A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB) is caused by homozygous or compound heterozygous mutation in the PI4KA gene (600286) on chromosome 22q11.

Mutation in the PI4KA gene also causes spastic paraplegia-84 (SPG84; 619621), a milder autosomal recessive disorder with onset in the first 2 decades of life.

Neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities (NEDSPLB) is a severe autosomal recessive disorder characterized by global developmental delay with impaired intellectual development and poor or absent speech, axial hypotonia, and peripheral spasticity and hyperreflexia. Affected individuals may have feeding difficulties with gastroesophageal reflux and poor overall growth, as well as microcephaly and nonspecific dysmorphic facial features. Additional features may include nystagmus, inability to walk, ataxia, abnormal movements, and seizures. Brain imaging shows hypomyelination with decreased white matter volume, cerebral and cerebellar atrophy, and thin corpus callosum. Polymicrogyria may be observed in rare cases. Some patients have a primary immunodeficiency or gastrointestinal disturbances similar to inflammatory bowel disease (summary by Verdura et al., 2021, Salter et al., 2021).

Verdura et al. (2021) reported 8 unrelated patients, ranging from 3 to 19 years of age, with a similar neurodevelopmental disorder characterized by global developmental delay with delayed or absent walking, severe impaired intellectual development, and delayed or absent speech and language. Most had poor overall growth, including microcephaly in some. The severity was variable: several patients were unable to walk or speak and were completely dependent for daily activities, whereas others could walk or stand with assistance, usually with an ataxic or wide-based gait, and speak a few words. Additional neurologic signs included spastic paraparesis or tetraparesis, hyperreflexia, ankle clonus, extensor plantar responses, nystagmus, and abnormal movements, such as dystonia, tremor, or choreoathetosis. One patient had severe hypotonia and an axonal sensory neuropathy. All except 2 patients had seizures of variable severity, including at least 2 with status epilepticus; the seizures occurred in infancy or early childhood. One patient had sensorineural hearing loss with bilateral iris and retinal coloboma, and another had prolonged brainstem auditory responses without hearing loss. Brain imaging in all patients showed diffuse hypomyelination, reduced white matter volume, thin corpus callosum, cerebral atrophy, enlarged ventricles, cerebellar atrophy or hypoplasia, and sometimes brainstem hypoplasia. One patient had perisylvian polymicrogyria. A few patients had neonatal hypotonia and feeding problems requiring tube feeding; others had gastroesophageal reflux. Some patients had features suggestive of an immunodeficiency, including recurrent respiratory infections, otitis media, and pneumonia. One patient had hypogammaglobulinemia with a low B cell count. Two patients had anemia requiring red blood cell transfusions. A few patients had nonspecific dysmorphic facial features, such as long asymmetric face, midface hypoplasia, micrognathia, high-arched palate, and dysplastic ears. Some of the males had cryptorchidism.

Salter et al. (2021) reported 6 unrelated patients (families 3-8), ranging from 5 to 24 years of age, with NEDSPLB. Five of the patients were ascertained through the GeneMatcher Program after exome sequencing identified biallelic mutations in the PI4KA gene. The patients presented in the first weeks or years of life with neurologic abnormalities, including irritability, hypotonia, motor delay, and nystagmus; patient 3 presented on the first day of life with refractory seizures consistent with epileptic encephalopathy and West syndrome. The patients had global developmental delay with mild to severe intellectual disability, often with speech delay. Some patients were unable to walk, whereas others could walk with support later in the first decade. All had spasticity of the lower limbs associated with increased muscle tone, hyperreflexia, and extensor plantar responses. Other variable features included tremor, ataxia, dysmetria, and dystonia. Some had feeding difficulties; 2 required a feeding tube. Many patients had nystagmus, a few had decreased visual acuity, and 1 had optic atrophy. P3 had severe microcephaly (-10 SD). Aside from P3, 3 additional patients had onset of generalized tonic-clonic seizures in the first decade. One patient had an axonal neuropathy, 1 had a foot deformity, and several had kyphosis. Brain imaging showed hypomyelinating leukodystrophy in all patients. More variable findings included cerebellar and/or pontine hypoplasia, progressive supratentorial atrophy, and thin corpus callosum. Three patients had variable gastrointestinal abnormalities ranging from persistent iron-deficiency anemia suggestive of inflammatory bowel disease (P3) to frank colitis necessitating proctocolectomy and terminal ileum resection (P5). Patient 3 had evidence of an immunodeficiency manifest as neutropenia, B-cell lymphopenia, hypogammaglobulinemia, decreased NK cells, and reduced T-cell subsets; this patient developed follicular non-Hodgkin lymphoma.

Clinical Variability

Pagnamenta et al. (2015) reported a family in which 3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers, consistent with arthrogryposis. Three had micrognathia and 2 had dolichocephaly. Muscle histology was reported to be within normal limits. The fetuses were conceived by nonconsanguineous parents of European ancestry; the parents had had 3 early miscarriages in addition to the affected fetuses.

The transmission pattern of perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA) in the family reported by Pagnamenta et al. (2015) was consistent with autosomal recessive inheritance.

The transmission pattern of NEDSPLB in the families reported by Verdura et al. (2021) was consistent with autosomal recessive inheritance.

In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with NEDSPLB manifest as perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA), Pagnamenta et al. (2015) identified compound heterozygous mutations in the PI4KA gene (R796X, 600286.0001 and D1854N, 600286.0002). The mutations, which were found by a combination of exome sequencing and linkage analysis, segregated with the disorder in the family. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The findings indicated the importance of phosphoinositide signaling in early brain development.

In 8 unrelated patients (patients 1-8) with NEDSPLB, Verdura et al. (2021) identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., 600286.0002-600286.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. In vitro studies of cells derived from some of the patients indicated that the mutations resulted in hypomorphic alleles with decreased protein expression and decreased PI4KA activity compared to controls. None of the patients had 2 complete loss-of-function mutations, suggesting that complete loss of PI4KA would be incompatible with life. The authors postulated that the PIK4A gene plays a role in myelination and brain development.

In 6 unrelated patients (families 3-8) with NEDSPLB, Salter et al. (2021) identified homozygous or compound heterozygous mutations in the PI4KA gene (see, e.g., 600286.0002; 600286.0011-600286.0014). The mutations were found by exome sequencing and segregated with the disorder in the families; the patients were ascertained through the GeneMatcher Program. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would disrupt PI4KA function. In addition to developmental delay, spasticity, and leukoencephalopathy, some patients had inflammatory bowel disease and/or immunodeficiency.