Most patients with JAK2-unmutated ET express CALR or MPL mutations, with respective estimated incidences of 22% and 3%, while approxmately 15% are wild-type for all 3 mutations (ie, they are triple-negative). However, JAK2 mutations also occur in about 60% of patients with ET, which underlines the need for BM examination in distinguishing JAK2-mutated ET from PV when the hemoglobin/hematocrit level is diagnostically equivocal (ie, as in “masked” PV). A JAK2 mutation is expected in PV, and its absence makes the diagnosis unlikely. In addition, recently discovered mutations, such as JAK2, CALR, and MPL, have proven useful in facilitating the diagnostic process. doi:10.1038/ marrow (BM) morphologic features remain the cornerstone of diagnosis in both essential thrombocythemia (ET) and polycythemia vera (PV). Parikh S, Goldstein A, Koenig MK, et al: Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. McGraw-Hill 2019 Accessed November 30, 2021. Online Metabolic and Molecular Bases of Inherited Disease. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. Shoffner JM: Oxidative phosphorylation diseases. The Online Metabolic and Molecular Bases of Inherited Disease. Robinson BH: Lactic acidemia: Disorders of pyruvate carboxylase and pyruvate dehydrogenase. Munnich A, Rotig A, Cormier-Daire V, Rustin P: Clinical presentation of Respiratory Chain Deficiency. Other manifestations can include congenital brain malformations, degenerative changes including Leigh disease, and facial dysmorphism.ġ. Seizures and ataxia are also frequent features. The most common features in infants and children with PDHC deficiency are delayed development and hypotonia. Clinical presentation of PDHC deficiency can range from fatal congenital lactic acidosis to relatively mild ataxia or neuropathy. Determination of lactate, pyruvate, and L:P ratio in cerebrospinal fluid is helpful in directing attention toward a possible mitochondrial disorder in cases with predominantly neurologic dysfunction and normal blood lactate levels, though further confirmatory testing will be required to establish a diagnosis.Ī low L:P ratio is observed in inherited disorders of pyruvate metabolism including pyruvate dehydrogenase complex (PDHC) deficiency. Many mitochondrial disorders have neurologic and myopathic features and may involve multiple organ systems. Mitochondrial disorders vary widely in presentation and age of onset. The L:P ratio is elevated in several, but not all, mitochondrial respiratory chain disorders. Though isolated elevated pyruvate is not diagnostic of any inborn error of metabolism, analysis with lactate may suggest an inborn error of metabolism as some present with lactic acidosis or a high lactate-to-pyruvate (L:P) ratio. Pyruvic acid, an intermediate metabolite, plays an important role in linking carbohydrate and amino acid metabolism to the tricarboxylic acid cycle, the fatty acid beta-oxidation pathway, and the mitochondrial respiratory chain complex.
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