Neutral Lipid Storage Disease With Myopathy

A number sign (#) is used with this entry because of evidence that neutral lipid storage disease without ichthyosis but with mild myopathy (NLSDM) is caused by homozygous or compound heterozygous mutation in the PNPLA2 gene (609059), which encodes adipose triglyceride lipase (ATGL), on chromosome 11p15.

Description

Neutral lipid storage disease with myopathy is an autosomal recessive muscle disorder characterized by adult onset of slowly progressive proximal muscle weakness affecting the upper and lower limbs and associated with increased serum creatine kinase; distal muscle weakness may also occur. About half of patients develop cardiomyopathy later in the disease course. Other variable features include diabetes mellitus, hepatic steatosis, hypertriglyceridemia, and possibly sensorineural hearing loss. Leukocytes and muscle cells show cytoplasmic accumulation of triglycerides (summary by Reilich et al., 2011).

Neutral lipid storage disease with myopathy belongs to a group of disorders termed neutral lipid storage disorders (NLSDs). These disorders are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Chanarin-Dorfman syndrome (CDS; 275630) is defined as NLSD with ichthyosis (NLSDI). Patients with NLSDM present with myopathy but without ichthyosis (summary by Fischer et al., 2007).

Clinical Features

Fischer et al. (2007) described 3 affected females from 3 families from the Netherlands, France, and Algeria who showed multisystem triglyceride storage and myopathy, inconstantly associated with delays in walking, variable cardiac abnormalities, and hepatomegaly. One suffered from diabetes with onset at age 12 and died from cardiovascular complications at age 34. Notably, the individuals with NLSDM did not show obesity, in spite of a defect in triglyceride degradation in fibroblasts and in marked triglyceride storage in liver, muscles, and other visceral cells. Fischer et al. (2007) referred to this form of NLSD as NLSDM (NLSD with myopathy).

Akiyama et al. (2007) reported a 35-year-old Japanese woman with NLSDM. She had delayed walking and slow running from childhood, and showed severe upper and lower limb involvement as an adult. She was unable to raise her arms and showed Gowers sign and a waddling gait. Ichthyosis was not present. She did not have cardiac involvement. Imaging showed fatty replacement of multiple skeletal muscles, and skeletal muscle biopsy and leukocytes showed accumulation of neutral lipid droplets.

Reilich et al. (2011) reported 6 patients, including 2 sibs, with NLSDM. All had onset in the twenties or thirties of a slowly progressive proximal muscle weakness usually affecting the upper limbs and sometimes involving the lower limbs. Distal weakness affecting the fingers and feet was also observed in some patients. All had increased serum creatine kinase and 4 had hyperlipidemia. One patient had sensorineural hearing loss since childhood, and 2 developed cardiac abnormalities, including increased left ventricular wall thickness, decreased ejection fraction (40-45%), and congestive heart failure later in the disease course. One patient had diabetes mellitus. All showed cytoplasmic lipid droplets, known as Jordans anomaly, in peripheral granulocytes. Muscle biopsy showed accumulation of lipid droplets in the subsarcolemmal area of type 1 fibers, and MRI showed dystrophic changes in the shoulder girdle and fatty degeneration in the spinal and gluteal muscles.

Lin et al. (2012) reported 3 unrelated Han Chinese patients with NLSDM. All had adult onset of progressive muscle weakness between 38 and 45 years of age manifest as difficulty walking and lifting heavy objects. Features included muscle pain, fatigue, and muscle atrophy in an asymmetric pattern. Both proximal and distal muscles were involved, to different degrees in different patients. Neck muscle involvement and fasciculation were noticed in all 3 patients. All had increased serum creatine kinase and muscle biopsy showed numerous lipid droplets. Leukocytes showed cytoplasmic lipid droplets. None had a family history of a muscle disorder.

Heterozygous Mutation Carriers

Janssen et al. (2013) reported follow-up of the Dutch patient with NLSDM reported by Fischer et al. (2007) and observed variable clinical features in 6 family members who were heterozygous for 1 of the PNPLA2 mutations found in the proband. The proband was symptomatic and diagnosed at age 4 years. In her thirties, she developed hearing loss, cardiac involvement, psoriasis, and insulin resistance. Heterozygous family members had a range of symptoms, including exercise intolerance, decreased muscle tone, progressive muscle weakness, and episodes of muscle pain; 2 had no muscle symptoms. None had cardiac or liver involvement or insulin resistance. All, however, had recurrent infections, as did the proband, 2 had hearing loss, and 1 had psoriasis. Peripheral leukocytes of carriers showed Jordans bodies in the 6 to 12% range. Muscle biopsy of 1 heterozygous carrier at age 35 years showed mild neutral lipid storage. Janssen et al. (2013) concluded that the wildtype PNPLA2 allele cannot fully compensate for a mutated dysfunctional allele, and suggested that some patients with mild lipid myopathy may be heterozygous mutation carriers.

Inheritance

The transmission pattern of NLSDM in the families reported by Lin et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 females with NLSDM, Fischer et al. (2007) found compound heterozygous or homozygous mutations in the PNPLA2 gene (609059.0001-609059.0004), which encodes adipose triglyceride lipase, also known as ATGL. Fischer et al. (2007) investigated PNPLA2 as a candidate gene for this disorder because this gene is activated by ABHD5, mutations in which cause NLSD with ichthyosis (275630). It was unclear why the NLSDM patients did not have ichthyosis, but it was observed that the lipid accumulation in the epidermis was lower in NLSDM than in CDS/NLSDI.

In 6 patients, including 2 sibs, with NLSDM, Reilich et al. (2011) identified homozygous or compound heterozygous mutations in the PNPLA2 gene (see, e.g., 609059.0002; 609059.0009-609059.0010). Most of the mutations resulted in a lack of protein expression. Activation of hormone-sensitive lipase by beta-adrenergic agents such as clenbuterol appeared to bypass the enzymatic block in PNPLA2-deficient patient cells in vitro, suggesting a possible therapeutic approach.

In 3 unrelated Han Chinese patients with neutral lipid storage disease with myopathy, Lin et al. (2012) identified 4 different mutations in the PNPLA2 gene (609059.0005-609059.0008). All mutations occurred in the homozygous or compound heterozygous state.

In a 35-year-old Japanese woman with NLSDM, Akiyama et al. (2007) identified a homozygous truncating mutation in the PNPLA2 gene (609059.0011). The mutation was not found in 100 control alleles or in 50 unrelated Japanese individuals.