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Hyperprolinaemia and Gyrate Atrophy of the Choroid and Retina in Members of the Same Family

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Hyperprolinaemia and Gyrate Atrophy of the Choroid and Retina in Members of the Same Family Br J Ophthalmol: first published as 10.1136/bjo.69.8.588 on 1 August 1985. Downloaded from British Journal of Ophthalmology, 69, 588-592 Hyperprolinaemia and gyrate atrophy of the choroid and retina in members of the same family E P DOUGLAS From the Department ofOphthalmology, Royal Infirmary, Glasgow G4 OSF SUMMARY A report is given of the occurrence of asymptomatic hyperprolinaemia type I in the father of a family in which two of the children have gyrate atrophy of the choroid and retina. Gyrate atrophy of the choroid and retina is an lished between these manifestations and the disease.' autosomal recessive disease' due to deficient activity Similarly, some patients with type II hyperpro- of the enzyme ornithine ketoacid aminotransferase. linaemia have had retarded mental development and There is resultant hyperornithinaemia, hyper- seizures, but again no direct association has been ornithinuria,23 and hypolysinaemia.4 established.' The typical eye findings are of circular areas of total choroidal and retinal atrophy, beginning at the BIOCHEMISTRY periphery. There is hyperpigmentation in the more The biochemical relationship between proline and intact retina around the areas of atrophy. It is ornithine metabolism is shown (Fig. 1). Proline is a associated with myopia, and there may be vitreous non-essential amino acid. Amino acids occur in the opacities. The electroretinogram (ERG) may be body fluids in the free form and in peptide linkage. initially normal' but with time usually becomes Proline is involved in brain metabolism, and cere- severely depressed or unrecordable. There are brospinal fluid (CSF) proline is increased in type I abnormalities of electro-oculogram (EOG) and dark and type II hyperprolinaemia.9 Proline is abundant in http://bjo.bmj.com/ adaptation. Defects ofthe retinal pigment epithelium its free form, and important pathways provide for its and choriocapillaris appear on fundus fluorescein biosynthesis and degradation. angiography. The proline derivative A-pyrroline-5-carboxylic Generalised manifestations include muscle weak- acid provides a link between the urea and tri- ness, abnormal electromyogram (EMG), and carboxylic acid cycles. atrophy of type II muscle fibres, with tubular aggre- Hydroxyproline, found in peptides and proteins, gates on electron microscopy,5 abnormal electro- arises by post-translational modification of peptide on October 2, 2021 by guest. Protected copyright. encephalograph (EEG) or seizures6 and abnormal proline. Excess proline regulates its metabolism to ERG.5 Clinically these changes are usually mild or enhance outflow through the ornithine pathway. absent. Proline competes with hydroxyproline and glycine Ornithine aminotransferase is lacking in fibro- for a common membrane carrier, which serves their blasts7 and lymphocytes.' This enzyme converts orni- uptake preferentially at concentrations in excess of thine into A-pyrroline-5-carboxylic acid (Fig. 1). 0 1 mM. As either amino acid (proline, hydroxypro- Hyperprolinaemia is an autosomal recessive line) proceeds to saturate its renal transport system, disease.' There are two types. Type I is due to competitive inhibition of the transport of the other deficient proline oxidase activity, and type II is due to amino acid and glycine occurs. Renal parenchyma deficient A-pyrroline-5-carboxylic acid dehydro- has a significant role in proline uptake and genase activity (Fig. 1). Both types are usually metabolism.' asymptomatic. In type I cases disease ofthe renal and Aminoglycinuria (proline, hydroxyproline, central nervous systems, delayed neurological glycine) occurs when plasma proline is greater than development, seizures, and EEG changes have been 0O8 mM. The intensity of the aminoglycinuria is recorded, but no direct connection has been estab- proportional to the degree of hyperprolinaemia. Hyperprolinuria results from the progressive satura- Correspondence to Miss E P Douglas. tion of the proline reabsorption sites in the renal 588 Br J Ophthalmol: first published as 10.1136/bjo.69.8.588 on 1 August 1985. Downloaded from Hyperprolinaemia andgyrate atrophy ofthe choroid and retina in members ofthe samefamily 589 TROPOCOLLAGEN PROTOCOLLAGEN PROLINE I Proline Oxidase (D 1* @APyrroline 5 A PYRROLINE carboxylic acid _ 5 CARBOXYLIC ACID dehydrogenase _//7 L GLUTAMIC ACID GLUTAMIC Y SEMIALDEHYDE (3) L Ornithine 2 ± GLUTAMATE Ketoamino YB6 *t KETOGLUTARIC ACID Transferase d(KETOGLUTARATE CITRATE - A r%.-%I& Ilk If-- UjNJIDI-KIITIrUIKIC,_I rllNt q * ARGININE OXALOACETATE SUCCINATE UREA,Y7 GUANIDO GLYCINE MALATE FUMARATE ARGININE ACETATE FtUMARATE q ADENOSYL METHIONINE ARGINOSUCCINATE CITRULLINE q ADENOSYL ASPARTATE CREATINE CREATINE Fig. 1 Pathways ofornithine andproline metabolism. tubule. Prolinuria thus results from an overflow (case 1), mother (case 2), elder son (case 3), mechanism. Hyperglycinuria and hyperhydroxypro- younger son (case 4), and daughter (case 5). linuria is due to a competitive inhibition of the site The daughter was first seen in 1971 aged 9 years, http://bjo.bmj.com/ shared by the three substrates.9 having been referred because of poor visual acuity. Proline accumulation is greater in type II than in Myopia of mild degree (-2.0 sphere right eye; -2-5 type I hyperprolinaemia. The degradation of proline sphere left eye) was found. Three years later her to glutamic acid through the proline intermediary is myopia had increased to a -9.0 sphere with -0-5 cyl less efficient than normal in type I hyperprolinaemia. at 20° in the right eye and -9 0 sphere with -1-0 cyl The enzyme proline oxidase involved in type I at 155° in the left eye. With this correction her vision hyperprolinaemia is a mitochondrial, membrane was 6/9 in both eyes. Her fundi at this time showed bound enzyme.9 the typical peripheral changes of stage I of gyrate on October 2, 2021 by guest. Protected copyright. Omithine arises from dietary or endogenous atrophy (Figs. 2a and b). Central field testing gave arginine by (1) action of arginase, (2) the arginine- normal results, but typical concentric constriction of glycine transamidase reaction-the first enzyme in the peripheral fields was present on perimetry. the pathway of creatine synthesis. The major At that time her younger brother (case 4), aged 8 enzymes of ornithine metabolism are intramito- years, was referred with poor visual acuity. He also chondrial, the ornithine entering the mitochondria had myopia of -3.0 sphere in the right eye and -2 5 through a specific transport system. The major path- sphere in the left. Fundal examination showed an way for the disposal of excess ornithine is through the almost identical stage I picture to that of his sister. mitochondrial enzyme ornithine ketoacid/ (Figs. 3a and b). A small retinal operculum was noted aminotransferase, which needs pyridoxal phosphate in his right eye. Central fields were again full, with as cofactor. It is this enzyme which is deficient in peripheral field constriction. gyrate atrophy with hyperornithinaemia. Lens changes were absent in both children. The children were referred for electrophysiology, which Case reports was normal. An initial diagnosis of cobblestone degeneration was made. The family under examination consists of father Although the myopia in both children continued to Br J Ophthalmol: first published as 10.1136/bjo.69.8.588 on 1 August 1985. Downloaded from 590 E P Douglas F1ig. Zb Fhind.s ofcase.). Fig. 2a Fundusqfcase5. increase, their visual acuity was maintained, and they ever, this was abandoned because of poor compli- had no subjective symptoms. ance and because of the apparent slow nature of the Several years later it was decided to assess their disease. Fasting amino acid profiles were also under- plasma and urinary ornithine levels. A fasting amino taken of the father, mother, and elder brother of the acid profile of blood and urine was therefore under- affected children (Tables 1, 2). taken. The results are shown in Tables 1 and 2. There The elder son (case 3) showed an elevated plasma was a hyperornithinuria, hyperornithinaemia, and proline and a high normal ornithine level, though hypolysinaemia, confirming the diagnosis of gyrate urinary levels of these were normal. At the late age of atrophy of the choroid and retina, although electro- 22 years, this son developed myopia, having pre- physiological testing at that time was still normal. viously had normal visual acuity and a normal Both children were treated with pyridoxine, which refraction. The most interesting results were those of http://bjo.bmj.com/ has a lowering effect on plasma ornithine," and a low the father. The blood sample showed a high normal protein diet which amino acid supplements. How- ornithine as might be expected from the parents,' on October 2, 2021 by guest. Protected copyright. rlig.Fgia 3aPundullsofcse4rnauidusso.n(.' g. r .s case 4. Br J Ophthalmol: first published as 10.1136/bjo.69.8.588 on 1 August 1985. Downloaded from Hyperprolinaemia andgyrate atrophy ofthe choroid and retina in members ofthe samefamily 591 Table 1 Biochemical amino acidprofile: plasma Plasma amino acids Case 1 (father) Case 2 Case 3 CaseS* Case 4* in mmolll (mother) (elder son) Results I Results 2 Hydroxyproline ND - 21 N ND - 41-8 HN 26-6 N 25-2 N Glutamicacid 104 N 48-7 N 33 LN 75 8 N 111 N 82-6 N Proline 1079 +++ 931 +++ 281 HN 554 + 285 HN 353 HN Glycine 244 N 265 N 214 N 307 N 228 N 195 N Ornithine 142 HN 92-5 N 89-6 N 139 HN 818 ++++ 659 ++++ Lysine 193 N 202 N 148 N 135 N 81-7 - 99 LN Arginine 58-4 N 93-4 N 73-1 N 42-8 LN 76 N 83-1 N *Patients affected with gyrate atrophy. +=increased. - =decreased. HN=high normal. LN=low normal. N=normal. ND=none detected. who are often obligate heterozygotes. 12 However, it subjects, and consisted of a blood sample and 24- also showed a markedly elevated plasma proline hour collection of urine. level. Proline and ornithine levels were normal in his Deproteinisation of plasma prior to aminoacid urine (Tables 1, 2).
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