eIF5A and hypusination-related disorders: literature review and case report of DOHH-related encephalopathy.

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Álvaro Beltrán-Corbellini, Adrián Valls-Carbó, Rafael Toledano, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3837969/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Aug, 2025 Read the published version in Journal of Neurodevelopmental Disorders → Version 1 posted 5 You are reading this latest preprint version Abstract Background Eukaryotic initiation factor 5A (eIF5A) and hypusination-related disorders (eIF5A-HRD) are recently described diseases caused by pathogenic heterozygous variants in the translation factor EIF5A or biallelic variants in the two enzymes involved in the post-translational synthesis of hypusine in the eIF5A precursor, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), necessary for its activation. We review the current knowledge regarding eIF5A-HRD, and report the case of the sixth and oldest known patient with DOHH-related disorder (DOHH-D), aiming to expand and discuss the molecular basis and the general and epilepsy phenotypes of this group of diseases. Results Literature review yielded one paper describing 7 individuals with eIF5A-related disorders (eIF5A-D), one reporting 5 subjects with DHPS-related disorders (DHPS-D) and one characterizing 5 individuals with DOHH-D. Main phenotypic features consisted of prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-severe neurodevelopmental disorders/intellectual disability and behavioral disorders. We report the case of a 24-years-old male with DOHH-D manifesting as Dravet-like syndrome. He displays microcephaly and neurodevelopmental delay with attention deficit with hyperactivity disorder, along with a happy demeanor. Basic language skills and ambulation capacity with crouch gait are preserved. Onset of epilepsy was at 8 months with refractory temperature-triggered hemiclonic seizures and status epilepticus , followed by nocturnal tonic-clonic seizures from adolescence. Fenfluramine was the most effective approach, reducing seizure intensity, duration and frequency, and contributing to cognitive and behavior improvements. No patient with eIF5A-D presented seizures. Taking our patient into account, 4/5 and 4/6 reported individuals with DHPS-D and DOHH-D, respectively, presented epilepsy. Seven out of 8 epilepsy patients debuted between 2 and 5 years, most of them presented developmental and epileptic encephalopathies or generalized epilepsies (5/8 with temperature or infection-triggered seizures), and 4/8 were refractory. We hypothesize that dysregulation of PRRT2 and EEF2K might contribute to the eIF5A-HRD phenotype. Conclusions eIF5A-HRD are recently described entities displaying neurodevelopmental disorders and microcephaly, and reported patients are scarce. More than 70% of DHPS-D and DOHH-D patients present epilepsy, 63% of them with temperature-triggered seizures. Valproic acid or fenfluramine may be effective. Rare homozygous or compound heterozygous missense variants in these genes should be screened in patients with encephalopathy and temperature-triggered seizures. eukaryotic translation factors DOHH DHPS EIF5A developmental and epileptic encephalopathy refractory epilepsy febrile seizures Dravet Syndrome fenfluramine Background Eukaryotic translation initiation factors (eIF) are a group of at least 12 proteins regulating global messenger RNA translation, along with eukaryotic translation elongation (eEF) and termination factors (eTF) 1 . These proteins display a direct role in cell physiology, development and response to stress, and its dysregulation has been linked to cancer, neurological and metabolic disorders 2 , 3 . Eukaryotic initiation factor 5A (eIF5A) and hypusination-related disorders (eIF5A-HRD) are recently-described diseases caused by variants in the genes coding for eIF5A or the enzymes involved in the post-translational synthesis of hypusine in the eIF5A precursor, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), necessary for its activation. eIF5A, is a key translation factor for cell proliferation and differentiation, apoptosis, autophagy, and development in eukaryotes 4 . eIF5A has been related to disorders such as cancer 5 , diabetes 6 or retroviral infections 7 . De novo heterozygous variants in EIF5A (MIM # 600187) have been associated to neurodevelopmental disorder with microcephaly, the Faundes-Banka syndrome (MIM # 619376), in 7 patients 8 . Bi-allelic loss-of-function variants in DHPS (MIM # 600944) have been also associated to neurodevelopmental disorder with microcephaly and epilepsy (MIM # 618480) in 5 individuals 9 . Most recently, Ziegler et al. have described bi-allelic loss-of-function variants in DOHH (MIM # 611262) in 5 individuals with similar neurodevelopmental disorder with microcephaly and epilepsy (MIM # 620066) 10 . The genotypic and phenotypic characterization of these conditions is still in its initial steps. In this work, we review the current knowledge regarding eIF5A-HRD, and report the case of a patient with DOHH-related disorder (DOHH-D) manifesting as a fenfluramine-responsive Dravet-like syndrome. We aim to expand and discuss the molecular basis and the phenotype of this group of diseases, and to better define the epilepsy features of patients with eIF5A-HRD. Methods A literature review was carried out, including the following descriptors in the thesaurus of MEDLINE: “eukaryotic translation factor, EIF5A, DHPS, DOHH, neurodevelopmental disorder, epilepsy, febrile seizures, Dravet syndrome and fenfluramine”. Articles in English and Spanish up to February 2024, along with their references, were included and screened by a team of neurologists with expertise in neurodevelopmental disorders and genetics. With respect to the case report, trio-exome sequencing (T-WES) was performed by BluePrint Genetics. Variants were described according to the Human Genome Variation Society nomenclature recommendations. Phenotypic characteristics were collected from the patient’s medical records, and seizure data were assessed from diaries filled out by the patient’s parents. Results Literature review yielded just one original paper describing 7 individuals with eIF5A-related disorders (eIF5A-D), one reporting 5 subjects with DHPS-related disorders (DHPS-D) and one characterizing 5 individuals with DOHH-D. Table 1 details the phenotypic and genotypic features of our patient in comparison to the rest of patients reported with eIF5A-D, DHPS-D and DOHH-D. Table 1 Modified from Ziegler et al 10 . General phenotype of patients diagnosed with eIF5A and hypusination-related disorders. DOHH-D (Beltrán-Corbellini et al.) N = 1 DOHH-D (Ziegler et al. 7 ) N = 5 DHPS-D (Ganapathi et al. 6 ) N = 5 EIF5A-D (Faundes V, et al. 5 ) N = 7 Gender Male 2/5 females 4/5 females 4/7 females Variants Homozygous for c.455C > T, p.(Pro152Leu) Ethnicity: Spanish (pat), Spanish (mat) 7 variants: one stop gain, two frameshift, 4 missense; compound heterozygous 4 variants: 1 missense, one start loss, one splice, one inframe deletion; compound heterozygous 7 variants: 5 missense, 1 stop gain, 1 frameshift; de novo heterozygous Prenatal Mat. hypertension 2/5 cardiac malformation 4/5 preeclampsia 5/6 (4 IUGR, 1 fetal ascites) Gestational age 39 weeks 0/5 preterm or postterm 2/5 preterm N/S Neonatal Poor feeding 2/5 poor feeding, 1/4 temperature instability, 3/5 hypotonia 1/5 premature instability 3/7 poor feeding Birth weight 3.100 Kg (-0.58 SD) 0/5 underweight 0/5 underweight 3/7 underweight Birth lenght 51 cm (+ 0.33 SD) 0/5 short stature 0/4 short stature 3/7 short stature Birth HC 36 cm (+ 1.03 SD) 0/3 congenital microcephaly 0/3 congenital microcephaly 3/7 congenital microcephaly Height or lenght at last evaluation 178 cm (normal stature) 4/5 short stature 2/5 short stature 2/7 short stature Weight at last evaluation 52.5 Kg (BMI 16.5, underweight) 4/4 underweight 0/5 underweight 2/7 underweight HC at last evaluation 50 cm (< 2 SD, microcephaly) 4/4 microcephaly 3/4 microcephaly 5/7 microcephaly Sitting/walking/speaking Yes/Yes/Yes 3/5 sitting, 3/5 walking, 1/5 speaking 5/5 sitting, 5/5 walking, 2/5 speaking 6/7 sitting, 6/6 walking, 6/6 speaking Sitting 9 months Walking 18 months Speaking 3 years Intellectual disability Yes 5/5 5/5 7/7 (1 mild) Behavioral Happy demeanor, ADHD 3/5 happy demeanor 1/5 autism, hand flapping 3/5 2/7 autism, 1/7 ADHD Epilepsy Yes 3/5 4/5 0/7 Tonus Hypotonia 5/5 hypotonia 4/5 hypotonia, 1/5 spasticity 1/5 hypotonia Brain MRI Normal 5/5 abnormal, 4/5 cortical atrophy 4/4 normal 2/2 normal Cardiac malformation No 3/5 0/5 3/4 Visual impairment No 3/5 nystagmus, 1/4 cortical visual impairment 0/5 3/7 strabismus, 1/7 glaucoma Recurrent infections No 3/5 1/5 0/7 DOHH-D: DOHH-related disorders; DHPS-D: DHPS-related disorders; EIF5A-D: EIF5A-related disorders; pat: paternal; mat: maternal; IUGR: intrauterine growth restriction; Kg: kilograms; SD: standard deviation; cm: centimeters; HC: head circumference; ADHD: attention deficit with hyperactivity disorder. Place for Table 1 . eIF5A-related disorders eIF5A is key for synthesizing bonds between successive proline residues resolving ribosomal stalling in eukaryotic cells 11 , among other functions. Increased somatic expression of EIF5A had been related to several cancers 12 . However, germline de novo heterozygous variants in EIF5A have been associated to neurodevelopmental disorder with microcephaly in up to 7 patients 8 . Faundes et al 8 . describe a variable combination of moderate-severe neurodevelopmental delay (NDD) and/or intellectual disability (ID) (7/7), autism spectrum disorders (ASD − 2/7), congenital microcephaly (3/7) among other perinatal processes such as intrauterine growth restrictions (3/7), facial dysmorphisms including micrognathia (5/7), cardiac and central nervous system anomalies (ventriculomegaly, white matter hyperintensities), along with other medical issues like joint hypermobility or eye anomalies. No patient presented seizures. In 4/7 individuals, the initial clinical suspicions were Kabuki syndrome-like or mandibulofacial dysostosis-like conditions. The authors report de novo heterozygous missense (5/7), nonsense (1/7) and frameshift (1/7) likely pathogenic (LP) or pathogenic variants (P). The codon for Arg109 was affected in 3/7, perhaps due to the propensity of codon CGA to methylation, deamination and CG-TA transition. In February 2024, 33 LP/P variants were reported in ClinVar (4 missense, 1 nonsense, 2 frameshift, 1 splice site, and the rest taking part in insertions or copy number variants including up to hundreds of genes) Basing on several types of functional studies, they suggest that decreased or impaired eIF5A function in their patients depends on reduced eIF5A-ribosome interactions due to mutation-specific mechanisms, and that phenotypes could be explained by impaired synthesis of specific proteins rich in poly-proline tracts, such as KMT2D and SF3B4. Regarding p.E122K, they argue that although a reduction in function was observed, it was not statistically significant compared to other variants, consistently with the milder phenotype of that individual. Besides, they suggest that haploinsufficiency of EIF5A may account for the phenotype of 17p13.1 microdeletion syndrome. No precision therapy is available for eIF5A-HRD. However, our colleagues also demonstrate partial improvement of eIF5A function and phenotypes over yeast and zebrafish models by spermidine, proposing a broader action of the former beyond hypusination, involving optimization of eIF5A-ribosome interaction 8 . DHPS-related disorders DHPS is the first enzyme involved in the sequential post-translational synthesis of hypusine in the eIF5A precursor, necessary for its activation 4 . This enzyme transfers the 4-aminoutyl moiety from spermidine to Lys50 in eIF5A. Bi-allelic loss-of-function variants in DHPS have been associated to neurodevelopmental disorder with microcephaly and epilepsy in up to 5 individuals 9 . Ganapathi et al 9 . describe an association of variable degrees of NDD/ID (5/5), ASD traits (4/5), hypotonia (4/5), preeclampsia (4/5) among other perinatal processes, microcephaly at last evaluation in 3/4 (but 0/3 congenital), dysmorphisms including deep set eyes (4/5) and normal brain MRI (4/4), along with other medical issues like skin conditions or low immunoglobulins levels. Moreover, 4/5 presented epilepsy. The authors report 4 biallelic inherited LP/P variants, including 1 missense, 1 start loss, 1 inframe deletion and 1 splice site. The c.518A > G (p.Asn173Ser) variant was found in trans with another variant in all 5 subjects, being suggested by the authors that this might be a founder variant. In this line, one allele resulted in complete lack of DHPS activity, while the other allele showed significantly diminished function (p.Asn173Ser). In February 2024, 24 LP/P variants were reported in ClinVar (1 missense, 2 frameshift, 1 splice site, and the rest taking part in insertions or copy number variants including up to hundreds of genes). Basing on functional studies, they propose that the reported genotypes lead to a decreased DHPS activity and reduced eIF5A hypusination. DOHH-related disorders DOHH is the second enzyme involved in the sequential post-translational synthesis of hypusine in the eIF5A precursor 4 . This enzyme hydroxylates the residue created in Lys50 by DHPS, finishing the synthesis of hypusine and activating eIF5A. Bi-allelic loss-of-function variants in DOHH have been described in up to 5 individuals with similar neurodevelopmental disorder with microcephaly and epilepsy 10 . Ziegler et al 10 . also describe a combination of NDD/ID (5/5), happy demeanor (3/5), hypotonia (5/5), variable visual impairment (4/5), microcephaly in 4/4 (but 0/3 congenital), brain MRI showing cortical atrophy (4/5), cardiac malformations (3/5), nystagmus (3/5), cortical visual impairment (1/4) and recurrent infections (3/5). In this case, 3/5 also presented epilepsy. The authors report 7 biallelic inherited LP/P variants, including 4 missense, 2 frameshift and 1 stop gain. In line with the lethality of homozygous knockout mice, every individual was thought to carry at least 1 variant with residual DOHH activity. In February 2024, 26 LP/P variants were reported in ClinVar (4 missense, 1 nonsense, 2 frameshift, and the rest taking part in insertions or copy number variants including up to hundreds of genes). Basing on several types of functional studies, our colleagues suggest that the assessed genotypes lead to a decreased DOHH activity with an increased accumulation of unhydroxylated eIF5A. Particularly, they suggest that the limitation of DOHH activity in individuals with missense variants is more likely accounted for reduced stability rather than loss of activity, and discuss that the variable residual activity of eIF5A across the three eIF5A-HRD, might explain the less severe phenotypes of eIF5A-D in comparison to DHPS-D or DOHH-D. Case report We report a 24-years-old male diagnosed with DOHH-related encephalopathy. Main clinical features consist of maternal hypertension during pregnancy, normal birth weight, length and head circumference, poor feeding during the first months, neurodevelopmental disorder with moderate-severe ID, attention deficit with hyperactivity disorder (ADHD), and refractory epilepsy with temperature and excitement-triggered seizures, diagnosed from the 8th month. Ambulation capacity was acquired, manifesting hypotonia, dystaxic and crouch gait, and varus knee. Speaking is limited to short simple 5–6 words sentences, with dysarthria. Behavior is characterized by a happy demeanor, with sporadic disruptions from adolescence. Physical examination at last evaluation (24 years-old), revealed normal stature, low body mass index, and microcephaly (known from the age of 4 years). Brain MRI showed no significant anomalies. He presented his first seizure at eight months. Between month 8 and the age of 7 years, he displayed both typical and lateralization-alternating hemiclonic febrile seizures with a frequency of four per year, including one episode of status epilepticus while in the swimming pool at the age of four years, characterized by sequential unrecovered generalized tonic-clonic seizures, and after which a routine EEG showed focal left frontal interictal epileptiform activity for the first time. Baseline EEGs during his first years were normal. Between seven and 16-years-old, afebrile focal unaware motor seizures appeared along with tonic seizures and falls. Seizures occurred during wakefulness and sleep, occasionally in clusters, and frequently triggered by temperature changes, excitement or physical activity. EEGs showed either focal left frontal or right posterior quadrant interictal activity. From 16-years-old onwards, seizures became mainly generalized tonic-clonic during sleep with a frequency of 4–5/month. Between 20 and 23-years old, EEGs revealed multifocal interictal activity. Nonetheless, last 24-hour video-EEG monitoring from 24-years-old onwards was unremarkable. Clobazam and levetiracetam resulted in partial improvements in seizure frequency, but provoked marked irritability. Clusters responded well to oral midazolam. Valproic acid contributed to behavior improvement. Lacosamide was associated with mild improvement in nocturnal tonic seizures. Fenfluramine was the most effective drug, reducing seizure intensity, duration and frequency by 50% from 20-years old onwards, contributing to the cessation of clusters, along with cognitive and behavior improvements. Lamotrigine, oxcarbazepine, perampanel and methylphenidate showed no effectiveness. Currently, the patient is on fenfluramine, clobazam, valproic acid and lacosamide. T-WES was performed when the patient was 24-years-old, displaying initial negative results. Five months later, sequence analysis was reassessed by a team of epileptologist with expertise in epilepsy genetics, along with geneticists of BluePrint Genetics, including further candidate genes and also rare bi-allelic missense variants. On this occasion, a likely pathogenic homozygous variant in DOHH (c.455C > T, p.Pro152Leu) was found, with both parents being non-consanguineous asymptomatic heterozygous carriers. Discussion Pathogenic variants in other eIF, eEF and closely related proteins have been previously identified as the cause of several neurological and developmental disorders. Variants in eIF2B subunits (MIM # 603896) 13 have been related to leukoencephalopathy with vanishing white matter, a chronic-progressive disease with episodes of acute worsening following intercurrent events. In this line, variants in EIF2S3 (MIM # 300148) 14 have been associated to ID and microcephaly, in EIF3F (MIM # 618295) 15 to ID, behavioral disorders, epilepsy and sensorineural hearing loss; in EIF4E (MIM # 615091) 16 to ASD, and in EIF4G1 (MIM # 614251) 17 to familial parkinsonism and idiopathic Lewy body disease. Regarding eEF factors, variants in EEF1A2 (MIM # 602959) have been linked to ID, ASD, epilepsy and ataxia, and in EEF2 and other proteins of the same pathway (MIM # 130610) to spinocerebellar ataxia, ID, central nervous system malformations and craniofacial abnormalities 18 . Additionally, variants in related proteins such as alanyl tRNA synthetase (AARS -MIM # 616339) have been associated to microcephaly, hypomyelination and epilepsy, and in ribosomal proteins such as RPS23 (MIM # 617412) to ID, brachycephaly, trichomegaly and hearing loss, or in RPL10 (MIM # 300998) to ID, ASD, and cerebellar hypoplasia 18 . Concerning our patient, his mother manifested hypertension during the third trimester of pregnancy. No other reported individual with DOHH-D displayed maternal hypertension. However, 4/5 DHPS-D individuals were diagnosed with preeclampsia. Basic speaking was acquired, on the contrary to most DOHH-D and DHPS-D, but as EIF5A-D cases. Hypotonia was present as in most DOHH-D and DHPS-D, along with dystaxic and crouch gait. No ADHD was described among DOHH-D patients, but happy demeanor was also reported. Brain MRI (9-years-old) was unremarkable, on the contrary to all DOHH-D individuals (cortical atrophy). No cardiac malformations, visual impairment or recurrent infections were present, opposite to most DOHH-D individuals (Table 1 ). Table 2 shows the description of the epilepsy features of our patient, and the rest of individuals diagnosed with hypusination-related disorders. No patient with EIF5A-D was diagnosed with epilepsy (it has been proposed that heterozygous variants in EIF5A-D allow higher residual activity of eIF5A, giving rise to milder phenotypes 10 ). Our patient presented with a phenotype resembling Dravet syndrome, including early hemiclonic, focal, tonic and tonic-clonic seizures, triggered by temperature elevation, infections and excitement, refractory to antiseizure medication, evolving to developmental and epileptic encephalopathy, and occurrence of tonic-clonic seizures during sleep after adolescence, along with posterior-predominant multifocal interictal activity. DOHH-D reported patients presented later epilepsy onsets, displaying mainly generalized epilepsies with 2/3 manifesting focal and generalized fever-triggered seizures. DHPS-D patients also presented with later epilepsy onsets, displaying mainly generalized epilepsies (2/4 with continuous spike-wave during sleep patterns) with 2/4 manifesting focal and generalized fever or infection-triggered seizures, along with posterior-predominant focal or multifocal interictal activity in 2/4. Regarding response to therapies, our patient is partially responsive to valproic acid, and 50% responder to fenfluramine along with cognitive and behavioral improvements, without response to several sodium channel blockers, except for low dose lacosamide used to improve nocturnal seizures 19 . Among the rest of DOHH-D reported patients, 2/3 were refractory and 1/3 controlled with unspecified anti-seizure medications. One out of 4 individuals with DHPS-D was reported to be refractory, the rest showing responses to oxcarbazepine, valproic acid and low-carbohydrate diet. Table 2 Epilepsy phenotype of hypusination disorders. DOHH-D (Beltrán-Corbellini et al.) N = 1 DOHH-D (Ziegler et al. 7 ) N = 5 DHPS-D (Ganapathi et al. 6 ) N = 5 Age at epilepsy onset 8 months Individual 2: 5 years Individual 3: 3 years Individual 5: NS Individual 1: 2 years Individual 2: 2.5 years (unclear episodes before) Individual 3: 4 years (suspicion) Individual 4: 5 years Individual 5: 5 years Seizure type 8 months-7 years: -Typical and hemiclonic febrile seizures -Status epilepticus while in the swimming pool 7–16 years -Focal unaware motor seizures -Tonic seizures -During wakefulness and sleep, occasionally in clusters, triggered by temperature changes, excitement or physical activity 16 years-onwards: -GTCS -Predominantly during sleep Individual 2: fever-triggered GTCS Individual 3: drop attacks at the age of 11 years, myoclonic seizures at the age of 15 years, fever-triggered focal and generalized seizures at the age of 16 years Individual 5: hyperextension of upper limbs Individual 1: absences Individual 2: single infection-triggered GTCS (staring episodes before) Individual 3: unclear staring spells Individual 4: fever-triggered focal seizure at the age of 5 years, infection-triggered generalized tonic status epilepticus at the age of 7 years Individual 5: absences and GTCS Epilepsy Syndrome DEE Individual 2: NS Individual 3: GE Individual 5: GE Individual 1: CSWS Individual 2: NS Individual 3: CSWS Individual 4: NS Individual 5: NS EEG 8 months-4 years: -Unremarkable routine EEG 4–20 years: -24-hour video-EEG showing focal left frontal or right posterior quadrant interictal activity. 20–23 years: -24-hour video-EEG showing multifocal interictal activity 23 years-onwards: -Unremarkable 24-hour video-EEG Individual 2: NS Individual 3: NS Individual 5: normal Individual 1: posterior temporal and parietal interictal activity Individual 2: focal bilateral temporal-occipital interictal activity Individual 3: multifocal interictal activity Individual 4: multifocal interictal activity Individual 5: NS Response to therapy and evolution VPA: behavior improvement) LEV: partial improvement in seizure frequency, but irritability. CLB: partial improvement in seizure frequency FFN: 50% responder, with improvement in intensity and duration and cessation of clusters, along with cognitive and behavior improvements. LTG, OXC, PER: no effectivity. Methylphenidate: no effectivity. Individual 2: controlled by ASMs, and stopping at the age of 11 Individual 3: NS Individual 5: NS Individual 1: Sulthiame led to a 25% reduction in nocturnal interictal activity. CBD/THC high ratio improved receptivity and sleep. Unresponsive to LEV, solumedrol, CLB, CLN, VPA, KD, prednisone. Individual 2: KD markedly improved language skills, stimulants improved ADHD Individual 3: partial improvement in the frequency of spells with OXC Individual 4: VPA led to a good seizure control Individual 5: responder to low carbohydrate diet and OXC DOHH-D: DOHH-related disorders; DHPS-D: DHPS-related disorders; NS: not specified; GTCS: generalized tonic-clonic seizures; DEE: developmental and epileptic encephalopathy; GE: generalized epilepsy; CSWS: continuous spike-wave during sleep; VPA: valproic acid; LEV: levetiracetam; CLB: clobazam; FFN: fenfluramine; LTG: lamotrigine; OXC: oxcarbazepine; PER: perampanel; ASM: anti-seizure medication; CBD/THC: cannabidiol/tetrahydrocannabinol; CLN: clonazepam; KD: ketogenic diet; ADHD: attention deficit with hyperactivity disorder. Place for Table 2 . The phenotype of our patient seems to be milder than the described for most of the rest of DOHH-D cases. Variant c.455C > T (p.Pro152Leu) in DOHH was previously reported by Ziegler et al. 10 in their individual 4 (along with other missense variant), and individual 5 (along with other truncating variant). Basing on several functional approaches, they describe a drastical reduction in the amount of DOHH protein in individual 4 (20% of controls), accounting it for protein instability rather than the loss of activity, along with an accumulation of the inactive unhydroxylated deoxyhypusine-containing eIF5A. Individual 4 of Ziegler et al. (2 missense variants, as our patient), was the only one acquiring speaking capacity (as our patient). However, he did not develop epilepsy, and did show cortical atrophy, cardiac malformations and horizontal nystagmus (opposite to our patient). This might indicate that homozygous or compound heterozygous missense variants could give rise to a milder neurodevelopmental phenotype, warranting future confirmation. Taking our patient into account, 5/8 displayed fever or infection-triggered seizures among DOHH-D and DHPS-D reported individuals with epilepsy, in some cases taking part of a wider Dravet-like phenotype. eIF5A has been reported as key for synthesizing bonds between successive proline residues during the elongation phase of translation process 11 . Thus, Faundes et al. have proposed that phenotypes of eIF5A-D patients could be explained by impaired synthesis of specific proteins rich in poly-proline tracts 8 . Loss-of-function variants in the widely-studied Proline-Rich Transmembrane Protein 2 (PRRT2), were identified in up to 18% of a cohort of 136 patients with febrile seizures (among other neurological and epilepsy syndromes), including febrile seizures plus, generalized epilepsy with febrile seizure plus and Dravet syndrome 20 . Moreover, PRRT2 has been demonstrated as an important negative modulator of sodium channels Nav1.2 (SCN2A gene) and Nav1.6 (SCN8A gene), leading to their hyperactivity if lacking 21 . Further, gain-of-function variants in SCN2A and SCN8A have been linked to Dravet-like phenotypes 22 . Although PRRT2 does not codify for long poly-proline tracts, it does include several proline-proline, and several proline-X-proline sequences in its proline-rich domain, and it could be hypothesized that febrile seizures in patients with eIF5A-HRD might be explained, at least partially, by a loss of function of PRRT2. On the other hand, eukaryotic elongation factor 2 kinase (EEF2K) phosphorylates and inactivates eukaryotic elongation factor 2 (EEF2, which catalyzes translation elongation), and thus, reducing the rate of protein synthesis. It has been observed that an increase in EEF2 function cooperates with the role of EIF5A during the elongation step of protein synthesis 23 . Furthermore, it has been reported that EEF2K knock out mice display enhanced GABAergic transmission, being less susceptible to seizures, and that EEF2K is upregulated in murine models of Dravet Syndrome, inactivating EEF2 24 . Taking this into consideration, it could be also hypothesized that decreased activity of EIF5A due to variants in DHPS and DOHH, might lead to a parallel inactivation of EEF2, and thus contributing to the arising of a fenfluramine-responsive Dravet-like phenotype. Finally, it has been reported that EIF5A point mutated form V81G in a certain strain of the yeast Saccharomyces cerevisiae , led to a strongly temperature-sensitive phenotype 25 . Overall, the genetics of Dravet Syndrome without mutations in SCN1A 26 , 27 and of epilepsies with fever-triggered seizures 28 is complex and remains to be clarified. In this context, these premises might establish an initial link associating eIF5A-HRD to these described neurodevelopmental and epilepsy phenotypes, definitely warranting further insight from future functional and clinical studies. As a literature review and a case report with hypotheses based on a small sample, this study has limitations. Further investigation will be needed in order to define the precise phenotype, the response to treatment, and the molecular basis of eIF5A-HRD. Conclusions eIF5A-HRD are recently described entities and reported patients are scarce. Main phenotypic features consist of prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-severe NDD/ID and behavioral disorders. More than 70% of DHPS-D and DOHH-D patients present epilepsy, 63% of them with temperature-triggered seizures, and half of them refractory. Valproic acid or fenfluramine may be effective. Rare homozygous or compound heterozygous missense variants in these genes should be screened in patients with encephalopathy and temperature-triggered seizures. T-WES should be periodically reanalyzed in multidisciplinary teams in order to optimize diagnostic yield. Abbreviations eIF eukaryotic translation initiation factors. eEF:eukaryotic translation initiation factors. eTF:eukaryotic translation termination factors. eIF5A:eukaryotic initiation factor 5A (protein). eIF5A-HRD:eIF5A and hypusination-related disorders. DHPS:deoxyhypusine synthase. DOHH:deoxyhypusine hydroxylase. EIF5A:eukaryotic initiation factor 5A (gene). DOHH-D:DOHH-related disorders. T-WES:trio-exome sequencing. eIF5A-D:eIF5A-related disorders. DHPS-D:DHPS-related disorders. NDD:neurodevelopmental delay. ID:intellectual disability. ASD:autism-spectrum disorders. LP:likely pathogenic. P:pathogenic. MRI:magnetic resonance imaging. ADHD:attention deficit with hyperactivity disorder. EEG:electroencephalogram. PRRT2:Proline-Rich Transmembrane Protein 2. EEF2K:eukaryotic elongation factor 2 kinase. EEF2:eukaryotic elongation factor 2 Declarations Ethics approval and consent to participate The local ethics committee waived the need for approval regarding this case report. Consent for publication Written consent for publication was obtained from the parents of the patient. Competing interests ABC, RT, IGM, ISMR and AGN have received support from, and served as paid consultants for UCB Pharma. AVC has no conflicts of interest. Funding This work has received no funding. Author’s contribution ABC: conceptualization; data curation; formal analysis; investigation; methodology; resources; supervision; visualization; original draft preparation; review and editing. AVC: data curation; formal analysis; resources; review and editing. RT: investigation; review and editing. IGM: investigation; review and editing. ISMR: investigation; review and editing. AGN: conceptualization; methodology; supervision; visualization; original draft preparation; review and editing. All authors read and approved the final manuscript. Acknowledgements We thank the patient’s family for their collaboration and consent for publishing this work. We also thank Ana Mingorance for her cooperation and expertise. Availability of data and materials The exome-sequencing data supporting this work have not been included in a public repository due to ethical restrictions, but are available from the corresponding author (ABC) on reasonable request. References - Verma M, Choi J, Cottrell KA, Lavagnino Z, Thomas EN, Pavlovic-Djuranovic S, et al. A short translational ramp determines the efficiency of protein synthesis. Nat Commun. 2019;10(1):5774. 10.1038/s41467-019-13810-1 . -Rubio A, Garland GD, Sfakianos A, Harvey RF, Willis AE. 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Mol Cell. 2012;48(4):641–6. 10.1016/j.molcel.2012.09.005 . -Martin HC, Jones WD, McIntyre R, Sanchez-Andrade G, Sanderson M, Stephenson JD, et al. Quantifying the contribution of recessive coding variation to developmental disorders. Science. 2018;362(6419):1161–4. 10.1126/science.aar6731 . -Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature. 2013;493(7432):371–7. 10.1038/nature11628 . -Chartier-Harlin MC, Dachsel JC, Vilariño-Güell C, Lincoln SJ, Leprêtre F, Hulihan MM, et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet. 2011;89(3):398–406. 10.1016/j.ajhg.2011.08.009 . -Kapur M, Ackerman SL. mRNA Translation Gone Awry: Translation Fidelity and Neurological Disease. Trends Genet. 2018;34(3):218–31. 10.1016/j.tig.2017.12.007 . -García-Morales I, Delgado RT, Falip M, Campos D, García ME, Gil-Nagel A. Early clinical experience with lacosamide as adjunctive therapy in patients with refractory focal epilepsy and nocturnal seizures. Seizure. 2011;20(10):801–4. 10.1016/j.seizure.2011.08.005 . -He ZW, Qu J, Zhang Y, Mao CX, Wang ZB, Mao XY, et al. PRRT2 mutations are related to febrile seizures in epileptic patients. Int J Mol Sci. 2014;15(12):23408–17. 10.3390/ijms151223408 . -Fruscione F, Valente P, Sterlini B, Romei A, Baldassari S, Fadda M, et al. PRRT2 controls neuronal excitability by negatively modulating Na + channel 1.2/1.6 activity. Brain. 2018;141(4):1000–16. 10.1093/brain/awy051 . -Mangano GD, Fontana A, Antona V, Salpietro V, Mangano GR, Giuffrè M, et al. Commonalities and distinctions between two neurodevelopmental disorder subtypes associated with SCN2A and SCN8A variants and literature review. Mol Genet Genomic Med. 2022;10(5):e1911. 10.1002/mgg3.1911 . - Dias CA, Gregio AP, Rossi D, Galvão FC, Watanabe TF, Park MH, et al. eIF5A interacts functionally with eEF2. Amino Acids. 2012;42(2–3):697–702. 10.1007/s00726-011-0985-0 . -Beretta S, Gritti L, Ponzoni L, Scalmani P, Mantegazza M, Sala M, et al. Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic elongation factor 2 kinase (eEF2K). Mol Autism. 2022;13(1):1. 10.1186/s13229-021-00484-0 . - Schrader R, Young C, Kozian D, Hoffmann R, Lottspeich F. Temperature-sensitive eIF5A mutant accumulates transcripts targeted to the nonsense-mediated decay pathway. J Biol Chem. 2006;281(46):35336–46. 10.1074/jbc.M601460200 . - Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Møller RS, Hjalgrim H, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82(14):1245–53. 10.1212/WNL.0000000000000291 . - Hartmann C, von Spiczak S, Suls A, Weckhuysen S, Buyse G, Vilain C, et al. Investigating the genetic basis of fever-associated syndromic epilepsies using copy number variation analysis. Epilepsia. 2015;56(3):e26–32. 10.1111/epi.12920 . - Olson HE, Poduri A. Towards understanding genetic risk in febrile seizures: innate immunity and neuronal excitability. Brain. 2022;145(2):416–7. 10.1093/brain/awac036 . Cite Share Download PDF Status: Published Journal Publication published 29 Aug, 2025 Read the published version in Journal of Neurodevelopmental Disorders → Version 1 posted Editorial decision: Major revision 03 Jan, 2025 Reviewers agreed at journal 09 Jul, 2024 Reviewers invited by journal 21 May, 2024 Editor assigned by journal 29 Feb, 2024 First submitted to journal 19 Feb, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3837969","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":305176581,"identity":"0e3449d4-d6a4-4f69-a8cd-b7355c6aafe4","order_by":0,"name":"Álvaro Beltrán-Corbellini","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-2743-0978","institution":"Hospital Ruber Internacional","correspondingAuthor":true,"prefix":"","firstName":"Álvaro","middleName":"","lastName":"Beltrán-Corbellini","suffix":""},{"id":305176582,"identity":"dae173f5-10d7-44d6-922b-92bd77c85d36","order_by":1,"name":"Adrián Valls-Carbó","email":"","orcid":"","institution":"Hospital Ruber Internacional","correspondingAuthor":false,"prefix":"","firstName":"Adrián","middleName":"","lastName":"Valls-Carbó","suffix":""},{"id":305176583,"identity":"086dfd52-237f-4cf3-b6df-b52ddef34e4f","order_by":2,"name":"Rafael Toledano","email":"","orcid":"","institution":"Hospital Ruber Internacional","correspondingAuthor":false,"prefix":"","firstName":"Rafael","middleName":"","lastName":"Toledano","suffix":""},{"id":305176584,"identity":"e969dd16-f0cf-4ad0-bad8-b23b5829280d","order_by":3,"name":"Irene García-Morales","email":"","orcid":"","institution":"Hospital Ruber Internacional","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"","lastName":"García-Morales","suffix":""},{"id":305176585,"identity":"70cc0c40-c9e6-4a58-ab16-54bcd3ed5a9a","order_by":4,"name":"Irene Sánchez-Miranda Román","email":"","orcid":"","institution":"Hospital Ruber Internacional","correspondingAuthor":false,"prefix":"","firstName":"Irene","middleName":"Sánchez-Miranda","lastName":"Román","suffix":""},{"id":305176586,"identity":"3d924d0c-361a-4b16-8dbe-3175383a8f07","order_by":5,"name":"Antonio Gil-Nagel","email":"","orcid":"","institution":"Hospital Ruber Internacional","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Gil-Nagel","suffix":""}],"badges":[],"createdAt":"2024-01-05 18:29:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3837969/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3837969/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s11689-025-09649-x","type":"published","date":"2025-08-29T15:57:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90344928,"identity":"bb424301-087a-44ca-9763-0b6208d015ab","added_by":"auto","created_at":"2025-09-01 16:07:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":758510,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3837969/v1/9b67ef60-127e-4574-b607-7368e9bf2d17.pdf"}],"financialInterests":"","formattedTitle":"eIF5A and hypusination-related disorders: literature review and case report of DOHH-related encephalopathy.","fulltext":[{"header":"Background","content":"\u003cp\u003eEukaryotic translation initiation factors (eIF) are a group of at least 12 proteins regulating global messenger RNA translation, along with eukaryotic translation elongation (eEF) and termination factors (eTF)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. These proteins display a direct role in cell physiology, development and response to stress, and its dysregulation has been linked to cancer, neurological and metabolic disorders\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEukaryotic initiation factor 5A (eIF5A) and hypusination-related disorders (eIF5A-HRD) are recently-described diseases caused by variants in the genes coding for eIF5A or the enzymes involved in the post-translational synthesis of hypusine in the eIF5A precursor, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), necessary for its activation. eIF5A, is a key translation factor for cell proliferation and differentiation, apoptosis, autophagy, and development in eukaryotes\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eeIF5A has been related to disorders such as cancer\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, diabetes\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e or retroviral infections\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eDe novo\u003c/em\u003e heterozygous variants in EIF5A (MIM # 600187) have been associated to neurodevelopmental disorder with microcephaly, the Faundes-Banka syndrome (MIM # 619376), in 7 patients\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Bi-allelic loss-of-function variants in DHPS (MIM # 600944) have been also associated to neurodevelopmental disorder with microcephaly and epilepsy (MIM # 618480) in 5 individuals\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Most recently, Ziegler et al. have described bi-allelic loss-of-function variants in DOHH (MIM # 611262) in 5 individuals with similar neurodevelopmental disorder with microcephaly and epilepsy (MIM # 620066)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe genotypic and phenotypic characterization of these conditions is still in its initial steps. In this work, we review the current knowledge regarding eIF5A-HRD, and report the case of a patient with DOHH-related disorder (DOHH-D) manifesting as a fenfluramine-responsive Dravet-like syndrome. We aim to expand and discuss the molecular basis and the phenotype of this group of diseases, and to better define the epilepsy features of patients with eIF5A-HRD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA literature review was carried out, including the following descriptors in the thesaurus of MEDLINE: \u0026ldquo;eukaryotic translation factor, EIF5A, DHPS, DOHH, neurodevelopmental disorder, epilepsy, febrile seizures, Dravet syndrome and fenfluramine\u0026rdquo;. Articles in English and Spanish up to February 2024, along with their references, were included and screened by a team of neurologists with expertise in neurodevelopmental disorders and genetics.\u003c/p\u003e \u003cp\u003eWith respect to the case report, trio-exome sequencing (T-WES) was performed by BluePrint Genetics. Variants were described according to the Human Genome Variation Society nomenclature recommendations. Phenotypic characteristics were collected from the patient\u0026rsquo;s medical records, and seizure data were assessed from diaries filled out by the patient\u0026rsquo;s parents.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eLiterature review yielded just one original paper describing 7 individuals with eIF5A-related disorders (eIF5A-D), one reporting 5 subjects with DHPS-related disorders (DHPS-D) and one characterizing 5 individuals with DOHH-D. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e details the phenotypic and genotypic features of our patient in comparison to the rest of patients reported with eIF5A-D, DHPS-D and DOHH-D.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eModified from Ziegler et al\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. General phenotype of patients diagnosed with eIF5A and hypusination-related disorders.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDOHH-D (Beltr\u0026aacute;n-Corbellini et al.) N\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDOHH-D (Ziegler et al.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDHPS-D\u003c/p\u003e \u003cp\u003e(Ganapathi et al.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEIF5A-D\u003c/p\u003e \u003cp\u003e(Faundes V, et al.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/5 females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/5 females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4/7 females\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomozygous for c.455C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.(Pro152Leu)\u003c/p\u003e \u003cp\u003eEthnicity: Spanish (pat), Spanish (mat)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 variants: one stop gain, two frameshift, 4 missense; compound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 variants: 1 missense, one start loss, one splice, one inframe deletion; compound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 variants: 5 missense, 1 stop gain, 1 frameshift; de novo heterozygous\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrenatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMat. hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/5 cardiac malformation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/5 preeclampsia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5/6 (4 IUGR, 1 fetal ascites)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/5 preterm or postterm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/5 preterm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN/S\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeonatal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePoor feeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/5 poor feeding, 1/4 temperature instability, 3/5 hypotonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/5 premature instability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/7 poor feeding\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.100 Kg (-0.58 SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/5 underweight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/5 underweight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/7 underweight\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth lenght\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 cm (+\u0026thinsp;0.33 SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/5 short stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/4 short stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/7 short stature\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth HC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 cm (+\u0026thinsp;1.03 SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/3 congenital microcephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/3 congenital microcephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/7 congenital microcephaly\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight or lenght at last evaluation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e178 cm (normal stature)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/5 short stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/5 short stature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2/7 short stature\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight at last evaluation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52.5 Kg (BMI 16.5, underweight)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/4 underweight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/5 underweight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2/7 underweight\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHC at last evaluation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 cm (\u0026lt;\u0026thinsp;2 SD, microcephaly)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/4 microcephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3/4 microcephaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5/7 microcephaly\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSitting/walking/speaking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes/Yes/Yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/5 sitting, 3/5 walking, 1/5 speaking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/5 sitting, 5/5 walking,\u003c/p\u003e \u003cp\u003e2/5 speaking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6/7 sitting, 6/6 walking,\u003c/p\u003e \u003cp\u003e6/6 speaking\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSitting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWalking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpeaking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntellectual disability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7/7 (1 mild)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBehavioral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHappy demeanor, ADHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/5 happy demeanor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/5 autism, hand flapping 3/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2/7 autism, 1/7 ADHD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0/7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTonus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHypotonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/5 hypotonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/5 hypotonia, 1/5 spasticity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1/5 hypotonia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/5 abnormal, 4/5 cortical atrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/4 normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2/2 normal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac malformation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/5 nystagmus, 1/4 cortical visual impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/7 strabismus, 1/7 glaucoma\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0/7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eDOHH-D: DOHH-related disorders; DHPS-D: DHPS-related disorders; EIF5A-D: EIF5A-related disorders; pat: paternal; mat: maternal; IUGR: intrauterine growth restriction; Kg: kilograms; SD: standard deviation; cm: centimeters; HC: head circumference; ADHD: attention deficit with hyperactivity disorder.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003ePlace for\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eeIF5A-related disorders\u003c/p\u003e \u003cp\u003eeIF5A is key for synthesizing bonds between successive proline residues resolving ribosomal stalling in eukaryotic cells\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, among other functions. Increased somatic expression of EIF5A had been related to several cancers\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, germline \u003cem\u003ede novo\u003c/em\u003e heterozygous variants in EIF5A have been associated to neurodevelopmental disorder with microcephaly in up to 7 patients\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFaundes et al\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. describe a variable combination of moderate-severe neurodevelopmental delay (NDD) and/or intellectual disability (ID) (7/7), autism spectrum disorders (ASD \u0026minus;\u0026thinsp;2/7), congenital microcephaly (3/7) among other perinatal processes such as intrauterine growth restrictions (3/7), facial dysmorphisms including micrognathia (5/7), cardiac and central nervous system anomalies (ventriculomegaly, white matter hyperintensities), along with other medical issues like joint hypermobility or eye anomalies. No patient presented seizures. In 4/7 individuals, the initial clinical suspicions were Kabuki syndrome-like or mandibulofacial dysostosis-like conditions.\u003c/p\u003e \u003cp\u003eThe authors report \u003cem\u003ede novo\u003c/em\u003e heterozygous missense (5/7), nonsense (1/7) and frameshift (1/7) likely pathogenic (LP) or pathogenic variants (P). The codon for Arg109 was affected in 3/7, perhaps due to the propensity of codon CGA to methylation, deamination and CG-TA transition. In February 2024, 33 LP/P variants were reported in ClinVar (4 missense, 1 nonsense, 2 frameshift, 1 splice site, and the rest taking part in insertions or copy number variants including up to hundreds of genes)\u003c/p\u003e \u003cp\u003eBasing on several types of functional studies, they suggest that decreased or impaired eIF5A function in their patients depends on reduced eIF5A-ribosome interactions due to mutation-specific mechanisms, and that phenotypes could be explained by impaired synthesis of specific proteins rich in poly-proline tracts, such as KMT2D and SF3B4. Regarding p.E122K, they argue that although a reduction in function was observed, it was not statistically significant compared to other variants, consistently with the milder phenotype of that individual. Besides, they suggest that haploinsufficiency of EIF5A may account for the phenotype of 17p13.1 microdeletion syndrome.\u003c/p\u003e \u003cp\u003eNo precision therapy is available for eIF5A-HRD. However, our colleagues also demonstrate partial improvement of eIF5A function and phenotypes over yeast and zebrafish models by spermidine, proposing a broader action of the former beyond hypusination, involving optimization of eIF5A-ribosome interaction\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDHPS-related disorders\u003c/p\u003e \u003cp\u003eDHPS is the first enzyme involved in the sequential post-translational synthesis of hypusine in the eIF5A precursor, necessary for its activation\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. This enzyme transfers the 4-aminoutyl moiety from spermidine to Lys50 in eIF5A. Bi-allelic loss-of-function variants in DHPS have been associated to neurodevelopmental disorder with microcephaly and epilepsy in up to 5 individuals\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGanapathi et al\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. describe an association of variable degrees of NDD/ID (5/5), ASD traits (4/5), hypotonia (4/5), preeclampsia (4/5) among other perinatal processes, microcephaly at last evaluation in 3/4 (but 0/3 congenital), dysmorphisms including deep set eyes (4/5) and normal brain MRI (4/4), along with other medical issues like skin conditions or low immunoglobulins levels. Moreover, 4/5 presented epilepsy.\u003c/p\u003e \u003cp\u003eThe authors report 4 biallelic inherited LP/P variants, including 1 missense, 1 start loss, 1 inframe deletion and 1 splice site. The c.518A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Asn173Ser) variant was found \u003cem\u003ein trans\u003c/em\u003e with another variant in all 5 subjects, being suggested by the authors that this might be a founder variant. In this line, one allele resulted in complete lack of DHPS activity, while the other allele showed significantly diminished function (p.Asn173Ser). In February 2024, 24 LP/P variants were reported in ClinVar (1 missense, 2 frameshift, 1 splice site, and the rest taking part in insertions or copy number variants including up to hundreds of genes). Basing on functional studies, they propose that the reported genotypes lead to a decreased DHPS activity and reduced eIF5A hypusination.\u003c/p\u003e \u003cp\u003eDOHH-related disorders\u003c/p\u003e \u003cp\u003eDOHH is the second enzyme involved in the sequential post-translational synthesis of hypusine in the eIF5A precursor\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. This enzyme hydroxylates the residue created in Lys50 by DHPS, finishing the synthesis of hypusine and activating eIF5A. Bi-allelic loss-of-function variants in DOHH have been described in up to 5 individuals with similar neurodevelopmental disorder with microcephaly and epilepsy\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eZiegler et al\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. also describe a combination of NDD/ID (5/5), happy demeanor (3/5), hypotonia (5/5), variable visual impairment (4/5), microcephaly in 4/4 (but 0/3 congenital), brain MRI showing cortical atrophy (4/5), cardiac malformations (3/5), nystagmus (3/5), cortical visual impairment (1/4) and recurrent infections (3/5). In this case, 3/5 also presented epilepsy.\u003c/p\u003e \u003cp\u003eThe authors report 7 biallelic inherited LP/P variants, including 4 missense, 2 frameshift and 1 stop gain. In line with the lethality of homozygous knockout mice, every individual was thought to carry at least 1 variant with residual DOHH activity. In February 2024, 26 LP/P variants were reported in ClinVar (4 missense, 1 nonsense, 2 frameshift, and the rest taking part in insertions or copy number variants including up to hundreds of genes).\u003c/p\u003e \u003cp\u003eBasing on several types of functional studies, our colleagues suggest that the assessed genotypes lead to a decreased DOHH activity with an increased accumulation of unhydroxylated eIF5A. Particularly, they suggest that the limitation of DOHH activity in individuals with missense variants is more likely accounted for reduced stability rather than loss of activity, and discuss that the variable residual activity of eIF5A across the three eIF5A-HRD, might explain the less severe phenotypes of eIF5A-D in comparison to DHPS-D or DOHH-D.\u003c/p\u003e \u003cp\u003eCase report\u003c/p\u003e \u003cp\u003eWe report a 24-years-old male diagnosed with DOHH-related encephalopathy. Main clinical features consist of maternal hypertension during pregnancy, normal birth weight, length and head circumference, poor feeding during the first months, neurodevelopmental disorder with moderate-severe ID, attention deficit with hyperactivity disorder (ADHD), and refractory epilepsy with temperature and excitement-triggered seizures, diagnosed from the 8th month. Ambulation capacity was acquired, manifesting hypotonia, dystaxic and crouch gait, and varus knee. Speaking is limited to short simple 5\u0026ndash;6 words sentences, with dysarthria. Behavior is characterized by a happy demeanor, with sporadic disruptions from adolescence. Physical examination at last evaluation (24 years-old), revealed normal stature, low body mass index, and microcephaly (known from the age of 4 years). Brain MRI showed no significant anomalies.\u003c/p\u003e \u003cp\u003eHe presented his first seizure at eight months. Between month 8 and the age of 7 years, he displayed both typical and lateralization-alternating hemiclonic febrile seizures with a frequency of four per year, including one episode of \u003cem\u003estatus epilepticus\u003c/em\u003e while in the swimming pool at the age of four years, characterized by sequential unrecovered generalized tonic-clonic seizures, and after which a routine EEG showed focal left frontal interictal epileptiform activity for the first time. Baseline EEGs during his first years were normal.\u003c/p\u003e \u003cp\u003eBetween seven and 16-years-old, afebrile focal unaware motor seizures appeared along with tonic seizures and falls. Seizures occurred during wakefulness and sleep, occasionally in clusters, and frequently triggered by temperature changes, excitement or physical activity. EEGs showed either focal left frontal or right posterior quadrant interictal activity. From 16-years-old onwards, seizures became mainly generalized tonic-clonic during sleep with a frequency of 4\u0026ndash;5/month. Between 20 and 23-years old, EEGs revealed multifocal interictal activity. Nonetheless, last 24-hour video-EEG monitoring from 24-years-old onwards was unremarkable.\u003c/p\u003e \u003cp\u003eClobazam and levetiracetam resulted in partial improvements in seizure frequency, but provoked marked irritability. Clusters responded well to oral midazolam. Valproic acid contributed to behavior improvement. Lacosamide was associated with mild improvement in nocturnal tonic seizures. Fenfluramine was the most effective drug, reducing seizure intensity, duration and frequency by 50% from 20-years old onwards, contributing to the cessation of clusters, along with cognitive and behavior improvements. Lamotrigine, oxcarbazepine, perampanel and methylphenidate showed no effectiveness. Currently, the patient is on fenfluramine, clobazam, valproic acid and lacosamide.\u003c/p\u003e \u003cp\u003eT-WES was performed when the patient was 24-years-old, displaying initial negative results. Five months later, sequence analysis was reassessed by a team of epileptologist with expertise in epilepsy genetics, along with geneticists of BluePrint Genetics, including further candidate genes and also rare bi-allelic missense variants. On this occasion, a likely pathogenic homozygous variant in DOHH (c.455C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Pro152Leu) was found, with both parents being non-consanguineous asymptomatic heterozygous carriers.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePathogenic variants in other eIF, eEF and closely related proteins have been previously identified as the cause of several neurological and developmental disorders. Variants in eIF2B subunits (MIM # 603896)\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e have been related to leukoencephalopathy with vanishing white matter, a chronic-progressive disease with episodes of acute worsening following intercurrent events. In this line, variants in EIF2S3 (MIM # 300148)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e have been associated to ID and microcephaly, in EIF3F (MIM # 618295)\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e to ID, behavioral disorders, epilepsy and sensorineural hearing loss; in EIF4E (MIM # 615091)\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e to ASD, and in EIF4G1 (MIM # 614251)\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e to familial parkinsonism and idiopathic Lewy body disease.\u003c/p\u003e \u003cp\u003eRegarding eEF factors, variants in EEF1A2 (MIM # 602959) have been linked to ID, ASD, epilepsy and ataxia, and in EEF2 and other proteins of the same pathway (MIM # 130610) to spinocerebellar ataxia, ID, central nervous system malformations and craniofacial abnormalities\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Additionally, variants in related proteins such as alanyl tRNA synthetase (AARS -MIM # 616339) have been associated to microcephaly, hypomyelination and epilepsy, and in ribosomal proteins such as RPS23 (MIM # 617412) to ID, brachycephaly, trichomegaly and hearing loss, or in RPL10 (MIM # 300998) to ID, ASD, and cerebellar hypoplasia\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eConcerning our patient, his mother manifested hypertension during the third trimester of pregnancy. No other reported individual with DOHH-D displayed maternal hypertension. However, 4/5 DHPS-D individuals were diagnosed with preeclampsia. Basic speaking was acquired, on the contrary to most DOHH-D and DHPS-D, but as EIF5A-D cases. Hypotonia was present as in most DOHH-D and DHPS-D, along with dystaxic and crouch gait. No ADHD was described among DOHH-D patients, but happy demeanor was also reported. Brain MRI (9-years-old) was unremarkable, on the contrary to all DOHH-D individuals (cortical atrophy). No cardiac malformations, visual impairment or recurrent infections were present, opposite to most DOHH-D individuals (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the description of the epilepsy features of our patient, and the rest of individuals diagnosed with hypusination-related disorders. No patient with EIF5A-D was diagnosed with epilepsy (it has been proposed that heterozygous variants in EIF5A-D allow higher residual activity of eIF5A, giving rise to milder phenotypes\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e). Our patient presented with a phenotype resembling Dravet syndrome, including early hemiclonic, focal, tonic and tonic-clonic seizures, triggered by temperature elevation, infections and excitement, refractory to antiseizure medication, evolving to developmental and epileptic encephalopathy, and occurrence of tonic-clonic seizures during sleep after adolescence, along with posterior-predominant multifocal interictal activity. DOHH-D reported patients presented later epilepsy onsets, displaying mainly generalized epilepsies with 2/3 manifesting focal and generalized fever-triggered seizures. DHPS-D patients also presented with later epilepsy onsets, displaying mainly generalized epilepsies (2/4 with continuous spike-wave during sleep patterns) with 2/4 manifesting focal and generalized fever or infection-triggered seizures, along with posterior-predominant focal or multifocal interictal activity in 2/4. Regarding response to therapies, our patient is partially responsive to valproic acid, and 50% responder to fenfluramine along with cognitive and behavioral improvements, without response to several sodium channel blockers, except for low dose lacosamide used to improve nocturnal seizures\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Among the rest of DOHH-D reported patients, 2/3 were refractory and 1/3 controlled with unspecified anti-seizure medications. One out of 4 individuals with DHPS-D was reported to be refractory, the rest showing responses to oxcarbazepine, valproic acid and low-carbohydrate diet.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEpilepsy phenotype of hypusination disorders.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDOHH-D (Beltr\u0026aacute;n-Corbellini et al.) N\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDOHH-D (Ziegler et al.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDHPS-D\u003c/p\u003e \u003cp\u003e(Ganapathi et al.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at epilepsy onset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndividual 2: 5 years\u003c/p\u003e \u003cp\u003eIndividual 3: 3 years\u003c/p\u003e \u003cp\u003eIndividual 5: NS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndividual 1: 2 years\u003c/p\u003e \u003cp\u003eIndividual 2: 2.5 years (unclear episodes before)\u003c/p\u003e \u003cp\u003eIndividual 3: 4 years (suspicion)\u003c/p\u003e \u003cp\u003eIndividual 4: 5 years\u003c/p\u003e \u003cp\u003eIndividual 5: 5 years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizure type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 months-7 years:\u003c/p\u003e \u003cp\u003e-Typical and hemiclonic febrile seizures\u003c/p\u003e \u003cp\u003e-Status epilepticus while in the swimming pool\u003c/p\u003e \u003cp\u003e7\u0026ndash;16 years\u003c/p\u003e \u003cp\u003e-Focal unaware motor seizures\u003c/p\u003e \u003cp\u003e-Tonic seizures\u003c/p\u003e \u003cp\u003e-During wakefulness and sleep, occasionally in clusters, triggered by temperature changes, excitement or physical activity\u003c/p\u003e \u003cp\u003e16 years-onwards:\u003c/p\u003e \u003cp\u003e-GTCS\u003c/p\u003e \u003cp\u003e-Predominantly during sleep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndividual 2: fever-triggered GTCS\u003c/p\u003e \u003cp\u003eIndividual 3: drop attacks at the age of 11 years, myoclonic seizures at the age of 15 years, fever-triggered focal and generalized seizures at the age of 16 years\u003c/p\u003e \u003cp\u003eIndividual 5: hyperextension of upper limbs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndividual 1: absences\u003c/p\u003e \u003cp\u003eIndividual 2: single infection-triggered GTCS (staring episodes before)\u003c/p\u003e \u003cp\u003eIndividual 3: unclear staring spells\u003c/p\u003e \u003cp\u003eIndividual 4: fever-triggered focal seizure at the age of 5 years, infection-triggered generalized tonic \u003cem\u003estatus epilepticus\u003c/em\u003e at the age of 7 years\u003c/p\u003e \u003cp\u003eIndividual 5: absences and GTCS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndividual 2: NS\u003c/p\u003e \u003cp\u003eIndividual 3: GE\u003c/p\u003e \u003cp\u003eIndividual 5: GE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndividual 1: CSWS\u003c/p\u003e \u003cp\u003eIndividual 2: NS\u003c/p\u003e \u003cp\u003eIndividual 3: CSWS\u003c/p\u003e \u003cp\u003eIndividual 4: NS\u003c/p\u003e \u003cp\u003eIndividual 5: NS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 months-4 years:\u003c/p\u003e \u003cp\u003e-Unremarkable routine EEG\u003c/p\u003e \u003cp\u003e4\u0026ndash;20 years:\u003c/p\u003e \u003cp\u003e-24-hour video-EEG showing focal left frontal or right posterior quadrant interictal activity.\u003c/p\u003e \u003cp\u003e20\u0026ndash;23 years:\u003c/p\u003e \u003cp\u003e-24-hour video-EEG showing multifocal interictal activity\u003c/p\u003e \u003cp\u003e23 years-onwards:\u003c/p\u003e \u003cp\u003e-Unremarkable 24-hour video-EEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndividual 2: NS\u003c/p\u003e \u003cp\u003eIndividual 3: NS\u003c/p\u003e \u003cp\u003eIndividual 5: normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndividual 1: posterior temporal and parietal interictal activity\u003c/p\u003e \u003cp\u003eIndividual 2: focal bilateral temporal-occipital interictal activity\u003c/p\u003e \u003cp\u003eIndividual 3: multifocal interictal activity\u003c/p\u003e \u003cp\u003eIndividual 4: multifocal interictal activity\u003c/p\u003e \u003cp\u003eIndividual 5: NS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse to therapy and evolution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVPA: behavior improvement)\u003c/p\u003e \u003cp\u003eLEV: partial improvement in seizure frequency, but irritability.\u003c/p\u003e \u003cp\u003eCLB: partial improvement in seizure frequency\u003c/p\u003e \u003cp\u003eFFN: 50% responder, with improvement in intensity and duration and cessation of clusters, along with cognitive and behavior improvements.\u003c/p\u003e \u003cp\u003eLTG, OXC, PER: no effectivity.\u003c/p\u003e \u003cp\u003eMethylphenidate: no effectivity.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndividual 2: controlled by ASMs, and stopping at the age of 11\u003c/p\u003e \u003cp\u003eIndividual 3: NS\u003c/p\u003e \u003cp\u003eIndividual 5: NS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndividual 1:\u003c/p\u003e \u003cp\u003eSulthiame led to a 25% reduction in nocturnal interictal activity.\u003c/p\u003e \u003cp\u003eCBD/THC high ratio improved receptivity and sleep.\u003c/p\u003e \u003cp\u003eUnresponsive to LEV, solumedrol, CLB, CLN, VPA, KD, prednisone.\u003c/p\u003e \u003cp\u003eIndividual 2: KD markedly improved language skills, stimulants improved ADHD\u003c/p\u003e \u003cp\u003eIndividual 3: partial improvement in the frequency of spells with OXC\u003c/p\u003e \u003cp\u003eIndividual 4: VPA led to a good seizure control\u003c/p\u003e \u003cp\u003eIndividual 5: responder to low carbohydrate diet and OXC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eDOHH-D: DOHH-related disorders; DHPS-D: DHPS-related disorders; NS: not specified; GTCS: generalized tonic-clonic seizures; DEE: developmental and epileptic encephalopathy; GE: generalized epilepsy; CSWS: continuous spike-wave during sleep; VPA: valproic acid; LEV: levetiracetam; CLB: clobazam; FFN: fenfluramine; LTG: lamotrigine; OXC: oxcarbazepine; PER: perampanel; ASM: anti-seizure medication; CBD/THC: cannabidiol/tetrahydrocannabinol; CLN: clonazepam; KD: ketogenic diet; ADHD: attention deficit with hyperactivity disorder.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003ePlace for\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe phenotype of our patient seems to be milder than the described for most of the rest of DOHH-D cases. Variant c.455C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Pro152Leu) in DOHH was previously reported by Ziegler et al.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e in their individual 4 (along with other missense variant), and individual 5 (along with other truncating variant). Basing on several functional approaches, they describe a drastical reduction in the amount of DOHH protein in individual 4 (20% of controls), accounting it for protein instability rather than the loss of activity, along with an accumulation of the inactive unhydroxylated deoxyhypusine-containing eIF5A. Individual 4 of Ziegler et al. (2 missense variants, as our patient), was the only one acquiring speaking capacity (as our patient). However, he did not develop epilepsy, and did show cortical atrophy, cardiac malformations and horizontal nystagmus (opposite to our patient). This might indicate that homozygous or compound heterozygous missense variants could give rise to a milder neurodevelopmental phenotype, warranting future confirmation.\u003c/p\u003e \u003cp\u003eTaking our patient into account, 5/8 displayed fever or infection-triggered seizures among DOHH-D and DHPS-D reported individuals with epilepsy, in some cases taking part of a wider Dravet-like phenotype. eIF5A has been reported as key for synthesizing bonds between successive proline residues during the elongation phase of translation process\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Thus, Faundes et al. have proposed that phenotypes of eIF5A-D patients could be explained by impaired synthesis of specific proteins rich in poly-proline tracts\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Loss-of-function variants in the widely-studied Proline-Rich Transmembrane Protein 2 (PRRT2), were identified in up to 18% of a cohort of 136 patients with febrile seizures (among other neurological and epilepsy syndromes), including febrile seizures plus, generalized epilepsy with febrile seizure plus and Dravet syndrome\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Moreover, PRRT2 has been demonstrated as an important negative modulator of sodium channels Nav1.2 (SCN2A gene) and Nav1.6 (SCN8A gene), leading to their hyperactivity if lacking\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Further, gain-of-function variants in SCN2A and SCN8A have been linked to Dravet-like phenotypes\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Although PRRT2 does not codify for long poly-proline tracts, it does include several proline-proline, and several proline-X-proline sequences in its proline-rich domain, and it could be hypothesized that febrile seizures in patients with eIF5A-HRD might be explained, at least partially, by a loss of function of PRRT2.\u003c/p\u003e \u003cp\u003eOn the other hand, eukaryotic elongation factor 2 kinase (EEF2K) phosphorylates and inactivates eukaryotic elongation factor 2 (EEF2, which catalyzes translation elongation), and thus, reducing the rate of protein synthesis. It has been observed that an increase in EEF2 function cooperates with the role of EIF5A during the elongation step of protein synthesis\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Furthermore, it has been reported that EEF2K knock out mice display enhanced GABAergic transmission, being less susceptible to seizures, and that EEF2K is upregulated in murine models of Dravet Syndrome, inactivating EEF2\u003csup\u003e24\u003c/sup\u003e. Taking this into consideration, it could be also hypothesized that decreased activity of EIF5A due to variants in DHPS and DOHH, might lead to a parallel inactivation of EEF2, and thus contributing to the arising of a fenfluramine-responsive Dravet-like phenotype. Finally, it has been reported that EIF5A point mutated form V81G in a certain strain of the yeast \u003cem\u003eSaccharomyces cerevisiae\u003c/em\u003e, led to a strongly temperature-sensitive phenotype\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Overall, the genetics of Dravet Syndrome without mutations in SCN1A\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and of epilepsies with fever-triggered seizures\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e is complex and remains to be clarified. In this context, these premises might establish an initial link associating eIF5A-HRD to these described neurodevelopmental and epilepsy phenotypes, definitely warranting further insight from future functional and clinical studies.\u003c/p\u003e \u003cp\u003eAs a literature review and a case report with hypotheses based on a small sample, this study has limitations. Further investigation will be needed in order to define the precise phenotype, the response to treatment, and the molecular basis of eIF5A-HRD.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eeIF5A-HRD are recently described entities and reported patients are scarce. Main phenotypic features consist of prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-severe NDD/ID and behavioral disorders. More than 70% of DHPS-D and DOHH-D patients present epilepsy, 63% of them with temperature-triggered seizures, and half of them refractory. Valproic acid or fenfluramine may be effective. Rare homozygous or compound heterozygous missense variants in these genes should be screened in patients with encephalopathy and temperature-triggered seizures. T-WES should be periodically reanalyzed in multidisciplinary teams in order to optimize diagnostic yield.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeIF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eeukaryotic translation initiation factors. eEF:eukaryotic translation initiation factors. eTF:eukaryotic translation termination factors. eIF5A:eukaryotic initiation factor 5A (protein). eIF5A-HRD:eIF5A and hypusination-related disorders. DHPS:deoxyhypusine synthase. DOHH:deoxyhypusine hydroxylase. EIF5A:eukaryotic initiation factor 5A (gene). DOHH-D:DOHH-related disorders. T-WES:trio-exome sequencing. eIF5A-D:eIF5A-related disorders. DHPS-D:DHPS-related disorders. NDD:neurodevelopmental delay. ID:intellectual disability. ASD:autism-spectrum disorders. LP:likely pathogenic. P:pathogenic. MRI:magnetic resonance imaging. ADHD:attention deficit with hyperactivity disorder. EEG:electroencephalogram. PRRT2:Proline-Rich Transmembrane Protein 2. EEF2K:eukaryotic elongation factor 2 kinase. EEF2:eukaryotic elongation factor 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThe local ethics committee waived the need for approval regarding this case report.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eWritten consent for publication was obtained from the parents of the patient.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eABC, RT, IGM, ISMR and AGN have received support from, and served as paid consultants for UCB Pharma. AVC has no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work has received no funding.\u003c/p\u003e\u003ch2\u003eAuthor\u0026rsquo;s contribution\u003c/h2\u003e \u003cp\u003eABC: conceptualization; data curation; formal analysis; investigation; methodology; resources; supervision; visualization; original draft preparation; review and editing. AVC: data curation; formal analysis; resources; review and editing. RT: investigation; review and editing. IGM: investigation; review and editing. ISMR: investigation; review and editing. AGN: conceptualization; methodology; supervision; visualization; original draft preparation; review and editing. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe thank the patient\u0026rsquo;s family for their collaboration and consent for publishing this work. 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Brain. 2022;145(2):416\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/brain/awac036\u003c/span\u003e\u003cspan address=\"10.1093/brain/awac036\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neurodevelopmental-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jndd","sideBox":"Learn more about [Journal of Neurodevelopmental Disorders](http://jneurodevdisorders.biomedcentral.com/)","snPcode":"11689","submissionUrl":"https://submission.nature.com/new-submission/11689/3","title":"Journal of Neurodevelopmental Disorders","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"eukaryotic translation factors, DOHH, DHPS, EIF5A, developmental and epileptic encephalopathy, refractory epilepsy, febrile seizures, Dravet Syndrome, fenfluramine","lastPublishedDoi":"10.21203/rs.3.rs-3837969/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3837969/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEukaryotic initiation factor 5A (eIF5A) and hypusination-related disorders (eIF5A-HRD) are recently described diseases caused by pathogenic heterozygous variants in the translation factor EIF5A or biallelic variants in the two enzymes involved in the post-translational synthesis of hypusine in the eIF5A precursor, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH), necessary for its activation. We review the current knowledge regarding eIF5A-HRD, and report the case of the sixth and oldest known patient with DOHH-related disorder (DOHH-D), aiming to expand and discuss the molecular basis and the general and epilepsy phenotypes of this group of diseases.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eLiterature review yielded one paper describing 7 individuals with eIF5A-related disorders (eIF5A-D), one reporting 5 subjects with DHPS-related disorders (DHPS-D) and one characterizing 5 individuals with DOHH-D. Main phenotypic features consisted of prenatal issues, hypotonia, dysmorphisms, microcephaly, moderate-severe neurodevelopmental disorders/intellectual disability and behavioral disorders. We report the case of a 24-years-old male with DOHH-D manifesting as Dravet-like syndrome. He displays microcephaly and neurodevelopmental delay with attention deficit with hyperactivity disorder, along with a happy demeanor. Basic language skills and ambulation capacity with crouch gait are preserved. Onset of epilepsy was at 8 months with refractory temperature-triggered hemiclonic seizures and \u003cem\u003estatus epilepticus\u003c/em\u003e, followed by nocturnal tonic-clonic seizures from adolescence. Fenfluramine was the most effective approach, reducing seizure intensity, duration and frequency, and contributing to cognitive and behavior improvements. No patient with eIF5A-D presented seizures. Taking our patient into account, 4/5 and 4/6 reported individuals with DHPS-D and DOHH-D, respectively, presented epilepsy. Seven out of 8 epilepsy patients debuted between 2 and 5 years, most of them presented developmental and epileptic encephalopathies or generalized epilepsies (5/8 with temperature or infection-triggered seizures), and 4/8 were refractory. We hypothesize that dysregulation of PRRT2 and EEF2K might contribute to the eIF5A-HRD phenotype.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eeIF5A-HRD are recently described entities displaying neurodevelopmental disorders and microcephaly, and reported patients are scarce. More than 70% of DHPS-D and DOHH-D patients present epilepsy, 63% of them with temperature-triggered seizures. Valproic acid or fenfluramine may be effective. Rare homozygous or compound heterozygous missense variants in these genes should be screened in patients with encephalopathy and temperature-triggered seizures.\u003c/p\u003e","manuscriptTitle":"eIF5A and hypusination-related disorders: literature review and case report of DOHH-related encephalopathy.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-03 13:08:46","doi":"10.21203/rs.3.rs-3837969/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-01-03T17:10:48+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-07-09T16:13:17+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-21T19:22:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-02-29T19:42:36+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neurodevelopmental Disorders","date":"2024-02-20T01:54:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neurodevelopmental-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jndd","sideBox":"Learn more about [Journal of Neurodevelopmental Disorders](http://jneurodevdisorders.biomedcentral.com/)","snPcode":"11689","submissionUrl":"https://submission.nature.com/new-submission/11689/3","title":"Journal of Neurodevelopmental Disorders","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c322a3a0-542b-4756-ae50-501f480ad6cc","owner":[],"postedDate":"June 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T16:02:15+00:00","versionOfRecord":{"articleIdentity":"rs-3837969","link":"https://doi.org/10.1186/s11689-025-09649-x","journal":{"identity":"journal-of-neurodevelopmental-disorders","isVorOnly":false,"title":"Journal of Neurodevelopmental Disorders"},"publishedOn":"2025-08-29 15:57:47","publishedOnDateReadable":"August 29th, 2025"},"versionCreatedAt":"2024-06-03 13:08:46","video":"","vorDoi":"10.1186/s11689-025-09649-x","vorDoiUrl":"https://doi.org/10.1186/s11689-025-09649-x","workflowStages":[]},"version":"v1","identity":"rs-3837969","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3837969","identity":"rs-3837969","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}