<i>PHKA2</i> variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only

Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole‐exome sequencing or targeted next‐generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%–20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH‐only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH‐only phenotype of PHKA2

Muscle phenotype and mutation load in 51 persons with the 3243A&gt;G mitochondrial DNA mutation

Background: Mitochondrial disorders are generally not associated with a clear phenotype-genotype relationship, which complicates the understanding of the disease and genetic counseling. Objective: To investigate the relationship between the muscle and blood mitochondrial DNA mutation load and phenotype. Design: Survey. Setting: The Neuromuscular Research Unit, Rigshospitalet, Copenhagen, Denmark. Participants: Fifty-one persons with the 3243A&gt;G point mutation of mitochondrial DNA, and 20 healthy control subjects. Methods: We recorded the maximal oxygen uptake (V̇O2max), maximal workload, resting and peak-exercise plasma lactate levels, muscle and blood mutation load, muscle morphology, and presence of diabetes mellitus and hearing impairment in all subjects. Results: Muscle mutation load (mean±SE, 50%±5%; range, 2%-95%) correlated with V̇O2max and resting plasma lactate level (P&lt;.001; R≥0.64). All persons except 5 with a muscle mutation load above 50% had abnormal V̇O2max and morphology on muscle biopsy findings. Persons with hearing impairment and diabetes mellitus had a muscle mutation load above 65%. The mutation load in blood (mean±SE, 18%±3%; range, 0%-61%) did not correlate with V̇O2max, resting plasma lactate levels, or presence of hearing impairment or diabetes mellitus. Conclusions: This study demonstrates a close relationship between the muscle mutation load and phenotype in persons carrying the 3243A&gt;G mutation. The lack of correlation between the mutation load in blood and symptoms from other tissues emphasizes the importance of assessing phenotype-genotype correlations in the same tissue in mitochondrial disease. The results indicate that the threshold of muscle mutation load at which oxidative impairment occurs can be as low as 50%, which is as much as 40% lower than that suggested by in vitro studies.</p

Limited diagnostic value of enzyme analysis in patients with mitochondrial tRNA mutations

We evaluated the diagnostic value of respiratory chain (RC) enzyme analysis of muscle in adult patients with mitochondrial myopathy (MM). RC enzyme activity was measured in muscle biopsies from 39 patients who carry either the 3243A&gt;G mutation, other tRNA point mutations, or single, large-scale deletions of mtDNA. Findings were compared with those obtained from asymptomatic relatives with the 3243A&gt;G mutation, myotonic dystrophy patients, and healthy subjects. Plasma lactate concentration, maximal oxygen uptake, and ragged-red fibers/cytochrome c-negative fibers in muscle were also determined. Only 10% of patients with the 3243A&gt;G point mutation had decreased enzyme activity of one or more RC complexes, whereas this was the case for 83% of patients with other point mutations and 62% of patients with deletions. Abnormal muscle histochemistry was found in 65%, 100%, and 85% of patients, respectively, in these three groups. The results indicate that RC enzyme analysis in muscle is not a sensitive test for MM in adults. In these patients, abnormal muscle histochemistry appears to be a better predictor of MM.</p

National clinical Genetic Networks - GENets - Establishment of expert collaborations in Denmark

Genetic conditions are often familial, but not all relatives receive counseling from the same institution. It is therefore necessary to ensure consistency in variant interpretation, counseling practices, and clinical follow up across health care providers. Furthermore, as new possibilities for gene-specific treatments emerge and whole genome sequencing becomes more widely available, efficient data handling and knowledge sharing between clinical laboratory geneticists and medical specialists in clinical genetics are increasingly important. In Denmark, these needs have been addressed through the establishment of collaborative national networks called Genetic Expert Networks or "GENets". These networks have enhanced patient and family care significantly by bringing together groups of experts in national collaborations. This promotes coordinated clinical care, the dissemination of best clinical practices, and facilitates the exchange of new knowledge.</p