Hyperekplexia 4

A number sign (#) is used with this entry because of evidence that hyperekplexia-4 (HKPX4) is caused by homozygous mutation in the ATAD1 gene (614452) on chromosome 10q23.

Description

Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures, and many have inguinal or umbilical hernia. Most patients die in the first months of life due to respiratory failure or other complications (summary by Piard et al., 2018).

For a general description and a discussion of genetic heterogeneity of hyperekplexia, see HKPX1 (149400).

Clinical Features

Ahrens-Nicklas et al. (2017) reported a large, highly consanguineous Kuwaiti family in which 6 infants had a severe neurologic disorder apparent from birth. Four of the patients died between 6 months and 2 years of age; detailed clinical information was available for 2 of the patients. The affected neonates presented with progressive extreme hypertonia, encephalopathy, respiratory failure, and early-onset refractory seizures. The proband was symptomatic from birth, but first examined at age 9 months. He had extreme hypertonia, contractures of the extremities, no spontaneous movement, and lack of response to tactile, visual, or auditory stimuli. He had minimally reactive pupils and absent gag and corneal reflexes, and he did not respond to painful stimuli. EEG showed hypsarrhythmia, and brain imaging showed progressive cerebral atrophy. His 2-month-old cousin was similarly affected, but had a slightly less severe phenotype in that he had spontaneous respiration and was awake and alert with reactive pupils. He had little spontaneous movement and tonic extension of the extremities. Brain imaging was unremarkable in the younger patient. Both patients also had inguinal hernia.

Piard et al. (2018) reported 3 sibs, born of consanguineous Tunisian parents, with HKPX4. The patients presented at birth with respiratory distress necessitating assisted ventilation. They had hypertonia with an exaggerated startle reflex, stiffness, tremor, adducted thumbs, brisk reflexes, and clonic movements. The patients had essentially no psychomotor development. EEG in 1 patient showed slow and disorganized background activity and multifocal epileptic discharges, whereas EEG was normal in another patient. More variable features included distal arthrogryposis, camptodactyly, kyphoscoliosis, high-arched palate, and poor or absent visual contact. Brain imaging performed in 1 patient soon after birth showed delayed myelination, although brain imaging in another patient was normal. The patients also had umbilical or inguinal hernias. All died between 3 and 6 months of age.

Wolf et al. (2018) reported a female infant, born of consanguineous parents, with a similar disorder. She was born in 1992 and died at age 8 months without a diagnosis. At birth, she was stiff and had hypertonia with contractures and closed fists, as well as myoclonic jerks that were amplified by mild physical stimulus. She had no spontaneous movements, continued to have rigidity, and had episodic hypoxia eventually resulting in death. Laboratory studies showed decreased GABA in the spinal fluid, but treatment with vigabatrin did not result in clinical improvement.

Inheritance

The transmission pattern of HKPX4 in the family reported by Ahrens-Nicklas et al. (2017) was consistent with autosomal recessive inheritance.

Clinical Management

Ahrens-Nicklas et al. (2017) treated 2 patients, who were first-cousins, with perampanel, an AMPAR antagonist. One child began treatment at 16 months of age, after brain imaging already showed severe cerebral atrophy. Although he continued to have severe neurologic deficits, there was some improvement in hypertonicity and seizure activity. The other patient was started on treatment at 2.5 months of age; he showed more significant functional improvement but did not have complete resolution of neurologic symptoms.

Molecular Genetics

In 3 affected members of a highly consanguineous Kuwaiti family with HKPX4, Ahrens-Nicklas et al. (2017) identified a homozygous nonsense mutation in the ATAD1 gene (E276X; 614452.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family and was consistent with linkage analysis. Patient cells showed significantly decreased mutant mRNA and absence of the protein on Western blot analysis, consistent with nonsense-mediated mRNA decay and a loss of function. Based on findings in animal models, Ahrens-Nicklas et al. (2017) postulated that the mutation resulted in a loss of function, likely causing increased AMPA receptor-mediated excitatory signaling due to impaired receptor recycling.

In 3 sibs, born of consanguineous Tunisian parents, with HKPX4, Piard et al. (2018) identified a homozygous 2-bp deletion in the ATAD1 gene (614452.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in heterozygous state at a low frequency in the gnomAD database. In vitro functional expression studies suggested that the mutation locks the mutant protein in an oligomeric state, causing defects in the disassembly of AMPA receptors from their binding proteins. Expression of the mutation into Atad1-null neurons resulted in decreased surface expression of GluA2 (GRIA2; 138247) compared to wildtype. Piard et al. (2018) postulated that the mutation may inhibit the recycling back and/or reinsertion of AMPARs to the surface following endocytosis, resulting in a decrease in the steady-state levels of these receptors at the cell surface. The results suggested a gain-of-function effect that decreases the population of excitatory postsynaptic AMPA receptors. Patient-derived fibroblasts showed normal mitochondrial morphology and respiratory chain activity, although there was some alteration in peroxisomal and mitochondrial proteins.

In a girl, born of consanguineous parents, with HKPX4, Wolf et al. (2018) identified a homozygous mutation in the ATAD1 gene that was predicted to result in a missense mutation and/or a splicing defect, causing severe or complete loss of protein function. Parental DNA was not available for segregation analysis, and functional studies of the variant were not performed. The patient, who was deceased, was born in 1992 and did not have a diagnosis until Wolf et al. (2018) performed targeted Sanger sequencing of the ATAD1 gene after reading the report of Ahrens-Nicklas et al. (2017).

Animal Model

Zhang et al. (2011) found that thorase-knockout (KO) mice were viable but significantly smaller than their wildtype littermates. Most thorase-KO mice died by postnatal day 25 with seizures associated with increased AMPA currents. Examination of thorase-KO brains revealed no substantial abnormalities in dendritic complexity, or number, density, or size of dendritic spines. However, thorase-KO brains showed elevated steady-state surface expression of the AMPAR subunits Glur1 (GRIA1; 138248) and Glur2 compared with wildtype littermates. Loss of thorase in thorase-KO brains resulted in reduced endocytosis of AMPARs, but not of transferrin receptors (190010). Conditional thorase-KO mice exhibited seizures and showed deficits in short-term memory and in hippocampal-dependent spatial working memory.

Ahrens-Nicklas et al. (2017) hypothesized that treatment of Atad1-null mice with perampanel, an AMPAR antagonist, would result in therapeutic benefit. Treatment of the mice did not result in significant prevention of cerebral volume loss, but there was a trend toward improvement. Treatment corrected some of the motor defects in the mice, decreased seizure activity, and resulted in prolonged survival compared to untreated mice.