Alpers-Huttenlocher syndrome

Abstract

Alpers-Huttenlocher syndrome is an uncommon mitochondrial disease most often associated with mutations in the mitochondrial DNA replicase, polymerase-γ. Alterations in enzyme activity result in reduced levels or deletions in mitochondrial DNA. Phenotypic manifestations occur when the functional content of mitochondrial DNA reaches a critical nadir. The tempo of disease progression and onset varies among patients, even in identical genotypes. The classic clinical triad of seizures, liver degeneration, and progressive developmental regression helps define the disorder, but a wide range of clinical expression occurs. The majority of patients are healthy before disease onset, and seizures herald the disorder in most patients. Seizures can rapidly progress to medical intractability, with frequent episodes of epilepsia partialis continua or status epilepticus. Liver involvement may precede or occur after seizure onset. Regardless, eventual liver failure is common. Both the tempo of disease progression and range of organ involvement vary from patient to patient, and are only partly explained by pathogenic effects of genetic mutations. Diagnosis involves the constellation of organ involvement, not the sequence of signs. This disorder is relentlessly progressive and ultimately fatal.

Figure 1

Electroecephalogram (EEG) epoch of a 7-year old female with Alpers-Huttenlocher syndrome. This figure demonstrates regional slowing in the parieto-occipital regions bilaterally with epileptiform discharges within the right occipital region. The scale legend depicted represents time (1 second interval) and amplitude (microvolts).

Figure 2

Functional and structural domains of the polymerase protein. A. Linear organization of the polymerase gamma protein. The N-terminal domain (NTD) region is the mitochondrial targeting sequence and is located at the N-terminal of the protein. The thumb subdomains (Th) of the protein and are found between the exonuclease and linker region as well as within the polymerase region [63]. The exonuclease domain contains essential motifs I, II, and III for its activity. The polymerase domain contains subdomains comprising the thumb (Th), palm, and finger, which contain motifs A, B, and C, respectively. There are two regions that make up the palm subdomain within the polymerase domain. The motifs located within the polymerase domain are critical for polymerase activity [23, 57]. The small arrows indicate position of the numbered amino acid position that begin a subdomain. B. Three dimensional structure of the human DNA polymerase holoenzyme [59]. The color scheme of the polymerase gamma catalytic subunit is the same as in A (light blue for the polymerase domain, dark blue for the exonuclease region, red for the accessory interacting domain (AID) domain and orange for the intrinsic processivity (IP) domain. The conserved motifs in the exonuclease (I, II, and III) and in the polymerase (A, B, and C) are colored in charcoal. The two accessory subunits are colored in green, for the proximal subunit, and grey for the distal subunit.

Figure 2

Functional and structural domains of the polymerase protein. A. Linear organization of the polymerase gamma protein. The N-terminal domain (NTD) region is the mitochondrial targeting sequence and is located at the N-terminal of the protein. The thumb subdomains (Th) of the protein and are found between the exonuclease and linker region as well as within the polymerase region [63]. The exonuclease domain contains essential motifs I, II, and III for its activity. The polymerase domain contains subdomains comprising the thumb (Th), palm, and finger, which contain motifs A, B, and C, respectively. There are two regions that make up the palm subdomain within the polymerase domain. The motifs located within the polymerase domain are critical for polymerase activity [23, 57]. The small arrows indicate position of the numbered amino acid position that begin a subdomain. B. Three dimensional structure of the human DNA polymerase holoenzyme [59]. The color scheme of the polymerase gamma catalytic subunit is the same as in A (light blue for the polymerase domain, dark blue for the exonuclease region, red for the accessory interacting domain (AID) domain and orange for the intrinsic processivity (IP) domain. The conserved motifs in the exonuclease (I, II, and III) and in the polymerase (A, B, and C) are colored in charcoal. The two accessory subunits are colored in green, for the proximal subunit, and grey for the distal subunit.