported
in the case of adolesecent- or adult-onset MTHFR deficiency [7–10]. The reason for rapid deterioration in these
patients is not known; but the lack of dietary supplements,
the use of nitrous oxide during general anesthesia, and
long-term use of the antiepileptic drug phenytoin have
been reported as risk factors for acute neurological deterioration [3, 11]. So, we speculate that the change in nutritional status through reductions in dietary intake and
intestinal absorption due to gastroenteritis might have
been responsible for the rapid deterioration seen in our
patient. Moreover, prolonged undernutrition due to refusal to eat could have aggravated his psychiatric symptoms. Another possible cause is that the common MTHFR
gene polymorphism (c. 665C > T) increases the thermolability of the enzyme [5]. Thus, a high fever may potentially
worsen psychiatric symptoms by causing inactivation of the
enzyme activity. Therefore, febrile infections may be an aggravating factor in patients with MTHFR deficiency.
The biochemical therapeutic goals in MTHFR deficiency are aimed at reducing plasma homocysteine and
normalizing methionine levels. Betaine is an endogenous
catabolite of choline, and high doses of betaine are the
mainstay of therapy for patients with MTHFR deficiency.
The beneficial effect of betaine is mediated through
betaine-homocysteine methyltransferase with the use of
an alternate methyl donor for remethylation of homocysteine to methionine (Fig. 1) [12]. Indeed, betaine supplementation has been shown to decrease homocysteine levels and
normalize methionine levels in patients with MTHFR deficiency [12]. Folic acid and supplementation with vitamins
B6 and B12 also play key roles in converting homocysteine
into methionine. As expected in our case, the supplementation with betaine and multi-vitamins resulted in a moderate
decrease in the level of total plasma homocysteine and
normalization of plasma methionine, that were associated
with the disappearance of psychosis and leukoencephalopathy and the recovery of motor functions.

Page 4 of 5

Conclusions
We reported the case of a school-aged boy with severe
MTHFR deficiency who presented with a slowly progressive mental decline and spastic paraplegia and who later
developed rapidly progressive psychosis and repetitive seizures following infectious gastroenteritis. Patients with
MTHFR deficiency are sensitive to febrile infections, which
may trigger new-onset neurological or psychic symptoms,
or worsen existing symptoms. Since MTHFR deficiency is
one of the treatable metabolic disorders not identified by
current newborn mass screening, we should consider the
possibility of MTHFR deficiency in adolescents with
mental retardation who display abnormally elevated
homocysteine in association with progressive neurological
or psychiatric dysfunction and leukoencephalopathy.
Abbreviations
FLAIR: Fluid-attenuated inversion recovery; MRI: Magnetic resonance imaging;
MTHFR: Methylenetetrahydrofolate reductase; SD: Standard deviation
Acknowledgements
We thank Dr. med. Matthias Baumgartne (Division for Metabolic Disease,
University Children's Hospital Zurich) and Dr. Tomiko Kuhara (Japan Clinical
Metabolomics Institute) for measurement of the MTHFR enzyme activity and
metabolomics analysis, respectively.
Funding
We received no funding support.
Availability of data and materials
All data are contained in the manuscript.
Authors’ contributions
SI wrote the draft manuscript. MN acquired the data, drafted the manuscript,
created the figure, and revised the manuscript. SA and TK were involved in
drafting of the manuscript. SK, HO, and HK revised the manuscript for important
intellectual content. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient and his parent for
publication of this Case report and any accompanying images. A copy of the
written consent is available for review by the Editor of this journal.
Ethics approval and consent to participate
As this case report does not meet the definition of human research, the authors
declare that ethics approval was not required for this case report.
CARE checklist
We adhered to the CARE guidelines for case reports.
Author details
1
Department of Neurology, Kansai Medical University, 2-5-1, Shinmachi,
Hirakata, Osaka 5731010, Japan. 2Department of Pediatrics, Jichi Medical
School, 3311-1, Yakushiji, Shimotsuke-shi, Tochigi 3290498, Japan.
Received: 16 December 2016 Accepted: 20 February 2017

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