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W4242028804 abstract "Purpose: To present long-term ocular complications and electroretinographic (ERG) findings in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency – 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 diagnosis, initiation of treatment and age at examination, inter-individual differences were present. Profound chorioretinal atrophy, severe visual impairment and progressive myopia had developed in two teenagers. Milder chorioretinopathy with or without subnormal 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 sometimes difficult to diagnose. Unusual chorioretinal findings should alert the ophthalmologist to the long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, especially if there is a history of neonatal hypoglycaemia or failure to thrive. Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a life-threatening disease of energy metabolism caused by mutations in the gene for the α-subunit of the trifunctional protein in the mitochondrial degradation of fatty acids (Wanders et al. 1990; Ijlst et al. 1994). The LCHAD enzyme, McKusick 600890, catalyses the third of the four steps in the β-oxidation of fatty acids and has the highest specificity towards chain lengths of 14–22 carbon atoms. The disorder has an autosomal recessive inheritance and is the second most common β-oxidation defect in the Swedish population, with an estimated incidence of 1 : 100.000. One mutation (1528 G>C) comprises more than 90% of mutated alleles in Swedish patients. Triglycerides offer an important source of energy, and a defect in the degradation can have deleterious effects during catabolic states. The diagnosis is usually established within the first 8 months of life because of decompensations during a catabolic state with hypoketotic hypoglycaemia accompanied by liver enlargement, muscular hypotonia and hypertrophic cardiomyopathy (Hagenfeldt et al. 1990). Determination of dicarboxylic and 3-hydroxy fatty acids in plasma followed by mutation analysis contributes to the diagnosis (Hagenfeldt et al. 1990; Ijlst et al. 1994). Emergency treatment with glucose infusion followed by a diet with reduced intake of fat (approximately 20% of calories), mainly composed of medium-chain triglycerides (MCT fat) supplemented with vitamins, minerals and essential fatty acids, has resulted in the reversion of these symptoms (Hagenfeldt et al. 1995). The children have a fasting intolerance, making night feeds necessary in the majority of cases and necessitating hospital care and glucose infusion during febrile infections. Long-term complications include ocular changes (Tyni et al. 1998a), peripheral neuropathy and mental retardation (Wanders et al. 1990; Gillingham et al. 1999; den Boer et al. 2002). Ocular complications beginning with retinal pigmentations and progressing to impaired retinal function with pathological electroretinography (ERG) have been described in case reports and in small case series since the late 1980s (Poll-The et al. 1988; Przyrembel et al. 1991; Bertini et al. 1992; Pons et al. 1996) followed by more detailed descriptions of the chorioretinal atrophy (Schrijver-Wieling et al. 1997) and an association to cataract (Uusimaa et al. 1997). Tyni et al. (1998a) reported the ocular changes in four long-term survivors and 15 infants, all dead before 14 months of age. A classification of the retinal stages was proposed from a normal/pale fundus with normal visual acuity (VA) and ERG (stage 1), clumping of the retinal pigment epithelium (RPE) in the posterior pole and ERG deterioration (stage 2), progression to chorioretinal atrophy (stage 3) and additional posterior staphyloma and extinguished ERG (stage 4). Finally, den Boer et al. (2002) reported retinopathy in nine of 31 surviving children (29%) in a study based on questionnaires to referring specialists and a median follow-up of 3.4 years, but no ocular details were described. Presently, there are 13 living children diagnosed with LCHAD deficiency in Sweden. In this paper, ocular findings, ERG results and long-term outcome in 10 of these children are reported. One patient is one of the longest-treated worldwide with 17 years of treatment. The rate of progression of the chorioretinopathy and the visual outcome were compared to age at diagnosis, time of treatment and other clinical parameters. Ten children from different parts of Sweden were diagnosed with LCHAD deficiency at the two participating hospitals. The diagnosis was based on the characteristic pattern of dicarboxylic acids and 3-hydroxy fatty acids in plasma and was verified by mutation analysis. Dietary treatment with low fat intake and supplementation of essential fatty acids including docosahexaenoic acid (DHA) (daily intake according to Swedish nutritional recommendations) commenced at time of diagnosis in all children. Nine children had continuous night feeds. During infections with fever, a carbohydrate-rich supplement or intravenous glucose infusions were administered. All 10 children underwent ocular examinations including assessment of best-corrected decimal VA with optotypes, stereopsis (Lang, Forch, Switzerland), ocular alignment, colour vision (HRR Hardy Rand Rittler, New York, USA), slit-lamp investigation, ophthalmoscopy, fundus photography and refraction under cycloplegia. ERG was performed in all 10 children after pupil dilatation and 30 min of dark adaptation. General anaesthesia was used and full-field ERGs were recorded in a Nicolet Viking analysis system (Nicolet Biomedical Instruments, Madison, Wisconsin, USA). The regional ethical committee of Uppsala approved of the study. A scoring system for the clinical background parameters was developed (Table 1). Medical records were scrutinized for important maternal, prenatal, neonatal and somatic data that were considered potential risk factors for long-term ocular complications. Decompensations were defined as periods when the families had any kind of contact with the hospital during infections. Each child was scored from 1 to 3 points regarding each clinical risk factor, and the summarized scores were compared to the ocular findings and ERG results. The children (seven girls and three boys) were diagnosed at a median age of 1 month (range 2 days to 13 months). One patient was diagnosed in the neonatal period before any symptoms had developed because of medical history in previous children in the family. Median age at first ocular examination was 14.5 months (range 5 weeks to 6 years), whereas duration of ocular follow-up was median 7.5 years (range 2.3–14.8 years). Two children had ocular examinations within 1 month of diagnosis. Retinal pathology was first noted at a median age of 3.6 years (range 14 months to 6 years). The initial pigmentary changes were subtle general pigmentations spread in the posterior poles. Four of the 10 children had developed retinal pigmentations at the first ocular examination. Six children had normal ocular fundi at first ocular examination at a median age of 11 months (range 5 weeks to 2.7 years). The older the children at time of examination, the more pronounced the ocular changes (cases 1, 2 and 4). The most severe stages of chorioretinal atrophies resulted in profound visual loss in one or both eyes because of extensive central chorioretinal atrophy, staphylomas and severe myopia (cases 1 and 4). Case 1 had fibrotic chorioretinal changes not described previously in children with LCHAD deficiency. Case 4 had severe general chorioretinal atrophy while case 2 had developed patchy areolar chorioretinopathy. Common findings in the other children were mottled/granular or diffuse pigmentations and atrophies in the posterior poles, especially peripapillar and perimacular, with no or minimal visual loss (cases 3, 5–8 and 10). However, case 9 had a more severe diffuse chorioretinal atrophy and severely pathological ERG already at 4 years of age (1-10 and Tables 2 and 3). Case 1, girl aged 17.5 years. The first ocular examination at 2.9 years of age demonstrated 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 present 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. 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 epithelial 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). Case 3, boy aged 16.5 years. Ocular examinations since the age of 6 have demonstrated 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). 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 photophobia 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) 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 retina 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 epithelium. In the left eye the retinal structure was slightly better preserved with a better foveal pit (G and H). 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 atrophy 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, M.D. 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 neuroretinal structure outside the fovea (E and F). Case 7, girl aged 7.5 years. The first fundus examination at 1.3 years demonstrated slightly irregular foveal reflexes. The girl developed increasing photophobia. At 2.6 years distinct macular pigmentations were detected. One year later additional circumscriptive hypopigmentations, especially peripapillary, were present. At 4.5 years visual acuity (VA) was normal for age, but scattered granular pigmentations, faint peripapillary atrophy (A, arrow 1) and homogenously pigmented maculae (A, arrow 2) were noted. The photophobia declined during the last 2 years. The latest fundus 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. Case 8, girl aged 5.5 years. This twin girl was born prematurely and developed retinopathy of prematurity stage 2, which resolved spontaneously. At 4 years mottled retinal pigmentations 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). 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 hyperpigmentations, more pronounced in the left eye. Case 10, boy aged 5 years. This boy had normal ocular fundi at 2.7 years of age. Subtle granular pigmentations were detected at 3.8 years and remained unchanged at 5 years of age. The chorioretinopathy was less pronounced in patients with early diagnosis (1st week of life) and early institution of dietary therapy (cases 6 and 7), while it was more severe in children with late diagnosis (cases 4 and 9). Three patients developed myopia while none had developed cataract at the time of follow-up. Clinical parameters suspected of having an influence on the development of long-term sequelae are presented in Table 1. Six children had a total score of 20 or more. All these children but one had chorioretinopathy grade 3 or 4. Eight patients were homozygous for the common mutation 1528 G>C and the remaining two had the same mutation on one allele. The other mutation has not yet been identified. ERG was moderately to severely pathological in seven of 10 children at latest follow-up (Table 2). They demonstrated markedly reduced scotopic and photopic A-wave and B-wave amplitudes. Five of them also had delayed implicit times of 30-Hz cone responses. The four teenagers (cases 1–4) all had moderately pathological ERG when the first ERG was performed. No child – not even the girl with the most severe chorioretinal atrophy – had an extinguished ERG. One girl (case 6) was followed annually with ERG, and had normal retinal function until 7 years of age when the amplitudes began to decline. Notable retinal pigmentations were detected almost 2 years earlier. One young child (case 9), who also had marked chorioretinal atrophy, had a markedly reduced ERG already at the first examination at 4 years of age. Three children had subnormal ERG (cases 5, 7 and 10) and slight to moderate retinal changes. Case 7 had repeated ERG examinations from 3 to 6 years of age and demonstrated decreasing rod and cone amplitudes beginning at the age of 6 despite high levels of DHA initiated at the age of 5. Case descriptions of the children, together with ocular history, are presented as legends to the fundus photographs (1-10). The results from the most recent ocular assessment, including ERG, are listed in Tables 2 and 3. In the present study, which to our knowledge is the second largest study on living children with LCHAD deficiency, chorioretinal changes of different severity were found in all 10 children. This is a higher frequency than reported previously and may be explained by a longer ocular follow-up period than in earlier reports. Hence, the present regimen seems not to prevent but possibly to delay the development of ocular symptoms. Normal ocular fundi at first ocular examination were present in six children at a median age of 11 months. Tyni et al. reported normal ocular fundi at initial assessment in seven slightly younger children, median age 4.8 months (range 3 days to 13 months). They also reported that five out of 11 children with retinal pigmentations at a median age of 9 months (range 4 months to 5 years) had pigmentation predominantly in the macular areas. Among the four long-term survivors, ages 5–31 years, all except one had developed retinopathy before 2 years of age and two had predominantly macular pigmentations initially (Tyni et al. 1998a). In the present study, half of the patients initially demonstrated subtle general pigmentations spread in the posterior poles and in the mid-periphery and not in the macular areas, a finding also described by Gillingham et al. (2005). In the children with macular pigmentations, the darker appearance of the macular region may be partly the result of perimacular atrophy, which increases the contrast to the surrounding retina. As long as the macula was pigmented homogenously, central VA seemed to remain stable. Three patients developed myopia during follow-up. The more severe myopia that occurred in two children with severe visual impairment might be caused by staphylomas and/or deficient emmetropization. Tyni et al. (1998a) reported myopia in three patients at the ages of 5, 6 and 12. Rare fundus findings were noted, especially in the most severely affected children. Case 1 developed peculiar fibroid chorioretinal changes, which progressed during childhood and resulted in severe unilateral visual impairment. This could be caused by a neovascular membrane resulting from a defect in Bruch’s membrane. Despite progressive chorioretinal degeneration in the other eye, the central vision remained normal. Case 2 had marked chorioretinal atrophic patches with bare sclera similar to the picture described by Tyni et al. (1998a). A notable observation was that case 4 – with the most severe chorioretinal atrophic findings, bare sclera and staphyloma (stage 4) – did not have an extinguished ERG. This is not in agreement with the staging suggested by Tyni et al. (1998a), where patients with similar ocular fundus pathology at ages 13 and 14 had extinguished ERG responses. Marked peripheral transitional zones with pigmentary clumping and smaller rounded atrophic areas at the border between central atrophic retina and peripheral normal retina were found only in this same patient. With time, there seemed to be a progression from central to peripheral parts. The underlying mechanism for this circumscript mode of progression is unclear but could be caused by the disturbed retinal metabolism. The most peripheral part of the retina, developed during late gestation, maintained its normal structure. To a large extent the ERG results were associated with the stages of chorioretinopathy, suggesting that ERG influences lag behind the extent of fundus changes and that disturbance of the retinal neuro-epithelium is in sequence with the damage in the RPE and progressive loss of choroid vessels. Retinal changes are the major ocular problems in children with LCHAD deficiency but the pathogenesis remains unknown. Flattened and hypopigmented RPE cells and secondary loss of choriocapillaris macrophages have been demonstrated while the peripheral parts of the ocular fundi have been normal (Tyni et al. 1998b). Mitochondrial fatty acid β-oxidation has been detected in the retinal pigmentation cells in vitro and the expression of the mitochondrial trifunctional protein (MTP) has been detected in the retinal pigmentation cells as well as in other layers of the retina in vitro (Tyni et al. 2002). However, Tyni et al. (2004) have also suggested that photoreceptor damage could play a contributory role in the pathogenesis of retinopathy LCHAD deficiency. Low plasma levels of essential fatty acids, especially DHA, have been discussed as a contributing cause of the retinopathy (Gillingham et al. 1999; Harding et al. 1999; den Boer et al. 2002). This has lately been suggested to be correlated to VA measured by Sweep visual evoked potentials (VEP) (Gillingham et al. 2005), as have accumulations of long-chain 3-hydroxyacylcarnitines (Schrijver-Wieling et al. 1997), which were found to be correlated negatively to ERG amplitude (Gillingham et al. 2005). In a previous study, we observed a more than 50% higher rate of lipolysis in a child with LCHAD deficiency treated with low-fat diet compared to her healthy, non-identical twin sister. The resulting increase in the levels of fatty acids and toxic β-oxidation intermediates could be one of the mechanisms behind the progressing ocular findings (Halldin et al. 2007). According to the initial findings by Gillingham et al. (1999, 2003), dietary treatment had a minimal effect on chronic degenerative complications like pigmentary retinopathy and vision loss. However, the same authors suggested recently that treatment with DHA could be correlated to improved VA measured by Sweep VEP (Gillingham et al. 2005). All our patients were treated with DHA to keep DHA within normal levels. A detailed ophthalmological assessment with ERG was conducted prior to initiation of higher DHA level treatment in just one patient. However, ERG amplitudes in this patient declined during a 2-year period despite the high levels of DHA. To conclude, early diagnosis and treatment of LCHAD deficiency seem beneficial with regard to chorioretinal complications but this has to be evaluated further. We suggest that all these children have an ocular examination within the first month of diagnosis and annual follow-ups. Fundus photography and repeated ERG examinations should be performed. In case of visual impairment, support with visual aids should not be delayed. Furthermore, because LCHAD deficiency may be difficult to diagnose, the ophthalmologists have an important role in early detection. Unusual chorioretinal findings – especially if there is a history of neonatal hypoglycaemia – or failure to thrive should lead to the suspicion of LCHAD deficiency. In addition, it is important that an evaluation of visual function and retinal pathology is included in the primary evaluation of all patients with a suspicion of a defect in the beta-oxidation system. Financial support was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institutet and from KMA, Stiftelsen Kronprinsessan Margaretas Arbetsnämnd för synskadade. We are grateful to Anne-Catherine Söderberg, M.D. for interpreting OCT results and to Jan Schutterman M.D. for retinal expertise." @default.
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W4242028804 title "Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a cross-sectional study with long-term follow-up" @default.
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