Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients

Abstract

BackgroundA small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases.ResultsDuring the clinical follow-up (range: 2–44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias.ConclusionThe genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.

Clinical and genetic characterization of a Chanarin Dorfman Syndrome patient born to diseased parents

“…Liver abnormalities can occur in greater than 80% of patients, ranging from hepatomegaly or liver steatosis to cirrhosis, and can be observed in young children, as occurred in this family [ 4 , 6 ]. Neurological impairment was not detected in our patients; however, intellectual disability has been reported in 20% of CDS subjects and in approximately 40% of those carrying the N209X mutation [ 10 – 12 ]. Sensorineural hearing loss was not present in our family; however, this condition occurs in 30% of CDS patients.…”

A novel mutation of ABHD5 gene in a Chanarin Dorfman patient with unusual dermatological findings

“…CK was also elevated in our patient, but myopathy was not detected in EMG and clinically there was no muscle weakness. However, muscle damage has been reported only in 40% of affected subjects [16].…”

Genome-wide scan and fine-mapping of rare nonsynonymous associations implicates intracellular lipolysis genes in fat distribution and cardio-metabolic risk

“…All four likely-causal genes identified in our hypothesis-free main-analysis of rare, intracellular triglyceride hydrolysis, was associated with unfavorable fat distribution, higher 3 3 5 atherogenic lipid levels and higher risk of type 2 diabetes and coronary artery disease further 3 3 6 supporting the main findings from the scan of rare variants. Rare loss-of-function mutations in 3 3 7 PNPLA2 cause a recessively-inherited lipid storage disease characterized by ectopic fat 3 3 8 deposition, known as neutral lipid storage disease with myopathy, which in some of the few 3 3 9 reported cases has been associated with dyslipidemia and diabetes (49)(50)(51)(52). Our study is suggesting that a deletion in hormone sensitive lipase (LIPE), present in ~5% of Amish people 3 4 3 but rarely detected in other populations, results in lower intracellular lipolysis, smaller adipocytes, insulin resistance and higher diabetes risk (53).…”