Summary
- Onset is within the first few weeks of life
- Profound developmental delay with arrest of motor and mental development
- Epilepsy
- Hypotonia
- Lack of visual fixation
- Optic atrophy
- Microcephaly is present at birth and there is a progressive reduction in brain growth (secondary microcephaly)
- Peripheral oedema
- Prognosis is poor with early age of death
- Brain MRI imaging shows severe cerebellar and brainstem atrophy from birth, with cerebral atrophy developing at a later stage
Main Clinical Features
Head
- Microcephaly, progressive (up to -6SD)
- Narrow forehead
- Sloping forehead
- Bitemporal narrowing
- Receding chin
- Full cheeks
Eyes
- Epicanthal folds
- Visual fixation absent from birth or lost in first months of life
- Absent visual evoked potentials
- Optic atrophy
Nose
- Short nose
Mouth
- Open mouth
Abdomen
- Gastrointestinal
- Poor feeding
Skeletal
- Hands
- Tapered digits
Muscle, soft tissues
- Oedema, peripheral
- Hypotonia, neonatal
Neurologic/Central Nervous System
- Lack of psychomotor development
- Infantile encephalopathy, progressive
- Hypotonia, severe
- Seizures (neonatal onset)
- Myoclonic jerks
- Status epilepticus
- Hypsarrhythmia seen on EEG
- Mental retardation, profound
- Absent speech
- Hyperreflexia
- Cerebellar atrophy, progressive
- Brain stem atrophy, progressive
- Enlarged ventricles
- Absent cortical responses of somatosensory evoked potentials
- Dysmyelination seen on MRI
- Pachygyria
- Polymicrogyria
- Lissencephaly
- Hypoplastic corpus callosum
Prognosis
For the UK family with three affected individuals, all spent 2–4 weeks in hospital until satisfactory breathing and feeding were established. All developed seizures associated with anoxia presented at birth or by one month. In the UK family, the three affected individuals had flexion infantile spasms with hypsarrhythmia on EEG within the first year of life. Seizures became tonic/clonic by the third year, fits occurred frequently with status epilepticus necessitating hospital admission. Their seizures were persistently difficult to control necessitating frequent changes of medication and dosage. Over the first 6 months, poor visual attention, fixing and following were noted, and all were diagnosed as having severe cortical visual inattention. All had moderate optic atrophy but otherwise a normal retina on fundoscopy; one had minor bilateral megalocornea (10 mm at 6 months, but there were no associated problems from this). Puffiness of the maxillary region of the face, and the dorsum of the hands and feet was present from birth, and persisted, but did not spread in extent. Over the first 3 years of life, it became clear that all had profound cognitive delay. Severe motor delay was present with no development, with a combination of central hypotonia and peripheral hypertonia. Thoracolumbar kyphoscoliosis (with no vertebral anomalies) and hip flexion deformity developed. The degree of microcephaly gradually increased over the years of follow up to -5 SD to -6 SD by 3 years. MRI was performed on all three affected children and showed the consistent and symmetrical findings of widespread coarse pachygyria with the posterior regions of the brain more affected than anterior, polymicrogyria prominent in the sylvian fissures, dilated ventricles (reflecting brain substance loss and not raised intraventricular pressure), hypoplastic corpus callosum, subependymal cysts, and hypoplastic pons. One of the three affected children had a small cerebellum shown on an MRI scan at 3 months.