Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a...

Introduction

Long-chain 3-hydroxyacyl-CoA dehy-drogenase (LCHAD) deficiency isa life-threatening disease of energymetabolism caused by mutations inthe gene for the a-subunit of the tri-functional protein in the mitochon-drial degradation of fatty acids(Wanders et al. 1990; Ijlst et al. 1994).

The LCHAD enzyme, McKusick600890, catalyses the third of the foursteps in the b-oxidation of fatty acidsand has the highest specificity towardschain lengths of 14–22 carbon atoms.The disorder has an autosomal reces-sive inheritance and is the secondmost common b-oxidation defect inthe Swedish population, with anestimated incidence of 1 : 100.000.One mutation (1528 G>C) comprisesmore than 90% of mutated alleles inSwedish patients. Triglycerides offeran important source of energy, and adefect in the degradation can havedeleterious effects during catabolicstates.

Case Series

Ocular characteristics in10 children with long-chain3-hydroxyacyl-CoAdehydrogenase deficiency: across-sectional study withlong-term follow-upKristina Tear Fahnehjelm,1,2 Gerd Holmstrom,3 Liu Ying,4,5 Charlotte BieneckHaglind,6,7 Anna Nordenstrom,6,7,8 Maria Halldin,8,9 Jan Alm,6,7 AntalNemeth6,7 and Ulrika von Dobeln8

1Department of Clinical Neuroscience, Karolinska Institut, Stockholm, Sweden2Department of Paediatric Ophthalmology and Strabismus, St Erik Eye Hospital,

Karolinska University Hospital, Huddinge, Sweden3Department of Ophthalmology, Uppsala University Hospital, Uppsala, Sweden4Department of Clinical Neurophysiology, Karolinska University Hospital,Huddinge, Sweden5Department of Ophthalmology, The South Hospital, Stockholm, Sweden6Department of Clinical Science and Technology, Karolinska Institut, Stockholm,Sweden7Children’s Hospital, Karolinska University Hospital, Huddinge, Sweden8Department of Laboratory Medicine, Division for Metabolic Diseases, KarolinskaInstitut, Stockholm, Sweden9Department of Endocrinology, Uppsala University Children’s Hospital, Uppsala,Sweden

ABSTRACT.

Purpose: To present long-term ocular complications and electroretinographic (ERG)

findings in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) defi-

ciency – a life-threatening metabolic disease – and the relation to age at diagnosis,

treatment and other clinical parameters.

Methods: Ten children with LCHAD deficiency underwent repeated ophthalmological

evaluations including ERG.

Results: All 10 children developed chorioretinal pathology. Regardless of age at diag-

nosis, initiation of treatment and age at examination, inter-individual differences were

present. Profound chorioretinal atrophy, severe visual impairment and progressive myo-

pia had developed in two teenagers. Milder chorioretinopathy with or without sub-

normal visual acuity was present in all other children. ERG was pathological in seven

children. The chorioretinopathy often started in the peripapillary or perimacular areas.

In one patient, unilateral visual impairment was associated with fibrosis.

Conclusion: Early diagnosis and adequate therapy might delay but not prevent the

progression of retinal complications. Late diagnosis with severe symptoms at diagnosis,

neonatal hypoglycaemia and frequent decompensations may increase the progression

rate of the chorioretinopathy. LCHAD deficiency, a potentially lethal disease, is some-

times difficult to diagnose. Unusual chorioretinal findings should alert the ophthalmolo-

gist to the long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, especially if there

is a history of neonatal hypoglycaemia or failure to thrive.

Key words: chorioretinal atrophy – electroretinography – LCHAD deficiency – myopia

Acta Ophthalmol. Scand.ª 2007 The Authors

Journal compilation ª 2007 Acta Ophthalmol Scand

doi: 10.1111/j.1600-0420.2007.01121.x

Acta Ophthalmologica Scandinavica 2007

1

The diagnosis is usually establishedwithin the first 8 months of lifebecause of decompensations duringa catabolic state with hypoketotichypoglycaemia accompanied by liverenlargement, muscular hypotonia andhypertrophic cardiomyopathy (Hagen-feldt et al. 1990). Determination ofdicarboxylic and 3-hydroxy fatty acidsin plasma followed by mutation anal-ysis contributes to the diagnosis(Hagenfeldt et al. 1990; Ijlst et al.1994). Emergency treatment with glu-cose infusion followed by a diet withreduced intake of fat (approximately20% of calories), mainly composed ofmedium-chain triglycerides (MCT fat)supplemented with vitamins, mineralsand essential fatty acids, has resultedin the reversion of these symptoms(Hagenfeldt et al. 1995). The childrenhave a fasting intolerance, makingnight feeds necessary in the majorityof cases and necessitating hospitalcare and glucose infusion during feb-rile infections.

Long-term complications includeocular changes (Tyni et al. 1998a),

peripheral neuropathy and mentalretardation (Wanders et al. 1990; Gill-ingham et al. 1999; den Boer et al.2002). Ocular complications beginningwith retinal pigmentations and pro-gressing to impaired retinal functionwith pathological electroretinography(ERG) have been described in casereports and in small case series sincethe late 1980s (Poll-The et al. 1988;Przyrembel et al. 1991; Bertini et al.1992; Pons et al. 1996) followed bymore detailed descriptions of thechorioretinal atrophy (Schrijver-Wiel-ing et al. 1997) and an association tocataract (Uusimaa et al. 1997). Tyniet al. (1998a) reported the ocularchanges in four long-term survivorsand 15 infants, all dead before14 months of age. A classification ofthe retinal stages was proposed froma normal ⁄pale fundus with normalvisual acuity (VA) and ERG (stage 1),clumping of the retinal pigment epi-thelium (RPE) in the posterior poleand ERG deterioration (stage 2), pro-gression to chorioretinal atrophy(stage 3) and additional posterior

staphyloma and extinguished ERG(stage 4). Finally, den Boer et al.(2002) reported retinopathy in nine of31 surviving children (29%) in a studybased on questionnaires to referringspecialists and a median follow-up of3.4 years, but no ocular details weredescribed.

Presently, there are 13 living chil-dren diagnosed with LCHAD defi-ciency in Sweden. In this paper, ocularfindings, ERG results and long-termoutcome in 10 of these children arereported. One patient is one of thelongest-treated worldwide with17 years of treatment. The rate of pro-gression of the chorioretinopathy andthe visual outcome were compared toage at diagnosis, time of treatmentand other clinical parameters.

Materials and Methods

Ten children from different parts ofSweden were diagnosed with LCHADdeficiency at the two participatinghospitals. The diagnosis was based on

Table 1. Clinical background data in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Point Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10

Age at diagnosis (months) 0–1 months (1p)

1–6 months (2p)

>6 months (3p)

2 3 2 3 3 1 1 3 3 3

Symptoms at diagnosis No symptoms (1p)

Clinical symptoms but

no acute illness (2p)

Severe symptoms* (3p)

3 3 3 3 2 1 3 2 2 2

Neonatal hypoglycaemia No (1p)

Yes (2p)

2 2 1 2 2 1 2 1 2 2

Gestational age >37 weeks (1p)

32–36 weeks (2p)

<32 weeks (3p)

1 1 1 2 2 1 1 3 3 1

Symptoms of toxicosis

during pregnancy

No (1p)

Elevated blood pressure (2p)

Toxicosis (3p)

2 1 3 3 2 1 1 3 2 2

Number of

decompensations

0–4 (1p)

5–10 (2p)

>10 (3p)

3 2 2 1 3 2 1 1 2 3

Psychomotor development Normal (1p)

Obvious developmental

delay (2p)

Severe developmental

problems (3p)

2 2 3 2 1 1 1 1 2 1

Epilepsia No (1p)

Yes (2p)

1 2 2 1 1 1 1 1 2 1

Night feeds Yes (1p)

No (2p)

1 1 2 1 1 1 1 1 1 1

Present age 0–5 years (1p)

5–10 years (2p)

>10 years (3p)

3 3 3 3 3 2 2 2 2 1

Total score 20 20 22 21 20 12 14 18 21 17

p ¼ points given in the developed scoring system.

*With elevated liver enzymes and cardiomyopathy and ⁄ or seizures.


2

the characteristic pattern of dicarbox-ylic acids and 3-hydroxy fatty acids inplasma and was verified by mutationanalysis. Dietary treatment with lowfat intake and supplementation ofessential fatty acids including docosa-hexaenoic acid (DHA) (daily intakeaccording to Swedish nutritional rec-ommendations) commenced at timeof diagnosis in all children. Ninechildren had continuous nightfeeds. During infections with fever,a carbohydrate-rich supplement orintravenous glucose infusions wereadministered.

All 10 children underwent ocularexaminations including assessment ofbest-corrected decimal VA with opto-types, stereopsis (Lang, Forch, Swit-zerland), ocular alignment, colourvision (HRR Hardy Rand Rittler,New York, USA), slit-lamp investiga-tion, ophthalmoscopy, fundus photo-graphy and refraction undercycloplegia. ERG was performed inall 10 children after pupil dilatationand 30 min of dark adaptation. Gen-eral anaesthesia was used and full-fieldERGs were recorded in a Nicolet Vik-ing analysis system (Nicolet Biomedi-cal Instruments, Madison, Wisconsin,USA). The regional ethical committeeof Uppsala approved of the study.

A scoring system for the clinicalbackground parameters was developed(Table 1). Medical records were scruti-nized for important maternal, prena-tal, neonatal and somatic data thatwere considered potential risk factorsfor long-term ocular complications.Decompensations were defined asperiods when the families had anykind of contact with the hospital dur-ing infections. Each child was scoredfrom 1 to 3 points regarding each clin-ical risk factor, and the summarizedscores were compared to the ocularfindings and ERG results.

Results

The children (seven girls and threeboys) were diagnosed at a median ageof 1 month (range 2 days to13 months). One patient was diag-nosed in the neonatal period beforeany symptoms had developed becauseof medical history in previous childrenin the family. Median age at firstocular examination was 14.5 months(range 5 weeks to 6 years), whereas

duration of ocular follow-up wasmedian 7.5 years (range 2.3–14.8years). Two children had ocular exam-inations within 1 month of diagnosis.

Retinal pathology was first noted ata median age of 3.6 years (range14 months to 6 years). The initial pig-mentary changes were subtle general

1

(A)

(C)

(E) (F)

(D)

(B)

2

2

1

2

2

Fig. 1. Case 1, girl aged 17.5 years. The first ocular examination at 2.9 years of age demon-

strated bilateral pigmentary retinopathy, a right exotropia and bilateral myopia ()3 D spherical

equivalent). The girl developed sensitivity to light and problems at dusk. At 8 years the visual

acuity (VA) had declined to 0.08 in the right eye, where a large chorioretinal fibrosis was pres-

ent in the macular area (A, arrow 1). At 9 years patchy areolar chorioretinal atrophies were

present in the left eye (B, arrows 2). The macula in the left eye appeared hyperpigmented and

sharply defined from the surrounding retina. At 16 years the chorioretinal fibrotic area in the

right eye had increased, as had the areolar chorioretinopathy in the left eye (C, arrow 1 and D,

arrows 2). VA was <0.1 in the right eye and 1.0 in the left eye with myopic glasses. Ocular

coherence tomography was performed at 15 years of age (E–F) and demonstrated a thickening

of the hyper-reflective retinal pigment epithelium and choriocapillaris in the right eye. Epiretinal

gliosis was present in the periphery of the fovea. The left eye was considered normal.

1

12

2

(A) (B)

Fig. 2. Case 2, boy aged 15.5 years. Ophthalmological assessment at diagnosis revealed normal

fundi. At 4 years binocular visual acuity was 0.63 and funduscopy demonstrated pigment epi-

thelial changes accentuated in the macular areas. At 15.5 years the ocular fundi demonstrated

severe chorioretinal atrophy with markedly mottled retina, white atrophic patches with bare

sclera (A and B, arrow 1) and homogenous pigmentations in the maculae (A and B, arrow 2).


3

pigmentations spread in the posteriorpoles. Four of the 10 children haddeveloped retinal pigmentations at thefirst ocular examination. Six childrenhad normal ocular fundi at firstocular examination at a median ageof 11 months (range 5 weeks to2.7 years).

The older the children at time ofexamination, the more pronouncedthe ocular changes (cases 1, 2 and 4).The most severe stages of chorioreti-nal atrophies resulted in profoundvisual loss in one or both eyes becauseof extensive central chorioretinal atro-phy, staphylomas and severe myopia(cases 1 and 4). Case 1 had fibroticchorioretinal changes not describedpreviously in children with LCHADdeficiency. Case 4 had severe generalchorioretinal atrophy while case 2 haddeveloped patchy areolar choriore-tinopathy. Common findings in theother children were mottled ⁄granularor diffuse pigmentations and atrophiesin the posterior poles, especially peri-papillar and perimacular, with no orminimal visual loss (cases 3, 5–8 and10). However, case 9 had a moresevere diffuse chorioretinal atrophyand severely pathological ERGalready at 4 years of age (Figs 1–10and Tables 2 and 3).

The chorioretinopathy was lesspronounced in patients with earlydiagnosis (1st week of life) and early

institution of dietary therapy (cases 6and 7), while it was more severe inchildren with late diagnosis (cases 4

11

1

1

(A) (B)

(C)(D)

(E) (F)

(G) (H)

Fig. 4. Case 4, girl aged 15 years. Retinal pigmentary changes in atrophic fundi were noted at

the first ocular examination at 14 months of age. At the age of 2 the girl had developed a right-

sided intermittent exotropia and nystagmus. From the age of 4 she developed increasing photo-

phobia and a need of good illumination, an extremely short working distance, progressive

severe chorioretinopathy and myopia. At 13.5 years the best-corrected visual acuity was

0.1 ⁄ 0.16 right and left eye and there was a severe myopia ()14.5 ⁄ )13 D). The ocular fundi

demonstrate profound chorioretinal atrophy, staphylomas with bare sclera, loss of choroidal

vessels, pale optic discs, thin retinal vessels and some faint retinal pigmentary deposits in the

macular areas (A and B) with sharply defined border areas and normal periphery. In the nasal

(C and D, braces 1) and temporal (E and F) peripheries, sharply defined border areas were

present between the atrophic and the more preserved retina in the outer periphery with circular

band of pigment clump (E and F, braces 1). Ocular coherence tomography performed at

15 years of age demonstrated chorioretinal atrophy; in the right eye there was an atrophic ret-

ina at all levels, predominately photoreceptors and ganglion cells. There was a hyper-reflectivity

from the pigment epithelium and choroid because of lack of normally reflecting pigment epithe-

lium. In the left eye the retinal structure was slightly better preserved with a better foveal pit

(G and H).

(B)

(A)

Fig. 3. Case 3, boy aged 16.5 years. Ocular

examinations since the age of 6 have demon-

strated macular pigmentations. At 12 years

nasal peripheral pigmentations were also

noted and these persisted at 16.5 years. The

ocular fundus photos, unfortunately of bad

quality, showed granular pigmentations (A

and B).


4

and 9). Three patients developed myo-pia while none had developed cataractat the time of follow-up.

Clinical parameters suspected ofhaving an influence on the develop-ment of long-term sequelae are pre-sented in Table 1. Six children had atotal score of 20 or more. All thesechildren but one had chorioretino-pathy grade 3 or 4. Eight patientswere homozygous for the commonmutation 1528 G>C and the remain-ing two had the same mutation onone allele. The other mutation has notyet been identified.

ERG was moderately to severelypathological in seven of 10 children atlatest follow-up (Table 2). They dem-onstrated markedly reduced scotopicand photopic A-wave and B-waveamplitudes. Five of them also haddelayed implicit times of 30-Hz coneresponses. The four teenagers (cases 1–4) all had moderately pathologicalERG when the first ERG was per-formed. No child – not even the girl

(A) (B)

(C) (D)

Fig. 5. Case 5, girl aged 12.5 years. This girl had the first ocular assessment at 6 years when

visual acuity (VA) was 0.9 ⁄ 0.8 right and left eye and the ocular fundi showed peripapillar atro-

phy and small granular pigmentations. At 10 years the VA had declined and the retinal changes

had progressed. At 12.5 years there were discrete mottled retinal pigmentations. The maculae

had a normal appearance. Courtesy of Olof Wennhall.

(A) (B)

(C) (D)

(E) (F)

Fig. 6. Case 6, girl aged 9 years. This is the only child where LCHAD deficiency was diagnosed pre-symptomatically during the first days of life.

At 5.7 years a distinct sparse granular pigmentation in the posterior poles, especially peripapillary and perimacularly, was detected (A and B).

There was no apparent difference 3 years later (C and D). The visual acuity was 0.9 right and left eye. Ocular coherence tomography performed

at the age of 7 was subnormal in the right eye. The left eye demonstrated a slight broadening and thinning of the foveal pit but normal neuroreti-

nal structure outside the fovea (E and F).


5

with the most severe chorioretinal atro-phy – had an extinguished ERG. Onegirl (case 6) was followed annually withERG, and had normal retinal functionuntil 7 years of age when the ampli-tudes began to decline. Notable retinalpigmentations were detected almost2 years earlier. One young child (case9), who also had marked chorioretinalatrophy, had a markedly reduced ERGalready at the first examination at4 years of age. Three children hadsubnormal ERG (cases 5, 7 and 10)and slight to moderate retinalchanges. Case 7 had repeated ERG

examinations from 3 to 6 years of ageand demonstrated decreasing rod andcone amplitudes beginning at the ageof 6 despite high levels of DHAinitiated at the age of 5.

Case descriptions of the children,together with ocular history, are pre-sented as legends to the fundus photo-graphs (Figs 1–10). The results fromthe most recent ocular assessment,including ERG, are listed in Tables 2and 3.

Discussion

In the present study, which to ourknowledge is the largest ocular study

on living children with LCHAD defi-ciency, chorioretinal changes of differ-ent severity were found in all 10children. This is a higher frequencythan reported previously and may beexplained by a longer ocular follow-up period than in earlier reports.Hence, the present regimen seems notto prevent but possibly to delay thedevelopment of ocular symptoms.

Normal ocular fundi at first ocularexamination were present in six chil-dren at a median age of 11 months.Tyni et al. reported normal ocularfundi at initial assessment in sevenslightly younger children, medianage 4.8 months (range 3 days to13 months). They also reported that

12

1 2

1 2

(A)

(B)

(C)

Fig. 7. Case 7, girl aged 7.5 years. The first

fundus examination at 1.3 years demonstrated

slightly irregular foveal reflexes. The girl devel-

oped increasing photophobia. At 2.6 years dis-

tinct macular pigmentations were detected.

One year later additional circumscriptive hyp-

opigmentations, especially peripapillary, were

present. At 4.5 years visual acuity (VA) was

normal for age, but scattered granular pig-

mentations, faint peripapillary atrophy (A,

arrow 1) and homogenously pigmented macu-

lae (A, arrow 2) were noted. The photophobia

declined during the last 2 years. The latest fun-

dus examination (B and C; photos taken with

a different red light colour filter) 2 years later

demonstrated slight progression. The VA was

1.0 right and left eye.

(A) (B)

(C) (D)

Fig. 8. Case 8, girl aged 5.5 years. This twin girl was born prematurely and developed retino-

pathy of prematurity stage 2, which resolved spontaneously. At 4 years mottled retinal pigmen-

tations were detected in the posterior pole but visual acuity remained normal (A and B). Two

years later the ocular fundi were unchanged (C and D).

(A) (B)

Fig. 9. Case 9, girl aged 5 years. This girl was born prematurely. Ocular assessments at 2 years

of age verified a left intermittent esotropia but fundi were normal. At 3 years sparse retinal

granular pigmentations were detected. At 5 years the girl was sensitive to light and the ocular

fundi demonstrated a pronounced diffuse chorioretinal atrophy and macular hyperpigmenta-

tions, more pronounced in the left eye.


6

five out of 11 children with retinalpigmentations at a median age of9 months (range 4 months to 5 years)had pigmentation predominantly inthe macular areas. Among the fourlong-term survivors, ages 5–31 years,all except one had developed retinopa-thy before 2 years of age and two hadpredominantly macular pigmentationsinitially (Tyni et al. 1998a).

In the present study, half of thepatients initially demonstrated subtlegeneral pigmentations spread in theposterior poles and in the mid-periph-ery and not in the macular areas, afinding also described by Gillinghamet al. (2005). In the children with mac-ular pigmentations, the darker appear-ance of the macular region may bepartly the result of perimacular atro-phy, which increases the contrast tothe surrounding retina. As long as themacula was pigmented homogenously,central VA seemed to remain stable.

Three patients developed myopiaduring follow-up. The more severemyopia that occurred in two childrenwith severe visual impairment mightbe caused by deficient emmetropiza-tion. Tyni et al. (1998a) reported myo-pia in three patients at the ages of 5,6 and 12.

Rare fundus findings were noted,especially in the most severely affectedchildren. Case 1 developed peculiarfibroid chorioretinal changes, whichprogressed during childhood and

resulted in severe unilateral visualimpairment. This could be caused by aneovascular membrane resulting froma defect in Bruch’s membrane. Despiteprogressive chorioretinal degenerationin the other eye, the central visionremained normal. Case 2 had markedchorioretinal atrophic patches withbare sclera similar to the picturedescribed by Tyni et al. (1998a). Anotable observation was that case 4 –with the most severe chorioretinalatrophic findings, bare sclera andstaphyloma (stage 4) – did not have anextinguished ERG. This is not in agree-ment with the staging suggested byTyni et al. (1998a), where patients withsimilar ocular fundus pathology at ages13 and 14 had extinguished ERGresponses. Marked peripheral transi-tional zones with pigmentary clumpingand smaller rounded atrophic areas atthe border between central atrophicretina and peripheral normal retinawere found only in this same patient.With time, there seemed to be a pro-gression from central to peripheralparts. The underlying mechanism forthis circumscript mode of progressionis unclear but could be caused by thedisturbed retinal metabolism. The mostperipheral part of the retina, developedduring late gestation, maintained itsnormal structure.

To a large extent the ERG resultswere associated with the stages ofchorioretinopathy, suggesting that

ERG influences lag behind the extentof fundus changes and that disturbanceof the retinal neuro-epithelium is insequence with the damage in the RPEand progressive loss of choroid vessels.

Retinal changes are the major ocu-lar problems in children with LCHADdeficiency but the pathogenesisremains unknown. Flattened and hyp-opigmented RPE cells and secondaryloss of choriocapillaris macrophageshave been demonstrated while theperipheral parts of the ocular fundihave been normal (Tyni et al. 1998b).Mitochondrial fatty acid b-oxidationhas been detected in the retinal pig-mentation cells in vitro and the expres-sion of the mitochondrial trifunctionalprotein (MTP) has been detected inthe retinal pigmentation cells as wellas in other layers of the retina in vitro(Tyni et al. 2002). However, Tyniet al. (2004) have also suggested thatphotoreceptor damage could play acontributory role in the pathogenesisof retinopathy LCHAD deficiency.

Low plasma levels of essential fattyacids, especially DHA, have been dis-cussed as a contributing cause of theretinopathy (Gillingham et al. 1999;Harding et al. 1999; den Boer et al.2002). This has lately been suggestedto be correlated to VA measured bySweep visual evoked potentials (VEP)(Gillingham et al. 2005), as have accu-mulations of long-chain 3-hydroxy-acylcarnitines (Schrijver-Wieling et al.1997), which were found to be corre-lated negatively to ERG amplitude(Gillingham et al. 2005). In a previousstudy, we observed a more than 50%higher rate of lipolysis in a child withLCHAD deficiency treated with low-fat diet compared to her healthy, non-identical twin sister. The resultingincrease in the levels of fatty acidsand toxic b-oxidation intermediatescould be one of the mechanismsbehind the progressing ocular findings(Halldin et al. 2007).

According to the initial findings byGillingham et al. (1999, 2003), dietarytreatment had a minimal effect onchronic degenerative complicationslike pigmentary retinopathy andvision loss. However, the sameauthors suggested recently that treat-ment with DHA could be correlatedto improved VA measured by SweepVEP (Gillingham et al. 2005). All ourpatients were treated with DHA tokeep DHA within normal levels. A

(A) (B)

(C) (D)

Fig. 10. Case 10, boy aged 5 years. This boy had normal ocular fundi at 2.7 years of age. Sub-

tle granular pigmentations were detected at 3.8 years and remained unchanged at 5 years of

age.


7

Table

2.Ocularcharacteristics

in10childrenwithlong-chain

3-hydroxyacyl-CoA

dehydrogenase

(LCHAD)deficiency.

Patient’s

age(years),latest

examination

Case

1

17.5

years

Case

2

15.5

years

Case

3

16.5

years

Case

4

14.9

years

Case

5

12.4

years

Case

6

8.8

years

Case

7

7.6

years

Case

8

5.5

years

(born

GW

29)

Case

9

5years

(born

GW

31)

Case

10

5years

VisualacuityRE

⁄LE

<0.1

⁄1.0

CC

0.65SC

⁄0.65CC

Noinfo

0.1

⁄0.16CC

0.8

⁄0.65CC

0.9

⁄0.9

CC

1.0

⁄1.0

SC

1.0

⁄1.0

SC

0.63

⁄0.4

SC

1.0

⁄1.0

SC

Refraction

RE

⁄LE

)6=

)0.5c170�

)4.5

=)1.5c0�

+1=

)1c90

�+

1=

)1c90

�Noinfo

)14.5

)13.0

)0.5c170�

+0.5

=)1.0c160�

)0.5

=)1c80�

)0.5

=)1c80�+

1.0

=)0.25c0

+1.0

=)0.25c0

+1.5

=)0.5c80�

+1.5

=)0.5c80�

+1=

)1c10�

)1c170�

+1.5

+1.5

Strabismus

Exotropia

No

Noinfo

Exotropia

Exophoria

Esophoria

Exophoria

No

Exotropia

LE

No

Fundusstage

33

34

22

22

32

Photophobia

Nyctalopia

+ +

+ )Noinfo

Noinfo

+ +

) )+ )

(+)

)+ )

+ )(+

)

)HRR

Norm

alLE

14years

Norm

al

Noinfo

Pathological

13.5

years

Norm

al

Norm

al

5.7

years

Norm

al

Norm

al

Noinfo

Norm

al

CAT

Norm

al

14years

Norm

al

Noinfo

Norm

al

13.5

years

Pathological

darkestlevel

Norm

al

5.7

years

Norm

al

Noinfo

Noinfo

Norm

al

Nystagmus

No

No

Noinfo

Yes

No

No

No

No

No

No

Ageatdiagnosis

5months

8months

4.5

months13months

8months

1week

1week

8months

10months

7months

1st

ocularassessm

ent2.9

years

8months

Norm

al

6years

14months

5.8

years

5months

Norm

al

15months

Norm

al

ROP–screening

Norm

al

ROPscreening

Norm

al

2.7

years

Norm

al

1st

retinalpathology

2.9

years

Fundus

4years

Macula

6years

Macula

14months

Macula

5.8

years

Fundus

5.7

years

Fundus

2.6

years

Macula

4years

Fundus

3years

Fundus

3.8

years

Fundus

SC¼

sinecorrectione;

CC¼

cum

correctione;

RE¼

righteye;

LE¼

lefteye;

HRR¼

HardyRandRittler;CAT¼

coneadaptationtest;GW¼

gestationalweek;ROP¼

retinopathyofprematurity.

Table

3.Electroretinography(ERG)findingsin

10childrenwithlong-chain

3-hydroxyacyl-CoA

dehydrogenase

(LCHAD)deficiency.

Patient

Case

1Case

2Case

3Case

4Case

5Case

6Case

7Case

8Case

9Case

10

AgeatERG

(years)

9;15;17.5

16.5

16.5

14

12.5

0.5–8.5

annually

3;5;6.5

64

5

ERG

findings

Progressive

pathological

Pathological

Pathological

Pathological

Subnorm

al

Progressive

pathologicalsince

7years

ofage

Progressive

subnorm

al

Pathological

Pathological

Subnorm

al

Rod

⁄coneaffected

PronouncedRE

Rod

⁄cone

affected

Rod

⁄cone

affected

Rod

⁄cone

affected

Delayed

30Hzflicker

response

Rod

⁄coneaffected

Decline

Rod

⁄cone

response

Rod

⁄cone

affected

Rod

⁄cone

affected

Borderlinerodand

delayed

30Hz

flicker

response

Latest

ERG*mixed

rod-coneresponse

103

⁄168

100

⁄193

139

⁄212

69

⁄137

175

⁄281

138

⁄223

161

⁄257

137

⁄199

59

⁄102

150

⁄245

Latest

ERG

�

rodandconeresponse

70

⁄65

78

⁄38

92

⁄47

61

⁄53

141

⁄98

83

⁄100

107

⁄112

74

⁄55

37

⁄27

90

⁄90

RE¼

righteye.

*Scotopic

a-

⁄b-w

ave(lV),besteye.

�Scotopic

rodb-w

aveandphotopic

30Hzflicker

coneresponse

(lV),besteye.


8

detailed ophthalmological assessmentwith ERG was conducted prior to ini-tiation of higher DHA level treatmentin just one patient. However, ERGamplitudes in this patient declinedduring a 2-year period despite thehigh levels of DHA.

To conclude, early diagnosis andtreatment of LCHAD deficiency seembeneficial with regard to chorioretinalcomplications but this has to be evalu-ated further. We suggest that all thesechildren have an ocular examinationwithin the first month of diagnosisand annual follow-ups. Fundus pho-tography and repeated ERG examina-tions should be performed. In case ofvisual impairment, support with visualaids should not be delayed. Further-more, because LCHAD deficiencymay be difficult to diagnose, the oph-thalmologists have an important rolein early detection. Unusual chorioreti-nal findings – especially if there is ahistory of neonatal hypoglycaemia –or failure to thrive should lead to thesuspicion of LCHAD deficiency. Inaddition, it is important that an evalu-ation of visual function and retinalpathology is included in the primaryevaluation of all patients with a suspi-cion of a defect in the beta-oxidationsystem.

Acknowledgements

Financial support was providedthrough the regional agreement onmedical training and clinical research(ALF) between Stockholm CountyCouncil and the Karolinska Institutetand from KMA, Stiftelsen Kronprin-sessan Margaretas Arbetsnamnd forsynskadade. We are grateful to Anne-Catherine Soderberg, MD forinterpreting OCT results and to JanSchutterman MD for retinal expertise.

ReferencesBertini E, Dionisi-Vici C, Garavaglia B et al.

(1992): Peripheral sensory-motor polyneur-

opathy, pigmentary retinopathy, and fatal

cardiomyopathy in long-chain 3-hydroxy-

acyl-CoA dehydrogenase deficiency. Eur J

Pediatr 151: 121–126.

den Boer ME, Wanders RJ, Morris AA, Ijlst

L, Heymans HS & Wijburg FA (2002):

Long-chain 3-hydroxyacyl-CoA dehydroge-

nase deficiency: clinical presentation and

follow-up of 50 patients. Pediatrics 109:

99–104.

Gillingham M, Van Calcar S, Ney D, Wolff J

& Harding C (1999): Dietary management

of long-chain 3-hydroxyacyl-CoA dehydro-

genase deficiency (LCHADD): a case

report and survey. J Inherit Metab Dis 22:

123–131.

Gillingham MB, Connor WE, Matern D, Ri-

naldo P, Burlingame T, Meeuws K & Har-

ding CO (2003): Optimal dietary therapy of

long-chain 3-hydroxyacyl-CoA dehydroge-

nase deficiency. Mol Genet Metab 79: 114–

123.

Gillingham MB, Weleber RG, Neuringer M

et al. (2005): Effect of optimal dietary ther-

apy upon visual function in children with

long-chain 3-hydroxyacyl CoA dehydroge-

nase and trifunctional protein deficiency.

Mol Genet Metab 86: 124–133.

Hagenfeldt L, von Dobeln U, Holme E, Alm

J, Brandberg G, Enocksson E & Lindeberg

L (1990): 3-Hydroxydicarboxylic aciduria –

a fatty acid oxidation defect with severe

prognosis. J Pediatr 116: 387–392.

Hagenfeldt L, Venizelos N & von Dobeln U

(1995): Clinical and biochemical presenta-

tion of long-chain 3-hydroxyacyl-CoA

dehydrogenase deficiency. J Inherit Metab

Dis 18: 245–248.

Halldin MU, Forslund A, von Dobeln U,

Eklund C & Gustafsson J (2007): Increased

lipolysis in LCHAD deficiency. J Inherit

Metab Dis 30: 39–46.

Harding CO, Gillingham MB, van Calcar

SC, Wolff JA, Verhoeve JN & Mills MD

(1999): Docosahexaenoic acid and retinal

function in children with long-chain 3-hy-

droxyacyl-CoA dehydrogenase deficiency.

J Inherit Metab Dis 22: 276–280.

Ijlst L, Wanders RJ, Ushikubo S, Kamijo T

& Hashimoto T (1994): Molecular basis of

long-chain 3-hydroxyacyl-CoA dehydro-

genase deficiency: identification of the

major disease-causing mutation in the

alpha-subunit of the mitochondrial trifunc-

tional protein. Biochim Biophys Acta 1215:

347–350.

Poll-The BT, Bonnefont JP, Ogier H et al.

(1988): Familial hypoketotic hypoglycaemia

associated with peripheral neuropathy, pig-

mentary retinopathy and C6-C14 hydrox-

ydicarboxylic aciduria. A new defect in

fatty acid oxidation?. J Inherit Metab Dis

11(Suppl. 2): 183–185.

Pons R, Roig M, Riudor E et al. (1996): The

clinical spectrum of long-chain 3-hydroxy-

acyl-CoA dehydrogenase deficiency. Pediatr

Neurol 14: 236–243.

Przyrembel H, Jakobs C, Ijlst L, de Klerk JB

& Wanders RJ (1991): Long-chain 3-hy-

droxyacyl-CoA dehydrogenase deficiency.


Schrijver-Wieling I, van Rens GH, Wittebol-

Post D, Smeitink JA, de Jager JP, de Klerk

HB & van Lith GH (1997): Retinal dystro-

phy in long chain 3-hydroxy-acyl-coA

dehydrogenase deficiency. Br J Ophthalmol

81: 291–294.

Tyni T, Kivela T, Lappi M, Summanen P,

Nikoskelainen E & Pihko H (1998a):

Ophthalmologic findings in long-chain 3-

hydroxyacyl-CoA dehydrogenase deficiency

caused by the G1528C mutation: a new

type of hereditary metabolic chorioretinop-

athy. Ophthalmology 105: 810–824.

Tyni T, Pihko H & Kivela T (1998b): Oph-

thalmic pathology in long-chain 3-hydrox-

yacyl-CoA dehydrogenase deficiency

caused by the G1528C mutation. Curr Eye

Res 17: 551–559.

Tyni T, Johnson M, Eaton S, Pourfarzam M,

Andrews R & Turnbull DM (2002): Mito-

chondrial fatty acid beta-oxidation in the

retinal pigment epithelium. Pediatr Res 52:

595–600.

Tyni T, Paetau A, Strauss AW, Middleton B

& Kivela T (2004): Mitochondrial fatty

acid beta-oxidation in the human eye and

brain: implications for the retinopathy of

long-chain 3-hydroxyacyl-CoA dehydroge-

nase deficiency. Pediatr Res 56: 744–750.

Uusimaa J, Vainionpaa L, Simila S, Mietti-

nen R & Nuutinen M (1997): L-3-hydroxy-

acyl-CoA dehydrogenase deficiency:

two cases with pigmentary retinopathy.


Wanders RJ, Ijlst L, van Gennip AH, Jakobs

C, de Jager JP, Dorland L, van Sprang FJ

& Duran M (1990): Long-chain 3-hydrox-

yacyl-CoA dehydrogenase deficiency: iden-

tification of a new inborn error of

mitochondrial fatty acid beta-oxidation.


Received on June 21st, 2007.

Accepted on September 27th, 2007.

Correspondence:

Kristina Tear Fahnehjelm

Department of Paediatric Ophthalmology

and Strabismus

St Erik Eye Hospital

B 54, Karolinska University Hospital,

Huddinge

S-141 86 Stockholm

Sweden

Tel: +46 8 585 800 00

Fax: +46 8 556 204 89

Email: [email protected]


9

Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a...

Documents

Transcript of Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a...