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Paediatric Neurology and Muscular Disease Unit, IRCCS Istituto Giannina Gaslini, Genoa, ItalyDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
Paediatric Neurology and Muscular Disease Unit, IRCCS Istituto Giannina Gaslini, Genoa, ItalyDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
The YWHAG gene (OMIM∗ 605,356) resides on Chr 7q11.23 and encodes the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (14–3–3γ), which is highly expressed in the brain. This protein regulates neuronal migration and its abnormal activity may cause morphological defects in the developing cortex. The scientific interest in the YWHAG gene firstly started in 1999, when the clinical influence was presumed due to the YWHAG location at the most telomeric end of the deletion region founded in Williams–Beuren syndrome (WBS) [
In recent years, only 14 subjects were described carrying de novo variants in YWHAG gene and epilepsy, basically recognized as developmental and epileptic encephalopathy (DEE) (Table 1).
Table 1Phenotypic features of our case compared to patients from the literature.
This report
Stern T et al. Am J Med Genet A 2021
Ye XG et al. Frontiers in Genetics 2021
Kim SY et al. Clinical Genetics 2021
Kanani F et al. Am J Med Genet A 2020
Guella I et al. American Journal of Human Genetics 2017
N° of pts
1
1
2
1
6
4
Gender
F
M
F
M
M
F
M
M
M
F
F
F*
F
F
F
Ethnicity
Italian
Ashkenazi Jewish
Chinese
Korean
Chinese
na
na
na
na
na
na
na
na
na
na
Age at last FU (y)
5
5
3
na
3
15
16
7
4
10
7.5
23
18
16
10
Sz onset (mo)
24
9
7
na
19
10
192
24
24
<60
na
<6
12
<72
6
Sz types
Myoclonic sz
Absences, myoclonic sz, focal-onset sz
Febrile sz, myoclonic sz
Febrile and afebrile GTC sz (DS)
Febrile sz, myoclonic sz
Absences, focal-onset and GTC sz
Isolated GTC sz
Absences
GTC sz
Frontal lobe sz
Absences
Absences, GTC and generalized myoclonic sz
Atypical absences, myoclonic and GTC sz
Absences, myoclonicsz, eyelid myoclonia
Focal-onset motor sz (febrile)
EEG findings
Generalized spike waves time-locked with myoclnic event
Generalized spike waves with bilateral frontal predominance
Generalized irregular polyspike-and-slow waves
na
Generalized spike-and-slow waves
na
na
Prolonged burst of generalized 2.5 Hz spike and wave activity
na
na
Normal
Generalized polyspike wave and slow wave discharges
Dysrhytmic background,sharp waves in bianterior quadrants
Bilateral fronto-temporal spike-waves
na
ASMs tested
VPA
VPA, LEV
VPA
na
VPA
LEV, ESM
None
VPA, LTG, ESM
VPA
VPA, CBZ
None
VPA, STP
CLZ, LTG, VPA, ESM
VPA, LTG
VPA
Treatment resistant?
No
No
No
na
No
No
na
No
No
No
na
No
No
No
No
Speech/Language
Normal
Normal
Normal
na
Normal
Normal
Normal
Delayed, echolalial
Mildly delayed
Mildly delayed
Delayed
Delayed
Delayed
na
na
Developmental delay
Mild Global
No
No
Global
No
Moderate global
Global
Global
Mild global
Global
Mild global
Moderate-severe
Mild-moderate
Mild
Global
Intellectual disability
X
No
No
na
No
Mild-moderate
Mild-moderate
Moderate
Mild
Moderate
Mild-moderate
Moderate
Mild-moderate
Mild
Mild-moderate
ASD
No
No
No
na
No
Yes
Yes
Yes
No
No
No
Yes
No, but ADHD
na
na
Dysmorphisms
Prominent forehead and spaced teeth
No
No
na
No
Down slating palpebral fissures, upturned nose, absent Cupid's bow, small ears, prominent forehead
Ptosis, down slating palpebral fissures, downturned corners of mouth
Upturned nose with thickened alae nasi, wide mouth
No
Upslanting palpebral fissures, short columella, broad mouth
We would like to share our experience with the description of a previously unreported YWHAG mutation in a patient with a mild phenotype.
2. Case report
We report on a 5-year-old female, born from healthy unrelated parents. Developmental milestones were normally achieved until 2 years of age when the onset of myoclonic seizures with normal interictal background EEG and no auditory-tactile stimuli reflex was documented. Epileptic myoclonias were seen during wakefulness, but also during drowsiness and in the lighter stages (N1 and N2) of the N-REM sleep state (Fig. 1). Myoclonic events were more evident in the eyelids, neck and forearms. Spontaneous generalized discharges were not always accompanied by clinical manifestations. EEG-video with polygraphic recording confirmed generalized epileptic spikes time-locked with sudden, brief, synchronous upper limbs jerks and deltoids EMG dischareges (Fig 1). Biochemical investigations were scarcely contributory. Conventional Magnetic Resonance Imaging (MRI) 1.5 Tesla was normal.
FIG. 1EEG with polygraphic recording of deltoids muscles (EMG1: right; EMG2: left), awake (A) and during drowsiness (B), showed spike-waves discharges time-locked with shock-like events of both arms and brief synchronous EMG bursts.
Seizures transiently ceased within two months with valproic acid monotherapy. After one year of follow-up, the girl experienced polymorphic focal-onset seizures with impaired awareness interspersed between long seizure-free periods (range, 3–6 months); during these latter periods, hyperactivity was noticed.
Motor developmental milestones were achieved in the upper limit of a normal age range (sitting position at 8 months, able to walk alone at 18 months) despite normal skills in language development.
On the other hand, the Griffith Mental Development Scales III documented a global developmental delay (general age-equivalent scores of 38 months instead of the 57 months chronological age) and showed widespread weaknesses in all developmental areas, even if motor skills were less compromised than language and communication (age-equivalent scores: Locomotor 42 months, Personal-Social 40 months, Hearing and Language 35 months, Eye and Hand Coordination Performance 38 months, Practical Reasoning 39 months).
Initial genetic investigations comprising next-generation sequencing (NGS) epilepsy panel and Array-CGH were inconclusive.
The exome sequencing (ES), using NGS (NextSeq 550 Illumina), identified a de novo mutation c.304del on exon 2. This frameshift mutation leads to an early protein synthesis termination (p.Ser102Alafs*7). Genetic data analysis was performed with Sentieon and VarSeq (V2.1.0) software. In silico variant prediction tools such as SIFT, PolyPhen, MutationTaster were used to assist with variant classification. Finally, pathogenicithy of the variant was confirmed with bidirectional Sanger sequencing and it was classified as pathogenic according to the American College of Medical Genetics (ACMG) criteria [
ACMG laboratory quality assurance committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology.
]. Only in two papers was recognized a milder phenotype with myoclonic epilepsy in three unrelated families (Table 1).
Our case supports the hypothesis of an epilepsy spectrum ranging from mild myoclonic epilepsy or febrile seizures up to severe DEE. Moreover, as depicted, myoclonic seizures could initially lead to a challenging diagnosis, misleading towards self-limited infantile seizures, although our case documented specific polymorphic seizures without auditory-tactile reflex and flares despite anti-seizure medication therapy [
]. We therfore hypotize a hierarchical continuum of learning disability rather than distinct entities being the most frequent pattern represented by a specific cognitive profile with motor skills less compromised than language and communication. Our case confirms the hypothesis of a mild phenotype with mioclonic epilepsy and neurodevelopmental delay even in the case of epilepsy-related to YWHAG mutation.
Case Report written following the CARE guidelines
Declaration of Competing Interest
All authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence the work. The work described has not been published previously and it is not under consideration elsewhere. None of the authors has any conflict of interest to disclose.
ACMG laboratory quality assurance committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology.
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