A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with hypotonia and seizures (NEDHS) is caused by homozygous or compound heterozygous mutation in the OTUD7A gene (612024) on chromosome 15q13.

See also chromosome 15q13.3 deletion syndrome (612001), which is a contiguous gene deletion syndrome that includes the OTUD7A gene and shows overlapping clinical features. Individuals who are heterozygous for the 15q13.3 deletion have a milder phenotype than those who are homozygous for the deletion.

Neurodevelopmental disorder with hypotonia and seizures (NEDHS) is an autosomal recessive disorder characterized by hypotonia apparent from early infancy, global developmental delay with severely impaired intellectual development, and early-onset seizures. Heterozygous mutation carriers show a milder neurocognitive disorder with learning disabilities, similar to chromosome 15q13.3 deletion syndrome (Garret et al., 2020; Suzuki et al., 2021).

Garret et al. (2020) reported a 28-month-old boy, born of consanguineous Portuguese parents, who presented in infancy with hypotonia and abnormal movements that evolved into infantile spasms with hypsarrhythmia on EEG. The spasms were controlled with vigabatrin. Subsequent EEG showed a continuous sleep and awake abnormal background pattern with frequent multifocal sharp waves. Brain imaging at 15 months of age showed nonspecific signal abnormalities in the globus pallidi and thalamus, enlarged subarachnoid space, sulcal widening of the cerebral hemispheres, and thin corpus callosum, all of which may have been related to vigabatrin treatment. The patient became seizure-free without medication at 18 months of age, but had recurrence of atypical absence seizures with a motor component at 28 months. He had global developmental delay with hypotonia, inability to walk (he achieved sitting at age 23 months), severely impaired intellectual development, poor speech with only a few words, and poor overall growth. His parents both had learning disabilities and completed middle school, but not high school. His brother also had nonspecific learning difficulties.

Suzuki et al. (2021) reported a 3-year-old Japanese boy, born of unrelated parents, who showed hypotonia and global developmental delay from birth. He sat at 36 months and stood with support at 39 months. He had severely impaired intellectual development and dysmorphic features, including large ears, downslanting palpebral fissures, tented upper lip, and scoliosis. He had 2 episodes of febrile seizures at 14 and 20 months of age, and an afebrile tonic seizure at age 3 years. Seizures occurred several times a month, but the number of seizures gradually decreased without medication. Brain imaging and EEG were normal.

The transmission pattern of NEDHS in the family reported by Garret et al. (2020) was consistent with autosomal recessive inheritance.

In a 28-month-old boy, born of distantly consanguineous Portuguese parents, with NEDHS, Garret et al. (2020) identified a homozygous missense mutation in the OTUD7A gene (L233F; 612024.0001). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each parent, both of whom had learning disabilities. The variant was not present in the gnomAD database. Patient fibroblasts showed decreased enzymatic activity of the 20S proteasome complex compared to controls. Although levels of the 20S and 26S proteosomes were normal, there were decreased amounts of the PA28 (see PA28A; 600654)-20S and free PA28 complexes, as well as decreased levels of certain PA28 and 20S proteasome subunits. Similar findings were observed in OTUD7A-null HAP1 cells. The reduced proteasome activity was associated with accumulation of insoluble proteins modified with K48-linked ubiquitin chains targeted for proteasome-mediated degradation, indicating disrupted protein homeostasis.

In a 3-year-old boy with NEDHS, Suzuki et al. (2021) identified compound heterozygous loss of the OTUD7A gene. He had a de novo heterozygous frameshift mutation (612024.0002) and a de novo heterozygous 1.6-Mb microdeletion of chromosome 15q13.3, which included the OTUD7A gene (see 612001). The point mutation was found by trio-based exome sequencing and confirmed by Sanger sequencing, whereas the deletion was identified through copy number variant analysis. Neither parent carried the mutation or the deletion. Studies of patient cells were not performed, but homozygous expression of the frameshift mutation in the C. elegans homolog resulted in impaired locomotion and disturbed synaptic transmission (see ANIMAL MODEL). The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons.

The OTUD7A homolog in C. elegans is otub2, which is expressed in the nervous system. Suzuki et al. (2021) found that C. elegans carrying a homozygous CRISPR/Cas9-generated mutation in the otub2 gene that corresponded to a frameshift mutation identified in a human patient (612024.0002) developed normally, but had impaired locomotion with disturbed movement patterns and smaller movement amplitudes compared to wildtype. This abnormality was not observed in heterozygous mutant worms. The authors concluded that the frameshift mutation is a loss-of-function allele and that the motor defects could have resulted from reduced synaptic transmission from motor neurons to body wall muscles.