Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease

John Vissing; Morten Duno; Marianne Schwartz; Ronald G Haller

doi:10.1093/brain/awp065

Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease

John Vissing, Morten Duno, Marianne Schwartz, Ronald G Haller

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

46 Citationer (Scopus)

Abstract

Udgivelsesdato: 2009-Jun

Originalsprog	Engelsk
Tidsskrift	Brain
Vol/bind	132
Udgave nummer	Pt 6
Sider (fra-til)	1545-52
Antal sider	7
ISSN	0006-8950
DOI	https://doi.org/10.1093/brain/awp065
Status	Udgivet - 2009

Bibliografisk note

Keywords: Adult; Cardiac Output; Exercise Test; Female; Forearm; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Lactic Acid; Male; Muscle, Skeletal; Mutation; Oxygen Consumption; Phenotype; RNA Splice Sites; Reverse Transcriptase Polymerase Chain Reaction

Adgang til dokumentet

10.1093/brain/awp065

Citationsformater

@article{f46f4ac064a511df928f000ea68e967b,

title = "Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease",

abstract = "Over 100 mutations in the myophosphorylase gene, which cause McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype-phenotype correlation has been identified in this condition. We evaluated physiologic and genetic features of two patients with a variant form of McArdle disease, associated with unusually high exercise capacity. Physiologic findings were compared to those in 47 patients with typical McArdle disease, and 17 healthy subjects. Subjects performed an ischaemic forearm exercise test to assess lactate and ammonia production. Peak oxidative capacity (VO2max) and cardiac output were determined, using cycle ergometry as the exercise modality. The two patients with atypical McArdle disease carried common mutations on one allele (R50X and G205S), and novel splice mutations in introns 3 [IVS3-26A>G (c.425-26A>G)] and 5 [IVS5-601G>A (c.856-601G>A)] on the other allele. Plasma lactate after ischaemic exercise decreased in all typical McArdle patients, but increased in the two atypical McArdle patients (10% of that in healthy subjects). Peak workload and oxidative capacity were 2-fold higher in patients with atypical McArdle disease compared to typical McArdle patients. Oxygen uptake, relative to cardiac output, was severely impaired in the 47 patients with typical McArdle disease, and partially normalized in the milder affected McArdle patients. These findings identify the first distinct genotype-phenotype relationship in McArdle disease, and indicate that minimal myophosphorylase activity ameliorates the typical McArdle disease phenotype by augmenting muscle oxidative capacity. The milder form of McArdle disease provides important clues to the level of functional myophosphorylase needed to support muscle oxidative metabolism.",

author = "John Vissing and Morten Duno and Marianne Schwartz and Haller, {Ronald G}",

note = "Keywords: Adult; Cardiac Output; Exercise Test; Female; Forearm; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Lactic Acid; Male; Muscle, Skeletal; Mutation; Oxygen Consumption; Phenotype; RNA Splice Sites; Reverse Transcriptase Polymerase Chain Reaction",

year = "2009",

doi = "10.1093/brain/awp065",

language = "English",

volume = "132",

pages = "1545--52",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "Pt 6",

}

TY - JOUR

T1 - Splice mutations preserve myophosphorylase activity that ameliorates the phenotype in McArdle disease

AU - Vissing, John

AU - Duno, Morten

AU - Schwartz, Marianne

AU - Haller, Ronald G

N1 - Keywords: Adult; Cardiac Output; Exercise Test; Female; Forearm; Glycogen Phosphorylase, Muscle Form; Glycogen Storage Disease Type V; Humans; Lactic Acid; Male; Muscle, Skeletal; Mutation; Oxygen Consumption; Phenotype; RNA Splice Sites; Reverse Transcriptase Polymerase Chain Reaction

PY - 2009

Y1 - 2009

N2 - Over 100 mutations in the myophosphorylase gene, which cause McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype-phenotype correlation has been identified in this condition. We evaluated physiologic and genetic features of two patients with a variant form of McArdle disease, associated with unusually high exercise capacity. Physiologic findings were compared to those in 47 patients with typical McArdle disease, and 17 healthy subjects. Subjects performed an ischaemic forearm exercise test to assess lactate and ammonia production. Peak oxidative capacity (VO2max) and cardiac output were determined, using cycle ergometry as the exercise modality. The two patients with atypical McArdle disease carried common mutations on one allele (R50X and G205S), and novel splice mutations in introns 3 [IVS3-26A>G (c.425-26A>G)] and 5 [IVS5-601G>A (c.856-601G>A)] on the other allele. Plasma lactate after ischaemic exercise decreased in all typical McArdle patients, but increased in the two atypical McArdle patients (10% of that in healthy subjects). Peak workload and oxidative capacity were 2-fold higher in patients with atypical McArdle disease compared to typical McArdle patients. Oxygen uptake, relative to cardiac output, was severely impaired in the 47 patients with typical McArdle disease, and partially normalized in the milder affected McArdle patients. These findings identify the first distinct genotype-phenotype relationship in McArdle disease, and indicate that minimal myophosphorylase activity ameliorates the typical McArdle disease phenotype by augmenting muscle oxidative capacity. The milder form of McArdle disease provides important clues to the level of functional myophosphorylase needed to support muscle oxidative metabolism.

AB - Over 100 mutations in the myophosphorylase gene, which cause McArdle disease, are known. All these mutations have resulted in a complete block of muscle glycogenolysis, and accordingly, no genotype-phenotype correlation has been identified in this condition. We evaluated physiologic and genetic features of two patients with a variant form of McArdle disease, associated with unusually high exercise capacity. Physiologic findings were compared to those in 47 patients with typical McArdle disease, and 17 healthy subjects. Subjects performed an ischaemic forearm exercise test to assess lactate and ammonia production. Peak oxidative capacity (VO2max) and cardiac output were determined, using cycle ergometry as the exercise modality. The two patients with atypical McArdle disease carried common mutations on one allele (R50X and G205S), and novel splice mutations in introns 3 [IVS3-26A>G (c.425-26A>G)] and 5 [IVS5-601G>A (c.856-601G>A)] on the other allele. Plasma lactate after ischaemic exercise decreased in all typical McArdle patients, but increased in the two atypical McArdle patients (10% of that in healthy subjects). Peak workload and oxidative capacity were 2-fold higher in patients with atypical McArdle disease compared to typical McArdle patients. Oxygen uptake, relative to cardiac output, was severely impaired in the 47 patients with typical McArdle disease, and partially normalized in the milder affected McArdle patients. These findings identify the first distinct genotype-phenotype relationship in McArdle disease, and indicate that minimal myophosphorylase activity ameliorates the typical McArdle disease phenotype by augmenting muscle oxidative capacity. The milder form of McArdle disease provides important clues to the level of functional myophosphorylase needed to support muscle oxidative metabolism.

U2 - 10.1093/brain/awp065

DO - 10.1093/brain/awp065

M3 - Journal article

C2 - 19433441

VL - 132

SP - 1545

EP - 1552

JO - Brain

JF - Brain

SN - 0006-8950

IS - Pt 6

ER -