The phenotypic spectrum of neutral lipid storage myopathy due to mutations in the PNPLA2 gene

Abstract

Neutral lipid storage disease is caused by mutations in the CGI-58 or the PNPLA2 genes. Lipid storage can be detected in various cell types including blood granulocytes. While CGI-58 mutations are associated with Chanarin-Dorfman syndrome, a condition characterized by lipid storage and skin involvement (ichthyosis), mutations in the patatin-like phospholipase domain-containing protein 2 gene (PNPLA2) were reported with skeletal and cardiac muscle disease only. We describe clinical, myopathological, magnetic resonance imaging (MRI), and genetic findings of six patients carrying different recessive PNPLA2 mutations. Pulse-chase labeling of control and patient cells with supplementation of clenbuterol, salmeterol, and dexamethasone was performed in vitro. The patients share a recognizable phenotype with prominent shoulder girdle weakness and mild pelvic girdle and distal muscle weakness, with highly elevated creatine kinase (CK) and cardiomyopathy developing at later stages. Muscle histology invariably reveals massive accumulation of lipid droplets. New muscle or whole-body MRI techniques may assist diagnosis and may become a useful tool to quantify intramuscular lipid storage. Four novel and two previously reported mutations were detected, affecting different parts of the PNPLA2 gene. Activation of hormone-sensitive lipase by beta-adrenergic substances such as clenbuterol appears to bypass the enzymatic block in PNPLA2-deficient patient cells in vitro. PNPLA2 deficiency is a slowly progressive myopathy with onset around the third decade. Cardiac involvement is relatively common at a later stage. Muscle MRI may detect increased lipid in a characteristic distribution, which could be used for monitoring disease progression. Beta-adrenergic agents may be beneficial in improving triacylglycerol breakdown in patients with PNPLA2 mutations.

Symptomatic lipid storage in carriers for the PNPLA2 gene

“…5,11,12,14 Here we report on additional unique findings in four carrier family members with diverse clinical involvement, including significant neutral lipid storage in muscle. The clinical features in these individuals included muscle weakness, episodes of muscle pain, sensorineural or conductive deafness and frequent infections in heterozygous individuals, carrying either the p.P195L or the mutation p.Frameshift319* in PNPLA2 (Table 1).…”

“…5,11,12,14,15 One might question whether the disorder is not more common than previously thought, and the diagnosis is missed in some of these milder patients owing to missing the diagnostic sign of Jordans' bodies (due to variable percentage of droplets in blood smear or the use of automated blood cell analysis) without specifically looking for the vacuoles by electron microscopy.…”

Myopathie à surcharge lipidique secondaire à une nouvelle mutation du gène PNPLA2

“…Les premiers symptômes sont une faiblesse musculaire proximale commençant le plus souvent aux membres supérieurs avec atteinte précoce de la ceinture scapulaire mais sans décollement important des omoplates. La plupart des patients ont également une atteinte distale des extenseurs des doigts et fléchisseurs des pieds [2]. Il n'y a pas d'atteinte faciale.…”

Clinical Reasoning: A 33-year-old man with cardiomyopathy and myopathy

“…Resultant weakness is typically proximal with prominent shoulder girdle involvement and may be asymmetric at onset. 7,9 Weakness may also involve distal extremities, particularly finger extensors and foot flexors. 7,9 Most patients develop symptoms by 30 years of age, although elevated CK and lipid accumulation is present prior to symptom onset.…”