The Turkish Journal of Pediatrics 2022; 64: 747-753

https://doi.org/10.24953/turkjped.2021.1662
Case Report

A rare case of hypomyelinating leukodystrophy-14

benefiting from ketogenic diet therapy
Aycan Ünalp1 , Melis Köse2 , Pakize Karaoğlu3 , Yiğithan Güzin3 , Ünsal Yılmaz1
1
Department of Pediatrics, Division of Pediatric Neurology, University of Health Sciences Turkey, İzmir Faculty of Medicine, İzmir;
2
Department of Pediatrics, Division of Inborn Errors of Metabolism, Katip Çelebi University Medical Faculty, İzmir; 3Department of
Pediatrics, Division of Pediatric Neurology, University of Health Sciences, Dr. Behçet Uz Childrens Education and Research Hospital,
İzmir, Turkey.

ABSTRACT
Background. Hypomyelinating leukodystrophy-14 (HLD14) is a rarely seen neurodevelopmental disease
caused by homozygous pathogenic ubiquitin-fold modifier 1 gene variants. The disease has an autosomal
recessive inheritance. All patients with this condition reported to date have drug-resistant epilepsy. The post-
translational modification of proteins with ubiquitin fold modifier 1 is defective in these patients and is thought
to be responsible for severe neurodevelopmental problems. There is no previous report on the effectiveness of
the ketogenic diet in the treatment of drug-resistant epileptic seizures in this disease. Therefore, we present a
pediatric case diagnosed with HLD14 and whose drug-resistant epileptic seizures were controlled by ketogenic
diet therapy.
Case. The patient was a three-year-old male with drug-resistant epilepsy and developmental delay. His brain
magnetic resonance imaging revealed cerebellar atrophy, periventricular white matter hypomyelination, and
ventricular enlargement. Whole-exome sequencing analysis identified a homozygous pathogenic variant in the
ubiquitin-fold modifier 1 gene on chromosome 13q13. Ketogenic diet therapy was initiated for his drug-resistant
seizures and subsequently reduced seizure frequency by more than 75%. The patient is still on ketogenic diet
therapy.
Conclusions. Ketogenic diet therapy may be beneficial for seizure control in HLD14 patients with drug-resistant
seizures.

Key words: drug-resistant epilepsy, hypomyelinating leukodystrophy-14, ketogenic diet therapy, children.

Hypomyelinating leukodystrophy-14 (HLD14, loss, and vision loss. Patients often require
OMIM:610553) is a rare neurodevelopmental gastric tube feeding and ventilator support,
disorder that occurs due to homozygous and most die within the first year of life. Brain
pathogenic UFM1 gene variants on chromosome imaging shows hypomyelination with cerebral
13q13. The disease starts in early infancy and and cerebellar atrophy.1
is characterized by microcephaly, hypotonia,
Protein modification enables the regulation and
and cognitive and motor delay. In addition,
expansion of genetic information. Ubiquitination
most patients have spasticity, extrapyramidal
is a protein modification system in which single
movements, drug- resistant seizures, hearing
or multiple ubiquitin molecules are attached
to a protein and act as a signal transmitter
that controls various cellular functions.2 The
Aycan Ünalp
[email protected]
ubiquitin-like modifier (UFM-1) has structural
similarities to ubiquitin. UFM-1 can be linked
Received 1st June 2021, revised 15th August 2021,
accepted 12th September 2021. to substrate proteins as a monomer or a lysine-
linked polymer. UFMylation is a specialized
This study was presented online as a poster at the 22th
National Pediatric Neurology Congress, 28 October-1 ribosomal modification to facilitate metazoan-
November 2020. specific protein biogenesis in the endoplasmic

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Ünalp A, et al Turk J Pediatr 2022; 64(4): 747-753

reticulum and is essential for nervous plump cheeks, microcephaly, high palate,
system development and function. The post- simian line, fusiform fingers, axial hypotonia
translational modification of proteins on lysine with increased muscle tone on extremities,
residues has an essential role in several cellular and dystonia. Edematous appearance in the
processes.3,4 Defective UFMylation is thought to limbs was noted. Deep tendon reflexes were
be responsible for severe neurodevelopmental normoactive with no pathological reflexes and
problems in HLD14. Ketogenic diet therapy limited dorsiflexion of the feet. He could not
(KDT), which is frequently used for drug- hold his head up and had no eye-tracking.
resistant epilepsy, may also be beneficial for He had bilateral sensorineural hearing loss.
myelination disorders.5 Complete blood count, serum biochemistry,
thyroid functions tests, vitamin B12 level
Here we report a pediatric patient with a and creatine kinase level were within normal
rare leukodystrophy, HLD14, who had drug- limits. Electroneuromyography was normal.
resistant seizures and benefited from KDT. Echocardiography revealed a patent foramen
ovale. Electroencephalogram (EEG) showed
Case Report generalized spikes and polyspike and slow
waves creating burst activities with suppression
The patient, a three-year-old boy, was delivered periods and was interpreted as modified
by cesarean section in the 38th week of gestation. hypsarrhythmia (Fig. 1a). He had frequent
This was the mother’s third pregnancy. He seizures as spasms which did not respond to
was born to consanguineous parents, after an multiple antiepileptic drugs. Brain magnetic
uneventful pregnancy. He had two healthy resonance imaging (MRI) showed cerebellar
older siblings. He had a history of admission for atrophy, hypoplastic corpus callosum, and
16 days in the neonatal period due to respiratory periventricular white matter hypomyelination
distress. A tracheostomy and mechanical (Fig. 2a-b). Magnetic resonance spectroscopy did
ventilation were required at the age of six not reveal any specific metabolite concentration.
months, after which feedings were initiated Metabolic tests (serum ammonia, lactate,
with a nasogastric tube. The patient was using pyruvate, biotinidase activity, tandem mass
phenobarbital, levetiracetam, vigabatrin, spectrometry with carnitine and acylcarnitine
and vitamin B6 for his seizures. On physical profile, urine organic acids, plasma and urine
examination, the patient weighed 28 kg (+3 amino acids, levels of lysosomal enzymes) were
SDS), had dysmorphic facial features including unremarkable. He was admitted to the inpatient
sloping forehead, micrognathia, low ears and ward due to having seizures while on multiple

Fig. 1a. Electroencephalogram before ketogenic diet therapy showed generalized spikes and polyspike and
slow waves creating bursts with suppression periods and was interpreted as modified hypsarrhythmia.
1b. Electroencephalogram after ketogenic diet therapy demonstrated mild epileptiform activity in the
parietooccipital and temporooccipital regions of the right hemisphere.

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Turk J Pediatr 2022; 64(4): 747-753 A Case of Hypomyelinating Leucodystrophy-14

Fig. 2a. Brain MRI axial series showing white matter hypomyelination (white arrows). 2b. Brain MRI sagittal
T1W series showing cerebellar atrophy and hypoplastic corpus callosum (black arrows).

antiepileptic drugs. The patient’s seizures minutes. Figure 1b shows improved epileptic
were in the form of apnea, focal spasms, and discharges on EEG after KDT. The patient’s
generalized tonic seizures. A classic KDT with seizures decreased and vigabatrin treatment
a 3.5:1 ratio (ratio of grams of fat to grams of was tapered and discontinued in the follow-
carbohydrate plus protein) was introduced up. Whole-exome sequencing analysis revealed
with -one meal per day when the patient was a single homozygous deletion in the promoter
two years old. This was gradually increased, region of UFM1, which is c.-273-271 delTCA.
and multivitamins were added. The variant is classified as “pathogenic” based
Using the hydrolyzed milk formulae  (Pepti- on American College of Medical Genetics
Junior®), and a 4:1 ketogenic ratio formula and Genomics (ACMG) recommendations.6
(KetoCal®), meals of 50 kcal/day were prepared Via segregation analysis, both the patient’s
for the patient via a nasogastric tube. The parents and his healthy siblings were found
patient’s beta-hydroxybutyrate levels in to be heterozygous carriers. The patient was
the blood were measured and ketone levels diagnosed with HLD14.
were monitored. Values between 4-6 mmol/L
No significant side effects of KD developed
were accepted as normal, but the patient was
considered to have hyperketonemia because his during follow-up. The patient’s quality of
values were above 6 mmol/L. On the 10th day of life and that of his family increased with the
KDT, the ratio was decreased to 2.5:1 due to this control of his seizures. It was observed that
state of hyperketonemia. the patient started to smile, make sounds, and
had increased movements in his head, arms,
The patient’s seizure frequency was reduced and legs. The family stated that the care of the
by more than 75% with KD. Before KDT, the patient improved as hisspasticity and dystonia
patient had an average of two seizures per decreased on KD.
day with a duration of 3-5 minutes. After the
third month of KDT, his seizures decreased A written consent form was obtained from the
to two times per week with a duration of 2-3 parents for publication purposes.

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Ünalp A, et al Turk J Pediatr 2022; 64(4): 747-753

Discussion neurodevelopment and neurodegeneration

via UFM1.8 Most evidence points to the role of
HLD14 is a severe neurodevelopmental UFM1 in endoplasmic reticulum homeostasis
disorder with autosomal recessive inheritance
and protection against apoptosis.9
in which most patients develop drug-resistant
epilepsy. Impairment of post-translational Muona et al.10 found that reducing the gene
protein UFMylation is thought to be responsible expression of UFM1 in the mouse brain resulted
for severe neurodevelopmental problems.1 in death on the first day of life. Postmortem
examination revealed microcephaly and
Hamilton et al.1 identified 16 pediatric
increased neuronal apoptosis markers in
patients with brain MRI findings suggesting
specific brain regions. They suggested that
hypomyelination with atrophy of the basal
infiltration could be spatially regulated and cell
ganglia and cerebellum (H-ABC) who have
type-specific; only selective neural cell lines are
a severe clinical phenotype with epileptic
vulnerable to promoter mutation.10 Available
encephalopathy and developmental delay.
data show that the UFM1 system is vital for
Similar to our patient, they found homozygous
neuronal development and function.2,11
pathogenic variants of the UFM1 gene in
these patients. All of their patients had severe Epilepsy is characterized by recurrent
clinical phenotype consisting of epileptic unprovoked seizures and is associated with
encephalopathy with early death.1 the involvement of neurons in the gray matter.
Early or resistant seizures can occur but are an
Nahorski et al.3 reported four children with a
homozygous missense mutation in the UFM1 unusual feature of disorders mainly affecting
gene from two related families with HLD14. brain white matter.12 While the focal onset and
Three of the patients died before the age of two. bilateral tonic-clonic seizures are more common
The patients presented with hyper or hypotonia, in some cohorts, generalized tonic-clonic,
malnutrition, and severe global developmental infantile spasm, and myoclonic seizures have
delay in infancy. They developed resistant also been reported.13-15
seizures in the first weeks or months of life, In a study conducted on patients with
and EEG showed hypsarrhythmia in two
leukodystrophy, the incidence of epilepsy
siblings. The patients had poor overall growth
was reported to be 49%. The incidence of
with secondary progressive microcephaly
epilepsy varies among different types of
and peripheral edema. Similarly, our patient
leukodystrophies and was found to occur more
had cerebellar atrophy, hypoplastic corpus
frequently in leukodystrophies classified as
callosum, and extensive periventricular white
astrocytopathy, compared to myelin diseases.
matter hypomyelination on brain imaging.
This finding is likely due to the role that
A new post-translational protein modification astrocytes play in the pathogenesis of epilepsy.
known as ubiquitination is a modification When astrocyte dysfunction occurs, it impairs
system in which single or multiple ubiquitin its extracellular glutamic acid and K+ elimination
molecules are attached to a protein, acting ability leading to extracellular accumulation of
as a signal transmitter that controls various glutamic acid and K+, thereby increasing the
cellular functions.7 The ubiquitin-like modifier excitability of neurons and inducing seizures.16
(UFM1) is a ubiquitin-like protein regulator Zang et al.17 also found leukodystrophies with
and is required for embryonic development. early subcortical involvement of white matter
Ubiquitin and UBL pathways play a role in were more prone to epilepsy than other types of
controlling multiple functions, including leukodystrophy. This may suggest subcortical
signal transduction, transcriptional regulation, white matter involvement is likely to affect
and stress response.2 Various studies show neighboring neurons in the cerebral cortex and
that there is a relationship between both can lead to epilepsy.

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Turk J Pediatr 2022; 64(4): 747-753 A Case of Hypomyelinating Leucodystrophy-14

Since our patient had epileptic encephalopathy growth.19 Therefore, it has been questioned
and his seizures could not be controlled despite whether a KD that supports CNS lipid
the use of three antiepileptic drugs, he was metabolism may be useful in hypomyelinating
considered to have drug-resistant epilepsy. disease.20,21 Unlike glucose, ketone bodies are
Thus, the decision was made to pursue KDT directly metabolized by the mitochondria,
with a ketogenic formula. The patient and his entering the tricarboxylic acid and oxidative
family were extremely compliant with the diet. phosphorylation pathways. It was thought that
As the patient had swallowing dysfunction feeding using the KD would provide direct
due to generalized muscle weakness, he was support for demyelinating axons by providing
fed with a nasogastric tube. Gastrostomy was mitochondrial integrity.5 Bypassing the need
not found to be appropriate due to his high for oligodendroglial support can correct axonal
weight. Since it was stated that subcutaneous mitochondrial functions (and morphology)
adipose tissue increased due to obesity and and correct energy deficits in the axons. It may
percutaneous endoscopic gastrostomy could even contribute to improved survival of mutant
not be done, his calorie intake was reduced to oligodendrocytes and improvement of PMD
40 kcal/day in the follow-up. pathology. The KD may be considered a future
treatment for myelin diseases. Its two critical
Lipids have an essential role in the normal
therapeutic goals are to provide cholesterol for
functioning of neurons and the structural
development of the brain. Neurodegenerative support of remyelinating oligodendrocytes and
diseases involve dysregulated lipid metabolism. to provide ketone bodies for metabolic support
In the central nervous system (CNS), of axons, and future clinical trials will reveal its
most of the myelin’s lipids are synthesized feasibility.5
by oligodendrocytes. Pelizaeus-Merzbacher Since our patient also had leukodystrophy, our
disease (PMD) is a fatal, untreatable, decision to use classic KD could have been more
hypomyelinating leukodystrophy. In PMD, appropriate because this option creates more
brain lipid metabolism is often disrupted
ketosis than the medium-chain triglyceride
as a result of the X-linked myelin gene
(MCT) KD, which is important for both seizure
PLP1 (proteolipid protein 1) duplication.
control and mitochondrial integrity in myelin
Overexpression in the PLP gene induces
diseases. As mentioned above, the effect of KDT
endoplasmic reticulum stress, damaging the
in hypomyelinating diseases is not directly
oligodendroglial trophic support on axons.
caused by an increase in lipids, but indirectly
Chronic injury leads to demyelination.7
by an increase in ketosis and an improvement
Unmyelinated axons need more energy to
in mitochondrial functions.
deliver the transmission, causing cells to
increase mitochondrial activity to produce this In conclusion, we emphasize that KDT should
required energy. Demyelination stimulates the be considered as a treatment option in this rare
inflammatory response, leading to increased leukodystrophy for drug resistant seizures.
reactive oxygen and nitrogen production.18
It has been shown in vitro and in vivo that
lipid supplementation increases myelination Ethical approval
in hypomyelinating pathologies and thus
A written consent form was obtained from the
supports repair.19
parents for publication purposes.
Consumption of a high-fat / low-carbohydrate
KD causes the liver to form ketone bodies. Author contribution
In the brain, ketone bodies such as beta-
hydroxybutyrate facilitate sterol synthesis, The authors confirm contribution to the paper
which is essential for myelin membrane as follows: study conception and design: AÜ,

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Ünalp A, et al Turk J Pediatr 2022; 64(4): 747-753

PK, YG; data collection: AÜ, MK, ÜY; analysis 7. Komatsu M, Chiba T, Tatsumi K, et al. A novel
and interpretation of results: AÜ, YG, PK; draft protein-conjugating system for Ufm1, a ubiquitin-
fold modifier. EMBO J 2004; 23: 1977-1986. https://
manuscript preparation: AÜ, YG. All authors doi.org/10.1038/sj.emboj.7600205
reviewed the results and approved the final
8. Homrich M, Wobst H, Laurini C, Sabrowski J,
version of the manuscript.
Schmitz B, Diestel S. Cytoplasmic domain of
NCAM140 interacts with ubiquitin-fold modifier-
conjugating enzyme-1 (Ufc1). Exp Cell Res 2014; 324:
Source of funding 192-199. https://doi.org/10.1016/j.yexcr.2014.04.003

The authors declare the study received no 9. Lemaire K, Moura RF, Granvik M, et al. Ubiquitin
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protect pancreatic beta cells from ER stress-induced
apoptosis. PLoS One 2011; 6: e18517. https://doi.
org/10.1371/journal.pone.0018517
Conflict of interest
10. Muona M, Ishimura R, Laari A, et al. Biallelic
The authors declare that there is no conflict of variants in UBA5 link dysfunctional UFM1
interest. ubiquitin-like modifier pathway to severe infantile-
onset encephalopathy. Am J Hum Genet 2016; 99:
683-694. https://doi.org/10.1016/j.ajhg.2016.06.020
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