Encephalopathy, Progressive, With Amyotrophy And Optic Atrophy

A number sign (#) is used with this entry because of evidence that progressive encephalopathy with amyotrophy and optic atrophy (PEAMO) is caused by homozygous or compound heterozygous mutation in the TBCE gene (604934) on chromosome 1q42.

Biallelic mutation in the TBCE gene can also cause hypoparathyroidism-retardation-dysmorphism syndrome (HRDS; 241410) and Kenny-Caffey syndrome (KCS1; 244460).

Description

PEAMO is a severe autosomal recessive neurodegenerative disorder characterized by delayed development with hypotonia apparent in infancy and subsequent motor regression. Most affected individuals are unable to or lose the ability to sit and show distal amyotrophy and weakness of all 4 limbs. The patients are cognitively impaired and unable to speak or have severe dysarthria. Additional features include optic atrophy, thin corpus callosum, and cerebellar atrophy (summary by Sferra et al., 2016).

Clinical Features

Sferra et al. (2016) reported 6 patients from 4 apparently unrelated families originating from the same geographic area in Italy near Naples with a similar infantile-onset neurodegenerative disorder. The patients ranged from 6 to 20 years of age. They presented between birth and 14 months of age with delayed psychomotor development and hypotonia, followed by progression of the disorder and regression of motor skills. Most lost the ability to sit and developed distal amyotrophy of all 4 limbs, with foot drop, ataxia, and spastic tetraplegia. Additional features included optic atrophy, severe dysarthria or inability to speak, and scoliosis. Cognitive impairment ranged from mild to severe. Only 1 patient had overt seizures: she developed partial seizures at age 12, which progressed to refractory seizures by age 18. Electrophysiologic and electromyographic studies in all patients were consistent with a motor neuropathy, and muscle biopsy showed denervation atrophy. Fibrillation potentials were found only in distal muscles. Brain imaging showed cerebellar atrophy and thin corpus callosum. Patients in the second decade had iron accumulation in the pallidum and substantia nigra, a pattern similar to that observed in NBIA (see, e.g., NBIA1, 234200). None of the patients had growth defects, endocrine abnormalities, or hypoparathyroidism, thus distinguishing this disorder from both HRDS and KCS1.

Inheritance

The transmission pattern of PEAMO in the family reported by Sferra et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 3 unrelated Italian families with PEAMO, Sferra et al. (2016) identified a homozygous missense mutation in the TCBE gene (I155N; 604934.0004). The mutation in 2 families was found by whole-exome sequencing and confirmed by Sanger sequencing; the mutation in a pair of affected monozygotic twins in the third family was found by mutation scan of the TBCE gene. Another patient (patient 2518864) with the disorder was found to be compound heterozygous for the I155N mutation and a frameshift mutation (604934.0005). The mutations segregated with the disorder in all families, and haplotype analysis of the families indicated a founder effect for I155N. Western blot analysis of patient fibroblasts showed significantly reduced amounts of mutant TBCE protein compared to controls, with lower levels in the patient with compound heterozygous mutations. RNA analysis of patient cells showed normal levels in the patient homozygous for I155N but decreased amounts of RNA in the compound heterozygous patient, suggesting that the 1-bp deletion resulted in nonsense-mediated mRNA decay. Patient cells showed decreased levels of polymerized alpha-tubulin (see 602529) and altered microtubule dynamics with decreased nucleation and markedly delayed microtubule repolymerization; microtubules were less abundant and strongly disorganized in both early and late stages of repolymerization, and there was loss of compaction in the Golgi apparatus. There was also abnormal mitotic morphology with abnormal mitotic spindles and disorganized microtubule arrangement. Sferra et al. (2016) concluded that the I155N allele is hypomorphic. The phenotype was similar to that of pmn/pmn mice who have a homozygous missense mutation in the Tbce gene (see ANIMAL MODEL).

Animal Model

Mice that are homozygous with respect to the progressive motor neuronopathy (pmn) mutation on chromosome 13 develop a progressive caudiocranial degeneration of their motor axons from the age of 2 weeks and die 4 to 6 weeks after birth (Schmalbruch et al., 1991). The mutation is fully penetrant and expressivity does not depend on the genetic background. Martin et al. (2002) identified the pmn mutation as a trp524-to-gly (W524G) substitution at the last residue of the Tbce protein that leads to decreased protein stability. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization. Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. The observations indicated that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggested that altered function of tubulin cofactors might be implicated in human motor neuron diseases. Bommel et al. (2002) independently identified a point mutation resulting in the trp524-to-gly substitution in the Tbce protein in pmn mice.

Homozygous pmn mice have a severe motor neuron disease characterized by motor axon dying back and progressive loss of motor units. In pmn mice, Schaefer et al. (2007) found that axonal microtubule loss in the phrenic and sciatic nerves first manifested distally and progressed proximally, in parallel with the axonal dying back neuronopathy. Studies of cultured pmn neurons showed loss of Tbce from the Golgi apparatus in motor neuron cells and in Schwann cells, microtubule loss resulting from defective axonal routing of tubulin from the Golgi, and impaired tubulin folding and dimerization. Similar results were found with knockdown of the Tbce gene in cultured motor neurons. The findings indicated that destabilization of Tbce in motor neurons is responsible for the axonal dying back process in pmn mice.