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. 2024 Jul;47(4):746-756.
doi: 10.1002/jimd.12738. Epub 2024 Apr 16.

Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy

Melanie B Gillingham  1 , Dongseok Choi  2   3 , Ashley Gregor  1 , Nida Wongchaisuwat  3 , Danielle Black  4 , Hannah L Scanga  5 , Ken K Nischal  5 , Jose-Alain Sahel  5 , Georgianne Arnold  4 , Jerry Vockley  4 , Cary O Harding  1 , Mark E Pennesi  3
Affiliations

Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy

Melanie B Gillingham et al. J Inherit Metab Dis. 2024 Jul.

Abstract

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.

Keywords: chorioretinopathy; long‐chain 3‐hydroxyacylCoA dehydrogenase deficiency; long‐chain fatty acid oxidation disorder; newborn screening.

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Conflict of interest statement

Competing Interest Statement:

This is a natural history study and no treatments were investigated. Authors have the following competing interests related to treatment and management of fatty acid oxidation disorders in general or to the development of retinal therapies in other unrelated disorders.

Dongseok Choi, Ashley Gregor, Nida Wongchaisuwat, Danielle Black, Hannah L Scanga and Georgianne Arnold have no competing interest.

Melanie B Gillingham has received speaker honorium from Ultragenyx Pharmaceutical Inc., Vitaflow, and Nutricia, and received research grant/funds from Nestle Bioscience and Reneo Pharmaceutical.

Ken K Nischal had received research funding from Ophtec, ORA, Essilor, consulting fees from Graybug Gene therapies, Krystal Inc, and honoraria from Santen.

Jose-Alain Sahal has equity in the following companies: Gensight, Sparing Vision, Avista, Tenpoint, Prophesee, Chronolife, Tilak Healthcare, SharpEye, Cilensee, and Vegavect. He has received research funding from Gensight, Sparing Vision and Meira, is a consultant for Avista Therapeutics and Tenpoint, and serves on the scientific advisory boards for the Gilbert foundation, the Foundation for Fighting Blindness, Institute of Ophthalmology Basel, and the Senses Institute Lausanne.

Jerry Vockley has received research funding from Ultragenyx Pharmaceutical Inc, Reneo Pharmaceutical and Nestle Bioscience.

Cary O Harding has received research funding from Reneo Pharmaceutical and Nestle Bioscience

Mark E Pennesi has received consulting fees from 4D Molecular Therapeutics, Adverum, Arrowhead Pharmaceuticals, AGTC, Aldebraran, Ascidian, Atsena, Astellas, BlueRock-Opsis, Coave, ClarisBio, Dompe, Editas, Edigene, Endogena, FFB, Ingel Therapeutics J-Cyte, Janssen, KalaTherapeutics, Kiora, Nacuity Pharmaceuticals, Ocugen, Ora, ProQR, Prime Editing, PTC Therapeutics, PYC Therapeutics, Ray Therapeutics, Rejuvitas, RestoreVision, RegenexBio, Sparing Vision, SpliceBio, Spotlight Therapeutics, Thea and Theranexus. He has received clinical trial support from AGTC, Biogen, Editas, FFB, ProQR, Reneuron. He has received fees as part of the Data Safety Montitoring Board (DSMB) for Akous, Gensight. He has equity in the following companies: Aldebaran, Atsena, Endogena, EnterX, Ingel Therapeutics, Kiora, Nacuity Pharmaceuticals, Ocugen, and ZipBio.

Figures

Figure 1.
Figure 1.. Fundus photos of patients diagnosed by family history or symptomatically.
(A) Fundus images from 4 patients in advancing order by age from 17 to 28 yrs. (left to right) who were diagnosed by NBS or due to a family history. (#1 = 17 yr, c.1528G>C/c.703C>T; #2 =18 yr, c.1528G>C/c.1528G>C; #3 = 18 yr, c.1528G>C/c.1528G>C; #4 = 28 yr, c.1528G>C/c.1132C>T) (B) Fundus images from 4 patients in advancing order by age from 18 to 30 yrs. (left to right) who were diagnosed after presenting symptomatically. (#5 = 18 yr, c.1528G>C/c.1678C>T, #6 = 21 yr, c.1528G>C/c.1528G>C ; #7 = 24 yr, c.1528G>C/c.1528G>C ; #8 = 30 yr, c.1528G>C/unk) Pigment mottling, loss of pigment and loss of choroidal vasculature was more pronounced with advancing age in A and B. However, loss of both pigment and choroidal vessels was earlier and more pronounced among patients who presented symptomatically (B) compared to those who were dx by family history (A). yr = years; genotype variants in HADHA. Note #2, #7& #8 also described in Wongchaisuwat et al.
Figure 2.
Figure 2.. Fundus autofluorescence of patients diagnosed by family history or symptomatically.
(A) Fundus autofluorescence from 4 patients advancing in age from 17 to 28 yr. (left to right) who were diagnosed due to a family history. (#1 = 17 yr, c.1528G>C/c.703C>T; #2 =18 yr, c.1528G>C/c.1528G>C; #3 = 18 yr, c.1528G>C/c.1528G>C; #4 = 28 yr, c.1528G>C/c.1132C>T) (B) Fundus autofluorescence from 4 patients advancing in age from 18 to 30 yr. (left to right) who were diagnosed after presenting symptomatically. (#5 = 18 yr, c.1528G>C/c.1678C>T, #6 = 21 yr, c.1528G>C/c.1528G>C ; #7 = 24 yr, c.1528G>C/c.1528G>C ; #8 = 30 yr, c.1528G>C/unk) Larger areas of hypoautofluorescence were visible among patients who presented symptomatically suggesting earlier and increased loss of retinal pigment epithelium. yr = years; genotype variants in HADHA. Note #2, #7& #8 also described in Wongchaisuwat et al.,
Figure 3.
Figure 3.. OCT Images from patients diagnosed by family history or symptomatically.
(A) OCT from 4 patients advancing in age from 17 to 28 yr. (left column) who were diagnosed due to a family history.(B) OCT from 4 patients advancing in age from 18 to 30 yr. (right column) who were diagnosed after presenting symptomatically. Retinal layers demonstrated normal thickness of retina layers in patients 1 and 3 and only some mild disruption to the RPE in patient 3. Patient 2 exhibited RPE thinning, disruption of the ellipsoid zone and thinning of the outer nuclear layer. Patient 4 demonstrated areas of RPE and outer retinal atrophy, and degenerative inner retinal cysts. Patient 5–8 demonstrated worse retinal changes. Patients 5 and 6 showed RPE atrophy with associated outer retinal loss. Patient 7 had inner retinal cysts, and loss of ellipsoid zone and punctate ONL thinning. Patient 8 exhibited severe chorioretinal atrophy with only residual inner retinal structures. Note #2, #7& #8 also described in Wongchaisuwat et al.,
Figure 4.
Figure 4.. Visual acuity and Electroretinogram amplitudes from patients diagnosed by family history or symptomatically.
(A) visual acuity (LogMAR) by age. Patients diagnosed by NBS or with TFPD had better visual acuity (lower LogMAR) than patients who were diagnosed after presenting symptomatically (A p=0.074; P p=0.003). (B) Scotopic B-wave amplitude (uV) of the brightest flash by age. Scotopic b-wave amplitudes declined with age.(A p=0.013; P p=0.4) (C) 30Hz flicker amplitude (uV) of the brightest flash by age. 30Hz flicker amplitudes decreased with age and by presentation.(A p=0.011; P p=0.011) Normal 95% confidence intervals for ERG amplitudes are shown in grey shading. Trend lines for NBS/family history and symptomatic were determined from the mixed effects analysis shown in Supplemental Table 2. A=age; P=presentation. NBS/family history (blue) or symptomatic (orange). Three patients did not carry c.1528G>C mutation but were diagnosed with other mutations in either HADHA/HADHB denoted as TFPD (green). OD=circle/OS=square
Figure 5:
Figure 5:. Contrast sensitivity, static perimetry and microperimetry from patients diagnosed by family history or symptomatically.
A) Contrast sensitivity by age. Normal range is illustrated by grey shading. Contrast sensitivity declined with age but the decline was greatest among patients who presented symptomatically. (A p=0.036; P p=0.005) (B) Static Perimetry by age. Static perimetry tended to decline with age but was significantly lower among patients who presented symptomatically. (A p=0.31 P p=0.019 univariate analysis) (C) Microperimetry mean sensitivity by age. Microperimetry declined with advancing age. (A p=0.035; P p=0.097) Trend lines for NBS/family history and Symptomatic are determined from the multivariate analysis for contrast sensitivity and the univariate analysis for Static Perimetry because of variable confounding in the multivariate analysis. A=age; P= presentation. NBS/family history (blue) or symptomatic (orange). Three patients did not carry c.1528G>C mutation but were diagnosed with other mutations in either HADHA/HADHB denoted as TFPD (green). OD=circle/OS=square
See this image and copyright information in PMC

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