EEF2-Related Neurodevelopmental Disorder Is Clinically Recognizable

Abstract

Introduction

EEF2 encodes eukaryotic elongation factor 2 which catalyzes the elongation phase of protein translation. It is ubiquitously expressed and important for neuronal function. EEF2 was first associated with adult-onset spinocerebellar ataxia type 26 (SCA26). A novel neurodevelopmental disorder associated with de novo heterozygous variants in EEF2 has been described. Only 6 patients have been described in the literature thus far. A 9-year-old child with de novo novel missense variant is described here. EEF2-related neurodevelopmental disorder appears to be clinically recognizable.

Case Presentation

A nine-year-old male with autism spectrum disorder was referred for genetic evaluation. On examination, he had relative macrocephaly and frontal prominence. Whole exome sequencing revealed a de novo c.1225 C>T: p. (R409W) variant in exon 9 of the EEF2 gene (NM_001961.3).

Discussion

A comparison of clinical findings suggests that relative macrocephaly/macrocephaly and prominent forehead are consistent and easily identifiable clinical features of EEF2-related neurodevelopmental disorder. The clinical spectrum of this disorder is still emerging. EEF2-related neurodevelopmental disorder should be considered in a child with autism, developmental delays/intellectual disability, macrocephaly/relative macrocephaly, and frontal prominence.

Established Facts

• EEF2-related neurodevelopmental disorder is associated with developmental delays/intellectual disability and autism.

• Macrocephaly or relative macrocephaly is usually present.

Novel Insights

• A nine-year-old male child is described here with EEF2-related neurodevelopmental disorder.

• This is the seventh patient with EEF2-related neurodevelopmental disorder.

• EEF2-related neurodevelopmental disorder is clinically recognizable by the findings of macrocephaly/relative macrocephaly, and frontal prominence.

Introduction

Dysregulation of protein translation is an important etiology of pediatric and adult neurological disorders. Protein translation consists of 4 steps: initiation, elongation, termination, and ribosome recycling. These steps are coordinated and catalyzed by different translation factors. EEF2 encodes eukaryotic translation elongation factor 2 (eEF2) which catalyzes the elongation phase of protein translation [1]. Due to its vital role in protein synthesis, it is ubiquitously expressed and evolutionally conserved. Neurons rely heavily on local translation to maintain synaptic proteome [2, 3]. Hence, a translational defect may lead to a neurological disorder [4]. A recurrent pathogenic variant p.P596H in EEF2 (OMIM: 130610.0001) is associated with adult-onset spinocerebellar ataxia type 26 (SCA26) [5]. A novel neurodevelopmental disorder (NDD) associated with de novo heterozygous variants in EEF2 has been described [6]. Only 6 patients have been described thus far [6–8]. We recently diagnosed the seventh patient, a 9-year-old male, with this condition. A comparison of clinical and genetic findings of all individuals described in the literature with this NDD is presented here.

Case Report

A nine-year-old male with autism spectrum disorder was referred for genetic evaluation. He was formally diagnosed with autism at 8 years old due to his poor eye contact and social isolation. He acquired developmental milestones on time, except for language milestones. He needed speech therapy for language delays during early childhood. Currently, he is in the fourth grade and has an individualized education plan. He does well in mathematics but needs special assistance in reading and writing. Family history is significant for the diagnosis of Charcot Marie Tooth (CMT) disease in his paternal grandfather. It is unclear if a molecular diagnosis of CMT was made.

On examination, his weight was 25.1 kg (10th centile), length was 133 cm (28th centile), and head circumference was 53.5 cm (68th centile). The head appeared large compared to the body size. There was frontal prominence (Fig. 1). Due to relative macrocephaly and prominent forehead, fragile X syndrome was clinically suspected. FMR1 assay showed normal repeat number, ruling out fragile X syndrome. Chromosome microarray was normal. Whole exome sequencing revealed a de novo c.1225 C>T: p.R409W variant in exon 9 of the EEF2 gene (NM_001961.3). This variant was not found in large population cohorts (gnomAD database v4.0.0) [9]. In silico prediction tools support deleterious nature of this variant (MutScore- 0.887; AlphaMissense-0.993), and it fulfills the supporting pathogenic (PP3) criteria per ACMG variant classification guidelines [10].

Fig. 1.

Frontal facial profile of the child.

Discussion

EEF2 encodes eukaryotic translation elongation factor 2 (eEF2), an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was first identified in association with autosomal dominant adult-onset spinocerebellar ataxia-26 (SCA26) [5]. It is characterized by progressive gait imbalance, upper limb incoordination, dysarthria, normal cognition, and isolated cerebellar atrophy on neuroimaging [11]. This late onset and slowly progressive disorder highlights the role of eEF2 in mediating synaptic plasticity and neurotransmission at synaptic junctions [12]. eEF2 pathway also plays a significant role in neurogenesis in the dentate gyrus of the hippocampus and is thus implicated in learning and memory [13]. A heterozygous Eef2 mouse model showed reduction of protein synthesis in the excitatory neurons of the prefrontal cortex and exhibited defective social behavior and elevated anxiety [14]. In line with these known functions of eEF2 and its role in cognition, memory, and social behavior, a NDD due to heterozygous de novo EEF2 variants has been recently described. Only six individuals have been described thus far. The common findings of this NDD are developmental delays, autism spectrum disorder, relative macrocephaly, and facial dysmorphism. All except one had de novo heterozygous missense variant, while one individual was reported with a de novo nonsense variant [7]. Our patient has de novo heterozygous missense variation, like most individuals with this condition. This variant has not been reported to be benign- or disease-causing in the literature or gnomAD database. However, a missense variant (c.1225 C>G) at the same position resulting in arginine to glycine substitution has been reported in one individual in the gnomAD database. The novel variation (c.1225 C>T) found in our patient causes arginine to tryptophan substitution at amino acid 409. MutScore, which is a newly developed pathogenicity predictor tool for missense variants, gives it a high score of 0.887. MutScore analysis is based on qualitative changes of the DNA substitution and positional clustering and has been shown to be particularly efficient for autosomal dominant conditions [15]. AlphaMissense which is another pathogenicity predictor tool for missense variants based on the impact of missense variation on protein structure and folding, also gives it a very high score of 0.993 [16]. Both of these prediction tools score missense variants on a scale of 0–1, where 1 is the maximum likelihood of pathogenicity. A comparison of pathogenicity scores as well as clinical and genetic findings of the individuals with EEF2-related NDD is presented in Table 1.

Table 1.

Clinical features and genetic findings of the patients with EEF2-related neurodevelopmental disorder

Patient	Our patient	Guo et al., 2023 [7]	Guo et al., 2023 [7]	Zhao and Mata-Machado, 2022 [8]	Nabais et al., 2021 [6]	Nabais et al., 2021 [6]	Nabais et al., 2021 [6]
Genotype	c.1225 C>T	c.82G>A	c.433C>T	c.2207C>T	c.82G>A	c.1163G>A	c.2305C>T
	p.R409W	p.V28M	p.Q145X	p.A736V	p.V28M	p.C388Y	p.H769Y
Inheritance	De novo	De novo	De novo	De novo	De novo	De novo	De novo
MutScore	0.887	0.723	NA	0.587	0.723	0.959	0.361
AlphaMissense	0.993	0.999	NA	0.984	0.999	0.999	0.502
Age at presentation	9 years	7 years	15 months	8 years	3 years	6 years	6 years
Gender	Male	Male	Female	Male	Male	Male	Male
Weight (centile/z-score)	25.1 kg (10th centile)	18.2 kg (1.5th centile)	9.6 kg (47th centile)	Obese BMI 99.4th centile	18 kg (85th centile)	19 kg (25th centile)	15.5 kg (Z = −2.2)
Length (centile/z-score)	133 cm (28th centile)	110.7 cm (Z = −2.43)	78 cm (53rd centile)	Tall stature	101 cm (50th centile)	111 cm (20th centile)	102 cm (Z = −2.5)
Head circumference (centile/z-score)	53.5 cm (68th centile)	53 cm (50–75th centile)	50 cm (Z = 3.08)	Unknown	52 cm (85–97th centile)	52.7 cm (80th centile)	52.3 cm (75th centile)
Motor delays	No	+	+	+	+	+	+
Speech delays	+	+	+	+	+	+	+
Behavioral issues	Autism spectrum disorder	Autism spectrum disorder	None described	Attention deficit hyperactivity disorder	None described	Autism spectrum disorder	None described
Distinct facial features	Relatively large head, prominent forehead, midfacial hypoplasia, deeply set eyes	Relatively large head, prominent forehead, midfacial hypoplasia, right microphthalmia	Relatively large head, prominent forehead, depressed nasal bridge, broad nasal tip, low columella, thin upper lip	–	Relatively large head, prominent forehead	Relatively large head, prominent forehead	Relatively large head, prominent forehead
		Small palpebral fissures, deeply set eyes, long philtrum, thin upper lip, low set ears
Neurologic abnormality	None described	None described	hypotonia	Balance issue, impaired tandem gait, dysmetria	Hypotonia, unsteady gait, high stepping	Poor motor coordination	None described
Neuroimaging	Not available	Mildly increased extraaxial fluid	Benign enlargement of ventricles and extra axial spaces	Slightly prominent retrocerebellar fluid	Enlargement of ventricles, diffuse thinning of corpus callosum, left temporooccipital focal dysplasia	Enlargement of ventricles and extra axial spaces	Enlargement of ventricles and extra axial spaces
Other medical issues	None	Right eye coloboma of iris and retina, left eye morning glory disc anomaly	Keratosis pilarisSparse eyebrows	Obesity	StrabismusFine sparse scalp hair, sparse eyebrows, hypoplastic and dystrophic toenails	Fine sparse scalp hair, brittle and fast-growing toenails	Fast-growing hairs and nails, hypoplastic nails of 5th toes
		Eczema					Short stature, failure to thrive
		Failure to thrive, gastrostomy tube feeding

cm, centimeters; kg, kilograms; +, present; NA, not applicable.

Macrocephaly/relative macrocephaly and prominent forehead appear to be the most consistent clinical features. Our patient was clinically suspected to have fragile X syndrome due to a relatively large head and prominent forehead. However, the fragile X repeat assay was normal. Speech delay is another common feature of this disorder. Autism/autistic behavioral trait is described in 3 of 7 patients. Our patient was referred to genetics after his diagnosis of autism. It appears that EEF2-related neurodevelopmental disorder may present as isolated autism spectrum disorder. Physical examination findings of relative macrocephaly and prominent forehead should alert the health care provider to the possibility of this condition. There is a well-known association of macrocephaly/relative macrocephaly with autism [17]. A subset of those with autism and large head has mutation in the gene “phosphatase and tensin homolog (PTEN).” With frequent use of whole exome sequencing in the evaluation of autism, many more individuals in this subcategory will likely be diagnosed with EEF2-related NDD.

Benign external hydrocephalus and enlarged ventricles are the frequent neuroimaging findings of EEF2-related NDD. Diffuse thinning of the corpus callosum has been reported once. Hypotonia, gait issues, balance, or coordination problems have been reported in 4 patients. It may be due to cerebellar involvement as in the EEF2-related SCA26. Apart from macrocephaly/relative macrocephaly and frontal prominence, other reported craniofacial features are mid facial hypoplasia, depressed nasal bridge, broad nasal tip, low columella, thin upper lip, and low-set ears. Strabismus was present in 1 patient, while 1 patient had microphthalmia, small palpebral fissures, coloboma, and optic disc anomaly. Thin sparse scalp hair, hypoplastic dystrophic nails, fast-growing hair and nails, eczema, and keratosis pilaris are the ectodermal findings associated with EEF2-related NDD. Finally, failure to thrive and short stature is reported in 2 patients.

The clinical spectrum of this disorder is still emerging. Relative macrocephaly/macrocephaly and prominent forehead are the most consistent and easily identifiable features. Like PTEN, EEF2 should be considered in a child with autism, developmental delays, macrocephaly/relative macrocephaly, and frontal prominence. Neuroimaging findings of enlarged ventricles and external hydrocephalus could also point towards this diagnosis. Hypotonia, cerebellar signs, and ectodermal findings could be additional clinical clues.

Acknowledgments

The authors would like to acknowledge Jessica Pugh, Carla Swanson, Paige Snyder, and Nicole Matthews from the division of Genetics at West Virginia University Medicine for their continuous support to this patient and his family.

Statement of Ethics

This report is a retrospective clinical observation. Ethical approval was not required for this study in accordance with local/national guidelines. Written informed consent was obtained from the parents for publication of the details of their child’s medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors have no funding to declare.

Author Contributions

Pankaj Prasun has drafted the initial and subsequent versions of the manuscript and was involved in patient care, laboratory interpretation, and counseling. Kamakhya Patra has revised the article for important intellectual content.

Funding Statement

The authors have no funding to declare.

Data Availability Statement

Data sharing is not applicable to this article as no new datasets were created or analyzed in this study.