Review Article: Progressive Neuronal Degeneration of Childhood With Liver Disease (Alpers-Huttenlocher Syndrome): A Personal Review

Abstract

Thirty-two autopsied cases of progressive neuronal degeneration of childhood with liver disease are reviewed. The typical clinical course is intractable seizures and liver failure following a period of developmental delay and failure to thrive in early infancy, but some children first present with seizures. Characteristic changes on the electroencephalogram, loss of visual-evoked potentials, occipital atrophy on computed tomographic scan, and particular changes on liver biopsy may assist diagnosis. Most patients succumb in less than 3 years, but some have a protracted survival into their teens, and very rarely they may present in early adulthood. Liver pathology comprises fatty change, hepatocyte loss, bile duct proliferation, fibrosis, and often cirrhosis. Gradual progression can be followed in sequential biopsies. Macroscopically, the cerebral cortex is variably involved, but usually there is patchy thinning and discoloration, with a striking predilection for the striate cortex. Microscopic changes include spongiosis, neuronal loss, and astrocytosis, which progresses down through the cortical layers. All areas may be affected but the calcarine cortex is usually most affected. Etiology is still obscure, though mitochondrial and slow viral disorders have been postulated.

Clinical and Molecular Features of POLG-Related Mitochondrial Disease

“…valproic acid dosing, liver failure occurs in AHS patients, and liver pathology cannot distinguish the samples that were treated with valproic acid (Harding 1990). Characteristic features of liver pathology in AHS require at least three of the following histological findings: (1) microvesicular steatosis, (2) bile ductular proliferation, (3) hepatocyte dropout, (4) bridging fibrosis or cirrhosis, (5) collapse of liver cell plates, (6) parenchymal disarray or disorganization of normal lobular architecture, (7) regenerative nodules, and (8) oncocytic change in scattered hepatocytes not affected by steatosis (Nguyen et al 2006).…”

Neuroimaging of mitochondrial disease

“…However, there is a wide variety of phenotypic expression involving multisystemic symptoms and signs varying in onset from infancy to adulthood and in severity from infantile Alpers syndrome to slowly progressive external ophthalmoplegia and ataxia, depending on where in the POLG gene mutations occur (Tzoulis et al 2006;Horvath et al, 2006). Neuropathological findings show extensive gliosis and neuronal loss predominantly in the occipital cortices and cerebellar cortex (Purkinje cells) and necrosis of subcortical deep nuclei, hippocampi, lateral geniculate body of the thalamus, and amygala (Harding, 1990). The MRI demonstrates T2/FLAIR hyperintensities in the majority of patients within the occipital regions, deep cerebellar nuclei, thalamus and basal ganglia (Tzoulis et al, 2006).…”

Neuroimaging in Mitochondrial Disorders

“…Although this spectrum was acquired at a long TE, a shorter TE will also demonstrate a lactate peak. as well as other metabolites of interest nucleus [61]. Cerebellar atrophy should be differentiated from cerebellar hypoplasia, as a major metabolic disorder that can mimic mitochondrial disorders with intellectual delay, seizures, hypotonia, vision defects, and other organ findings are the congenital disorders of glycosylation.…”