Neurodevelopmental Disorder With Progressive Microcephaly, Spasticity, And Brain Anomalies

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) is caused by homozygous mutation in the PLAA gene (603873) on chromosome 9p21.

Description

NDMSBA is an autosomal recessive neurodevelopmental disorder characterized by infantile onset of progressive microcephaly and spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy. Brain imaging may show myelinating abnormalities and white matter lesions consistent with a leukoencephalopathy, as well as structural anomalies, including thin corpus callosum, gyral abnormalities, and cerebral or cerebellar atrophy. Some patients die in early childhood (summary by Falik Zaccai et al., 2017 and Hall et al., 2017).

Clinical Features

Falik Zaccai et al. (2017) reported a large consanguineous Israeli family in which 6 individuals had a severe neurodevelopmental disorder characterized by infantile onset of progressive microcephaly, spastic quadriparesis, and global developmental delay. A similarly affected patient from an unrelated consanguineous family from the same geographic region was also identified. The patients presented between 2 and 4 months of age with rapidly progressive spasticity and extrapyramidal signs, including dystonic posturing, rigidity, and hypomimia. All had severe mental and language delay and impaired motor function. Six patients had an abnormally exaggerated startle response, and 3 developed seizures. Most patients showed failure to thrive. Other features included progressive chest deformities with pectus carinatum, kyphosis, contractures of the large joints and hyperextensibility of the small joints, rocker-bottom feet, hypertrichosis, and hyperhidrosis of the palms and feet. Brain imaging showed progressive leukoencephalopathy, white matter atrophy, delayed myelination, thin corpus callosum, and enlarged ventricles or cortical atrophy.

Hall et al. (2017) reported 10 patients from 4 consanguineous families of Pakistani or Saudi Arabian origin with a severe neurodevelopmental disorder resulting in death from central apnea or pneumonia between 12 days and 6 years in all patients. The patients presented at birth with truncal hypotonia, little spontaneous movement, increased limb tone, feeding difficulties, hirsutism, and mild dysmorphic features. They had bulbar symptoms manifest as poor sucking and respiratory insufficiency. Eight patients developed seizures between ages 1 week and 2 years, and EEG often showed hypsarrhythmia. The patients exhibited progressive microcephaly and spasticity, and had essentially no developmental progress, with lack of gross and fine motor skills, absent language, and profound mental retardation. Dysmorphic features included short nose, long or flat philtrum, cupid bow lip, high-arched palate, low-set and posteriorly rotated ears, micrognathia, single palmar crease, and postaxial polydactyly. Brain imaging showed delayed myelination, thin corpus callosum, simple immature gyral pattern, and progressive cerebral and cerebellar atrophy. More variable features included optic atrophy (in 3 of 5 patients old enough to be examined), nystagmus (4 patients), dorsal edema of the hands and/or feet (4 patients), and roving eye movements.

Inheritance

The transmission pattern of NDMSBA in the families reported by Falik Zaccai et al. (2017) and Hall et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 patients from 2 unrelated consanguineous Israeli families with NDMSBA, Falik Zaccai et al. (2017) identified a homozygous missense mutation in the PLAA gene (L752F; 603873.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was found in heterozygous state in 3 of 92 residents from the local village (prevalence of 3.3%); haplotype analysis indicated a common ancestral haplotype in the 2 families. Functional studies showed that patient cells had decreased levels of prostaglandin-E2 (PGE2) compared to controls, in both the unstimulated and stimulated state, suggesting that the mutation abrogated normal phospholipase-A2 (PLA2) activation and the ability of PLAA to induce prostaglandin biogenesis; this defect could be rescued with wildtype PLAA. Although patient cells also showed abrogation of LPS-induced expression of certain cytokines, the NFKB and Wnt signaling pathways did not appear to be affected. Patient cells did not show ubiquitin depletion or accumulation of misfolded proteins compared to control cells. The findings implicated a role for the PLAA/PLA2/PGE2 axis in proper brain development.

In 7 infants from 3 consanguineous Pakistani families with a lethal form of NDMSBA, Hall et al. (2017) identified a homozygous missense mutation in the PLAA gene (G23V; 603873.0002). The mutation was found by homozygosity mapping, candidate gene sequencing, and exome sequencing; it was confirmed by Sanger sequencing and segregated with the disorder in all of the families. Haplotype analysis indicated a common founder rather than a recurrent mutation. Expression of this mutation into mice (see ANIMAL MODEL) showed that it caused a 70% reduction in protein levels, confirming that it destabilizes protein structure. Studies of cells derived from the mutant mice showed disruption of ubiquitin-mediated trafficking of membrane proteins through the endolysosomal pathway, which resulted in impaired synaptic vesicle recycling and function at both central and peripheral synapses. However, PLA2 activity was normal in mutant mouse brain, suggesting that impaired phospholipid signaling was not the primary cause of neurodysfunction in these patients.

Animal Model

Falik Zaccai et al. (2017) found that Plaa-null mice exhibited perinatal lethality. Mutant embryos were smaller than wildtype and had abnormal or underdeveloped spleens, underdeveloped and immature lungs, and less mature and differentiated cortical neurons compared to wildtype. These changes were associated with decreased levels of PGE2 in certain tissues.

Hall et al. (2017) found that homozygous loss of Plaa was embryonic lethal in mice. There were no changes in ubiquitin expression or proteasomal activity in the absence of Plaa. However, Plaa-null cells showed disrupted trafficking of recycled membrane proteins from early to late endosomes. The findings suggested that loss of mammalian Plaa disrupted ESCRT (Endosomal Sorting Complexes Required for Transport) localization and ubiquitin-dependent internalization of receptors and their ligands into late endosomes for lysosomal degradation. Homozygous mice bearing the hypomorphic human PLAA mutation G23V (603873.0002), generated by CRISPR/Cas9 editing, were viable, but showed early-onset progressive neurologic dysfunction with smaller brains and reductions in corpus callosum and cerebellar volumes compared to controls. Mutant mice also showed tremor and motor disorders, including altered gait, neuromuscular weakness and wasting, hypomotility, reduced grip strength, and kyphosis. These features were consistent with a disturbance in cerebellar motor circuits; cerebellar Purkinje cells from mutant mice showed abnormal migration patterns and dendritic branching. Proteome analysis showed abnormal expression of proteins involved in vesicular transport. Examination of the neuromuscular junction in mutant mice showed decreases in synaptic vesicle numbers with enlarged endosomal and vacuolar structures, consistent with impaired vesicle fusion and recycling, resulting in defective synaptic function. Mutant brains showed specific accumulation of K63-polyUb species, also consistent with a defect in post-endocytic degradation of ubiquitylated membrane proteins.