axial hypotonia

Six patients from 4 unrelated families of mixed ethnic backgrounds have been reported.  Infants within the first 4 to 6 months of life had evidence of developmental delay and neurodevelopmental regression.  Poor feeding and breathing difficulties are often noted in this period.  Other later signs are axial hypotonia, abnormal movements such as tremor, spasticity, hyperkinetic movements, dystonia with eventual regression of milestones.  Joint contractures and kyphoscoliosis may develop. 

Microcephaly was noted in several infants and brain imaging in all patients reveals abnormal T2- weighted signals in the brainstem and specifically in the basal ganglia.  Decreased activity in muscle mitochondrial respiratory complexes I, III, and IV has been documented.  Lactate may be increased in serum and the CSF.  Postmortem studies show brain vascular proliferation and gliosis in basal structures.

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.