Mitochondrial Dna Depletion Syndrome 4a (Alpers Type)

A number sign (#) is used with this entry because mitochondrial DNA (mtDNA) depletion syndrome-4A (MTDPS4A), which manifests as Alpers syndrome, is caused by homozygous or compound heterozygous mutation in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG; 174763) on chromosome 15q26.

Description

Mitochondrial DNA depletion syndrome-4A, also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in the cerebral gray matter with reactive astrocytosis and liver cirrhosis. The disorder is progressive and often leads to death from hepatic failure or status epilepticus before age 3 years (review by Milone and Massie, 2010).

Some affected individuals may show mild intermittent 3-methylglutaconic aciduria and defects in mitochondrial oxidative phosphorylation (Wortmann et al., 2009).

For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

Neuropathologic changes characteristic of Alpers syndrome, namely laminar cortical necrosis, may also be seen in some patients with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), caused by mutation in the FARS2 gene (611592), and COXPD24 (616239), caused by mutation in the NARS2 gene (612803).

Clinical Features

Bernard Alpers (1931) described the neuropathology and clinical features in a 4-month-old girl with a one-month illness characterized by intractable generalized seizures. He termed the disorder 'diffuse progressive degeneration of the gray matter of the cerebrum.' Morse (1949) reported a brother and sister with hereditary myoclonus epilepsy who were later reported by Ford et al. (1951) as having from 'familial degeneration of the cerebral gray matter in childhood,' similar to the cases of Alpers (1931). Familial cases were also reported by Palinsky et al. (1954) and Christensen and Hojgaard (1964).

Alberca-Serrano et al. (1965) reported a family in which 4 of 6 sibs were affected with spastic diplegia due to anoxic encephalopathy, which they termed 'Alpers' syndrome. The parents were unrelated. Several relatives of the father may have had the same disorder. All affected members had reacted to infections with violent convulsions. The authors suggested that this represented a familial susceptibility and that the cerebral damage was secondary to anoxia.

Blackwood et al. (1963) described 2 sibs in whom diffuse cerebral degeneration (Alpers disease) was associated with cirrhosis of the liver. Wefring and Lamvik (1967) described brother and sister who developed convulsions at ages 11 and 14 months, followed by progressive hypotonia, dementia, and jaundice 4 and 2 weeks before death at the ages of 15 and 20 months. In addition to the typical findings of Alpers disease, the liver showed extensive atrophy with fibrosis, inflammation and bile duct proliferation. The diagnosis was made at autopsy.

Sandbank and Lerman (1972) reported 3 sibs with Alpers disease, characterized by progressive mental retardation, seizures, rigidity, and degeneration of the cerebral cortex. Neuropathologic examination showed disorganization of the cerebral cortex with neuronal loss and astroglial proliferation. There were abnormal mitochondria of variable sizes, some with electron dense inclusions. The authors suggested autosomal recessive inheritance.

Huttenlocher et al. (1976) reported 2 sibships with 2 affected children in each. Clinical features included early onset (average 2 years) of delayed motor development, vomiting, multifocal seizures, status epilepticus, stupor, hypotonia, paralysis, increased CSF protein, and later onset of hepatic disease. Intermittent unexplained fever occurred frequently. None of the children survived beyond age 3 years. Pathologic examination showed degeneration of the cerebral gray matter with loss of neurons and reactive astrocytosis in the brain and fatty accumulation and cirrhosis in the liver. The authors rejected the idea of anoxic encephalopathy and suggested that the syndrome was a familial disorder with autosomal recessive inheritance. Huttenlocher et al. (1976) noted that hepatic involvement was absent in some cases reported earlier, including the case reported by Alpers (1931).

Harding (1990) reviewed the clinical, neurologic, electrophysiologic, and histopathologic features of Alpers syndrome in 32 patients. Birth was usually normal, with some developmental delay in infancy, often with hypotonia and bouts of vomiting. The seizure disorder usually had an abrupt onset and although clinical signs of liver disease often appeared later, biochemical evidence of liver disease was sometimes present before the onset of seizures. EEG and visual evoked potentials were abnormal. Most patients died before the age of 3 years. Less frequently, late presentation occurred, even up to 25 years of age. Some patients also had visual disturbances. Liver pathologic findings, including fatty changes, abnormal bile duct architecture, and fibrosis, were unrelated to anticonvulsant therapy. Neuropathology showed severe cortical neurodegeneration and astrocytosis. In 12 of the 26 families in their series, 2 or 3 sibs were affected, including one pair of twins.

Frydman et al. (1993) reported the cases of 8 patients from 2 families. Onset in the first family was prenatal; in the 4 patients who were examined, severe microcephaly, intrauterine growth retardation, and typical manifestations of fetal akinesia, including retrognathia, joint limitations, and chest deformity, were found. The second family presented with an early infantile form. All of the affected offspring had micrognathia and 1 had findings of fetal akinesia, comparable to those seen in the other family. Microcephaly was mild at birth and progressed with age. Refractory neonatal convulsions, swallowing difficulties, and pneumonia complicated the clinical course of patients in both families, and all of the infants died before age 20 months. Comprehensive biochemical and metabolic studies in both families yielded normal results, and the diagnosis was supported by demonstration of extensive progressive brain atrophy on computerized tomography and typical histologic findings; for example, the parietal cortex showed spongy state with focally accentuated severe loss of neurons. The cerebellar cortex showed severe loss of almost all granular cells and persistent Purkinje cells. Anomalies of dendritic arborization were also seen. Both families were of Israeli Arab ethnicity and the parents were first cousins in both cases.

Harding et al. (1995) reported the unusual cases of 2 unrelated girls, aged 17 and 18, with a progressive encephalopathy, visual signs and symptoms, multiple types of drug-resistant seizures, and liver failure. Brain imaging showed lesions in the occipital lobe, and EEG showed slow waves with polyspikes. Both patients had a rapid degenerative course and died within 8 months of onset.

De Vries et al. (2007) reported 3 unrelated patients with Alpers syndrome due to POLG mutations. Age at onset was 4 to 8 months, and all died by 17 months of age. All showed severe failure to thrive, developmental retardation, hypotonia, seizures, and liver insufficiency. Two had delayed cerebral myelination and 1 had cerebral atrophy. Urinary amino acids showed different patterns, including intermediates of the tricarboxylic acid cycle, 3-methylglutaconic aciduria, ethylmalonic aciduria, dicarbonic aciduria and high lactate levels. All 3 patients also had significant decreases in ATP production, consistent with a defect in mitochondrial oxidative phosphorylation.

Wiltshire et al. (2008) reported a 17-year-old girl who presented with intractable epilepsy and recent onset of mild clumsiness. Developmental milestones, intelligence, vision, and hearing were otherwise normal. During the next 2 months, she had repeated admissions for status epilepticus or encephalopathy, and showed stepwise neurologic deterioration with memory impairment, slurred speech, and hemiparesis. Treatment with a variety of anticonvulsant agents coincided with progressive liver deterioration. MRI findings were initially normal but showed progressive abnormality with increased signal on T2-weighted images in the cortical and subcortical white matter and basal ganglia. She died at age 17 years, 9 months, of respiratory failure secondary to her neurologic condition. Genetic analysis identified compound heterozygous mutations in the POLG gene.

Among 136 children with a variety of severe neurologic defects, Isohanni et al. (2011) identified 7 patients from 6 families with compound heterozygous POLG mutations. Disease onset was acute or subacute, often with preceding infection. All had a severe encephalopathic phenotype with intractable epilepsy and liver involvement, except 1 patient who did not have liver involvement. All those exposed to valproate developed fatal liver toxicity. Isohanni et al. (2011) concluded that although POLG mutations are not a common cause of isolated epilepsy or ataxia in childhood, the POLG gene should be studied in children with a progressive epileptic encephalopathy with liver involvement.

Clinical Variability

Kurt et al. (2010) reported 4 patients with a POLG-related hepatocerebral disorder with psychomotor delay, seizures, and liver disease, most consistent with Alpers syndrome. An unrelated girl and boy were compound heterozygous for the P1073L (174763.0022) and A467T (174763.0002) mutations. Both had developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility, reminiscent of the allelic disorder MNGIE syndrome (MTDPS4B; 613662). Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. The boy had status epilepticus with coma, cholestasis, optic atrophy, hyperplastic gastropathy with gastric ulcer, and death at age 3 years, 4 months. In addition, 2 boys were compound heterozygous for P1073L and W748S (174763.0013) and G848S (174763.0006), respectively. One child had severe attention-deficit/hyperactivity disorder with motor and verbal tics, status epilepticus with coma and myoclonus, liver dysfunction, and cavitation in the cerebrum, thalamus, cerebellum, and basal ganglia. He died at age 13 years. The other child had poor growth, hypotonia, seizures, and intestinal hypomotility and died at age 10 months. Kurt et al. (2010) emphasized the phenotypic variability associated with POLG mutations, and noted that various signs and symptoms can occur in each associated disorder. Three of the 4 children had gastrointestinal dysmotility, suggesting that the P1073L mutation may be associated with that particular feature.

Biochemical Features

Cases with a disturbance in pyruvate metabolism and NADH oxidation (Gabreels et al. (1981, 1984)) have been described.

In a patient with mtDNA depletion and Alpers syndrome, Naviaux et al. (1999) found global reduction in respiratory chain complex I, II/III, and IV activity and deficiency of mitochondrial DNA polymerase gamma activity.

Gauthier-Villars et al. (2001) confirmed the mitochondrial respiratory chain abnormalities in the liver of 4 unrelated patients with Alpers syndrome. One patient had a complex I deficiency, another a complex IV deficiency, and 2 had a combined deficiency of complexes I and IV.

Molecular Genetics

Naviaux and Nguyen (2004) reported 3 patients with Alpers syndrome who were homozygous for a mutation (E873X; 174763.0008) in the POLG gene. They later published a correction (Naviaux and Nguyen, 2005) stating that 2 affected patients from 1 family with Alpers syndrome were compound heterozygous for 2 mutations in the POLG gene: E873X and A467T (174763.0002). Naviaux and Nguyen (2005) stated that the existence of a common 4-bp insertion in the POLG gene yielded the incorrect initial results. The clinical features of the family had been described by Naviaux et al. (1999).

In 4 patients with Alpers syndrome, Davidzon et al. (2005) identified compound heterozygosity for 2 mutations in the POLG gene (174763.0006 and 174763.0013). Liver biopsies from 3 patients showed mitochondrial DNA depletion ranging from 87 to 94%, and all 4 patients showed decreased activity of mtDNA-encoded respiratory chain complexes.

Ferrari et al. (2005) identified mutations in the POLG gene in 8 patients with Alpers syndrome.

Genotype/Phenotype Correlations

Nguyen et al. (2005) reported a child with Alpers syndrome who was homozygous for the A467T mutation in the POLG gene (174763.0002). Unlike other children with the disorder, he showed late onset at age 8.5 years and death by age 9 years.

In a study of the cellular phenotype derived from 24 children with biallelic POLG mutations, 21 of whom had a clinical diagnosis of Alpers syndrome, Ashley et al. (2008) found that the cellular mtDNA content reflected the genotype. Those with mtDNA depletion in the liver and/or muscle had at least 1 missense or nonsense mutation in a catalytic domain, either the polymerase or exonuclease region. Four of 10 patients analyzed in detail showed a progressive, mosaic pattern of mtDNA depletion in fibroblasts, and all had biallelic mutations in POLG catalytic domains. These patients had a severe clinical phenotype with early onset before 1 year of age, hepatic involvement, and death by 16 months of age. Their cells showed respiratory chain defects. Patients with 2 mutations in the linker region of the gene did not show mtDNA depletion and had the mildest phenotype with onset in childhood or adolescence and little liver involvement. The study also found that the average mtDNA content declined with serial passage in cell culture in patients with mtDNA depletion, which Ashley et al. (2008) postulated was a result of mtDNA replication stalling, indicating the requirement for both catalytic actions of POLG in mitochondrial replication.

Heterogeneity

Genetic Heterogeneity

Wortmann et al. (2009) reported 3 unrelated patients, 2 of Dutch and 1 of German origin, with mild intermittent 3-methylglutaconic aciduria associated with a hepatocerebral syndrome. The first patient had subepidermal hemorrhage and bilateral mild periventricular leukomalacia at birth. At age 3.5 months, she had epilepsy, hypertonia, and delayed psychomotor development. From age 2 years, she had unexplained encephalopathic periods with atonia, apneas, and stupor. Brain MRI showed mild periventricular leukomalacia, irregularly widened ventricles, gracile corpus callosum, and partial pachygyria. She also had transient elevation of liver enzymes, indicating hepatic involvement. She died of cardiorespiratory failure in an encephalopathic state at age 3 years. The second patient was born at 26 weeks' gestation with intrauterine growth retardation. He had an infantile encephalopathy with epilepsy, delayed psychomotor development, hypo- and hyperthermia, resistance to pain, and severe failure to thrive. At age 9 years he had a stroke-like episode with hemiplegia after valproic acid administration. He also had multiorgan failure with liver dysfunction, but recovered. The third patient had severe microcephaly, dysmorphic features, psychomotor retardation, no development, hypotonia, epilepsy, and failure to thrive. She suffered from recurrent episodes of hyperthermia, liver dysfunction, and intractable seizures, and died at the age of 2.5 years. Biochemical studies of all these patients suggested a defect in mitochondrial oxidative phosphorylation. Although a molecular basis for the disorder was not established, Wortmann et al. (2009) noted that the patients had a similar phenotype to those reported by De Vries et al. (2007), who had Alpers syndrome.

History

As noted by Harding (1990) in a review of Alpers syndrome, there was much confusion in the past regarding the nosology, pathogenesis, and diagnosis of the disease. Some reported cases seemed to be caused by anoxia at birth or illness, whereas others were familial with normal births. Cerebral damage was also thought to be a result of intractable seizures or hepatic toxicity, and hepatic damage was believed in some cases to be caused by anticonvulsive drugs.