Encephalopathy, Progressive, Early-Onset, With Brain Atrophy And Thin Corpus Callosum

A number sign (#) is used with this entry because of evidence that early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is caused by homozygous or compound heterozygous mutation in the TBCD gene (604649) on chromosome 17q25.

Description

PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity. Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. The disorder shows progressive features, including microcephaly, consistent with a neurodegenerative process (summary by Miyake et al., 2016; Flex et al., 2016).

Clinical Features

Miyake et al. (2016) reported 8 children from 4 unrelated families with a severe early-onset neurodegenerative encephalopathy. Four patients from 2 unrelated nonconsanguineous Japanese families presented at birth or in the first weeks of life with severe hypotonia and almost no movement, often necessitating mechanical ventilation. In addition to no head control, visual tracking, or eye contact, they had arthrogryposis, absence of deep tendon reflexes, poor muscle volume, and growth failure with postnatal microcephaly. Two sibs had bone fractures and the other 2 sibs had seizures, which were associated with hypsarrhythmia in 1. More variable features included tongue fasciculations and optic nerve atrophy. Brain imaging showed variable diffuse atrophy of the cerebrum, cerebellum, brainstem, and spinal cord, and laboratory studies showed increased serum creatine kinase in some patients. Two sibs from a Chinese family had normal development until 4 months of age, followed by neurologic deterioration and developmental regression, severe hypotonia similar to the other patients, and intractable seizures. These patients also had microcephaly, delayed myelination, thin corpus callosum, and reduced white matter volume. All 6 of these patients were immobile, and most were mechanically ventilated; 3 died. Two sibs from an Iraqi-Jewish family had a slightly less severe but similar phenotype: they had onset of severe and intractable seizures at 9 and 11 months of age, respectively, associated with severe developmental regression, delayed psychomotor development, muscle weakness and atrophy, hypertonia, and hyperreflexia, but were able to walk.

Flex et al. (2016) reported 7 children from 5 unrelated families with severely delayed psychomotor development apparent since infancy, moderate to profound intellectual disability, and poor or absent language. Most of the children had hypotonia and all had spastic tetraplegia: 6 had scoliosis, 4 were never able to walk, and 3 never achieved sitting or head control. Six patients had optic atrophy and 4 had microcephaly. Variable dysmorphic features included sparse eyebrows, upslanting palpebral fissures, hypertelorism, micrognathia, and widely spaced teeth. Most patients had swallowing or feeding difficulties and/or chronic constipation. Brain imaging showed cortical atrophy and secondary hypomyelination, followed by cerebellar atrophy, consistent with slowly progressive neurodegeneration. Flex et al. (2016) noted that there were no signs of brain malformation, such as cortical dysplasia or simplified gyral pattern.

Inheritance

The transmission pattern of PEBAT in the families reported by Miyake et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 children from 4 unrelated families with PEBAT, Miyake et al. (2016) identified homozygous or compound heterozygous mutations in the TBCD gene (604649.0001-604649.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 5 missense mutations, 1 nonsense mutation, and 1 splice site mutation. In vitro functional expression studies showed that the mutants had variably impaired binding to ARL2, TBCA (610058), and beta-tubulin, suggesting that they decreased formation of microtubule chaperone complexes. In vivo experiments using olfactory projection neurons in Drosophila confirmed that the TBCD mutations caused a loss of function, with an inability to rescue abnormal dendritic and axonal projections in tbcd mutants. Miyake et al. (2016) suggested that TBCD depletion may result in an abnormal microtubule network and abnormal microtubule trafficking of mitochondria in the human brain, resulting in decreased energy supply to neuronal cells and subsequent neuronal degeneration.

In 7 patients from 5 unrelated families with PEBAT, Flex et al. (2016) identified biallelic mutations in the TBCD gene (see, e.g., 604649.0006-604649.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 7 missense mutations and 1 splice site mutation. Fibroblasts from 3 patients and cellular transfection studies showed that the missense mutations caused variably decreased levels of TBCD protein, consistent with instability of the mutant proteins. In vitro functional expression studies showed that most of the mutant TBCD proteins had decreased interaction with beta-tubulin, suggesting a loss-of-function effect. Patient fibroblasts showed altered microtubule dynamics with accelerated microtubule polymerization, showing an overall shift toward a more rapidly growing and stable microtubule population. These findings were consistent with loss-of-function or hypomorphic mutations because TBCD overexpression prevents the growth of microtubules. Patient cells also showed an aberrant mitotic spindle with disorganized, tangle-shaped microtubules and reduced aster formation, although the rate of cell proliferation was unchanged. The findings suggested that altered microtubule dynamics have an impact on neuronal function and survival in the brain.