Lipodystrophy, Familial Partial, Type 6

A number sign (#) is used with this entry because of evidence that familial partial lipodystrophy-6 (FPLD6) is caused by homozygous mutation in the LIPE gene (151750) on chromosome 19q13.

For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

Description

Familial partial lipodystrophy-6 (FPLD6) is characterized by abnormal subcutaneous fat distribution, with variable excess accumulation of fat in the face, neck, shoulders, axillae, back, abdomen, and pubic region, and reduction in subcutaneous fat of the lower extremities. Progressive adult-onset myopathy is seen in some patients, and there is variable association with diabetes, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and hepatic steatosis (Zolotov et al., 2017).

Clinical Features

Carboni et al. (2014) described a sister and brother, born of consanguineous Italian parents, who had partial lipodystrophy associated with muscular dystrophy. The sister, who had had menstrual irregularity from youth, developed abnormal subcutaneous fat distribution at age 33 years, with accumulation in the neck, abdomen, and axillae, and progressive reduction of subcutaneous fat in the legs. She was diagnosed with diabetes at age 43, and examination at 50 years of age showed abnormal fat accumulation in the neck, abdomen, clavicular regions, axillae, labia majora, back, and area below the triceps, with concomitant reduction of subcutaneous fat in the legs. The patient also exhibited mild proximal muscle weakness involving both shoulder and hip girdle muscles. Her 49-year-old brother also had fat distribution anomalies, with increased subcutaneous adipose tissue of the abdomen and axillae and reduced subcutaneous fat in the legs. His muscle strength was normal. Both sibs had high levels of creatine kinase, and the sister also had elevated levels of triglycerides and cholesterol. Muscle biopsy from the sister showed dystrophic changes but normal immunohistochemical labeling of the proteins responsible for most common muscular dystrophies; trichome and oxidative stains revealed no evidence of mitochondrial disease. MRI in the sister showed fat accumulation in the neck, back, and abdomen; reduced subcutaneous fat in the lower limbs; and hepatic steatosis. Increased T2 signal was seen in the posterior thigh muscle and tibialis anterior and posterior, extensor digitorum longus, and soleus muscles. The brother's MRI showed nonhomogeneous subcutaneous fat distribution, with fat predominance in the anterior abdomen and reduced fat in the lower limbs; T2 signal was increased in the posterior leg muscle.

Zolotov et al. (2017) reported a 41-year-old woman and her 36-year-old brother, from a consanguineous Israeli Arab family, who exhibited marked symmetric accumulation of subcutaneous fat in the face, neck, axillae, and trunk, with loss of subcutaneous fat from the lower extremities and progressive symmetric myopathy during adulthood. In addition, the sister had diabetes and the brother had hepatic steatosis. A 23-year-old younger brother reported muscle wasting of his lower extremities and recent difficulty climbing stairs, but his body fat distribution appeared to be normal. All 3 affected sibs had mild to severe hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, and mildly elevated aminotransferase and uric acid levels with consistently high creatine kinase levels, compared to their 6 unaffected sibs.

Inheritance

Carboni et al. (2014) studied an Italian sister and brother with partial lipodystrophy associated with muscular dystrophy. The authors stated that, given the patients' parental consanguinity and discordant genders, the likely mode of inheritance was autosomal recessive.

Molecular Genetics

Albert et al. (2014) sequenced 12 lipolytic-pathway genes in 24 Old Order Amish individuals whose fasting serum triglyceride levels were at the extremes of the distribution, and detected a 19-bp deletion in the LIPE gene (151750.0001) in an individual whose triglyceride level was at the upper extreme. Genotyping for the LIPE deletion in 2,738 participants in the Amish Complex Disease Research program identified 1 individual who was homozygous for the deletion ('DD' genotype) and 140 heterozygotes; thus, 5.1% of the Amish persons carried the deletion compared with 0.2% of non-Amish persons of European descent. Three of the 9 sibs of the proband were also homozygous for the deletion. All 4 sibs exhibited impaired lipolysis and altered metabolic traits, including systemic insulin resistance and diabetes. Association analyses showed that heterozygous carriers of the deletion had an increased risk of dyslipidemia, with elevated triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol, hepatic steatosis, systemic insulin resistance, and diabetes. All 4 homozygous sibs received a diagnosis of type 2 diabetes (T2D; 125853) before 50 years of age, and heterozygous carriers had a risk of T2D that was 1.8 times that of noncarriers. In addition, MRI in a homozygous sib showed evidence for redistribution of body fat, with an increase in visceral fat and a decrease in subcutaneous fat of the extremities, resulting in a significant increase in the abdominal-to-calf subcutaneous fat ratio compared to a noncarrier sib. Adipose tissue from 2 of the homozygous sibs showed absence of hormone-sensitive lipase, small adipocytes, impaired lipolysis, insulin resistance, and inflammation. Transcription factors responsive to PPARG (601487) and downstream target genes were downregulated in their adipose tissue, altering the regulation of pathways influencing adipogenesis, insulin sensitivity, and lipid metabolism.

In an Italian sister and brother from a consanguineous family with a late-onset form of partial lipodystrophy, originally reported by Carboni et al. (2014), Farhan et al. (2014) performed genomewide autozygosity mapping and whole-exome sequencing, and identified a frameshift mutation in the LIPE gene (151750.0002) that segregated with disease in the family. The mutation was not found in the NCBI dbSNP, 1000 Genomes Project, Human Gene Mutation, or Exome Variant Server databases, or in in-house control exomes.

In an Israeli Arab sister and brother with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy, Zolotov et al. (2017) performed Sanger and exome sequencing and identified homozygosity for a nonsense mutation in the LIPE gene (E1035X; 151750.0003) that segregated with disease in the family. The authors concluded that LIPE deficiency in humans is associated with adult-onset progressive multiple symmetric lipomatosis, lower extremity lipodystrophy, and myopathy, along with metabolic abnormalities such as diabetes, hypertriglyceridemia, and hepatic steatosis.

Exclusion Studies

In a sister and brother from a consanguineous Italian family with partial lipodystrophy associated with muscular dystrophy, Carboni et al. (2014) analyzed 13 known lipodystrophy-associated genes and found no pathogenic mutations. Respiratory chain enzyme dose and sequencing of whole mitochondrial DNA were normal, and SNP array analysis excluded copy number variations of pathogenic relevance shared between the sibs.