Neonatal intractable myoclonus is a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants ha...
Neonatal intractable myoclonus is a severe neurologic disorder characterized by the onset of intractable myoclonic seizures soon after birth. Affected infants have intermittent apnea, abnormal eye movements, pallor of the optic nerve, and lack of developmental progress. Brain imaging shows a progressive leukoencephalopathy. Some patients may die in infancy. There is phenotypic and biochemical evidence of mitochondrial dysfunction (summary by Duis et al., 2016).
▼ Clinical Features
Duis et al. (2016) reported 2 unrelated patients who presented shortly after birth with nearly continuous nonrhythmic large-amplitude myoclonic jerks associated with intermittent apnea. Neither patient had visual fixation, and both had hypotonia. Additional features included abnormal saccades, nystagmus, ptosis, and optic nerve pallor. Both had minimal developmental progress. One patient died at age 3 months, whereas the other was alive at age 5 years with microcephaly, poor feeding requiring gastrostomy tube, recurrent apnea, developmental arrest, myoclonus, and choreiform movements. EEG showed background slowing but no epileptiform discharges during myoclonus, suggesting that the myoclonus may be of spinal cord origin. Brain imaging was initially normal, but showed increased T2-weighted signals in the brainstem and pons in the surviving patient at age 2 years. Muscle biopsy, performed in 1 patient, showed nonspecific myopathic features with increased fiber size variability and atrophy of type 1 fibers. There was borderline mitochondrial complex IV deficiency.
Rydzanicz et al. (2017) reported a male infant, born of unrelated Polish parents, with neonatal intractable myoclonus. He had hypotonia, treatment-resistant clonic seizures, no spontaneous eye opening, and evidence of hearing loss. Brain imaging showed Dandy-Walker variant, narrowing of the corpus callosum, progressive leukoencephalopathy, progressive ventricular dilation, and delayed myelination. EMG studies showed muscle fibrillations. There was also evidence of reinnervation potentials corresponding to axonal-demyelinating lesions with neuropathic damage to the muscle. The patient had muscle atrophy and respiratory insufficiency, and he died at age 12 months.
▼ Molecular Genetics
In 2 unrelated patients with NEIMY, Duis et al. (2016) reported different de novo heterozygous frameshift mutations in the KIF5A gene (c.2854delC, 602821.0011 and c.2934delG, 602821.0012), both of which were predicted to result in a stop-loss with read-through of the normal termination codon to create an elongated protein with 14 additional residues. The predicted abnormal protein was the same in both cases. The c.2854delC mutation was found in case 1 by whole-exome sequencing. The c.2934delG mutation was initially found in case 2 by DaRe et al. (2013) by sequencing of a panel of genes involved in mitochondrial function. Both mutations were confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutations were predicted to result in a dominant-negative effect on the kinesin complex, thus disrupting organelle transport in neurons. The clinical features were consistent with mitochondrial dysfunction within neurons, likely resulting from abnormal mitochondrial transport due to an abnormal kinesin 'motor.' Duis et al. (2016) noted that the C-terminal region of KIF5A binds GABARAP (605125), which clusters neurotransmitter receptors by mediating interaction with microtubules. These data suggested that the myoclonus in these patients may be caused by increased neuronal excitation due to aberrant GABA signaling.
In a male infant with NEIMY, Rydzanicz et al. (2017) identified a de novo heterozygous stop-loss mutation in the KIF5A gene (602821.0013). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. Rydzanicz et al. (2017) speculated that the mutation induced abnormal binding to TRAK2 (607334) or other kinesin adaptor proteins.