A progressive mitochondrial disorder that predominantly affects the gray matter of the brain and is characterized by the clinical triad of progressive developmental delay, intractable seizures, and liver failure. The prognosis is generally poor and exacerbations can be triggered by stress or infections.
Alpers-Huttenlocher Syndrome; Alpers Disease; Alpers Diffuse Degeneration of Cerebral Gray Matter with Hepatic Cirrhosis; Alpers Progressive Infantile Poliodystrophy; Progressive Sclerosing Poliodystrophy; Progressive Cerebral Poliodystrophy; Progressive Neuronal Degeneration of Childhood with Hepatic Cirrhosis; Spongy Glioneuronal Dystrophy; Spongy Degeneration of the Gray Matter; Diffuse Cerebral Degeneration of Infancy; Mitochondrial DNA Depletion Syndrome-4A; Christensen Disease; Christensen-Krabbe Disease.
The disorder was probably first described by the German neurologist Alfons Maria Jakob (1884-1931, whose name also appears in Creutzfeld-Jakob Disease), although some experts credit the American neurologist William N. Bullard with the first description in 1890. Still, the disease is named after the American neuropathologist Bernard Jacob Alpers (1900-1981), who described the disease in a 4-month-old girl in 1931 while working with A.M. Jakob in Hamburg. Peter Huttenlocher (1931-2013), a German born pediatric neurologist who at the age of 18 years immigrated to the USA, described the associated hepatic features and confirmed the autosomal recessive inheritance of the disease.
The disease affects both genders equally with a prevalence of approximately 1 in 100,000 individuals.
Autosomal recessive. Consanguinity is not common in affected families. Certain affected individuals may inherit the genetic predisposition for the disorder. In the vast majority of patients with Alpers Syndrome, the disorder is caused by mutations in the POLG (Polymerase gamma) gene on chromosome 15q26.1 that encodes the alpha subunit of POLG, which is involved in the replication of mitochondrial DNA. This defect is most noticeable in brain, liver, and muscle cells and affects their energy levels. In the past some researchers used to believe that Alpers Syndrome may be a manifestation of childhood prion disease.
Acute impairment of the mitochondrial function leading to a potentially reversible, cytotoxic cerebral edema could play an important pathogenetic role in Alpers Syndrome. Mitochondrial mutations or deletions may cause a defect in the electron transport chain and result in impaired oxidative phosphorylation, oxidative stress, and metabolic disturbances.
The often diagnostic clinical tetrad consists of episodic psychomotor regression, refractory seizures, liver disease with micronodular cirrhosis, and cortical blindness. The typical clinical course is characterized by intractable seizures and liver failure following a period of insidious, but progressive developmental delay, failure to thrive, bouts of vomiting, and marked hypotonia. The majority of patients appear healthy prior to the onset of the disease, which is early in life and typically starts with convulsions (most often in the second year of life). Approximately one quarter of ...