Epileptic Encephalopathy, Early Infantile, 44

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-44 (EIEE44) is caused by compound heterozygous mutation in the UBA5 gene (610552) on chromosome 3q22.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Clinical Features

Muona et al. (2016) reported 9 patients from 5 unrelated families, mostly of Finnish descent, with early infantile-onset encephalopathy. The patients presented in the first weeks or months of life with irritability, jitteriness, back arching, and poor eye contact. Additional features included severely delayed psychomotor development, truncal hypotonia, spasticity, dystonic or athetoid movements, postnatal microcephaly, and short stature. There were no distinctive dysmorphic features, although some were noted to have an expressionless face. All but 1 developed seizures, including myoclonic seizures, in the first year of life; 1 patient had hypsarrhythmia. Eight of the patients, 7 of Finnish descent, had severe intellectual deficit with absent motor skills and no speech. The ninth patient, of Irish and Romanian descent, had delayed psychomotor development but was able to smile and laugh, with some ability to feed herself. Brain imaging showed nonspecific features in some patients, including delayed myelination and cerebral or cerebellar atrophy. Four patients died between 5 and 21 years of age. Neuropathologic examination showed nonspecific features consistent with a progressive encephalopathy, including atrophy and necrosis.

Colin et al. (2016) reported 5 children, ranging in age from 2.5 to 6 years, from 4 unrelated families with early-onset encephalopathy. The patients had failure to thrive, microcephaly, axial hypotonia often with peripheral hypertonia or spasticity, delayed psychomotor development with severe intellectual disability, poor visual pursuit, absent speech, and abnormal movements such as dystonia and opisthotonus. Three children had onset of severe and intractable seizures in the first months of life; the 2 remaining patients did not have overt seizures, although 1 of these patients had abnormal EEG finding. Brain imaging showed variable abnormalities, including thin corpus callosum, cortical atrophy, cerebellar atrophy, and white matter changes. One child died at age 2.5 years.

Inheritance

The transmission pattern of EIEE44 in the families reported by Muona et al. (2016) and Colin et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 5 unrelated families of Finnish or European descent, with EIEE44, Muona et al. (2016) identified biallelic mutations in the UBA5 gene (610552.0001-610552.0005). The mutations were found by exome sequencing, and the patients were ascertained from several large consortiums of patients with neurodevelopmental disorders. All patients carried a hypomorphic missense variant (A371T; 610552.0001) on 1 allele, and this variant had an allele frequency of 0.28% in the European population. The other allele was either truncating or resulted in a severe loss of enzyme function. The findings suggested that affected individuals had 1 variant with a major and 1 with a milder hypomorphic effect on UBA5 function. Muona et al. (2016) suggested that different combinations of biallelic UBA5 variants may have phenotypic consequences that range in severity. Fibroblasts from patients from 2 families had decreased amounts of UBA5 mRNA and protein levels and demonstrated impaired formation of UFM1 (610553)-UBA5 intermediates, consistent with a decrease in E1-like activity and an attenuated ability to transfer activated UFM1 to UFC1 (610554) compared to wildtype.

In 5 patients from 4 unrelated families with EIEE44, Colin et al. (2016) identified biallelic mutations in the UBA5 gene (610552.0001; 610552.0006-610552.0011). Seven mutations were identified: the common A371T variant, 4 additional missense mutations, and 2 truncating mutations. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Three families were of European or American descent; 1 was of Kuwaiti descent. In vitro functional expression studies showed that all the mutations resulted in impaired formation of UBA5-UFM1 and UFM1-UFC1 conjugates, although to different degrees. Two patients without overt epilepsy were compound heterozygous for 2 missense mutations; Colin et al. (2016) postulated that the missense mutations in these patients may have conferred a less severe phenotype than did truncating mutations.

Animal Model

Muona et al. (2016) found that conditional knockdown of Ufm1 in mice resulted in death within the first day of life. Postmortem examination showed microcephaly and markers of increased neuronal apoptosis in the occipital region of the neopallium.

Colin et al. (2016) found that disruption of the Ufm1 cascade, including specific deletion of Uba5, in C. elegans resulted in defects in neurotransmission due to increased ACh release in the neuromuscular junction. Morpholino knockdown of the uba5 gene in zebrafish resulted in numerous motility defects and induced abnormal movements suggestive of seizures.