Brief Communication

Diffuse Multicystic Encephalomalacia in a
Preterm Baby Due to Homozygous
Methylenetetrahydrofolate Reductase
→T Mutation
677 C→

Journal of Child Neurology
Volume 23 Number 6
June 2008 695-698
© 2008 Sage Publications
10.1177/0883073807312371
http://jcn.sagepub.com
hosted at
http://online.sagepub.com

Canan Aygun, MD, Bilge Tanyeri, MD, Meltem Ceyhan, MD, Hasan Bagc¸, PhD,
and Sukru Kucukoduk, MD
Methylenetetrahydrofolate reductase catalyzes the formation
of 5-methyltetrahydrofolate from 5,10-methylentetrahydrofolate and produces folate for the methylation of homocysteine to
methionine. Due to insufficient conversion of homocysteine to
methionine, plasma homocysteine levels increase in methylenetetrahydrofolate reductase deficiency. Homocysteine is an
amino acid that contains a neurotoxic sulfur molecule and
can induce neuronal apoptosis. Methylenetetrahydrofolate

reductase deficiency is 1 of the etiological factors that causes
neurological symptoms and signs in the newborn and childhood
period. Here, we report a premature baby with prenatal onset
diffuse multicystic encephalomalacia and cerebellar atrophy due
to homozygous methylenetetrahydrofolate reductase mutation.

M

in the newborn and childhood period.4 Here, we report a
premature baby with prenatal onset diffuse multicystic
encephalomalacia and cerebellar atrophy due to homozygous methylenetetrahydrofolate reductase mutation.

ethylenetetrahydrofolate reductase catalyzes the
formation of 5-methyltetrahydrofolate from 5,10methylentetrahydrofolate and produces folate for
the methylation of homocysteine to methionine. The gene
for methylenetetrahydrofolate reductase is located on chromosome 1p36.3, and defects of this gene result in inherited
disorders of folate metabolism.1 In methylenetetrahydrofolate reductase deficiency, due to insufficient conversion of
homocysteine to methionine, plasma homocysteine levels
increase. Homocysteine is an amino acid that contains a
neurotoxic sulfur molecule and can induce neuronal apoptosis. Additionally, it increases neuronal vulnerability to
excitotoxicity.2 The association between plasma homocysteine levels and increased risk of thrombosis and stroke has
been demonstrated.3 There also are reports showing that
methylenetetrahydrofolate reductase deficiency is 1 of the
etiological factors causing neurological symptoms and signs
From the Department of Pediatrics, Neonatology Unit (CA, BT, SK),
Department of Radiology (MC), and Department of Medical Biology
(HB), Ondokuz May¸s University Faculty of Medicine, Samsun, Turkey.
Address correspondence to: Bilge Tanyeri, MD, Ondokuz May¸s Üniversitesi T¸p Fakültesi Neonatoloji Ünitesi 9.kat Kurupelit, 55139,
Samsun, Turkey; e-mail: btanyer@yahoo.com.
Aygun C, Tanyeri B, Ceyhan M, Bagc¸ H, Kucukoduk S. Diffuse multicystic encephalomalacia in a preterm baby due to homozygous methylenetetrahydrofolate reductase 677 C→T mutation. J Child Neurol.
2008;23:695-698.

Keywords: multicystic encephalomalacia; methylenetetrahydrofolate reductase mutation

Case Report
A male infant was the second child of unrelated parents. He
was born at 30 weeks of gestation by means of vaginal delivery from an uncomplicated pregnancy. The 19-year-old
mother, without appropriate antenatal care, did not have
any obstetric ultrasonographic evaluation that reported
vaginal hemorrhage before the onset of labor. He weighed
1450 grams (75–90 percentile), height was 40 cm (75–90
percentile), head circumference was 27.5 cm (25–50 percentile). He was transferred to the neonatal intensive care
unit of a local hospital because of respiratory distress. Apgar
scores were not recorded. The baby was hypotonic and
hypothermic on admission with a bulging 1 × 1 cm anterior fontanel. Moro and sucking reflexes were absent.
The baby was diagnosed as respiratory distress syndrome, and he was put on a mechanical ventilator and
received 1 dose of exogenous surfactant. He had an
umbilical vein catheter that was kept in place for 9 days.
On the fourth day of life, his clinical situation deteriorated,
sepsis work-up was performed, and antibiotic therapy

695
Downloaded from jcn.sagepub.com at WESTERN OREGON UNIVERSITY on May 26, 2015

696

Journal of Child Neurology / Vol. 23, No. 6, June 2008

Figure 1. Coronal cranial ultrasonography images reveal dilated lateral ventricles and periventricular cysts. White star, cystic encephalomalacia; black arrow, dilated lateral ventricles.

Figure 2. Cranial computerized tomography shows conglomerated
large cysts on the frontal area, dilated lateral ventricles and periventricular hemorrhage. Black star, cystic encephalomalacia; black arrow,
periventricular hemorrhage; V, lateral ventricle.

was started. Meanwhile, he developed acute renal failure and because of resistant hyperkalemia, peritoneal
dialysis was performed. Due to the unavailability of portable
ultrasonography, cranial ultrasonography could not be done
until the fifth day of life, which showed periventricular
and parenchymal anechoic cysts and dilated lateral ventricles (Figure 1). According to these results, tests for
thrombophilia were ordered. Protein C and protein S
and antithrombin levels were within the normal limits.
Prothrombin 20210 A mutation was not detected. Cranial
computerized tomography was performed on the 19th day
of life and showed diffuse cysts conglomerated in the frontal
region. Periventricular white matter hemorrhage and bilateral lateral ventricle dilatation were also shown (Figure 2).
The patient died on the 32nd day of life. Blood culture
results were negative. Postmortem cranial magnetic resonance imaging demonstrated diffuse bilateral hemisphere
cystic encephalomalacia and hypoplastic cerebellum. There
were bilateral hyperintensities on T1-weighted images in
hemispheral white matter areas that revealed multifocal
hemorrhages and dilated lateral ventricles (Figure 3).
Homozygous methylenetetrahydrofolate reductase mutation (677 C→T) was detected after the baby’s death, so
plasma homocysteine levels could not be studied. His family refused autopsy.

Discussion
The defect on the elimination of homocystine by transsulfuration is a 677 C→T mutation. Homozygosity for
methylenetetrahydrofolate reductase 677 C→T gene variant, which is the most common genetic defect in folate
metabolism, is reported as high as 10–15% in North
American and European populations.5 The mutation
modifies the risk for several multifactorial diseases such
as vascular arteriosclerotic or thrombotic disease, colonic
cancer, acute leukemia, neural tube defects, and pregnancy complications.6 Otherwise severe methylenetetrahydrofolate reductase deficiency is a rare cause of
inborn error of metabolism. Patients with severe methylenetetrahydrofolate reductase deficiency exhibit developmental delay, motor and gait abnormalities, peripheral
neuropathy, hypotonia, and seizures.7
Recently, the changes in the central nervous system
due to methylenetetrahydrofolate reductase deficiency
have been identified. Al Tawari et al reported 4 siblings
with methylenetetrahydrofolate reductase deficiency who
had demyelination in the white matter and cerebral atrophy in cranial computerized tomography and cranial magnetic resonance imaging.8 One child of this family had
ventriculomegaly and hypoplasia of pons, medulla, and

Downloaded from jcn.sagepub.com at WESTERN OREGON UNIVERSITY on May 26, 2015

Diffuse Multicystic Encephalomalacia in a Preterm Baby / Aygun et al

697

Figure 3. Postmortem cranial magnetic resonance imaging images (A) T2-weighted hypointensitiy (B) T1-weighted hyperintensity periventricular
hemorrhage (black arrow). Dilated lateral ventricle (V) and cystic encephalomalacia on frontoparietal region (black star).

cerebellum on magnetic resonance imaging. Baethmann
et al also discussed the unknown etiology of hydrocephaly
and its possible relationship with methylenetetrahydrofolate
reductase deficiency.9 Chen et al showed a reduction in cerebellar size and dilation of lateral ventricles in homozygous
methylenetetrahydrofolate reductase–deficient mice, which
were similar to our patient.10
The response of the brain to pre-, peri-, or postnatal
anoxia, inflammation, and trauma shows different pathological findings according to the time of the insult. Cerebral
malformations may occur in the first and second trimester,
and after the second trimester, white and gray matter damage and necrosis, cavitation, and gliosis may be observed.
Generally, cystic formation within white matter occurs in 1
to 3 weeks.11-13 Cysts were detected on the fifth day of life
in our patient, indicating the beginning of the brain damage
in the intrauterine period. Chou et al reported a baby whose
twin died in utero.14 The first cranial ultrasonography of
that baby was normal but diffuse encephalomalacia was
found in the cranial ultrasonography performed at the first
month of life. In this baby, the ultrasonography and cranial
computerized tomography showed cerebral hemispheral
density loss in the 8th and 12th day of life. These findings
also suggest that the time required for the cystic changes to
appear is nearly 2 weeks in a newborn.
Increased prevalence of heterozygous inhibitor deficiencies have been described in newborns with porencephaly and
intracerebral hemorrhage.15 Deficiencies in the anticoagulant pathways leading to perinatally acquired porencephalic

cysts have been investigated by Debus et al. They retrospectively studied 24 neonates and children for the presence of
factor V Leiden mutation, protein C deficiency, antithrombin, lipoprotein A, and antiphospholipid antibodies. They
showed genetically acquired thrombophilic risk factors in 16
of these babies.16 Methylenetetrahydrofolate reductase
mutation was not studied in these series, but the study is
important to highlight the association between thrombophilia and perinatally acquired porencephalic cysts.
According to the available data, multicystic encephalomalacia in our patient had begun in intrauterine life and
methylenetetrahydrofolate reductase deficiency is the etiological factor for these lesions. We conclude that searching
for this mutation in encephalomalasic lesions of the brain in
newborns will reveal the effect of this mutation on brain
development and perinatal thrombosis.

Acknowledgment
We thank Hande Turker, MD (Ondokuz Mayis University
Hospital), for the English revision of the manuscript.

References
1. Födinger M, Wagner OF, Hörl WH, et al. Recent insights into the
molecular genetics of the homocysteine metabolism. Kidney Int.
2001;59:238-242.

Downloaded from jcn.sagepub.com at WESTERN OREGON UNIVERSITY on May 26, 2015

698

Journal of Child Neurology / Vol. 23, No. 6, June 2008

2. Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a
DNA damage response in neurons that promotes apoptosis and
hypersensitivity to excitotoxicity. J Neurosci. 2000;20:6920-6926.
3. Günther G, Junker R, Sträter R, et al. Symptomatic ischemic
stroke in full-term neonates: role of acquired and genetic prothrombotic risk factors. Stroke. 2000;31:2437-2441.
4. Larsen TB, Norgaard-Pedersen B, Lundemose JB, et al. Sudden
infant death syndrome, childhood thrombosis, and presence of
genetic risk factors for thrombosis. Thromb Res. 2000;98:233-239.
5. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111-113.
6. Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical consequences. Am J Pharmacogenomics. 2001;1:189-201.
7. Rossenblatt DS, Fenton W. Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly
WS, Vale D, eds. The Metabolic and Molecular Bases of Inherited
Disease. 8th ed. New York: McGraw-Hill; 2001:3897-3933.
8. Al Tawari AA, Ramadan DG, Neubauer D, et al. An early onset
form of methylenetetrahydrofolate reductase deficiency: a
report of a family from Kuwait. Brain Dev. 2002;24:304-309.

9. Baethmann M, Wendel U, Hoffmann GF, et al. Hydrocephalus
internus in two patients with 5,10- methylenetetrahydrofolate
reductase deficiency. Neuropediatrics. 2000;31:314-317.
10. Chen Z, Schwahn BC, Wu Q, et al. Postnatal cerebellar defects
in mice deficient in methylenetetrahydrofolate reductase. Int J
Dev Neurosci. 2005;23:465-474.
11. Barkovich AJ. Pediatric Neuroimaging. 3rd ed. Philadelphia:
Lippincott, Williams & Wilkins; 2000:157-250.
12. Barnes PD. Imaging of the central nervous system in pediatrics
and adolescence. Pediatr Clin North Am. 1992;39:743-776.
13. Naidich TP, Chakera TMH. Multicystic encephalomalacia: CT
appearance and pathologic correlation. J Comput Assist Tomogr.
1984;8:631-636.
14. Chou YH, Tsou Yau KI, Wang PJ, et al. Multicystic encephalomalacia in a surviving monochorionic twin. Zhonghua Min Guo
Xiao Er Ke Yi Xue Hui Za Zhi. 1993;34:474-479.
15. Albizetti M, Andrew M, Monagle P. Hemostatic abnormalities.
In: de Alarcón PA, Werner EJ, eds. Neonatal Haematology.
Cambridge: Cambridge University Press; 2005:310-348.
16. Debus O, Koch HG, Kurlemann G, et al. Factor V Leiden and
genetic defects of thrombophilia in childhood porencephaly.
Arch Dis Child Fetal Neonatal Ed. 1998;78:F121-F124.

Downloaded from jcn.sagepub.com at WESTERN OREGON UNIVERSITY on May 26, 2015