Eye (2010) 24, 507–518 & 2010 Macmillan Publishers Limited All rights reserved 0950-222X/10 $32.00 www.nature.com/eye Inherited metabolic M Rajappa, A Goyal and J Kaur REVIEW disorders involving the eye: a clinico-biochemical perspective Abstract Introduction The diagnosis of inborn errors of metabolism is challenging for most physicians. Improvements The field of inherited metabolic disorders (IMDs) in medical technology and greater knowledge of is often thought to have been born in 1902 when the human genome are resulting in significant Archibald Garrod published his first paper changes in the diagnosis, classification, and describing alkaptonuria and first coined the term treatment of inherited metabolic disorders ‘inborn error of metabolism’. Although this (IMDs). Many known inborn errors of discovery did occur in professional circles, it went 1 metabolism will be recognised earlier or treated largely unnoticed and fell into obscurity. Garrod differently because of these changes. It is recognised that some human disorders were due important that physicians recognise the clinical to enzyme deficiencies and these were because of signs of IMDs and know when to propose genetic abnormalities inherited in an autosomal advanced laboratory testing or referral to a recessive manner. These insights were virtually higher centre for better patient management. ignored for 70 years and these ideas were brought 2 Ocular manifestations occur in various to fruition by Barton Childs in 1970. metabolic disorders. Although there is an Inherited metabolic disorders are challenging extensive understanding of many inborn errors for most physicians. The number of known IMDs of metabolism at the biochemical, molecular, is probably as large as the number of presenting and metabolic levels, little is known about their symptoms that may indicate metabolic 3–5 pathogenesis. In particular, how systemic disturbances. Furthermore, physicians know metabolic disease contributes to ocular defects they may not encounter certain rare IMDs during a lifetime of practice. There is an accelerating Department of Ocular remains to be elucidated in IMDs. The Biochemistry, Dr Rajendra occurrence of eye abnormalities could be due to demographic switch from communicable Prasad Centre for direct toxic mechanisms of abnormal metabolic diseases to genetic disorders. The expression of a Ophthalmic Sciences, All products or accumulation of normal metabolites genetic disease is the combined effect of genes India Institute of Medical Sciences, New Delhi, India by errors of synthetic pathways or by deficient and the environment. There are 25 million births energy metabolism. A detailed in India annually; 0.8 million are born with congenital malformations; 0.35 million with Correspondence: J Kaur, ophthalmological assessment is essential. Department of Ocular Definitive diagnosis and management of glucose-6-phosphatase deficiency; 25 000 with Biochemistry, Dr Rajendra patients with IMDs is ideally carried out by a IMDs; 20 000 with Down’s syndrome, 15 000 with Prasad Centre for combination of specialists, including an congenital hypothyroidism; 14 000 with Ophthalmic Sciences, All India Institute of Medical ophthalmologist, paediatrician, biochemist, and thalassaemia; and 5000 with sickle cell anaemia. In India, biochemical screening of 4400 cases of Sciences, Ansari Nagar, New medical geneticist. Recent advances in the Delhi 110029, India mental retardation revealed that 5.75% (256 diagnosis and treatment of IMDs have Tel: þ 91 11 26593161; 6,7 substantially improved the prognosis for many cases) were due to various IMDs. Fax: þ 91 11 26588919. of these conditions. Inborn metabolic disorders constitute a E-mail: kaurjasbir@ rediffmail.com Eye (2010) 24, 507–518; doi:10.1038/eye.2009.229; heterogeneous group of disorders affecting the published online 2 October 2009 metabolic pathways with an underlying genetic defect. IMDs are individually rare, but Received: 17 July 2008 Accepted in revised form: Keywords: IMDs; galactosaemia; Wilson’s collectively common. IMDs are becoming 6 August 2009 disease; gyrate atrophy of the retina; screening increasingly recognised wherein early diagnosis Published online: 2 October and testing for IMDs and appropriate treatment interventions are 2009 Inborn errors of metabolism and the eye M Rajappa et al 508 mandatory to reduce the morbidity and mortality rates process in confined to the eye or as part of a systemic among the newborns.8 Early diagnosis is crucial for three disease. The age of onset of ocular abnormalities in reasons.6 First, IMDs are rapidly progressive and cause metabolic disease is variable, but onset often begins in irreversible damage early in the course of the disease. childhood, infancy, or from birth. This paper discusses Second, the treatment can often be effective, the major IMDs associated with eye abnormalities. if commenced early and long-term outcome may be Ophthalmologic manifestations occur in various improved. Lastly, correct early diagnosis helps in genetic metabolic disorders. Although there is an extensive counselling. understanding of many inborn errors of metabolism at The latest discoveries in the human genome project the metabolic, biochemical, and molecular levels, their and advances in medical technology have resulted in exact pathogenesis remains to be established. The significant alterations in the diagnosis, classification, and mechanisms by which systemic metabolic disease treatment of IMDs. These changes will aid in early contributes to ocular defects remains to be elucidated. recognition and treatment of many known IMDs. It is The various mechanisms involved could be due to direct absolutely essential that doctors diagnose IMDs early toxic mechanisms of abnormal metabolic products, and whenever necessary, refer the patient to a tertiary accumulation of normal metabolites by errors of care centre for better care, detailed laboratory workup, synthetic pathways, or by deficient energy metabolism. and management. The latest breakthroughs in the Single gene defects result in abnormalities in the diagnosis and treatment of IMDs have significantly synthesis or catabolism of proteins, carbohydrates, or fats improved the prognosis for many of these conditions.9 (Table 1). Most are due to a defect in an enzyme or transport protein, which results in a block in a metabolic pathway (Figure 1). Effects are due to toxic Eye and IMDs accumulations of substrates before the block, The eye is the fourth most common system affected by intermediates from alternative metabolic pathways, and/ genetic disease.10 More than 200 loci for genetic ocular or defects in energy production and utilisation caused by diseases have been mapped so far11,12 and the quest a deficiency of products beyond the block.13 Every continues. Hereditary eye abnormalities can either metabolic disease has several forms that vary in age of manifest as primarily isolated disorders in which disease onset, clinical severity, and often, mode of inheritance. Table 1 Classifications of inherited metabolic disorders13,14 A. Small molecule disorders B. Organelle disorders Carbohydrate metabolism Lysosomal disorders eg: Mucopolysaccharidoses, galactosaemia eg: Sphingolipidoses, glycoproteinoses, mucopolysaccharidoses, gangliosidoses (Gaucher’s disease, Niemann-Pick’s disease, Metachromatic leukodystrophy, Krabbe0s disease) Protein metabolism Mitochondrial disorders eg: Gyrate atrophy of the retina, cystinosis, Marfan’s syndrome, eg: Defects in mitochondrial b-oxidation of fatty acids, Leigh’s homocystinuria, Costeff’s optic atrophy syndrome or type III 3- disease, Alper’s disease, citric acid cycle defects, pyruvate methylglutaconic aciduria, urea cycle defects dehydrogenase deficiency, Kearns-Sayre’s syndrome, Leber’s hereditary optic neuropathy Lipid metabolism Peroxisomal disorders eg: Fish eye disease, sphingolipidoses, Zellweger’s syndrome eg: Zellweger’s syndrome, pseudo-Zellweger’s syndrome, (peroxisome biogenesis disorders), Refsum’s disease (deficiency neonatal adrenoleukodystrophy, pseudo-neonatal of phytanic acid oxidase), Bassen-Kornzweig’s syndrome adrenoleukodystrophy, rhizomelic chondrodysplasia punctata, hyperpipecolic acidaemia Nucleic acid metabolism eg: Lesch-Nyhan’s syndrome Porphyrin metabolism eg: Porphyrias Metal metabolism eg: Wilson’s disease, Menke’s disease, haemochromatosis Eye Inborn errors of metabolism and the eye M Rajappa et al 509 Environmental factors may trigger the onset and severity have a major role in diagnosis of patients with IMDs. of disease. It also depends on degree of accumulation of Hereditary diseases of the eye have symmetrical bilateral toxic substances before metabolic block, for example, involvement, as do those in metabolic disorders. Severe diet, intercurrent infection, fasting drugs, and so on. visual impairment is seen usually around 2 months of Recognition of IMDs is important as it is quite common age, when eye contact develops in most children. In fact, in incidence. The indications for metabolic studies to rule poor vision may be defective in first few weeks of life. out the possibility of IMDs are discussed in Table 2. Early Anomalies of the eye are easily recognised as in cataracts diagnosis is important, as in most cases, dietary in galactosaemia. In others as in peroxisomal diseases, restriction and early therapy prevents onset of disability. fundoscopic examination may be normal in the neonatal Prenatal diagnosis using amniocentesis and chorionic period, whereas recordings of electroretinogram (ERG) villus