The Eye Mirroring Inherited Metabolic Disorders

Kristina Teär Fahnehjelm

A few decades ago many children with inborn errors of metabolism died early. Today, with
better diagnostic procedures and more efficient treatment they often reach adulthood.
However, somatic or ocular complications are common as long-term sequels. Early diagnosis
does not make already existing ocular complications vanish but often, although not always,
treatment can stop progression. It is therefore important for the paediatric ophthalmologist to
be acquainted with the pathogenesis of metabolic disorders and to get a good knowledge of
how, why and when the eyes are affected. Although the individual inherited inborn errors of
metabolism are rare diseases, taken as a group, they affect approximately 1 child per 2500. In
the following a few common inherited metabolic disorders with severe ocular complications
are presented.
Mucopolysaccharidosis I (MPS I) Hurler
Mucopolysaccharidoses are lysosomal storage diseases, due to deficiencies of different
enzymes, where MPS I – Hurler is the most common. It is a life-threatening disease where
corneal clouding can be one of the first presenting signs and thus also a diagnostic clue. The
world wide incidence of MPS I has been reported to be 1/100 000 newborns. More than 90
mutations in the gene coding for the lysosomal enzyme -L-iduronidase are known to cause
deficiency or absence of the enzyme. This abnormality leads to intra- and extracellular
accumulation of the glucosaminoglucans (GAG), causing cell death, tissue damage and
disturbance of normal tissue growth as well as excessive excretion of GAG in the urine. The
children, who usually grow normally until six months of age, will manifest severe skeletal
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deformations, short stature, scoliosis, coarsening of facial features, large heads,
communicating hydrocephalus, mental retardation, hepatosplenomegaly, and cardiac
complications. Death, in untreated children, usually occurs during the first decade of life
(Wraith 2005). Ocular characteristics apart from corneal clouding (Fig. 1) include protruding
wide set eyes, atypical eyebrows, retinal dystrophies, glaucoma, chronic papilloedema and
optic atrophy. Also posterior visual pathway pathology or visual cortical abnormalities have
been reported due to accumulation of storage material in the white matter of the CNS.
Figure 1. Corneal photography from 7-year-old girl with MPS I- Hurler. Stem cell
transplantation was performed at 19 months of age and a retransplantation at 21 months of
age (left). Notice slight remaining corneal opacities. Best corrected visual acuity is 0.8 right
and left eye respectively. The intraocular pressures and ocular fundi are normal (right)
Early allogeneic stem cell transplantation (SCT), where a HLA matched graft is given to a
conditioned patient, has been used as a treatment since the early 1980-ies. SCT has been
shown to reduce the accumulation of GAG in visceral organs and to increase survival and
stabilising long-term neuro-cognitive functions. Today SCT is offered to children below two
years of age with a normal intellectual development (Wraith 2005) but SCT performed even
earlier, at 12 months of age, is preferable. With regard to eye symptoms, various degrees of
improvement of the corneal clouding after SCT have been reported. However, despite early
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improvement of retinal conditions with SCT, it has been suggested that retinal dysfunction
will still progress (Gullingsrud et al. 1998).
As life expectancy increases in children with MPS I-H, it becomes more important to detect
remaining ocular complications and additional SCT related complications, such dry eye
syndrome and cataract. In a Swedish study corneal opacities diminished in four children with
MPS I (one of them shown in figure 2), after SCT before 2 years of age (Fahnehjelm et al.
2006). Although early SCT thus seems to be beneficial, no objective grading of the corneal
opacities was made and the number of patients was limited. In accordance with previous
studies, no patient had a complete resolution of the corneal opacities. However, the best
corrected visual acuity (BCVA) was good in these 4 patients, in comparison with patients in
other international studies, partly maybe due to early intervention with glasses for hyperopia.
No patient has needed corneal transplantation, developed cataract and/or glaucoma.
Figure 2. MPS I – Hurler patient, 7- years-old, same girl as in Fig 1. Here with her healthy
twin brother
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A recent follow-up has been made of five of seven Swedish patients with MPS I who had
SCT before 23 months of age. The median age in the group was 8 years, BCVAwas  0.5 in
the majority of the patients despite mild/moderate opacities while high hyperopia (+4.0 to
+9.0 spherical equivalent) was present in all patients. Keratometry values were low and axial
lengths short in comparison with reference material (Fahnehjelm, Törnquist& Winiarski
accepted ACTA Ophthalmol April 2010) Our hypothesis is that the storage of GAG will lead
to increased rigidity of the cornea and sclera, with a flattening of the curvature of the cornea
and a reduction of the refractive power of the corneal surface. This, together with the reduced
axial length, can explain the high incidence of hyperopia in the MPS I patients. Detection of
refractive errors and prescription of glasses are important in order to avoid amblyopia.
Photochromatic glasses were shown to be beneficial in minimizing photophobia, increasing
comfort and optimizing visual function.
To conclude, children with MPS 1-H show a variety of ocular symptoms. Early SCT seems
beneficial in reducing, but not eliminating, corneal opacities. The clinical evaluation of MPS
I children in their early years offers a challenge to the paediatric ophthalmologist.
Retinoscopy might be difficult to perform due to dull fundus reflexes and/or severe
photophobia but is important to measure the refraction since high hyperopia is common. It is
possibly caused by storage of glucasaminoglucans that affect the refractive power of the
cornea. Intraocular pressure is often recorded as falsely high, due to corneal stiffness.
In the future, stromal transplantation of mesenchymal cells might be a solution for reduction
of corneal opacities. Enzyme replacement therapy has so far not been shown beneficial in
reducing corneal opacities, probably due to reduction of enzyme transport to the avascular
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
LCHAD (Long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiency is a life-threatening
disorder of deficient fat metabolism. The LCHAD enzyme catalyzes the -oxidation of fatty
acids and has the highest specificity towards chain lengths of 14-22 carbon atoms. The
disease is inherited in an autosomal recessive manner and is the second most common -
oxidation defect in Sweden with an estimated incidence of 1:100.000. As triglycerides offer
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an important source of energy, a defect in the degradation can have deleterious effects during
catabolic states.
The diagnosis is usually established within the first eight months of life, based on life
threatening hypoketotic hypoglycaemia accompanied by liver enlargement, muscular
hypotonia and hypertrophic cardiomyopathy. Measurements of dicarboxylic and 3-hydroxy
fatty acids in plasma followed by mutation analysis contribute to the diagnosis. Emergency
treatment with glucose infusion followed by a diet with reduced intake of fat (approximately
20% of calories), mainly composed of medium chain triglycerides, supplemented with
vitamins, minerals and essential fatty acids, has resulted in reversion of the above symptoms.
Neonatal death is a major risk. The surviving children have a fasting intolerance making night
feeds necessary in the majority of cases and necessitating hospital care and glucose infusion
during febrile infections.
Figure 3. The ocular fundi in a 13-year-old girl with LCHAD- deficiency. Notice small
granular pigmentations, peripapillar atrophy and normal maculae. Electro Retino Graphy
(ERG) was subnormal
Long-term complications include peripheral neuropathy, mental retardation and
chorioretinopathy. Flattened and hypopigmented retinal pigment epithelium cells and
secondary loss of choriocapillaris macrophages have been demonstrated in the central parts,
while the peripheral parts of the ocular fundii have been normal (Tyni et al. 1998b). The
retinal findings can be graded: Stage 1 is a normal/ pale fundus with normal visual acuity and
electroretinograhy (ERG); Stage 2 a fundus with clumping of the retinal pigment epithelium
in the posterior pole and ERG deterioration (Figure 3); Stage 3 a fundus with progression to
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chorioretinal atrophy , and Stage 4 a fundus with additional posterior staphyloma and
extinguished ERG (Tyni et al. 1998a).
Presently, there are 12 living children diagnosed with LCHAD deficiency in Sweden. One
patient has been treated for 18 years and is one of the longest treated worldwide. Ten of the
patients have been included in our study (Fahnehjelm et al. 2007). They all showed
chorioretinal changes of different severity. This is a higher frequency than previously reported
and may be explained by a longer ocular follow-up. Hence, the present regimen seems not to
prevent but possibly to delay the development of ocular symptoms. The ERG responses
correlated with the stages of chorioretinopathy, suggesting that disturbance of the retinal
neuro-epithelium paralleled the damage of the retinal pigment epithelium and the progressive
loss of choroid vessels.
All patients were treated with Omega 3 (docosahexaenoic acid /DHA/) to keep DHA within
normal levels. Low plasma levels of essential fatty acids, especially DHA, have previously
been suggested as a contributing factor for the retinopathy (Gillingham et al. 1999). A
correlation between DHA levels and VA measured by Sweep VEP (Gillingham et al. 2005)
has been seen in these children. The accumulation of long-chain 3-hydroxyacylcarnitines has
also been found to be negatively correlated to ERG amplitude (Gillingham et al. 2005).
In conclusion, children with LCHAD-deficiency should have an ocular examination within
the first month of diagnosis and thereafter annually. The ophthalmologist has an important
role in early detection, since LCHAD deficiency may be difficult to diagnose. Unusual
chorioretinal findings, especially if there is a history of neonatal hypoglycaemia or failure to
thrive, should lead to the suspicion of LCHAD deficiency. Fundus photography and repeated
ERGs should be performed. Furthermore, it is important that an ocular evaluation is done of
all patients with a suspected defect in the beta oxidation system.
Mitochondrial diseases
Mitochondrial diseases lead to dysfunction of the respiratory chain affecting the cellular
energy metabolism of all organs, giving rise to a variety of symptoms from any organ at all
ages. With an estimated minimum prevalence of 1/5000 the mitochondrial diseases can be
regarded as one of the most common groups of inborn errors of metabolism. The respiratory
chain consists of five enzyme complexes (I-V) located in the mitochondrial inner membrane
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with the main function to generate adenosine triphosphate (ATP). This process is under dual
genetic control, with communication between the nuclear and mitochondrial genomes.
Isolated complex I deficiency is the most common mitochondrial respiratory chain defect.
There is a wide variety of clinical phenotypes. Subacute necrotizing encephalopathy (Leigh
syndrome) and Leigh-like syndrome are common manifestations in infants.
Causative mutations are found in mitochondrial DNA (mtDNA) as well as in nuclear DNA
(nDNA). Mutations in mtDNA are maternally inherited while nuclear mutations most often
are autosomal recessively inherited. In children, a multi-system disease is often seen, with a
failure to thrive, encephalopathy, visual and hearing impairment, severe muscle weakness and
dysfunction of the heart, liver, kidneys, and endocrine organs.
Mitochondrial disease may lead to ocular problems. Dominant optic atrophy (DOA) and
Leber’s hereditary optic atrophy (LHON) are both non-syndromic optic neuropathies with
mitochondrial aetiology. Optic nerve hypoplasia (ONH) has also been described in relation to
mitochondrial disease.
In a recently Swedish study (Fahnehjelm et al 2010), ocular or visual problems were much
more common than previously reported, occurring in 12 of 13 patients with mitochondrial
disease. Optic atrophy occurred in 5 out of the 12 patients with an ocular diagnosis. One
patient had a unilateral thickening of the nerve fibre layer and teleangiectatic microangiopathy
in his left eye, similar to previously reported findings in asymptomatic carriers with LHON
mutations. Motility problems with dysmetric saccades, asymmetrical smooth pursuits,
instability in fixation, and gaze paralysis were common indicating an involvement of extra
ocular muscles, brainstem, basal ganglia and cerebellum, which also was confirmed with MRI
pathology. Flash and/or pattern VEP were pathological in 60% of the patients.
With regard to the extra-ocular muscles, it is interesting to note that the abundant
mitochondria in these energy-demanding muscles have been shown to respire at slower rates
than mitochondria in skeletal muscles. The activity of complex I has shown to be lower than
in normal extra-ocular muscle, which could explain the eye movements abnormalities in the
patient in the present study, since saccadic and pursuit movements are energy dependent and
thus sensitive to mitochondrial dysfunction.
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In conclusion, patients with complex I deficiency suffer different ocular disorders including
optic atrophy and eye motility problems. The patients with severe somatic dysfunctions and
brain damage also had the most severe visual impairment, motility dysfunctions and ocular
Young patients with inherited errors of metabolism and ocular manifestations present
challenges to paediatric ophthalmologists but also make everyday practice multi-dimensional
and exciting. The patients offer an opportunity to cooperate with colleagues from different
disciplines. This encourages new clinical research and supplies opportunities to design
various multidisciplinary scientific studies, hopefully resulting in clinical progress, beneficial
outcomes and clinically relevant follow-up programs/clinical guidelines for ocular
manifestations in children with inborn errors of metabolism.
Fahnehjelm K T, Törnquist A L, Malm G & Winiarski J (2006): Ocular findings in four
children with mucopolysaccharidosis I-Hurler (MPS I-H) treated early with haematopoietic
stem cell transplantation. Acta Ophthalmologica Scandinavica 84: 781-785.
Fahnehjelm K T, Törnquist A L, Olsson M & Winiarski J (2007): Visual outcome and
cataract development after allogeneic stem-cell transplantation in children. Acta
Ophthalmologica Scandinavica 85: 724-733.
Fahnehjelm, K T, Olsson M, Naess K, Wiberg M, Ygge J, Martin L, V Döbeln U (2010:
Visual function, ocular motility and ocular characteristics in patients with mitochondrial
complex I deficiency. ACTA Ophthalmologica Jan 8. Epub ahead of print.
Gillingham M, Van Calcar S, Ney D, Wolff J & Harding C (1999): Dietary management of
long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). A case report and
survey. J Inherit Metab Dis 22: 123-131.
Gillingham M B, Weleber R G, Neuringer M, Connor W E, Mills M, van Calcar S, Ver
Hoeve J, Wolff J & Harding C O (2005): Effect of optimal dietary therapy upon visual
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function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional
protein deficiency. Mol Genet Metab 2005 Sep-Oct;86(1-2):124-33.
Gullingsrud E O, Krivit W & Summers C G (1998): Ocular abnormalities in the
mucopolysaccharidoses after bone marrow transplantation. Longer follow-up. Ophthalmology
105: 1099-1105.
Tyni T, Kivelä 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 chorioretinopathy.
Ophthalmology 105: 810-824.
Tyni T, Pihko H & Kivelä T (1998b): Ophthalmic pathology in long-chain 3-hydroxyacyl-
CoA dehydrogenase deficiency caused by the G1528C mutation. Curr Eye Res 17: 551-559.
Wraith J E (2005): The first 5 years of clinical experience with laronidase enzyme
replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother 6: 489-506.


Ovanstående är ett utdrag ur:

Advances in Pediatric Ophthalmology Research. Gunnar Lennerstrand and Gustaf Öqvist Seimyr, Eds. The Sigvard & Marianne Bernadotte Research Foundation for Children Eye Care. Stockholm, 2010.

Utgiven med anledning av Stiftelsens 20-års jubileum.


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