Nine patients, 2 sibling pairs and 5 singleton cases, with POLGI mutations associated with infantile fatal encephalopathy and hepatopathy, 8 having typical Alpers’ syndrome (Alpers’ hepatopathic poliodystrophy) and one a severe floppy infant syndrome with hepatic failure, are reported from the National Institute of Neurology, Milano; Meyer Children’s Hospital, Florence; University of Verona; University Hospital, Monza, Italy; and University Children’s Hospital, Hamburg, Germany. Patient 1, a boy, developed a torticollis after a few months of life and 2 episodes of sudden head drop at 10 months, followed by psychomotor arrest and regression, hypotonia, ataxia and myoclonus, first focal and later, generalized, with weakness requiring ventilatory assistance. Seizures were accompanied by a disorganized basal EEG pattern and multiple foci of paroxysmal activity. Brain MRI showed symmetrical lesions of basal ganglia, thalami, cerebellar dentate nuclei, and left occipital cortical and subcortical regions. MRS revealed an abnormal accumulation of lactic acid in the putamen and a reduction of the N-acetyl aspartate peak, an index of neuronal loss. Cholestatic jaundice, hypoglycemia and hypocoagulation followed and were accompanied by neurologic deterioration and death at 30 months of age. In two of the 8 patients with Alpers’ syndrome, severe acute liver failure followed administration of valproate for control of myoclonus. Autopsy performed in 3 cases of Alpers’ syndrome showed diffuse encephalomalacia and severe liver steatosis with lobular fibrosis and bile ductile proliferation. Analysis of POLGI, a major disease gene in mitochondrial disorders, revealed that all patients carried different allelic mutations, 2 nonsense and 7 missense changes, associated with a heterogeneous spectrum of clinical outcomes. [1]

COMMENT. The clinical syndromes associated with POLGI mutations, the gene encoding the subunit of mitochondrial DNA (mtDNA) polymerase (pol-yA), include familial progressive external ophthalmoplegia, autosomal recessive sensory atactic neuropathy with ophthalmoplegia, juvenile sensory and cerebellar atactic syndrome with myoclonus epilepsy, and Alpers’ hepatopathic poliodystrophy, first described by Alpers in 1931, and later by Ford (1951), Blackwood et al, 1963, and Huttenlocher et al, 1976. Huttenlocher emphasized the coincident hepatic cirrhosis. Alpers’ syndrome is characterized by refractory seizures (epilepsia partialis continua), progressive neurologic deterioration, and progressive hepatic failure. The present report shows that POLGI, found in 8 of 10 cases examined over 10 years, is a prevalent disease gene in Alpers’ syndrome, and tissue-specific, partial mtDNA-depletion is a molecular feature of the disease.

The hepatic complication has sometimes been attributed to valproate toxicity during treatment of refractory seizures, and 2 of the above Italian cases received valproate just prior to acute liver failure. In a report of 13 cases of Alpers’ syndrome (termed progressive neuronal degeneration) from Great Ormond Street Hospital, London, UK [2], 4 patients received sodium valproate and 2 of the 4 died. Both had abnormal liver enzymes before treatment, and valproate was not accepted as the primary cause, a genetically determined metabolic explanation being preferred.