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Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

AIAN-27-465
10.4103/aian.aian_253_24
Letters to the Editor
Neurodevelopmental Disorder with Severe Motor Impairment and Absent Language (NEDMIAL) Due to DHX30 Mutations: First Indian Report of Two Cases
Gunasekaran Pradeep Kumar
Sharma Yashu
Bhatia Vikas 1
Saini Arushi Gahlot
Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
1 Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Address for correspondence: Dr. Arushi Gahlot Saini, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India. E-mail: doc.arushi@gmail.com
Jul-Aug 2024
16 8 2024
27 4 465466
02 4 2024
04 7 2024
18 7 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
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pmcDear Editor,

An 18-month-old boy presented with global developmental delay predominant in the motor and language domains. At this age, he was able to hold the neck and turn from supine to prone partially, but could not sit unsupported. He attained mouthing and could grasp a toy when placed in his hands, but could not reach out or transfer them between his hands. He had attained cooing, followed by monosyllables, and had social smile and stranger anxiety. He was first born to nonconsanguineously married parents. He had a delayed cry at birth (cried after physical stimulation), but there was no history of neonatal encephalopathy, seizures, respiratory distress, or hypoglycemia. He was initiated on breastfeeding immediately after birth. On examination, he had microcephaly, wide intercanthal distance, upturned nose, prominent columella, mild retrognathia, stubby hand, tapering fingers, flat feet [Figure 1a–d], central hypotonia, normal fundi, and hand stereotypies in the form of slow, writhing movements at the wrist, intermittent hand flapping, and frequent rubbing of the face. He was evaluated for a genetic etiology of developmental delay. Mass spectrometry from blood and urine was normal. Neuroimaging showed nonspecific hyperintensities in the periventricular and deep white matter of bilateral frontoparietal regions. Whole exome analysis showed a heterozygous, missense variation c.2344C>T in exon 15 of DHX30 gene located on chromosome 3, resulting in the amino acid substitution of tryptophan for arginine at the codon 782 (p.Arg782Trp), suggestive of neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL). The variant was confirmed by Sanger sequencing and was not detected in the parents. It was reported as pathogenic in the ClinVar database. The in silico predictions of the variant are damaging by SIFT and MutationTaster2 software.

Figure 1 (a–d) Microcephaly, wide intercanthal distance (a), prominent columella, mild retrognathia (b), stubby hand and tapering fingers (c), and flat feet (d)

A 12-month-old boy presented with global developmental delay. He was not able to sit without support and did not use bisyllables. His developmental quotients were 25% in the gross motor domain, 40% in the fine motor domain, 35% in the language domain, and 40% in the social domain. He was first born to nonconsanguineously married parents. Perinatal period was uneventful, and family history was unremarkable. On examination, he had facial dysmorphism with low-set ears, micrognathia, microcephaly (head circumference 42 cm, -3.17 Z), and central hypotonia. Fundus examination was normal. Magnetic resonance imaging of the brain revealed nonspecific periventricular white matter changes attributed to developmental change. Mass spectrometry from blood and urine was normal. Whole exome analysis showed a heterozygous, missense variation c.1562G>A in exon 8 of DHX30 gene located on chromosome 3, resulting in the amino acid substitution of histidine for arginine at the codon 521 (p.Arg521His), suggestive of NEDMIAL. The observed variation has previously been reported (p.Arg493His) in patients affected with neurodevelopmental disorders.[1] The variant was not detected in the parents and was reported as pathogenic in the ClinVar database. The in silico predictions of the variant are damaging by SIFT, PolyPhen-2 (HumDiv), and MutationTaster2 software.

NEDMIAL (MIM#617804) is an autosomal dominant, neurodevelopmental disorder recently described by Lessel et al.[1] in 2017 and is caused by heterozygous pathogenic variation in the DHX30 (DExH-box helicase 30) gene (MIM*616423) on chromosome 3p21.31.[12] The DHX30 gene encodes ATP-dependent RNA helicases that are involved in unwinding of the RNA duplex and remodeling of the structure of RNA–protein complexes.[2] RNA helicases are involved significantly in the metabolism of cellular RNA. DHX30 was initially assigned a role in the antiviral functions of the cell, including antiretroviral activity in 2008, and subsequently assigned a role in differentiation during embryogenesis and early development in mouse models in 2015.[345] Finally, the involvement of DHX30 in intellectual disability (ID) was uncovered in 2017 by Lessel et al.,[1] and they reported several de novo missense variants in individuals with intellectual disability, gait, and speech abnormalities.

NEDMIAL is a neurodevelopmental disorder characterized by severe psychomotor delay, minimal or absent speech development, and central hypotonia from early years in life, resulting in feeding difficulties and either inability to walk or an ataxic gait in those who achieve ambulation. Neurodevelopmental problems include intellectual disability and autism spectrum disorder. These cognitive disturbances are often accompanied by behavioral problems such as repetitive hand flapping, stereotypies, reduced concentration, or sleep.[26] Facial dysmorphism may be nonspecific and may include microcephaly, synophrys, low-set ears, micrognathia, high-arched palate, tapered fingers, overlapping teeth, and overlapping toes.[678] In the early years, the phenotype may overlap with genetic syndromes such as Rett’s, Angelman, Prader–Willi, or Fragile-X syndrome.[69] Seizures, sleep disturbances, joint hypermobility, and pleasant/smiling behavior have been reported.[128] Primary amenorrhea in NEDMIAL was reported by Miyake et al.[10] in a 19-year-old Brazilian female in 2021. Cross et al.[9] observed cryptorchidism and adducted thumbs in two American siblings of 15 months and 3 weeks of age with NEDMIAL disorder. Ueda et al.[6] reported delayed puberty in a 22-year-old Japanese male in 2021.

The neuroimaging features of NEMDIAL are nonspecific and vary from normal to delayed myelination, cerebral and cerebellar atrophy, ventricular dilatation, and corpus callosum abnormalities.[167] Due to the limited number of reported cases, no specific genotype–phenotype correlation has been noted, but missense variations within the helicase core motif have been associated with a severe phenotype, whereas patients with haploinsufficiency, protein-truncating variants, and mosaicism have been associated with milder phenotype of the disorder.

In conclusion, NEDMIAL is a newly recognized neurodevelopmental disorder with global developmental delay, marked speech impairment, central hypotonia, and subtle dysmorphic features. Due to the phenotypic overlap with several neurodevelopmental disorders in the early years, genetic testing would offer correct diagnosis. Currently, there are no specific neuroimaging, electrophysiologic, or biochemical markers, but this may change with more descriptions of the cases. We have presented the first Indian report of two children with NEDMIAL.

Ethical publication statement

We conﬁrm that we have read the journal’s position on issues involved in ethical publication and aﬃrm that this report is consistent with those guidelines.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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