A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF) is caused by heterozygous mutation in the PURA gene (600473) on chromosome 5q31.

Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF) is characterized by severe hypotonia at birth associated with respiratory difficulties, including apnea and hypoventilation, and feeding difficulties. Many infants require ventilatory support or feeding tubes. Affected patients have global developmental delay, often never achieving walking or speech, although the severity can be variable. Additional common features may include seizures, exaggerated startle reflex, abnormal movements, and dysmorphic facial features. Brain imaging often shows hypomyelination and parenchymal atrophy. A subset of patients may have systemic features, such as cardiac defects, scoliosis, endocrine anomalies, constipation, or cryptorchidism (summary by Reijnders et al., 2018).

Lalani et al. (2014) reported 11 unrelated children with a similar neurodevelopmental disorder characterized by neonatal hypotonia, severely delayed psychomotor development, early-onset feeding difficulties, and significant respiratory insufficiency. Almost all had early-onset seizures, often myoclonic, but also generalized. Most had an abnormal EEG pattern, and 2 developed an epileptic encephalopathy consistent with a clinical diagnosis of Lennox-Gastaut syndrome. Hypomyelination or delayed myelination was noted on brain imaging studies in 4 individuals. Most patients were nonverbal and nonambulatory. Dysmorphic facial features were variable and nonspecific except for myopathic facies, often with open mouth and high-arched palate, nystagmus, and strabismus in many patients. Lalani et al. (2014) noted the phenotypic overlap with chromosome 5q31.3 microdeletion syndrome (Brown et al., 2013).

Hunt et al. (2014) reported 4 unrelated girls with neurodevelopmental delay. Two patients were severely affected, with hypotonia and apneic episodes at birth and severely delayed psychomotor development; neither could walk at ages 4 and 6 years, respectively, and both were essentially nonverbal. Both patients also had dysconjugate gaze and either seizures or seizure-like episodes. Brain MRI of both patients showed delayed myelination. The other 2 girls, 12 and 14 years of age, were able to walk with a broad-based gait and could speak with limited vocabulary. One was hypotonic and had seizure-like episodes. Brain imaging was normal in these 2 patients. All patients had mild but variable dysmorphic features, including hypotonic facies, prominent or high forehead, telecanthus, and upslanting palpebral fissures. One girl had gonadotropin-dependent precocious puberty and another had elevated prolactin levels soon after birth as well as blunted cortisol response to stress, suggesting that endocrine abnormalities may be part of the disorder.

The Deciphering Developmental Disorders Study (2015) reported 3 female patients with global developmental delay and various syndromic features who carried heterozygous de novo mutations in the PURA gene. One additionally had generalized hypotonia, cafe-au-lait spot, and unsteady gait; the second had delayed CNS myelination, epicanthus, short nose, deep philtrum, and edema; and the third had microcephaly, facial asymmetry, strabismus, hypertelorism, bilateral ptosis, overlapping toe, and anxiety.

Tanaka et al. (2015) reported 6 unrelated children, ranging from 6 months to 15 years of age, with moderate to severely delayed psychomotor development, lack of speech, and hypotonia. One was noted to have neonatal apnea. Two patients had seizure-like activity, and 5 had variable visual impairment, mainly esotropia and strabismus, although 1 had cortical visual impairment. Four patients had variable dysmorphic features, such as epicanthal folds, high-arched palate, dolichocephaly, hypertelorism, and broad forehead. Four had variable brain imaging abnormalities, including delayed myelination, enlarged ventricles, thin corpus callosum, and periventricular white matter changes.

Mayorga et al. (2018) reported a 2-year-old girl with NEDRIHF. She presented in the first week of life with hypotonia, poor feeding, failure to thrive, seizures, and apnea requiring ventilatory support. Hiccuping was noted during the neonatal period. EEG showed a burst suppression pattern and hypsarrhythmia. Brain imaging revealed cerebellar vermis hypoplasia, cystic dilatation, mega cisterna magna, and hypomyelination. She also had anemia requiring blood transfusion with negative hematologic work-up, and hypoglycorrhachia without peripheral hypoglycemia. CSF lactate was also decreased. Mutation in the SLC2A1 gene (GLUT1; 138140) was excluded, although there was reduced expression of GLUT1 in patient red blood cells compared to controls. During the first months of life, she developed left ventricular hypertrophic myocardiopathy although cardiac function remained normal. At age 2 years, she had a social smile and strabismus, but could not sit on her own and was nonverbal.

Reijnders et al. (2018) reported 32 individuals with NEDRIHF who ranged in age from infancy to young adult. Some patients were noted to have hiccups in utero and more than half were born after 41 weeks' gestation. All newborns had neonatal problems, including significant generalized hypotonia, feeding difficulties (81%), and respiratory insufficiency with apnea and congenital hypoventilation (48%). Many required oxygen supplementation, mechanical ventilation, and/or tube feeding. Hypersomnolence (66%), hypothermia (37%), and exaggerated startle response (58%) were also observed in a significant number of patients. All had global developmental delay with severely delayed walking or inability to walk and moderate to severely impaired intellectual development with poor or often absent speech; 42% never achieved independent ambulation and 91% were nonverbal. Gait, if achieved, was often unstable and broad-based or ataxic. Abnormal movement was sometimes observed: 3 had spasticity, several had stereotypic hand movements, and 6 had dystonia or chorea-like movements. Five had a peripheral neuropathy. Sixteen (50%) patients had onset of various types of seizures in the first decade; in some cases the epilepsy was refractory. About 30% of patients had abnormal findings on brain imaging, including delayed myelination, white matter abnormalities, parenchymal atrophy, and underdeveloped rostrum of the corpus callosum. About half had visual problems or eye anomalies, most often strabismus, although 4 had nystagmus, and 3 reportedly had cortical visual impairment. Several patients had scoliosis, progressive hip dysplasia, and joint hyperlaxity, which may have been related to chronic hypotonia and delayed motor development. Most had dysmorphic facial features, commonly including hypotonic facies, high anterior hairline, full cheeks, almond-shaped palpebral fissures, well-defined philtrum, and retrognathia. A subset of patients had systemic involvement, including cardiac defects, constipation, gastroesophageal reflux, cryptorchidism, short stature, small hands and feet, and endocrine abnormalities, such as vitamin D deficiency or aberrant sex hormone levels.

Choi et al. (2021) reported 5 unrelated Korean patients with NEDRIHF associated with point mutations in the PURA gene and 2 additional patients with a similar phenotype associated with larger interstitial deletions at chromosome 5q31.3, including the PURA gene. There were no phenotypic differences between patients with point mutations and those with larger deletions (see also CYTOGENETICS). All 7 patients, who ranged from 3 to 18 years of age, had hypotonia and severe global developmental delay with inability to walk or speak. Many had poor visual fixation and tracking, sometimes with nystagmus. Feeding difficulties requiring tube feeding was common (80%), and apnea or respiratory distress in the neonatal period was observed in 3 patients (43%). Several patients had an exaggerated startle response or jerky movements; 2 patients had well-controlled seizures. Brain imaging showed decreased cerebral volume and delayed myelination. Five patients had distinctive facial features, including tented upper lip vermilion, long philtrum, strabismus, and depressed nasal bridge with anteverted nares. The 18-year-old girl had primary amenorrhea.

The heterozygous mutations in the PURA gene that were identified in patients with NEDRIHF by Reijnders et al. (2018) occurred de novo.

Brown et al. (2013) reported 2 unrelated children with a severe neurodevelopmental disorder associated with de novo heterozygous deletions of chromosome 5q31.3. Both patients presented at birth with significant hypotonia, central apnea, and myoclonic jerks. One child was conceived by in vitro fertilization. One child was nonverbal and nonambulatory at 6 years of age, whereas the other was standing with support and able to indicate needs with gestures at age 2, both consistent with delayed psychomotor development. Brain imaging in both patients showed diffuse T2-weighted white matter lesions and shallow immature sulcation in the frontal lobes, with evidence of delayed myelination in 1 patient who underwent serial imaging. The shortest region of deletion overlap in these patients was 101 kb, including the PURA gene, which Brown et al. (2013) considered to be the best candidate for the phenotype.

In 2 unrelated Korean patients (patients 1 and 2) with NEDRIHF, Choi et al. (2021) identified heterozygous interstitial deletions (0.45 and 2.5 Mb, respectively) of chromosome 5q31.2-q31.3 encompassing the PURA gene. Parental testing was not available. Functional studies were not performed. The phenotype was similar to that of patients with point mutations in the PURA gene.

Lalani et al. (2014) identified de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0001-600473.0005) in 11 (0.52%) of 2,117 pediatric patients with various neurodevelopmental disorders who underwent whole-exome sequencing. There were 4 truncating mutations, 5 missense mutations, and 2 in-frame deletions. Functional studies of the variants were not performed, but the presence of truncating mutations suggested at least a partial loss of protein function as responsible for the phenotype.

In 4 unrelated girls with NEDRIHF, Hunt et al. (2014) identified 4 different de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0006-600473.0008). Two mutations were truncating frameshifts, 1 was missense, and 1 was an in-frame deletion. The mutations were found by whole-exome sequencing; functional studies of the variants were not performed.

In 6 unrelated children with NEDRIHF, Tanaka et al. (2015) identified 6 different de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0008-600473.0010). The mutations, which were found by whole-exome sequencing, comprised missense, frameshift, and small intragenic deletions. Functional studies of the variants were not performed.

In a 2-year-old girl with NEDRIHF, Mayorga et al. (2018) used whole-exome sequencing to identify a de novo heterozygous frameshift mutation in the PURA gene (c.586delA). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a truncated dysfunctional protein.

Reijnders et al. (2018) reported 32 unrelated patients with NEDRIHF associated with de novo heterozygous mutations in the PURA gene. Most patients were identified through whole-exome sequencing in a research or clinical setting. There were missense, small deletions, and frameshift mutations that occurred throughout the gene. All missense variants occurred in a PUR domain. Although several mutations were recurrent (see, e.g., K97E, 600473.0004; F271del, 600473.0001; and F233del, 600473.0008), patients with the same mutations showed remarkable phenotypic variability. Functional studies of the variants and studies of patient cells were not performed. However, using molecular modeling, the authors classified the mutations according to their predicted effects on domain folding and protein function. Overall, there were no genotype/phenotype correlations.

In 5 unrelated patients (patients 3-7) with NEDRIHF, Choi et al. (2021) identified de novo heterozygous mutations in the PURA gene. There were 4 missense and 2 nonsense variants. Functional studies of the variants and studies of patient cells were not performed.

Khalili et al. (2003) found that Pura -/- mice appeared normal at birth, but at 2 weeks of age, they developed neurologic problems characterized by severe tremor and spontaneous seizures, and they died by 4 weeks. Regions of the hippocampus and cerebellum of Pura -/- mice showed severely lower numbers of neurons compared with wildtype littermates, and lamination of these regions was aberrant at time of death. Immunohistochemical analysis of Mcm7 (600592), a marker for DNA replication, revealed lack of proliferation of precursor cells in these regions in Pura -/- mice. Proliferation was also low or absent in several other tissues of Pura -/- mice, including those of myeloid lineage, whereas those of Pura +/- mice were intermediate. Evaluation of brain sections indicated reduced myelination and pathologic development of oligodendrocytes and astrocytes. At postnatal day 5, a critical time for cerebellar development, Pura and Cdk5 (123831) were both at peak levels in bodies and dendrites of Purkinje cells of wildtype mice, but both proteins were absent in dendrites of Pura -/- mice. Immunohistochemical analysis revealed dramatic reduction in both phosphorylated and nonphosphorylated neurofilaments in dendrites of the Purkinje cell layer and of synapse formation in the hippocampus. Khalili et al. (2003) concluded that PURA has a role in developmentally timed DNA replication in specific cell types.

Lalani et al. (2014) found that mutant Caenorhabditis elegans animals homozygous for a null allele of the PURA ortholog plp-1 were sterile and had defective locomotion compared to wildtype, suggesting a role for PURA in both germline and somatic neuronal tissues.