Systematic study of ophthalmological findings in 10 patients with PEX1-mediated Zellweger spectrum disorder

Figures & data

Table 1. Genetic and clinical characteristics at first presentation and last examination.

ID	Sex, age (years)	Estimated disease duration (years)	Genetic analysis		Presence of systemic symptoms and age at symptom onset/diagnosis (years)
			Allele 1 Allele 2	Protein change	Neurological symptoms (age in years) and white matter abnormalities on MRI (yes/none, age in years at first description)	Dysmorphic features at first presentation	Hearing loss (age)	Cognitive functioning	Liver disease (age in years)	Dental abnormalities (age in years)
A1	F, 25.0	24.3	c.2528 G>A	p.Gly843Asp	Decreased deep tenson reflexes (18) None	Broad nasal bridge, epicanthal folds	Yes^† (8 months)	No intellectual deficits	None	Amelogenesis imperfecta (7)
A2	M, 20.1	20.1	c.2528 G>A	p.Gly843Asp	Decreased deep tenson reflexes (16) Cerebellar ataxia None	Broad nasal bridge, high forehead, mild epicanthal folds	Yes^† (5 weeks)	No intellectual deficits	None	Amelogenesis imperfecta (7)
B1	M, 26.7	26.2	c.2528 G>A	p.Gly843Asp	None	Low-set ears, underdeveloped ear lobes, high forehead, single transverse palmar crease	Yes^† (1 year)	No intellectual deficits	None	Amelogenesis imperfecta (N/A)
B2	M, 25.0	24.3	c.2528 G>A	p.Gly843Asp	Pes cavus Decreased deep tenson reflexes (21) Yes (12)	Low-set ears, underdeveloped ear lobes, high forehead	Yes^† (9 months)	Mild intellectual deficit	None	Amelogenesis imperfecta (N/A)
C1	M, 17.5	17.0	c.2528 G>A	p.Gly843Asp	None	Epicanthal folds, broad nasal bridge, underdeveloped ear lobes, single transverse palmar crease	Yes^† (6 months)	Mild intellectual deficit	Hepatomegaly (2)	Amelogenesis imperfecta (N/A)
C2	F, 11.0	10.8	c.2528 G>A	p.Gly843Asp	Cerebellar ataxia None	Epicanthal folds, broad nasal bridge, high forehead, single transverse palmar crease	Yes^† (10 months)	Mild intellectual deficit	None	Amelogenesis imperfecta (N/A)
D1	F, 19.1	19.0	c.2528 G>A c.2097_2098insT	p.Gly843Asp p.Ile700Tyrfs Ter42	Global hypotonia Areflexia Epilepsy/West syndrome (1.5) Yes (8)	Low-set ears, broad nasal bridge, syndactyly, epicanthal folds	Yes^† (20 months)	Moderate/severe intellectual deficit	Splenomegaly Liver cirrhosis (13)	Amelogenesis imperfecta (N/A)
E1	F, 44.1	43.5	c.2528 G>A	p.Gly843Asp	Cerebellar ataxia Yes (30)	Low-set ears and attached ear lobes, high forehead	Yes^† (9 months)	Mild intellectual deficit	Splenomegaly Liver cirrhosis (43)	Amelogenesis imperfecta (N/A)
E2	M, 39.4	39.0	c.2528 G>A	p.Gly843Asp	Cerebellar ataxia Yes (34)	Low-set ears and attached ear lobes, epicanthal folds, high forehead, transverse palmar creases	Yes^† (24 months)	Mild intellectual deficit	None	Amelogenesis imperfecta (N/A)
F1	M, 6.8	5.2	c.2528 G>A	p.Gly843Asp	None	High forehead, epicanthal folds	Yes^‡ (18 months)	Mild intellectual deficit	Hepatomegaly (2)	N/A

F, female; M, male; N/A, not available.

^†Hearing aids.

^‡Cochlear implants.

Table 2. Ophthalmological findings at first and last examination.

ID	Sex, age (years)	First ophthalmic symptoms, (age, months)	Retinal findings at first examination (age)	Eye movement and anterior segment findings at last examination	Fundus findings at last examination					Figure
					Optic disc	Macula	Periphery	SD-OCT findings	Fundus autofluorescence
A1	F, 25.0	Nyctalopia and reduced visual acuity (12)	Hyperpigmentations (2y10m)	Normal	Normal	Atrophy with foveal sparing	Bone-spicule hyperpigmentation Mild attenuation of retinal vasculature	Cystoid fluid collections in ONL Loss of ELM integrity	Hyperautofluorescent speckles	2A-2C
A2	M, 20.1	Nyctalopia (12)	Abnormal macular reflex (1y10m)	Normal	Normal	Atrophy	Round hyperpigmentations	Large cystoid fluid collections in ONL, retinoschisis aspect^† OD: Loss of ELM integrity	Hyperautofluorescent speckles	2D-2F
B1	M, 26.7	Nystagmus and nyctalopia (8)	Leopard retinopathy (3 years)	Convergent strabismus nystagmus	Waxy	Hyper- and hypopigmentations	Bone-spicule and round hyperpigmentations Mild attenuation of retinal vasculature	Loss of ELM integrity OD: Large cystoid fluid collections in ONL, retinoschisis aspect^‡ OS: parafoveal residual irregular cystoid fluid collections in ONL and confluent central fluid collection	Diffuse hyperautofluorescent speckles	2 G-2I
B2	M, 25.0	Nyctalopia (18)	RP (9 years)	Partial iris transillumination	Waxy, pale	Bone-spicule hyperpigmentations with foveal sparing	Bone-spicule and round hyperpigmentations, partial obliterated vasculature	Parafoveal cystoid fluid collections in ONL Loss of ELM integrity and retinal lamination	Diffuse hyperautofluorescent speckles	2J-2 L
C1	M, 17.5	Nystagmus (8)	Chorioretinal dystrophy (1.5y)	Saccadic eye movements	Normal	Bone-spicule hyperpigmentations	Bone-spicule and round hyperpigmentations	OS: loss of retinal lamination	Diffuse hyperautofluorescent speckles	2M-2O
C2	F, 11.0	Nyctalopia (36)	Abnormal retina, not further specified (1.5y)	Saccadic eye movements	Normal	Bone-spicule hyperpigmentations	Bone-spicule and round hyperpigmentations Mild attenuation of vasculature	Central cystoid fluid collections in ONL	Diffuse hyperautofluorescent speckles	2P-2 R
D1	F, 19.1	No fixation, nystagmus (36)	Leopard retinopathy (5 months)	Nystagmus in all directions Posterior synechiae Liquefied lens	N/A	N/A	N/A	N/A	N/A
E1	F, 44.1	Nystagmus and reduced visual acuity (6)	Pigmentary retinopathy (9 months)	Mild nuclear and posterior subcapsular cataract	Pale	Atrophy	Bone-spicule and round hyperpigmentations Partially obliterated vasculature	Loss of retinal lamination, residual confluent cystoid fluid collections. OD: aspect of lamellar macular hole	Diffuse hyperautofluorescent speckles	2S-2 U
E2	M, 39.4	Reduced visual acuity (4)	RP (4 months)	Mild nuclear cataract	Pale	Atrophy	Bone-spicule hyperpigmentation	Small residual confluent irregularly-shaped cystoid fluid collections in ONL	N/A
F1	M, 6.8	Nyctalopia (21)	RP (22 months)	Normal	Normal	RPE alterations	Pigmented clumps and bone-spicule hyperpigmentation	Cystoid fluid collections in ONL	N/A

SD-OCT, spectral-domain optical coherence tomography; F, female; M, male; ONL, outer nuclear layer; N/A, not available; ELM, external limiting membrane; OD, right eye; OS, left eye; RP, retinitis pigmentosa; RPE, retinal pigment epithelium.

^†Received treatment with oral acetazolamide 500 mg/day.

^‡Received treatment with oral acetazolamide 750 mg/day.

Table 3. Visual function at last examination.

ID	Sex, age (years)	Mean BCVA ODS (logMAR)	Mean SER ODS (dioptre)	ffERG (age in years and months)	Visual field pattern	Mean macular sensitivity on microperimetry (dB)
						OD	OS
A1	F, 25.0	0.72	3.38	Severe rod dysfunction and reduced cone function (2y10m)	Mild peripheral constriction	7.3	7.6
A2	M, 20.1	0.88	2.81	N/A	Peripheral constriction with some mid-peripheral scotomas (Figure 2a)	11.3 (Figure 2b)	1.9
B1	M, 26.7	0.55	6.63	Reduced rod function Mild reduction of cone function (7y)	Central and mid-peripheral scotoma	N/A^†	12.0
B2	M, 25.0	0.96	3.06	Severe reduction of rod and cone function (5y)	Central island (Figure 2c)	14.6 (Figure 2d)	11.7
C1	M, 17.5	0.77	3.75	N/A	Central island	N/A^‡	N/A^‡
C2	F, 11.0	0.59	1.94	N/A	Mild peripheral constriction	N/A^‡	N/A^‡
D1	F, 19.1	LP±	N/A	N/A	N/A	N/A	N/A
E1	F, 44.1	0.92	7.31	RCD, not further specified (9 m)	N/A^†	11.3	7.4
E2	M, 39.4	1.52	6.50	RCD, not further specified (4 m)	Central island	N/A	N/A
F1	M, 6.8	0.20	2.25	No recordable responses (2y)	N/A^‡	N/A^‡	N/A^‡

BCVA, best-corrected visual acuity; ODS, both eyes; SER, spherical equivalent of refractive error; ffERG, full-field electroretinography; OD, right eye; OS, left eye; F, female; M, male; LP, light perception; RCD, rod-cone dystrophy; N/A, not available.

^†Unreliable measurements.

^‡Too young to reliably perform the measurements.

Figure 1. Typical findings in patients with mild Zellweger spectrum disorder (ZSD) with biallelic variants c.2528 G>A (p.Gly843Asp) in PEX1 on fundus photographs, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT).

All patients had a hyperautofluorescent speckle-pattern on FAF (b, e, h, k, n, q, t) and varying degrees of integrity loss of the external limiting membrane (ELM) and ellipsoid zone (EZ) on SD-OCT (c, f, i, l, o, r, u).

A, B, C, Right eye of a 25-year-old patient (A1) with on fundus photos (a) macular atrophy, bone-spicule hyperpigmentation and mild attenuation of retinal vasculature and on SD-OCT (c) integrity loss of the ELM and cystoid fluid collections in the outer nuclear layer (ONL).

D, E, F, Left eye of a 20-year-old patient (A2) with on fundus photos (d) round hyperpigmentations, and on SD-OCT (F) large cystoid fluid collections in the ONL with retinoschisis aspect.

G, H, I, Right eye of a 26-year-old patient (B1) with on fundus photos (g) bone-spicule and round hyperpigmentations and mild attenuation of retinal vasculature and on SD-OCT (i) large cystoid fluid collections in ONL with retinoschisis aspect.

J, K, L, Left eye of a 25-year-old patient (B2) with on fundus photos (j) bone-spicule and round hyperpigmentation with partial obliteration of retinal vasculature and on SD-OCT (l) loss of retinal lamination and parafoveal cystoid fluid collection in the ONL.

M, N, O, Left eye of a 17-year-old patient (C1) with on fundus photos (m) bone-spicule and round hyperpigmentations and on SD-OCT (o) loss of retinal lamination.

P, Q, R, Left eye of an 11-year-old patient (C2) with bone-spicule and round hyperpigmentations and mild attenuation of retinal vasculature on fundus photos (P) and on SD-OCT (R) central cystoid fluid collections in the ONL.

S, T, U, Right eye of a 44-year-old patient (E1) with on fundus photos (s) bone-spicule and round hyperpigmentations with partial obliteration of retinal vasculature and on SD-OCT (u) loss of retinal lamination and aspect of lamellar macular hole.

Figure 2. Typical findings on perimetry and microperimetry in patients with mild Zellweger spectrum disorder (ZSD).

(a) 90 degrees visual field measurement on Octopus 900 of patient A2 demonstrating peripheral constriction and mid-peripheral scotoma. Colour-coded heatmap reflects percentage deviation from healthy population.

(b) Heatmap of macular sensitivity of patient A2 on microperimetry, with grey loci reflecting areas of no sensitivity (absolute scotoma). Mean sensitivity is shown in white.

(c) 30 degrees visual field measurement on Octopus 900 of patient B2 demonstrating severe visual field constriction. Colour-coded heatmap reflects percentage deviation from healthy population.

(d) Heatmap of macular sensitivity of patient B2 on microperimetry, with grey loci reflecting areas of no sensitivity (absolute scotoma). Mean sensitivity is shown in white.

Figure 3. Mild craniofacial dysmorphic features and amelogenesis imperfecta in adults with mild Zellweger spectrum disorder (ZSD). Patients with comparatively mild ZSD had varying degrees of.

(a) low-set ears,

(b) attached earlobes, and

(c) amelogenesis imperfecta. Written informed consent was obtained from all patients for publication of these images.