Neurologic symptoms and signs in the present cohort revealed the diagnostic criteria of hyperekplexia
] namely, abnormal excessive fetal movements, stiffness immediately after delivery, exaggerated startle reflex and non-habituating exaggerated head retraction reflex (HRR) resulting in violent rhythmic jerks and breath holding episodes. They also had congenital hip dislocation. In addition, they had microcephaly and documented optic atrophy in all of the five ascertained patients. The EEG, done in four of six patients, showed no epileptic discharges, and the background was characterized by diffuse slow activity with low valtage for age, and synchronized jerks mostly myogenic in origin.
The brain imaging in early life in five of these patients (Figure
) showed a constant finding of brain underdevelopment and immaturity manifested by simplified gyral pattern and enlargement of the CSF spaces. The frontal and temporal lobes had very few gyri and shallow sulci giving the lobes a smooth appearance
]. This was less remarkable in the frontoparietal region close to the Rolandic fissure. The Sylvian fissures were open wide and not operculized in two patients. The cortical thickness was normal. The occipital horns of the lateral ventricles were enlarged giving the appearance of colpocephaly. The cerebellum in these patients was generally small with poorly developed folia and large cisterna magna. The brain stem was normal as well with no signs of underdevelopment or hypoplasia.
Our cases fulfilled all clinical criteria to be diagnosed as HPX
]. They also showed good response to clonazepam, the drug of choice being a GABA agonist. Nevertheless, they differed from all the reported cases of HPX in that they were associated with microcephaly, optic atrophy and severe brain malformations. Also unlike the usually favorable prognosis of HPX in humans, the present cases had universally lethal outcome, and all the six patients died within 6 weeks.
The pedigree of our patients is consistent with autosomal recessive inheritance, although the number of affected individuals is vividly higher than the ratio predicted by classical mendelian genetics. Nevertheless, this is most likely an unfavorable outcome of a purely probabilistic 25% recurrence risk. We have observed this frequently in autosomal recessive neurogenetic disorders in this Region with high rate of consanguinity
]. None of the known hyperkplexia genes were present within the overlapping regions of homozygosity between the two patients for whom DNA samples were available. Homozygosity scan and exome sequencing, as described before
], are underway to identify the disease causing mutation in this family.
Hereditary hyperekplexia (HPX) is characterized by features consisting of generalized stiffness immediately after birth, normalizing during the first years of life. The stiffness increases with handling and disappears during sleep
]. There is also fetal posture with clenched fists and anxious stare
]. Excessive startle reflex to unexpected auditory, somatosensory and visual stimuli, is present at birth. Consciousness is unaltered during startle response. The tonic spasms mimic generalized tonic seizures leading to apnea and may lead to death
]. Non-habituating exaggerated head-retraction reflex (HRR) elicited by tapping the tip of the nose, forehead (glabellar tap) or face
], is considered by some as a clinical hallmark for diagnosis. Other associated features include periodic limb movements in sleep and hypnogogic myoclonus
], and inguinal, umbilical or epigastric hernias due to increased intra-abdominal pressure
]. Congenital dislocation of the hip, sudden infant death syndrome (SIDS)
] and abnormal intrauterine fetal movements
] have also been reported.
Diagnosis of HPX is mainly clinical, and all laboratory tests are typically normal including CT and MRI of the brain. Electroencephalogram (EEG) is usually normal but may show fast spikes (myogenic origin) initially during the tonic spasm followed by slowing of the background activity with eventual flattening corresponding to the phase of apnea, bradycardia and cyanosis. Electromyography (EMG) shows a characteristic almost permanent muscular activity with periods of electrical quietness, whereas nerve conduction velocity is normal
Unlike the universally lethal outcome observed in our cases, the prognosis of HPX in humans is usually favourable with spontaneous amelioration of the hypertonia with increasing age but delayed gross motor development is usually observed. The tone is usually almost normal by the age of 3 years although hypertonia may recur in adult life. The exaggerated startle response, however, persists to adulthood leading to unprotected falls without loss of consciousness. Shahar et al.
] reviewed the outcome of 39 cases of sporadic HPX during the neonatal period and early infancy and reported that the debilitating symptoms of HPX gradually resolved in all 39 infants treated with low dose of clonazepam. However, and in contrast to human hyperekplexia/startle disease, GlyT2
mutations result in early neonatal lethality in mice, cows and dogs
Malformations of cortical development, a prominent feature of the present cohort, constitute a diverse group of structural brain disorders reflecting deranged neuronal proliferation, migration or organization
]. Recently, mutations in one gene (WDR62
) were reported to cause a wide spectrum of severe cerebral cortical malformations including microcephaly, simplified gyral pattern, callosal abnormalities, and cerebellar hypoplasia
]. Nevertheless, the reported phenotype of WDR62
gene mutations did not include HPX. On the other hand, Goraya et al.
] reported a case of HPX in a girl with posterior fossa malformation. Another case with unusual presentation of cerebral dysgenesis in a neonate associated with hyperekplexia was reported by Parveen et al.
] but the clinical course and EEG findings favoured startle epilepsy secondary to cerebral dysgenesis as the diagnosis in the neonate they reported.