Alpers Syndrome: An Unusual Etiology of Failure to Thrive

Mangalat, Nisha; Tatevian, Nina; Bhattacharjee, Meenakshi B.; Rhoads, J. Marc

doi:10.3109/01913123.2012.666334

Cited by 2 publications

(5 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other changes have been reported, although uncommonly detected It is intriguing that one pediatric patient who had AHS clinically had histologically normal liver on postmortem . A number of mitochondrial abnormalities were observed (Table ) . A mosaic of cytochrome c oxidase (COX) activity was reported in the liver of six infants (0–5 years) and two older patients (12‐ and 39‐years‐old, respectively) .…”

Section: Resultsmentioning

confidence: 98%

“…A total of 11 liver biopsies and 2 postmortem liver samples were identified. Tissue source for 17 patients was not specified . Of the patients reviewed, there were 28 infants/children (range 0–8.5 years), one 12‐year‐old adolescent, and a 39‐year‐old adult …”

Section: Resultsmentioning

confidence: 99%

“…Tissue source for 17 patients was not specified. 9,13,30,31,36,[38][39][40][41][42][43] Of the patients reviewed, there were 28 infants/children (range 0-8.5 years), one 12-year-old adolescent, and a 39-year-old adult. 41 Microvesicular fatty changes, microvesicular steatosis, fibrosis, and cirrhosis were prominent features.…”

Section: Livermentioning

confidence: 99%

“…13 A number of mitochondrial abnormalities were observed (Table 4). 13,38,43 A mosaic of cytochrome c oxidase (COX) activity was reported in the liver of six infants (0-5 years) 31,35,38,41 and two older patients (12-and 39years-old, respectively). 41 "Ragged-red" changes (increased density of mitochondria accumulating at the periphery of the hepatocytes) were detected in only the two older patients, suggesting that these changes may be uncommon in the younger population.…”

Section: Livermentioning

confidence: 99%

See 3 more Smart Citations

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

View full text Add to dashboard Cite

We performed a systematic review of the clinical, molecular, and biochemical features of polymerase gamma (POLG)-related epilepsy and current evidence on seizure management. Patients were identified from a combined electronic search of articles using Ovid Medline and Scopus databases, published from January 2000 to January 2015. Only patients with a confirmed genetic diagnosis of POLG mutations were considered. Seventy-two articles were included for analysis. We identified 128 pathogenic variants in 372 patients who had POLG-related epilepsy. Among these, 84% of the cases harbored at least one of these pathogenic variants: p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser. A bimodal distribution of disease onset was present in early childhood (<5 years) and adolescence; female patients had a later presentation than male patients (median age 4.00 vs. 1.83 years, p-value = 0.041). Focal-onset seizure including convulsive, myoclonus, and occipital seizures was common at the outset and was refractory to pharmacotherapy. We confirmed that homozygous pathogenic variants located in the linker region of POLG were associated with later age of onset and longer survival compared to compound heterozygous variants. In addition, biochemical and molecular heterogeneities in different tissues were frequently observed. POLG-related epilepsy is clinically heterogeneous, and the prognosis is, in part, influenced by the location of the variants in the gene and the presence of hepatic involvement. Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.

show abstract

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Livermentioning

confidence: 99%

Section: Livermentioning

confidence: 99%

See 2 more Smart Citations

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

View full text Add to dashboard Cite

show abstract

“…mtDNA depletion as well as abnormal mitochondrial morphology and functions have been reported in liver biopsy specimens from patients. 9,29 Therefore, we asked how POLG mutation induces mitochondrial changes in AHS iPSCs-Hep. To this end, we compared expression levels of POLG in cell types with and without POLG mutation.…”

Section: (Supporting Figs 2 and 3)mentioning

confidence: 99%

Valproic acid‐induced hepatotoxicity in alpers syndrome is associated with mitochondrial permeability transition pore opening‐dependent apoptotic sensitivity in an induced pluripotent stem cell model

Guo

Ying

et al. 2015

Hepatology

View full text Add to dashboard Cite

Valproic acid (VPA) is widely used to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy, but potentially causes idiosyncratic liver injury. Alpers-Huttenlocher syndrome (AHS), a neurometabolic disorder caused by mutations in mitochondrial DNA polymerase gamma (POLG), is associated with an increased risk of developing fatal VPA hepatotoxicity. However, the mechanistic link of this clinical mystery remains unknown. Here, fibroblasts from 2 AHS patients were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to hepatocyte-like cells (AHS iPSCs-Hep). Both AHS iPSCs-Hep are more sensitive to VPA-induced mitochondrial-dependent apoptosis than controls, showing more activated caspase-9 and cytochrome c release. Strikingly, levels of both soluble and oligomeric optic atrophy 1, which together keep cristae junctions tight, are reduced in AHS iPSCs-Hep. Furthermore, POLG mutation cells show reduced POLG expression, mitochondrial DNA (mtDNA) amount, mitochondrial adenosine triphosphate production, as well as abnormal mitochondrial ultrastructure after differentiation to hepatocyte-like cells. Superoxide flashes, spontaneous bursts of superoxide generation, caused by opening of the mitochondrial permeability transition pore (mPTP), occur more frequently in AHS iPSCs-Hep. Moreover, the mPTP inhibitor, cyclosporine A, rescues VPA-induced apoptotic sensitivity in AHS iPSCs-Hep. This result suggests that targeting mPTP opening could be an effective method to prevent hepatotoxicity by VPA in AHS patients. In addition, carnitine or N-acetylcysteine, which has been used in the treatment of VPAinduced hepatotoxicity, is able to rescue VPA-induced apoptotic sensitivity in AHS iPSCs-Hep. Conclusion: AHS iPSCs-Hep are more sensitive to the VPA-induced mitochondrial-dependent apoptotic pathway, and this effect is mediated by mPTP opening. Toxicity models in genetic diseases using iPSCs enable the evaluation of drugs for therapeutic targets. (HEPATOLOGY 2015;61:1730-1739

show abstract

Alpers Syndrome: An Unusual Etiology of Failure to Thrive

Cited by 2 publications

References 10 publications

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Valproic acid‐induced hepatotoxicity in alpers syndrome is associated with mitochondrial permeability transition pore opening‐dependent apoptotic sensitivity in an induced pluripotent stem cell model

Contact Info

Product

Resources

About