Diffuse Progressive Degeneration of the Gray Matter of the Cerebrum

Alpers, Bernard J.

doi:10.1001/archneurpsyc.1931.02230030027002

Cited by 191 publications

(62 citation statements)

References 7 publications

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“…Recently, case studies of two children with early-onset encephalopathy and liver failure associated with Twinkle mutations were reported (Hakonen et al 2007). The phenotype was close to Alpers hepatocerebral syndrome (Alpers 1931), which is caused by mutations in POLG. Thus, Twinkle mutations result in a highly nonspecific clinical spectrum, and no suggestive biochemical changes have thus far been identified, explaining in part why the diagnosis remains difficult.…”

Section: Introductionmentioning

confidence: 69%

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

et al. 2016

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The C10orf2 gene encodes Twinkle, a protein involved in mitochondrial DNA (mtDNA) replication. Twinkle mutations cause mtDNA deletion or depletion and are associated with a large spectrum of clinical symptoms including dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and early-onset encephalopathy. The diagnosis remains difficult because of the wide range of symptoms and lack of association with specific metabolic changes. We report herein a child with early-onset encephalopathy, unusual abnormal movements, deafness, and axonal neuropathy. All laboratory investigations were normal with the exceptions of high alpha-fetoprotein levels and an abnormal glycosylation profile. These abnormal parameters resulted in misdiagnosis as a previously unidentified congenital disorder of glycosylation (CDG) type I syndrome. Whole exome sequencing revealed two point mutations in C10orf2 that were confirmed by Sanger sequencing; neither had been previously reported. This report enlarges the clinical phenotype of Twinkle mutations and suggests that an abnormal glycosylation profile suggestive of CDG type I associated with high blood alpha-fetoprotein levels without obvious cause should prompt Twinkle sequencing.

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Section: Introductionmentioning

confidence: 69%

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

et al. 2016

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“…The neuropathological features of PNDC may not be specific to a single aetiology but rather the result of various underlying defects, as in Leigh syndrome. ebral cortex (53). Subsequently, the term 'Alpers syndrome' has been applied to patients with similar neuropathology but the criteria for this (diagnosis remain vague.…”

Section: Alpers Syndrome and Progressive Neuronal Degeneration Of Chimentioning

confidence: 99%

Mitochondrial respiratory chain disorders and the liver

Morris

1999

Liver

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Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood but they are probably under-diagnosed, partly due to under-recognition and partly due to the difficulty of investigation. It is particularly important to look for mitochondrial disorders if the liver disease presents with hypoglycaemia and lactic acidaemia or if it is accompanied by neurological, muscle or renal tubular abnormalities. Respiratory chain defects have been demonstrated in a number of patients who die of liver failure following severe epilepsy; this includes at least some cases of Alpers syndrome or 'progressive neuronal degeneration of childhood'. In mitochondrial liver disease, histology usually shows steatosis, often accompanied by fibrosis, cholestasis and loss of hepatocytes. Unless the clinical picture suggests a particular syndrome, such as Pearson syndrome, biochemical assays and histochemistry should be the initial investigations. Ideally, investigations should be carried out on liver as well as more standard tissues, such as muscle, since defects can be tissue-specific. Nuclear defects and nitDNA point mutations are probably responsible for many cases of mitochondrial liver disease but, as yet, the only identified molecular abnormalities are mtDNA rearrangements and mtDNA depletion. Treatment of mitochondrial liver disease is unsatisfactory. If the disease is confined to the liver, transplantation may be appropriate but in several patients transplantation has been followed by the appearance of disease in other organs, particularly the I brain.Mitochondria are subcellular organelles whose primary role is the oxidation of fuels to produce energy. This process is accomplished by a series of enzymes known as the mitochondrial respiratory chain. Mitochondria are the site of many other metabolic pathways but the term 'mitochondrial disease' is generally used to refer to those conditions associated with respiratory chain defects. Since the oxidation of fuels is important for almost all cells, defects of the mitochondrial respiratory chain can cause disease in any organ of the body. Liver disease is a relatively common problem in respiratory chain disorders that present during infancy. These genetic disorders are the sub,ject of the current review. Secondary defects of tlhe respiratory chain caused, for example, by drugs or toxins, can also lead to liver disease but these disorders are only considered briefly in the section on pathogenesis, where key references are giiven. Mitochondrial biochemistryMany oxidative reactions occur within mitochondria, including the D-oxidation pathway for fatty acids, the oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex and the oxidation of acetyl-CoA by the tricarboxylic acid cycle. These reactions all generate reduced cofactors, such as the reduced forms of flavin adenine dinucleotide (FADH2) and nicotinamide adenine dinucleotide (NADH). The mitochondrial respiratory chain couples the reoxidation of these cofactors to the for...

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“…1 Recessive inheritance, indicating that Alpers' syndrome was a monogenic disorder, was first noted by Sandbank and Lerman, 2 who were also the first to propose that this was an inherited mitochondrial disorder. The associated liver disease and recessive inheritance were first reported by Huttenlocher and colleagues.…”

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confidence: 95%

POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion

Naviaux

Nguyen

2004

Annals of Neurology

418

225

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Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein.

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Diffuse Progressive Degeneration of the Gray Matter of the Cerebrum

Cited by 191 publications

References 7 publications

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

Mitochondrial respiratory chain disorders and the liver

POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion

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