Progressive dyskinetic spastic paresis in siblings: a new disorder of pyruvate oxidation

Case 1: 12 year old girl, 2^nd of 4 children of consanguineous Iraqi parents with bilateral, dyskinetic, spastic paresis. Until 4 years of age normal development, than increasing tremor and dystonia, rigor and spasticity of the lower, later of the upper extremities. Progressively scoliosis, loss of gait, loss of speech, hypertrophic cardiomyopathy and symptomatic epilepsy developed. Therapy with intrathecal Baclofen slightly stabilized the situation.

Case 2: her 6 year old brother started with similar symptoms at the age of 4 ½ years: progressive spasticity and dystonia of the upper extremity, rigor, scoliosis and subluxation of the left hip. His cognitive functions were normal.

Both patients had repeated episodes with elevated lactate in serum (until17mmol/l) and urine. cMRI of the girl was described as normal at age 6. At age 11 cMRI showed symmetrical, bilateral striatal lesions. The activity of respiratory chain complexes (RCC) I-IV in frozen muscle was reported to be normal.

Typical signs of a mitochondrial disorder (episodic lactic acidosis, typical MRI pattern) prompted us to repeat the muscle biopsy at age 11 and to analyze mitochondrial function in a fresh muscle biopsy. RCC I-V activity was normal, however pyruvate oxidation was significantly decreased, but pyruvate dehydrogenase complex was completely normal. This result was confirmed in fibroblasts. Thus we could identify in these patients disorder of pyruvate oxidation. We started ketogenic diet in both patients with poor success, however treatment with high-dose thiamine (200mg/d) for now six months stabilized the symptoms and even improved the dystonia in the boy. This might point to a hitherto not described thiamine dependent disorder of pyruvate oxidation.