Gales et al.

Orphanet Journal of Rare Diseases (2018) 13:29

DOI 10.1186/s13023-018-0767-9

REVIEW Open Access

Adolescence/adult onset MTHFR deficiency

may manifest as isolated and treatable
distinct neuro-psychiatric syndromes
Ana Gales1, Marion Masingue2, Stephanie Millecamps8, Stephane Giraudier4,5,6, Laure Grosliere2, Claude Adam1,
Claudio Salim7, Vincent Navarro1,3 and Yann Nadjar2*

Abstract
5,10-Methylene-tetrahydrofolate reductase (MTHFR) deficiency is a genetic disorder that can occur at any age and
can be easily detected by increased homocysteinemia. In adolescence/adult onset forms, the clinical picture is often
complex with association of various neurological features and thrombosis.
Here we report the cases of two adult siblings who experienced focal epilepsy at 18 years old as a first disease
manifestation, without other symptom during several years. Upon diagnosis, both patients received metabolic
treatment comprising B9, B12 and betaine which has stopped the occurrence of seizures, allowing discontinuation
of anti-epileptic drugs.
Among 24 reviewed adolescent/adult onset patients with MTHFR deficiency in the literature, clinical manifestations
included gait disorder (96%, from motor central or peripheral origin), cognitive decline (74%), epileptic syndromes
(50%), encephalopathy (30%), psychotic symptoms (17%), and thrombotic events (21%). A total of 41% presented a
single neurological manifestation that could stay isolated during at least 3 years, delaying achievement of the
diagnosis. Brain MRI showed a mostly periventricular white matter changes in 71% of cases. All patients stabilized or
improved following metabolic treatment.
Despite being rare, adolescence/adult onset MTHFR deficiency can nevertheless be successfully treated. Therefore,
homocysteinemia should be tested in various unexplained neuro-psychiatric syndromes like epilepsy or spastic
paraparesis, even if isolated, since waiting for completion of the clinical picture is likely to increase the risk of
irreversible neurological damage.
Keywords: Metabolic disease, Clinical neurology examination, All epilepsy/seizures, Gait disorders/ataxia, MRI

Background absence of methylmalonicaciduria, which is present in co-

5,10-Methylene-tetrahydrofolate reductase (MTHFR) defi- balamin metabolism disorders. The disease onsetis usual-
ciency (OMIM number #607093) is a rare disorder affect- lyin the neonatal period or childhood with the occurrence
ing the metabolism of folate and sulfur-containing amino of neurological symptoms such as encephalopathy, psycho-
acids [1]. The enzymatic deficiency results in a reduction in motor delay, gait disorder and epilepsy, all of which may
synthesis of 5- methyl-tetrahydrofolate (5MTHF), the bio- also be associated with thrombotic events [2]. Neonatal
logically active form of folate, which is a cofactor necessary formsare usually more severe [1] and are related to the
for the re-methylation of homocysteine into methionine. lowest level of residual MTHFR activity [3, 4]. Patients with
Biological hallmarks are moderately low plasmatic folate adolescent/adult onset are rare, with a very heterogeneous
levels, hyperhomocysteinemia, hypomethioninemia and neurological presentation. They suffer from spastic parapar-
esis, psychotic episodes, cognitive disorder, and relapsing
* Correspondence: [email protected] encephalopathy [5]. Metabolic therapeutic strategies aim at
2
Neurology Department, Reference Center for Lysosomal Diseases, (i) enhancing methionine synthesis (using B9 and B12
Neurogenetics and Metabolism Unit, AP-HP, GH Pitié-Salpêtrière-Charles Foix, vitamins), (ii) bypassing methionine synthase using betaine
Paris, France
Full list of author information is available at the end of the article (cofactor of another enzyme involved in homocysteine

© The Author(s). 2018 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
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Gales et al. Orphanet Journal of Rare Diseases (2018) 13:29 Page 2 of 8

remethylation), and (iii) supplementing methionine if according to [8] was also found. The missense mutation in
needed [6, 7]. Metabolic therapies were shown to be effect- exon 7 affected a highly conserved residue, and was
ive in children and adults to stop disease progression, and predicted to be deleterious by in silico analyses with SIFT,
sometimes improve neurological disabilities [7]. Few cases PolyPhen and Mutation taster. This mutation has never
of adolescent/adult onset of MTHFR deficiencies are been associated to MTHFR deficiency previously. The stop-
accompanied by epilepsy, and those are usually associated loss mutation, previously reported [9], was predicted to lead
with additional neurological symptoms [5]. Here we report to the addition of 50 residues at the end of the protein.
a 32 years-old male patient with pharmaco-resistant frontal Genetic analysis showed that the father carried the missense
epilepsy as the unique manifestation of MTHFR deficiency in exon 7 whereas the mother carried the stop-loss in exon
for the past 14 years, and for whom metabolic treatment 12 (and the c.665C > T polymorphism in exon 5), thus con-
initiated 6 years after his first seizure allowed strong reduc- firming the diagnosis of MTHFR deficiency with compound
tion of anti-epileptic drugs without recurrence of any heterozygosity. Metabolic treatment started at the age of 24,
seizure. His sister, who also suffered initially from isolated with folinic acid (50 mg per day), betaine (12 g per day), and
epilepsy, was only started on metabolic treatment 14 years cyanocobalamin (2 mg per week). This allowed a sustained
after her initial seizure, and hence developed additional 50% reduction in homocysteinemia to 80 μmol/l.Valproic
clinical features of MTHFR deficiency. The literature on acid and clozabam were progressively stopped and lamotri-
adolescent/adult onset MTHFR deficiency was also gine dose was decreased to 100 mg a day. The patient has
reviewed, with a focus on epilepsy, for characterization been followed for 5 years after valproic acid stop and for
ofthe clinical presentation, evolution and response to meta- 18 months since the decrease of lamotrigine to 100 mg, and
bolic treatment. has shown no recurrence of seizure. Since metabolic treat-
ment was introduced, he reported clear improvement in
Case reports cognition, mainly memory and attention, and was able to
Patient n°1 (32 year-old man) born from non- live independently from his parents and work as a gardener.
consanguineous parents had a normal psychomotor His sister (patient n°2, 40 year-old) had normal school
development during childhood but with low scholastic performances during adolescence despite behavioral dis-
performances and an attention deficit from the age of turbances such as obsessions and addiction to cannabis.
14. At 18 years-old, the patient experienced his first epi- Similarly to her brother she presentedcomplex partial
leptic seizure, described as an abrupt arrest of speech, seizures at 18 years old (same ictal semiology) but never
with stereotypical motor behaviors followed by convulsive with generalization. Under valproic acid treatment, she
seizures. Several identical seizures occurred, requiring had no recurrence of seizures. At 27 years, she experi-
three antiepileptic drugs to decrease their frequency to enced sub-acute neurological symptoms with drowsiness,
two per year: lamotrigine (200 mg/day), valproic acid cognitive disorder, visual hallucinations and paraparesis
(1000 mg/day), and clozabam (10 mg/day). Neurological from central origin, with spontaneous partial improve-
examinationwas normal except for mild cognitive impair- ment. She was again hospitalized at 32 for sub-acute
ment (Mini Mental State Examination -MMSE- 25/30, worsening of the same symptoms. MMSE was measured
Frontal Assessment Battery -FAB- 16/18), and subtle at 22/30. Brain MRI showed diffuse periventricular and
upper motor neuron signs in lower limbs. The EEG subcortical hypersignals of the white matter (Fig. 2). Spinal
recorded the presence of left fronto-temporal spike-and- cord MRI showed a bilateral posterior-lateral hyper-signal
waves on a bilateral and symmetric alpha (8 Hz) back- at C2 level. EEG showed a slow background theta activity
ground activity (Fig. 1). The brain MRI was normal. At and generalized paroxysmal discharges of spike-and-waves.
24 years of age, homocysteinemia, tested because found To investigate an unexplained tachycardia, a contrasted CT
highly increased in his sister, was found abnormally high thoracic angiography was performed and showed a bilateral
at 193 μmol/l (4.5 < N < 13.5 μmol/l), whereas plasmatic pulmonary embolism. Homocysteinemia, tested because of
folate levels were normal with no macrocytic anemia. association of thrombosis and unexplained encephalopathy,
Plasmatic methionine was low (20 < N < 30 μmol/l). The was found elevated at 130 μmol/l, with decreased plasmatic
EMG, ophthalmological examination, and echocardiog- methionine level, and decreased plasmatic folate levels
raphy, performed to investigate disorders associated to (2.1 nmol/l; 6 < N < 40). Electromyography (EMG) showed
hyperhomocysteinemia from genetic causes, were all a pure motor axonal neuropathy. Echocardiography of the
normal (not shown). Genetic analysis of the MTHFR gene supra aortic trunks was normal. The genetic analysis
identified two heterozygous point mutations: (i) amissense confirmed that she carried the MTHFR mutations detected
mutation in exon 7 (c.1162C > T, p.(Arg388Cys)); (ii) a stop- on her brother. At 32 years old, a metabolic treatment was
loss mutation in exon 12 (c.1970G > C, p.(*657Serext*50)). initiated with folinic acid (75 mg per day), betaine (12 g per
A heterozygous c.665C > T, p.(Ala222Val) polymorphism in day), and cyanocobalamin (1 mg per day), which allowed to
exon 5 corresponding to the c.677C > T nucleotide change keephomocysteinemia stable at levels around 70 μmol/l
Gales et al. Orphanet Journal of Rare Diseases (2018) 13:29 Page 3 of 8

Fig. 1 Electroencephalogram (patient n°1). Bilateralfronto-temporal spike-and-waves (arrow), followed by a left temporo-frontal spike (arrow head)
on a symmetric alpha (8 Hz) background activity (longitudinal montage)

and improved her clinical condition (gait, cognition, behav- learning disabilities before the age of 10 were also in-
ior). Valproic acid was then progressively discontinued in cluded, as many of those patients did not have a specific
few months. At 40 years of age, the patient has had no re- neurologic evaluation during childhood). Asymptomatic
currence of seizures. Unlike her brother she still has gait patients were not included but were notified if they
difficulties with paraparesis and cannot walk without sup- were siblings of a reported patient in the table com-
port. After 4 years of metabolic treatment a cerebral MRI piling main demographic and clinical characteristics
did not show worsening signs (not shown). of reviewed patients [see Additional file 1 - legend].
Among 192 patients assessed by Froese et al. [1], 163
Review had MTHFR mutations, and 22 of them were eligible
A literature review was performed on adolescent/adult for this review. Patients were excluded when their age
onset MTHFR deficiencies. Patients assessed were those of neurological onset was not known (n = 19) or when it
identified by Froese et al. [1] who undertook a thorough occurred before the age of 10 (n = 122). Clinical, bio-
compilation of all MTHFR deficient patients reported in chemical, and radiological characteristics of the 22 pa-
the literature (N = 192 patients from 171 families) [1]. tients and of the two patients reported here are
The selection criteria were the following: (i) patients described in Table 1 (combined data). Additional tables
with genetic confirmation of MTHFR deficiency; and compile the individual data of all 24 patients included
(ii) onset of neurological symptoms occurring after in this review [see Additional file 1], as well as their
10 years of age (however patients who presented mild mutations [see Additional file 2], respectively.

Fig. 2 Brain MRI showing white matter changes (patient n°2). Periventricular and subcortical hyper signals with sparing of the U fibers (Axial T2 FLAIR)
Gales et al. Orphanet Journal of Rare Diseases (2018) 13:29 Page 4 of 8

Among the 24 patients with adolescent/adult onset patients (5/24) suffered from thrombosis (venous or ar-
MTHFR deficiency, 12 patients suffered from epilepsy terial). Globally, gait disorder was the most prominent
(50%), with different epileptic syndromes: generalized symptom occurring in 96% of patients (23/24), mainly
tonic clonic seizures (n = 4), focal seizures (n = 3), ab- due to lower limbs weakness (21/23; 91%) either from
sence seizures (n = 1), juvenile myoclonic epilepsy (JME) central (19/19; 100% ofpatients had upper motor neuron
then progressive myoclonic epilepsy (PME) (n = 1), and signs including 14/17–82%-with lower limbs spasticity),
not documented in other patients (n = 3). Epilepsy was or peripheral origin (10/14; 71%had a peripheral neur-
the first manifestation of disease in 7/12 patients (58%), opathy). Ataxia was less frequent (7/20; 35%). Cognitive
isolated in 6 patients. Sufficient clinical and EEG data to decline was also frequently found (17/23; 74%). Four pa-
correctly describe the epileptic syndrome were only tients had psychotic symptoms (4/24; 17%). Figure 3
available for three patients (5, 6 and 10). Patient n°5, a shows temporal aspects of onset of different neurological
15 year-old girl, experienced absence type seizures at and thrombotic symptoms. Twenty-four percent of pa-
13.5 years of age which were successfully treated by so- tients (4/17) initially had at least two symptoms, whereas
dium valproate. Six months after epilepsy onset, she de- 41% (7/17) only suffered from one symptom for at least
veloped a spastic paraparesis and cognitive difficulties, 3 years. Most patients had periventricular white matter
associated with white matter hypersignals on MRI. Folic abnormalities (12/17; 71%). Six patients had a spinal
acid at 25 mg/day stopped the seizures and reduced cord MRI, one showed bilateral posterior-lateral hyper-
MRI white matter abnormalities. Patient n°6, a 17 year- signal, and two evidenced spinal cord atrophy. Homo-
old girl, suffered from mild learning disabilities and had cysteinemia was strongly increased in all patients (mean
her first seizures characterized by morning myoclonic value = 177.3 μM +/− 49.5; range: 115–320), whereas
jerks at 14 years of age. EEG revealed a 4-Hz polyspike methioninemiawas low in 77% of patients (13/17).
waves consistent withJME. Although sodium valproate Among18 metabolically treated patients (no data for the
was efficient during several months, levetiracetam treat- 6 remaining patients), 83% (15/18) improved at least
ment had to be added in order to control her seizures. partially while 17% (3/18) remained stable. No patient
By the age of 15 she presented paraparesis and ataxia, presented clinical worsening after metabolic treatment
cognitive decline, and increased seizures frequency with was introduced. Mean length of follow up after initiation
slowing and disorganization of the EEG, which of metabolic treatment (always at diagnosis) was 3.7 years
prompted a diagnosis of PME. Under betaine 6 g/day, +/− 4.5 (0–16). Metabolic treatment allowed to halve
folinic acid 25 mg/day, and methionine 20 mg/kg/day, homocysteinemia (mean homocysteinemia under treat-
all symptoms improved. Seizure frequency decreased ment was 76.1 μM +/− 22.2, 50–118). Patients received
from daily to every few months, although the patient still B9 vitamins (18/18; 100%), B12 vitamins (16/18; 89%),
required a triple anti-epileptic treatment (zonisamide, betaine (15/18; 83%), B6 vitamins (8/18; 44%), methio-
lamotrigine, levetiracetam). Patient n°10 presented gen- nine (3/18; 17%), riboflavin (2/18; 11%), and thiamine
eralized tonic-clonic seizures at 19 years-old which were (1/18; 5%), sometimes in a complex temporal sequence.
successfully treated by phenytoin, without preventing Two patients improved upon B9 supplementation, with
the onset of leg weakness 2 months after his first sei- or without B12, whereas four patients needed adjunction
zures. EEG demonstrated predominant theta waves with- of betaine to B9/B12 vitamins to further decrease homo-
out paroxysmal discharges. Brain MRI revealed diffuse cysteine levels. Genotype/phenotype correlation was
bilateral hyperintensities in the deep white matter. The hard to predict, as four adolescent/adult onset patients
authors suggested that phenytoin may have precipitated [see in Additional file 1] had a sibling with a more severe
MTHFR deficiency symptoms by aggravating the disease beginning in childhood, whereas one patient with
remethylation impairment. Betaine 6 g/day, folic acid neurological onset at 26 years old had a sibling asymp-
15 mg/day and pyridoxal phosphate 30 mg/day allowed tomatic at 37 years old with the same mutations.
clinical and radiological improvement, and the patient
did not experience recurrence of seizures under Conclusions
zonisamide. We report the cases of two young adult siblings who ex-
Overall among all 24 reviewed patients, the mean age perienced epilepsy as the only symptom of MTHFR defi-
of onset of neurological symptoms was 22.4 year-old ciency during 14 years (including 8 under metabolic
(+/− 12.1, 11–54), excluding mild learning disabilities re- treatment) for one and 9 years for the other one. They
ported in 29% of patients (6/21) (Table 1). The first harbored the stop-loss c.1970G > C mutation that re-
neurological manifestations were heterogeneous: gait places the stop codon by a serine, extending the MTHFR
disorder (11/24, 46%), epilepsy (7/24; 29%), cognitive de- protein by 50 additional amino acids at its C-terminal
cline (5/24; 21%), psychosis (3/24; 12%), encephalopathy segment. This stop-loss mutation was previously re-
(1/24; 4%), and stroke (n = 1; 4%). A total of 21% of ported as homozygous in 2 severely affected French
Gales et al. Orphanet Journal of Rare Diseases (2018) 13:29 Page 5 of 8

Table 1 Characteristics of adolescence/adult onset MTHFR deficient patients (N = 24 patients)

Mean age at neurological onset (n = 24) 22.4 (+/− 12.1, 11–54)
Age at diagnosis (n = 21) 28.8 (+/− 15.3, 11–67)
Age at description (n = 24) 30 (+/− 16.2, 12–69)
Thrombosis 5/24 (21%)
Mild learning disabilities 6/21 (29%)
Acuteness of occurrence of at least one 11/20 (55%)
neurological symptoma
Neurological presentationb Gait disorder 11/24 (46%) LL Weakness 10/10 (100%). 3/10 associated with UL weakness.
1/10 with left sided weakness
UMN signs 7/7 (100%)
Spasticity 5/6 (83%)
Peripheral Neuropathy 3/4 (75%)
Ataxia 4/8 (50%)
Epilepsy 7/24 (29%) GTCS 4/7 (57%), 1 with myoclonus mimicking JME
Absence 1/7 (14%)
Focal seizures 2/7 (28%)
Cognitive decline 5/24 (21%)
Psychosis 3/24 (12%)
Encephalopathy 1/24 (4%)
Stroke 1/24 (4%)
Neurological symptoms till last follow up Gait disorder 23/24 (96%) LL Weakness 21/23 (91%). 6/23 associated with UL weakness.
1/10 with left 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 3/9 (33%)
Cognitive decline 17/23 (74%)
Psychosis 4/24 (17%)
Encephalopathy 6/20 (30%)
Other 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 (n = 1), coma (n = 1).
Delay between first neurological manifestation 2.8 +/− 2.9, 0–9
and occurrence of other neurological symptomc
Evolution under treatment Improvement 15/18 (83%)
Stabilization 3/18 (17%)
Cerebral MRI White matter abnormalities 12/17 (70%)
Normal 3/17 (18%)
Cerebral atrophy 7/17 (41%)
Spinal cord MRI Normal 3/6 (50%)
SCA 2/6 (33%)
PCHS 1/6 (17%)
Biological data Initial homocysteinemia 177.3 +/− 49.5, 115–320
(n = 16)
Gales et al. Orphanet Journal of Rare Diseases (2018) 13:29 Page 6 of 8

Table 1 Characteristics of adolescence/adult onset MTHFR deficient patients (N = 24 patients) (Continued)

Initial methioninemia Low 13/17 (77%), Normal 4/17 (23%)
Homocysteinemia after 76.1 +/−22.2, 50–118
treatment (n = 13)
Encephalopathy was defined as an acute or sub-acute onset of cognitive decline with drowsiness and/or confusion
a
Seizures and strokes were not considered in this row
b
Four patients had mixed neurological presentations and were counted twice (patientsn°9; 15; 16; and 19)
c
Symptoms considered: gait disorder, cognitive disorder, epilepsy, psychosis, encephalopathy, and stroke

patients with early onset disease (< 1 year old) [9]. In the protein could display altered binding to SAM while
our patients the allele with this stop-loss mutation also still retaining some residual enzymatic activity [10].
carried the c.665C > T, p.(Ala222Val) polymorphism in Froese and al. compared genotypes of patients with
exon 5 (corresponding to the c.677C > T nucleotide MTHFR deficiency according to early onset (< 1 year
change according to [8]), that was previously suggested to old; n = 64) versus late onset (> 1 year old; n = 51) [1].
worsen MTHFR deficit for patients carrying other They classified genotypes in seven categories according
MTHFR variants [9]. The other mutation we identified to the type of mutations (missense/splicing/other) and
(c.1162C > T) has never been associated with MTHR defi- location of mutations (catalytic domain versus regulatory
ciency. Its mutation frequency in control databases is domain). They found a significant difference only for 2/7
similar to that already reported for other MTHFR causing genotype categories: late onset patients had more fre-
mutations [see Additional file 2]. Since our two patients quently two missense mutations located in the regula-
first experienced symptoms in adulthood, it is likely that tory domain (14% vs 3%), and less frequently two
the c.1162C > T mutation does not severely affect MTHFR splicing mutations in the regulatory domain (4% vs
enzymatic activity, that was shown to be correlated to the 19%). Missense mutations only correlate with a milder
severity of the disease [1]. Since the mutation is located phenotype when both located in the regulatory domain,
outside the catalytic domain of the protein, lying within as two missense mutations in the catalytic domain were
the predicted S-adenosyl methionine (SAM)-binding site, found equally in early-onset (28%) and late-onset (29%)

Fig. 3 Initial clinical presentation and evolution of symptoms in adolescence/adult onset MTHFR deficiency (N = 24 patients). The initial clinical
symptom(s) is/are indicated on the left. The delay for onset of other symptoms is represented by the box length, and within the box (in years),
followed by the nature of the symptoms. Patients were classified from the shortest to the longest delays of onset of other symptoms
Gales et al. Orphanet Journal of Rare Diseases (2018) 13:29 Page 7 of 8

patients. For the sub-category of very late onset patients never completely normalized. However, very few had a
(> 10 years old; n = 24) reviewed here, the data fit with complete disappearance of their symptoms due to irre-
those findings: 29% of patients had two missense muta- versible neurological damage accumulating over time,
tions in the catalytic domain, 17% two missense muta- highlighting the need for shorter diagnostic delays in
tions located in the regulatory domain, and 0% two MTHFR deficiency.
splice mutations in the regulatory domain. Concerning This could be achieved if homocysteinemia was tested
clinical variability among siblings, it is interesting to ob- earlier as a screening test for MTHFR deficiency. Values
serve that patient n°7, who suffered from a gait disorder reported in adolescent/adult onset MTHFR deficiency
since 15 years old, had an asymptomatic 37 year-old were consistently above 100 μM (4.5 < N < 15), even for
brother harbouring the same mutations. On the other very late onset patients, strongly evoking a genetically-
hand, four other patients we included in our manuscript sustained metabolic defect, and notvitamins or renal
(n°5, 15, 19, 20) had siblings who had an earlier pediatric filtration deficiencies, which can also be associated
onset, however never < 1 year old. Therefore, the same withhyperhomocysteinemia.
genotype can lead to some limited variability of the Homocysteine is likely to promote thrombotic events,
clinical expression of the disease. but it is not known why such events are far less frequent
The review of all 24 patients shows that epilepsy oc- in MTHFR deficiency than in classic homocystinuria
curs in 50% of adolescent/adult onset MTHFR deficient despite both deficiencies being associated with similar
patients with a highly variable phenotype and a variable homocysteinemia levels [11]. Hypomethioninemia may
response to anti-epileptic drugs. The core symptom was decrease global methylation reactions in the central
gait disorder (96%) from both central and peripheral eti- nervous system, hence possibly affecting myelin, as
ologies. Mode of onset was also variable, some patients attested by white matter abnormalities often found in
experiencing sub-acute onset of symptoms, sometimes cerebral MRIs of MTHFR deficient patients [12].
following chronic evolution of symptoms. Thrombotic In conclusion, these two patients broaden the pheno-
events were not as frequent (5/24; 21% of patients) as typic spectrum of epilepsy in adolescent/adult onset
reported in homocystinuriadue to cystathionine beta MTHFR deficiency. The literature review showed that
synthase (CBS) deficiency [11]. Even though almost all epilepsy, and other isolated neurological symptoms like
patients (21/24) ended up suffering from a combination spastic paraparesis or cognitive decline, may be the
of neurologic symptoms, at the onset, 76% of them (13/17) unique manifestations of MTHFR deficiency during several
suffered from a single symptom. The delay from onset to years. Even though adolescent/adult onset MTHFR defi-
occurrence of a second symptom could be as long as 9 years ciency is a rare disease, it is a treatable one, for which meta-
(patient n°2). The delay from onset to diagnosis was rather bolic treatment comprising B9, B12 and betaine can
long (mean 5.75 years). Only two patients were diagnosed prevent disease progression and promote improvement.
when only suffering from a single symptom, including our Assessment of homocysteinemiashould be performed in
patient n°1 who was tested for homocysteinemia after the selected patients even if suspicion of MTHFR deficiency is
diagnosis of his sister. Brain MRI can help to achieve low. We suggest that plasma homocysteine levels be tested
diagnosis, but thewhite matter changes observed arenot a in case of occurrence of the following symptoms with
constant or a specific sign. unknown etiologies:unexplained epilepsy with or
Metabolic treatment is mainly based on B9, B12 without normal brain MRI, spastic paraparesis, motor
vitamins, and betaine. Almost all patients have received predominant peripheral nerve disease with central
those 3 components simultaneously (15/18). All five signs, young onset cognitive disorder, encephalopathy,
epileptic patients with data regarding evolution under atypical psychosis (with visual hallucinations, cognitive
metabolic treatment had decreased frequency and inten- disorder, drowsiness), and young onset thrombosis. In
sity of seizures, which allowed a decrease or a discon- case of hyperhomocysteinemia, metabolic treatment
tinuation of antiepileptic treatment. Among our case should be started without delay.
reports, patient n°1, had his epilepsy resolved and
Additional files
remained free of other symptoms for 8 years, until last
follow-up. Interestingly, his older sister (patient n°2), Additional file 1: ‘Clinical, biochemical, and radiological characteristics of
diagnosed at a later age, experienced gait difficulties 24 adolescent/adult onset MTHFR deficient patients’. This large table
9 years after the appearance of epilepsy, suggesting that compiles the main demographic and clinical characteristics of patients
with adolescent/adult onset MTHFRdeficiency. (DOCX 79 kb)
the early start of metabolic treatment of her brother pre-
Additional file 2: ‘MTHFR mutations of 24 adolescent/adult onset
vented the worsening of his disease. Among 18 patients MTHFR deficiency patients from the literature [1] and presently
for whom evolution under metabolic treatment was reported’. This table compiles the mutations of all 24 MTHFR
reported, all stabilized or improved clinically, while their deficient patients with an adolescent/adult onset that were reviewed
in this manuscript. (DOCX 23 kb)
homocysteinemia levels, although strongly reduced,
Gales et al. Orphanet Journal of Rare Diseases (2018) 13:29 Page 8 of 8

Abbreviations Received: 23 October 2017 Accepted: 12 January 2018

5MTHF: 5- methyl-tetrahydrofolate; B12: Vitamin B12, ie, cobalamin;
B9: Vitamin B9, ie, folic acid; C2: 2nd cervical vertebrae;
EEG: Electroencephalography; EMG: Electromyography; FAB: Frontal References
assessment battery; GTCS: Generalized tonico clonic seizure; JME: Juvenile 1. Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Gueant JL, et al.
myoclonic epilepsy; LL: Lower limbs; MMSE: Mini mental state examination; Mutation update and review of severe Methylenetetrahydrofolate Reductase
MRI: Magnetic resonance imagery; MTHFR: 5,10-Methylene-tetrahydrofolate deficiency. Hum Mutat. 2016;37(5):427–38.
reductase; PME: Progressive myoclonic epilepsy; UL: Upper limbs; 2. Huemer M, Mulder-Bleile R, Burda P, Froese DS, Suormala T, Zeev BB, et al.
UMN: Upper motor neuron Clinical pattern, mutations and in vitro residual activity in 33 patients with
severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency. J
Inherit Metab Dis. 2016;39(1):115–24.
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Funding 4. Sibani S, Christensen B, O'Ferrall E, Saadi I, Hiou-Tim F, Rosenblatt DS, et al.
The present work has not been funded by a sponsor however costs for Characterization of six novel mutations in the methylenetetrahydrofolate
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Availability of data and materials
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Ethics approval and consent to participate
Metab. 2010;99(1):1–3.
Not applicable
12. Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-
Cacan S, et al. Mice deficient in methylenetetrahydrofolate reductase
Consent for publication exhibit hyperhomocysteinemia and decreased methylation capacity,
Patients n°1 and n°2 - followed by Dr. Nadjar- have both given their oral with neuropathology and aortic lipid deposition. Hum Mol Genet.
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Competing interests
Ana Gales, Marion Masingue, Stephanie Millecamps, Stephane Giraudier,
LaureGrosliere, Claude Adam and Vincent Navarro, report no disclosures.
Claudio Salim, one of the co-authors of this review is employed by Orphan
Europe, the marketing authorization holder of Cystadane (ie, anhydrous
betaine).
Yann Nadjar received speech honoraria from Actelion and Orphan Europe;
and received travel funding from Actelion, Shire and Genzyme.

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