A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with poor growth and behavioral abnormalities (NEDGBA) is caused by homozygous or compound heterozygous mutation in the ATP9A gene (609126) on chromosome 20q13.

Neurodevelopmental disorder with poor growth and behavioral abnormalities (NEDGBA) is an autosomal recessive disorder characterized by global developmental delay, moderately to severely impaired intellectual development, often with absent speech, and behavioral abnormalities, including hyperactivity, short attention span, and ADHD. Affected individuals show failure to thrive with poor overall growth; some have microcephaly. Additional features may include nonspecific facial dysmorphism, hypotonia, and feeding difficulties (Vogt et al., 2022; Meng et al., 2023).

Vogt et al. (2022) reported 3 patients from 2 unrelated consanguineous families of Syrian (family A) and Turkish (family B) descent, respectively, with a similar neurodevelopmental disorder who were ascertained through the GeneMatcher program after exome sequencing identified biallelic loss-of-function mutations in the ATP9A gene. The patients, who ranged from 4.5 to 12 years of age, showed global developmental delay with mildly delayed walking, poor fine motor skills, impaired intellectual development (IQ of 50 to 60 in 1 individual who was able to attend a special school), and poor speech development. All had a short attention span, 1 had hyperactivity, and 2 had sleep disturbances. The patients showed failure to thrive and poor overall growth with postnatal microcephaly (down to -3.58 SD); 2 had short stature. They had feeding difficulties with frequent emesis, gastroesophageal reflux, and chronic gastritis, requiring tube feeding in 1 individual. Common dysmorphic features included smooth philtrum and thin upper lip; 1 patient had strabismus and another had a high-arched palate. One individual had impaired vision due to hyperopia and astigmatism. Brain imaging was performed in 2 patients: 1 had normal results, whereas the other (patient 3 from family B) had hypoplasia of the cerebellar vermis and corpus callosum and delayed myelination.

Mattioli et al. (2021) reported 3 patients from 2 unrelated consanguineous families of Pakistani (family 1) and Iranian (family 2) origin with NEDGBA. Two sibs in family 1 were 28 and 21 years of age, whereas the only affected individual in family 2 was 11 years old. They all showed severe intellectual disability with poor or absent speech, poor gross and fine motor skills, and variable behavioral abnormalities, including ADHD, stereotypic movements, autistic features, and aggression. The 11-year-old had onset of seizures at 3 years, which were well-controlled. The patients had strabismus, eye squint, impaired vision, and nonspecific dysmorphic features. One patient had mild microcephaly (-3.12 SD). Brain imaging, performed in the 11-year-old, was normal.

Meng et al. (2023) reported 3 patients from 2 unrelated families, 2 sibs from a nonconsanguineous Chinese family (family 1) and 1 child from a consanguineous Pakistani family (family 2), with NEDGBA. A 15-year-old boy in family 1 showed developmental delay since infancy and had severe intellectual disability, absent speech, lack of social interactions, sleep disturbances, and ADHD. Physical examination showed coordination deficits, limb muscle weakness with hyporeflexia, joint hypermobility, and knee and elbow contractures. His younger sister had a similar phenotype. An 11-year-old girl from family 2 had global developmental delay, impaired intellectual development (IQ of 58), absent speech, hypotonia, delayed fine motor skills, speech problems, sleep disturbances, and ADHD. All had small head circumference and poor overall growth. They were severely disabled and highly dependent on their caregivers. Brain imaging showed variable and nonspecific abnormalities in all patients.

The transmission pattern of NEDGBA in the families reported by Vogt et al. (2022) was consistent with autosomal recessive inheritance.

In 3 patients from 2 unrelated consanguineous families with NEDGBA, Vogt et al. (2022) identified homozygous loss-of-function mutations in the ATP9A gene (609126.0001 and 609126.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither was present in the gnomAD database. Patient fibroblasts showed almost absent ATP9A mRNA expression, consistent with a loss of function.

In 2 sisters, born of consanguineous Pakistani parents (family 1) with NEDGBA, Mattioli et al. (2021) identified a homozygous splice site mutation in the ATP9A gene (609126.0003). The mutation, which was found by whole-exome sequencing and homozygosity mapping and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function. Another patient, an 11-year-old boy born of consanguineous Iranian parents (family 2), with a similar disorder was also found to have a homozygous splice site variant in the ATP9A gene (c.327+1G-T) that was absent in gnomAD and segregated with the disorder in the family. However, he also carried several homozygous variants in other genes that may have contributed to the phenotype (e.g., CCDC88C, 611204 and ZNF407, 615894).

In 3 children from 2 unrelated families with NEDGBA, Meng et al. (2023) identified homozygous or compound heterozygous nonsense mutations in the ATP9A gene (609126.0004-609126.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Leukocytes derived from 1 of the patients showed significantly decreased ATP9A mRNA and protein levels compared to controls. In vitro studies showed that 2 of the mutations (609126.0004 and 609126.0005) failed to colocalize with ATP9A interacting partners and were unable to rescue endocytic defects in Atp9a-null rat primary cortical neurons, consistent with a loss of function.

Meng et al. (2023) found that Atp9a-null mice, generated through CRISPR/Cas9 technology, had decreased overall survival and increased infertility compared to control mice. Atp9a-null mice displayed behavioral abnormalities, including impaired muscle strength, impaired hippocampus-dependent spatial learning and memory, and hyperactive/hyperkinetic movements. Pyramidal neurons from the motor cortex and neurons from the hippocampus of mutant mice showed reduced dendritic arborization and reduced density of dendritic spines compared to controls, suggesting damaged neurite morphology and synaptic structure. Electrophysiologic studies confirmed impaired excitatory synaptic transmission in the primary motor cortex and hippocampus. These findings implicated ATP9A in the regulation of synaptic function in the brain.