F41. Expanding the phenotype-genotype correlations of PNPLA2 mutations

Abstract

Introduction Neutral lipid storage disease with myopathy (NLSD-M), due to diverse PNPLA2 mutations, usually presents with an asymmetrical weakness, proximal involvement of upper limbs and posterior compartment of lower limbs. NLSD-M can be associated with other co-morbidities, like diabetes mellitus, hyperlipidemia, and most commonly, cardiomyopathy, which can be detected in almost 50% of patients. Although clinical manifestations begin around the third decade, late onset disease with unusual symptoms, such as fatigue and exercise intolerance, has been reported. Magnetic resonance imaging (MRI) of skeletal muscles reveals fatty degeneration, with a predilection for shoulder girdle and lower limb muscles. Electromyographic (EMG) features have been reported in one patient, where complex repetitive discharges (CRD) and myotonic discharges were detected in a few muscles. Methods Description of the clinical, neurophysiological, muscle MRI, pathological and genetic findings of a novel mutation in the PNPLA2 gene. This work received ethics board approval. Results Two sisters (aged 31 years at first examination), born 3 years apart from consanguineous parents, presented with a 2 year history of progressive motor deficits, proximal/asymmetric in upper limbs and distal/symmetric in lower limbs. The most severely affected muscles were: deltoids, biceps, external cuff rotators, gastrocnemius and tibialis anterior muscles. EMG recordings showed diffuse short-duration motor unit potentials, with asymmetrical distribution; some long duration, polyphasic potentials in distal muscles; profuse CRD in the biceps and tibialis anterior and sparse CRD in paravertebral muscles. MRI revealed an asymmetrical fatty replacement in the posterior compartment of thigs and legs, paravertebral musculature, deltoids and biceps. Jordans’ anomaly, characterized by lipid accumulation in leukocytes, was detected in peripheral blood smears in both patients. Muscle biopsy showed cytoplasmic vacuoles, suggestive of neutral lipid accumulation. Genetic analysis revealed a homozygous deletion in exon 6 of PNPLA2 gene (c.995delG), not yet described in the literature. Five years after the initial symptoms, the elder sister was completely dependent for upper limb activities, although she had independent walking, while the younger sister had only minor fine motor skills impairment. Creatine phosphokinase levels increased in a stepwise manner over the years in the elder sister (97–2840 UI/L), while stable levels were found in the younger one (621–681 UI/L). Cardiomyopathy was not present in those patients. Conclusion NLSD-M due to PNPLA2 gene mutations should be suspected in patients presenting with an asymmetrical myopathy with upper limb predominance; profuse and also asymmetrical EMG and MRI abnormalities, even without cardiomyopathy. Although some mutations have been described, genotypical variability seems to be common, so novel mutations should be sought for genetic counselling purposes.