Bilateral macular drusen in acquired partial lipodystrophy with type 2 membranoproliferative glomerulonephritis

Background

Lipodystrophy is an ultrarare condition characterised by generalised or partial loss of adipose tissue (lipoatrophy), often with corresponding pathological accumulation of adipose tissue (lipohypertrophy) elsewhere in the body. The global prevalence of lipodystrophy is approximately 1.3–4.7 per 1 000 000.1 The condition can be acquired or inherited, with the ratio of affected men to women varying significantly depending on subtype; congenital generalised and familial partial lipodystrophy (PLD) 1:1–2, acquired generalised lipodystrophy 1:3 and acquired PLD 1:4.2 Changes in the AGPAT2, LMNA and PPARγ genes give rise to familial forms of the condition.3 There are no known monogenic causes for acquired PLD, but risk alleles in LMBN2 have been associated with an increased likelihood of developing the condition.4 The acquired form is most commonly seen in HIV patients receiving highly active antiretroviral therapy.5

Lipodystrophy is commonly associated with metabolic dysfunction, such as insulin resistance, altered lipid metabolism and renal disease.6 This is unsurprising as the adipose tissue is metabolically dynamic and integral to the endocrine system in regulating metabolic homeostasis. Due to its rarity and heterogeneity, patients with lipodystrophy syndrome may frequently be missed or misdiagnosed. This is of concern as the condition is progressive with significant metabolic consequences, which may potentially be life-threatening.

Very little is known about the ocular manifestations of lipodystrophy syndrome. Previously, retinal drusen, retinal pigment epithelium (RPE) atrophy,7 choroidal neovascularisation (CNV),8 vitreous haemorrhage and enophthalmos secondary to lipid atrophy have been reported.9 Here we provide a detailed structural and functional correlation for macular drusen associated with acquired PLD syndrome, a rare and important differential for inherited macular dystrophies.

Case presentation

A 35-year-old woman had noticed over the past year that she was straining to see the fine details and suffering from evening tension headaches. She visited an optician who noted bilateral retinal drusen and referred her to Moorfields Eye Hospital NHS Foundation Trust. She reported photosensitivity, but no issues with dark adaptation, photopsia, colour vision, distortion, nyctalopia or visual field loss. Her previous ocular history included right amblyopia from childhood. The patient had a medical history of acquired PLD, in a cephalothoracic distribution, which was diagnosed at age 7 years. Her condition was managed by the National Severe Insulin Resistance Service at the Addenbrooke’s Hospital, Cambridge. She had previous cosmetic treatment involving adipose tissue transposition from the thighs to the face. She suffered from renal dysfunction with one affected kidney, and was found to be C3 nephritic factor positive with a low serum C3 suggestive of type 2 membranoproliferative glomerulonephritis (MPGN-II). She had no drug history or known allergies. She was a non-smoker with no alcohol intake, and worked as a graphic designer. She was born full-term and the pregnancy had been uncomplicated. Her mother is of Scottish descent and her father is Syrian; no consanguinity. She had a family history of diabetes on her paternal side. Otherwise, there was no relevant family history other than her older sister had a squint and amblyopia.

Investigations

The best-corrected visual acuity was 0.50 and 0.00 LogMAR in the right and left eye, respectively. Refraction was +4.50/–1.00 ×115 in the right eye and +2.50/–1.00 ×85 in the left eye, indicating a hypermetropic anisometropia with astigmatism. General inspection of the face revealed bilateral deep sulci. Examination of the eyelids revealed bilateral anterior and posterior margin blepharitis. Anterior segment examination was remarkable for punctate epithelial erosions and an abnormal tear film breakup time of <10 s consistent with evaporative dry eyes. Funduscopy showed bilateral drusen, most dense in the temporal macula with clusters superior and inferior to the temporal vascular arcades (figure 1); there was no evidence of RPE atrophy, macular haemorrhage, exudation or CNV. Multimodal retinal imaging was performed including ultra-widefield colour fundus and autofluorescence, which revealed hyperautofluorescent macular drusen (figure 1). Spectral domain optical coherence tomography confirmed the location of the drusen between the RPE and Bruch’s membrane, and the absence of intraretinal and subretinal fluid (figure 2). Humphrey visual field was normal in both eyes. Full-field and pattern electroretinogram (ERG) was performed. The full-field ERG was normal, suggesting normal generalised retinal function. The pattern ERG was within normal limits to a standard field stimulus; however, to a large field stimulus, it did not demonstrate the expected increase in amplitude in either eye, suggesting mild peripheral macular dysfunction with intact central macular function (figure 2). Multifocal ERG was also performed and confirmed no central macular dysfunction, but far eccentric areas were subnormal. Given the higher density of drusen in the peripheral macula, we postulated that this accounted for the mild peripheral macular dysfunction.10 The patient underwent genetic testing with a retinal and macular dystrophy-targeted gene panel consisting of 236 causal genes, but no pathogenic variants of significance were detected.10

Differential diagnosis

Sorsby fundus dystrophy is a progressive autosomal dominant macular dystrophy. This condition is caused by mutations involving the TIMP3 gene. It is known to present between the third and sixth decade of life with characteristic thickening of the basement membrane and drusenoid deposits that later develop into areas of atrophy. Typically, patients demonstrate disrupted dark adaptation and nyctalopia, progressing to a loss of central vision.11

Doyne honeycomb retinal dystrophy, also known as dominant drusen or malattia leventinese, is caused by one specific variant in EFEMP1 (p.Arg345Trp). Characteristically, small radial and large round drusen are visible in the posterior pole and juxtapapillary area.11 12 Patients are generally asymptomatic. If visual symptoms are apparent, these may include reduced central vision, metamorphopsia and photopsia.

Familial benign fleck retinopathy is an autosomal recessive condition that belongs to the group of flecked retina syndromes. It is caused by biallelic variants in the PLA2G5 gene.11 Affected individuals do not suffer from visual dysfunction nor do they demonstrate electrophysiological deficits. They present from an early age with non-progressive subretinal drusenoid deposits that extend far into the peripheral retina; however, unlike our patient, these deposits are foveal sparing.12

Pattern dystrophy is an autosomal dominant condition, comprising a heterogeneous group of macular disorders with various patterns of macular pigmentary alterations. The most common mutation is in the PRPH2 gene although variants in other genes, such as CTNNA1 have been reported.13 It is often an incidental finding on routine examination as affected individuals are often asymptomatic, although mild reduction in vision and metamorphopsia may occur.

Certain systemic disorders, such as MPGN-II and lipodystrophy can manifest as early-onset retinal drusen or drusen-like deposits. MPGN-II can present with basal laminar (also known as cuticular) drusen in the second decade of life. These small yellow–white clustering drusen are found in the macula and peripheral retina. They are easily visualised by fluorescein angiography and were first described as having a ‘starry sky’ appearance. Over time, reduced central vision secondary to CNV, serous macular detachment and macular atrophy may ensue.11

Treatment

Despite the extensive macular drusen, the patient retained normal vision in her left eye, hence no intervention was required. An Amsler grid was provided so the patient could monitor for any changes such as distortion or scotomas associated with a possible CNV. The patient was advised to maintain a healthy, balanced diet rich in antioxidants and avoid cigarette smoke. Lid hygiene advice and ocular lubricants were prescribed for her blepharitis and dry eyes.

The mainstay metabolic management of lipodystrophy includes dietary macronutrient restriction and regular exercise, as well as the use of hypoglycaemic and hypolipidemic medications where indicated. Currently, the only drug approved for metabolic control in lipodystrophy is metreleptin, which can be used as an adjunct to diet, and has been found to be more effective in those with general rather than PLD.6 Additional first-line treatments include metformin for treatment of diabetes and insulin resistance, statins for hyperlipidaemia, and ACE inhibitors or angiotensin receptor blockers for hypertension. Consideration should be given to the psychological impact of the condition and referrals should be made accordingly for psychological therapy and cosmetic surgery.6

Outcome and follow-up

Annual follow-up was arranged to monitor the retinal findings. The patient remained stable without any deterioration in vision or associated symptoms over a 1-year period. There was no evidence of CNV or RPE atrophy. The blepharitis was well controlled with conservative management.