Lipodystrophy is a rare metabolic disorder resulting from adipose tissue abnormalities. Lipodystrophy can be divided by aetiology into primary (genetically determined) and secondary (acquired over a lifetime due to other conditions, treatments, or external factors). When only certain parts of the body are affected, it is referred to as partial lipodystrophy, whereas global damage to fat tissue is considered the generalised form.1 Familial partial lipodystrophy (FPLD) subtype 4 is an autosomal dominant inherited disorder associated with defects in PLIN1, the gene encoding Perilipin 1, a component of lipid droplet membranes that is essential for lipolysis and lipid deposition.2 Pathogenic PLIN1 variants are linked to lipodystrophy, but their interpretation is disputed.

Only a few dozen cases of FPLD subtype 4 have been reported worldwide with variable clinical presentations but repeatedly included a Cushingoid appearance with classic central obesity and loss of subcutaneous adipose tissue, especially in the buttocks and lower extremities. Muscular hypertrophy has also been reported, particularly in the lower extremities and arms. The clinical picture is dominated by diabetes mellitus and frequently accompanied by increased insulin resistance and hypertriglyceridaemia. The severity of hypertriglyceridaemia varies from asymptomatic to complications such as recurrent pancreatitis, hepatic steatosis, or cutaneous xanthomatosis.1,2

In addition to metabolic disturbances, other manifestations include arterial hypertension, cardiomyopathy, nephropathy, and hyperandrogenic conditions. Diagnostics also rely on laboratory changes and genetic testing. In some types of familial lipodystrophy, specific changes on magnetic resonance imaging (MRI) or densitometric examination have been described.3,4

Due to the rarity of this disorder, comprehensive treatment guidelines are not yet available.1,2 However, diet is essential for the management of metabolic complications of lipodystrophy. Furthermore, metreleptin therapy is effective for metabolic complications in hypoleptinaemic patients with generalised lipodystrophy and select patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may also be helpful (e.g., metformin for diabetes and statins or fibrates for hyperlipidaemia).5 Here, we present a case of FPLD subtype 4 with normal leptin range that responded to volanesorsen therapy.

A 30-year-old woman with newly diagnosed type 2 diabetes mellitus and no significant prior medical history was referred to our department for recurrent severe hypertriglyceridaemia. First, a pathological level of triglycerides (TGs) was detected together with diabetes mellitus. Her family history included her mother’s early death from an unknown disease at 46 years of age and her brother requiring treatment for dyslipidaemia and hypertension. The patient was a non-smoker and abstinent from alcohol. Her chronic medication regimen included four antihypertensive drugs (perindopril, amlodipine, indapamide, and nebivolol), atorvastatin, and insulin. She had previously used fenofibrate but discontinued it on her own.

The patient’s appearance was slightly muscular with notable loss of fat tissue on the lower limbs and gluteal area (Fig.1). Her BMI was 26.2 kg/m2 and waist circumference 87 cm. In the ambulance, her blood pressure was simultaneously measured as 210/80 mmHg in the left arm and 205/85 mmHg in the right arm.

Figure 1, Figure 2, Figure 3, Figure 4, Figure 5

The referring physician had repeatedly measured hypertriglyceridaemia, with levels between 10 and 39 mmol/L on irregular fenofibrate therapy. During our examination, the serum was lipemic, initially preventing analysis. After performing repeated sample dilutions, a baseline serum TG level of 167 mmol/L was established. Blood glucose was 18 mmol/L. Most other laboratory parameters were unevaluable due to lipemia.

Clinically, the patient complained of a markedly itchy rash all over her body, occasional abdominal pain, and mild deterioration in vision. Based on these findings, a strict dietary intervention with close glycaemic control was initiated. Despite this regimen, her TG levels decreased slowly, measuring 115 mmol/L 3 days later. Administration of chronic antihypertensive therapy yielded a good effect during hospitalisation; therefore, baseline antihypertensive drug and statin levels were verified from the first samples. Low drug levels in the blood indicated the patient’s poor adherence to pharmacotherapy at home.

During this first hospitalisation, abdominal ultrasound revealed enlargement and increased echogenicity of the liver and spleen. Ophthalmological examination showed retinal lipemia without diabetic retinopathy. After 2 days of hospitalisation, the patient discharged herself against medical advice. At discharge, she was re-educated about dietary measures and referred to a nutritional therapist, and her therapy with omega-3 fatty acids, fenofibrate, and spironolactone was adjusted. The patient refused adipose tissue biopsy, oral antidiabetic drugs, and statin treatment.

Two weeks later, the patient attended an outpatient check-up. Spironolactone had been discontinued by the patient’s general practitioner, and the patient had neglected to attend her nutritional appointment. The patient’s average blood pressure was 160/120 mmHg, and her laboratory tests revealed a TG level of 26.16 mmol/L.

At her next outpatient visit at our hypertension centre, her mean blood pressure was 145/92 mmHg. Blood analysis confirmed effective levels of antihypertensive drugs. The patient complained of recurrent pruritic xanthomatosis and abdominal pain. Laboratory tests excluded endocrine causes of secondary arterial hypertension and hypertriglyceridaemia, showing normal levels of TSH, plasma metanephrines, cortisol, aldosterone, renin, aldosterone/renin ratio, oestradiol, testosterone, DHEAS, and 17OH-progesterone. Significant elevation of TGs to 76.70 mmol/L was confirmed.

Despite established conservative therapy, severe hypertriglyceridaemia persisted, but secondary causes of hypertriglyceridaemia (endocrine, metabolic, drug, renal, dietary) were excluded. Some part of the high TG values may have been caused by persistent hyperglycaemia and possible metabolic dysfunction-associated steatotic liver disease, which we could not rule out in this case. We collected samples for genetic testing with suspicion of a possible genetic origin of the disease (Fig.2). The patient was again advised strict dietary measures and insulin administration was re-initiated.

Familial chylomicronaemia syndrome (FCS) was also considered as part of the differential diagnosis, but such a diagnosis is unlikely according to the European scoring system.6 The patient’s leptin levels were within the normal range.

Due to refractory triacylglycerolaemia causing severe bothersome eruptive xanthomatosis, visual impairment, and abdominal pain due to hepatosplenomegaly without confirmed pancreatitis, and pending genetic testing results and approval of biological therapy, we initiated plasmapheresis via the cubital vein using physiological saline and albumin solution substitution. The treatment was complicated by weakness, tremor, and transient hypotension. After three sessions, the patient’s TG level dropped to 4.9 mmol/L and her symptoms resolved (Fig.3). As fenofibrate was insufficiently effective, this treatment was temporarily discontinued to exclude a paradoxical reaction to the medication. The patient agreed to start statin and metformin therapy.

Two weeks later, the patient relapsed with xanthomatosis and a TG level of 72.10 mmol/L. Plasmapheresis was attempted with pre-treatment for a considered allergic and anxiety reaction. However, a severe anxiety reaction necessitated interrupting the procedure, and the patient refused further plasmapheresis from the peripheral access. After another 2 weeks, a temporary central haemodialysis catheter was placed, allowing weekly plasmapheresis without complications (Fig.4).

One month after catheter insertion, severe tunnelitis necessitated catheter removal and cessation of plasmapheresis. The patient refused catheter reinsertion and did not agree to further plasmapheresis.

Genetic testing was performed using targeted massive parallel sequencing of a custom gene panel associated with dyslipidaemia (available upon request), focusing initially on familial hyperchylomicronaemia. No pathogenic variants in LPL, APOC2, APOA5, LMF1, or GPIHBP1 genes were identified that could explain the patient’s condition. Subsequently, all genes in the panel were analysed. Variants with an allelic frequency >1% in the GnomAD database (v4.1.0) or classified as benign/likely benign by at least three submitters in ClinVar (without conflicting classifications) were filtered out. Extended bioinformatic analysis, including the evaluation of all frameshift, potential splice site-disrupting, nonsense, and start-loss variants across the panel, detected PLIN1 variant c.46-4_50del. This variant is a 9-bp deletion that spans the exon 3 acceptor splice site. As variants affecting splicing have been described in association with FPLD subtype 4, we considered this diagnosis and identified many common features in our patient.7 No other family members were available for clinical examination and genetic testing to enable segregation analysis.

To support the diagnosis of FPLD, we performed supplementary pelvic MRI and densitometry scans, but they did not yield conclusive findings to support the diagnosis.3,4 The patient’s normal leptin levels did not exclude the diagnosis of partial lipodystrophy.1

Because of refractory triacylglycerolaemia causing severe bothersome eruptive xanthomatosis, visceral organomegaly, and visual impairment, we considered other therapeutic approaches. Treatment with metreleptin is not approved for partial lipodystrophy but, in some cases, it can be administered under compassionate use exemptions. Nonetheless, there is a high risk that our patient would be a nonresponder due to normal leptin levels.8

Based on the efficacy and safety of volanesorsen for the treatment of metabolic complications in patients with FPLD from the COMPASS study and others,9,10,11 we anticipated a benefit of this drug in our patient. Volanesorsen is a second-generation antisense oligonucleotide that inhibits apo C-III mRNA. It strongly induces lipoprotein lipase and hormone-sensitive lipase and has other mechanisms that enhance TG clearance from the human body. The drug was primarily developed to treat FCS and is not approved for the treatment of lipodystrophy.12,13 In a seemingly hopeless situation, it was decided to discuss the case with the institutional committee and to treat volanesorsen under a compassionate use program.

Treatment was initiated according to the standard weekly dosing regimen for FCS, with excellent results, even after extending the dosing regimen to every 2 weeks. Subsequently, due to the adverse effects described below, in agreement with the patient and the institutional committee, the dosage regimen was extended to once every 4 weeks, with a persistent effect. Despite the absence of a change in platelet counts at regular check-ups, systemic adverse reactions occurred within hours after administration and lasted for a maximum of 24 hours. Each administration of volanesorsen was associated with nausea, sometimes accompanied by vomiting. This was satisfactorily compensated by the use of ondansetron before volanesorsen. The patient repeatedly complained of body pains resembling flu-like syndrome, together with migraine conditions, lasting up to 24 hours post-injection. These unpleasant pains were unresponsive to paracetamol or metamizole, but satisfactory pain relief was achieved with rectal indomethacin suppositories. Premedication with corticosteroids or antihistamines had no effect; with the next application it did not get worse, and the patient was without any other symptoms (fever, high CRP or IgE, urticaria). Therefore, this situation appeared to have been an idiosyncratic reaction. The patient was repeatedly offered the option to discontinue the medication, which she refused, and she was grateful for the treatment itself.

Within 3 months of starting subcutaneous treatment, the patient exhibited near normalisation of her lipid profile (Fig.5). Following effective reduction of her hypertriglyceridaemia, the irritating xanthomatosis and abdominal discomfort were completely eliminated, and the patient’s vision problems completely subsided. The hepatosplenomegaly remained unchanged.