lack of fixation

This is a progressive disorder in which psychomotor regression and loss of speech develop by 1 to 2 years of age, often appearing as the first sign of abnormalities.  Cognitive impairment can progress to profound intellectual disability.  Older patients have limb and truncal ataxia and experience frequent falls.  Muscle tone in the limbs is increased and children often exhibit dyskinesia, dystonia, and axial hypotonia.  General muscle weakness is often present.  No abnormalities have been seen on brain imaging.

Some patients develop a nephropathy with renal insufficiency, hypertension, and hyperechogenic kidneys though deterioration of the renal disease is slow.  Renal biopsy in one patient revealed tubulointerstitial nephritis but no individuals have reached end-stage renal failure.

There are extensive and, in most cases, progressive CNS abnormalities resulting in severe neurodevelopmental deficits.  Infants at birth have progressive truncal hypotonia and limb spasticity.  Motor deficits result in little spontaneous movement, resulting in poor sucking, and respiratory difficulties.  Language does not develop and there is profound mental retardation. Progressive microcephaly is a characteristic finding.  There are often extrapyramidal signs such as rigidity and dystonic posturing.

Dysmorphic features include a short nose, high-arched palate, low-set and posteriorly rotated ears, micrognathia, postaxial polydactyly, hirsutism, pectus carinatum, contractures of large joints, and hyperextensibility of small joints.

Brain imaging shows a progressive leukoencephalopathy, cerebral and cerebellar atrophy, and delayed myelination.  The corpus callosum is often thin and the ventricles appear enlarged.  The lifespan is generally short with death occurring in infancy or early childhood.