TEXT
A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-76 (DEE76) is caused by hom*ozygous or compound heterozygous mutation in the ACTL6B gene (612458) on chromosome 7q22. Heterozygous mutation in the ACTL6B gene can cause a less severe neurodevelopmental disorder (IDDSSAD; 618470).
Description
Developmental and epileptic encephalopathy-76 (DEE76) is an autosomal recessive neurodevelopmental disorder characterized by early-onset, usually refractory, seizures, severely delayed global development, hypotonia, peripheral spasticity, and abnormalities on brain imaging, mainly cerebral atrophy and delayed myelination. Some patients may have additional features, such as scoliosis or microcephaly. The disorder may result in death in childhood (summary by Bell et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Clinical Features
Karaca et al. (2015) reported 2 sibs (patients BAB6569 and BAB6570), born of consanguineous parents (family HOU2448), with a neurodevelopmental disorder. Clinical details were limited, but the patients were reported to have severely impaired intellectual development, microcephaly, seizures, and some autistic behaviors. Maddirevula et al. (2019) reported a 13-month-old girl (patient 17-1447), born of consanguineous parents, with a neurodevelopmental disorder. Clinical details were limited, but the patient reportedly presented with hyperekplexia and global developmental delay. Brain imaging showed agenesis of the corpus callosum, mild dilatation of the ventricles, mild atrophic changes, a simplified gyral pattern with prominent sulci, and mild posterior colpocephaly. Family history revealed that a similarly affected brother had died at 2 months of age. Fichera et al. (2019) reported 2 sibs, born of unrelated Italian parents (family A), with onset of severe refractory seizures in the first week of life. The seizures occurred several times per day, and EEG showed slowed background activity and frequent slow spike-wave complexes. The patients had profoundly impaired psychom*otor development, poor overall growth with microcephaly (-5 SD), short stature (-2.3 to -4.6 SD), spastic tetraplegia, kyphoscoliosis, and poor feeding necessitating feeding tubes. At 4 and 10 years of age, the patients were nonverbal, nonambulatory, unable to sit unassisted, and lacked purposeful movements. Subsequently, a second unrelated patient (family B) with a similar disorder was identified. She had onset of refractory seizures around 2 months of age with essentially no further development. At age 4, she had microcephaly (-6 SD), spastic tetraplegia, no language, and a feeding tube. Family history revealed that she had had a pair of similarly affected monozygotic twin brothers who died from pneumonia at 4 and 5 years of age; DNA was not available from these sibs. Brain imaging in all patients, including the deceased twin boys, showed diffuse volume loss, widespread hypomyelination, white matter atrophy, thinning of the corpus callosum, and hypoplasia of the cerebellar vermis. Bell et al. (2019) reported 11 children from 10 unrelated families (R1-R10) with a similar phenotype consistent with DEE76. The patients ranged from 5 months to 8 years of age; 3 died between 2 and 5 years of age. All had severe global developmental delay with impaired intellectual development, absent speech, and inability to walk independently. All except 1 had onset of various types of seizures in infancy; 1 child had onset of seizures at 3 years of age. EEG studies showed slow background activity and multifocal interictal epileptiform abnormalities. Additional features included axial hypotonia, peripheral spasticity, and feeding difficulties; a few patients had microcephaly. Brain imaging in most patients showed variable abnormalities, including cerebral atrophy, periventricular white matter abnormalities, delayed myelination, thin corpus callosum, cerebellar atrophy, and, less commonly, focal cortical dysplasia or asymmetric gyral pattern. Yuksel et al. (2019) reported a highly consanguineous Turkish family in which 6 children had DEE76. Three patients had died in childhood, and DNA was available only from the 3 living patients. The patients had severe global developmental delay, epileptic encephalopathy, axial hypotonia, muscle atrophy, and dystonia or spasticity of the upper limbs. Other common features included failure to thrive and poor visual pursuit/eye contact. EEG showed variable abnormalities including generalized slow activity and variable spike-wave complexes or multifocal discharges. Brain imaging showed variable abnormalities including cerebral atrophy, periventricular or more diffuse white matter abnormalities, abnormal or delayed myelination, and cerebellar atrophy. One patient initially had a thin corpus callosum that later reached a normal size, consistent with delayed myelination. Some patients were noted to have dysmorphic features, including frontal bossing, bulbous nose, deep-set eyes, downturned corners of the mouth, high-arched palate, open mouth with misaligned teeth, large ears, and strabismus. One patient had anal stenosis and abnormality of the thorax.
Inheritance
The transmission pattern of DEE76 in the families reported by Bell et al. (2019) was consistent with autosomal recessive inheritance.
Molecular Genetics
In 2 sibs (patients BAB6569 and BAB6570), born of consanguineous parents (family HOU2448), with DEE76, Karaca et al. (2015) identified a hom*ozygous missense mutation in the ACTL6B gene (R298Q; 612458.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The family was part of a cohort of 128 mostly consanguineous families with neurogenetic disorders that underwent whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed. In a 13-month-old girl (patient 17-1447), born of consanguineous parents, with DEE76, Maddirevula et al. (2019) identified a hom*ozygous nonsense mutation in the ACTL6B gene (C333X; 612458.0002). The variant, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was classified as 'likely pathogenic' according to ACMG criteria. In 2 sibs, born of unrelated Italian parents (family A), with DEE76, Fichera et al. (2019) identified a hom*ozygous nonsense mutation in the ACTL6B gene (Q274X; 612458.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Subsequent screening of a cohort of 85 unrelated patients with a similar disorder identified a Sicilian girl (family B) with a hom*ozygous missense mutation in ACTL6B (G349S; 612458.0004). This mutation segregated with the disorder in the family and was not found in public databases, including gnomAD. Family history revealed that this girl had had a pair of similarly affected monozygotic twin brothers who died at 4 and 5 years of age; DNA was not available from these patients. Functional studies of the variants and studies of patient cells were not performed, but the nonsense variant was predicted to result in nonsense-mediated mRNA decay and a loss of function. In 11 children from 10 unrelated families with DEE76, Bell et al. (2019) identified hom*ozygous or compound heterozygous mutations in the ACTL6B gene (see, e.g., 612458.0004-612458.0008). The mutations, which were found by exome sequencing from various research and clinical laboratories, were confirmed by Sanger sequencing and segregated with the disorder in the families. Most of the mutations were nonsense, frameshift, or splicing mutations, although 2 French-Canadian families had a hom*ozygous 1-bp deletion (c.1279del) that extended the reading frame (Ter427AspextTer33; 612458.0005), 1 family had a hom*ozygous G349S missense variant, 1 had an in-frame deletion (phe147del; 612458.0006), and 2 unrelated patients were compound heterozygous for a missense and a nonsense mutation. The mutations occurred in different domains throughout the gene. Detailed in vitro functional expression studies performed on wildtype human neurons, human neurons with knockdown of the ACTL6B gene, and patient-derived induced human neuronal pluripotent stem cells (iPSCs) carrying the Ter427AspextTer33 mutation showed that ACTL6B is mostly absent from dividing cells, but present in post-mitotic neurons mainly after day 5. Patient-derived iPSCs had decreased ACTL6B mRNA, but normal protein levels. The authors noted that the Ter427AspextTer33 mutation escapes nonsense-mediated mRNA decay and that the protein is expressed, whereas other mutations may be subject to nonsense-mediated mRNA decay. Knockdown of ACTL6B in human neurons resulted in almost absent MAP2 (157130) staining, a marker for dendritic development, enlarged nuclear size, and delayed neuronal maturation and differentiation; these abnormalities were also observed in Ter427AspextTer33 cells and could be rescued by expression of the wildtype gene. The Ter427AspextTer33 variant showed increased BRG1 (SMARCA4; 603254) binding compared to controls, and this was associated with altered expression of the actin-associated proteins TPPP (608773) and FSCN1 (602689) during early neuronal development. Neuronal induced fibroblasts from another patient with recessive mutations showed similar changes. Expression of certain recessive mutations failed to rescue the phenotype in knockout cells, suggesting that the mutations cause a loss of function. Bell et al. (2019) hypothesized that recessive mutations in ACTLB6 interrupt the dynamic of the BAF complex, resulting in impaired neuronal differentiation and dendritic formation. The findings indicated the importance of chromatin remodeling machinery in brain disease. In 3 children from a highly consanguineous Turkish family with DEE76, Yuksel et al. (2019) identified a hom*ozygous intragenic in-frame deletion in the ACTL6B gene (val421_cys425del) that segregated with the disorder in the family. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed.
