CYAN EXHIBIT 1028
`
`NUTRITION AND RETINAL
`
`DEGENERATIONS
`
`Vitamin A, Taurine, Omithine, and Phytanic Acid
`
`ELIOT L. BERSON, MD
`
`Retinal degenerations represent a significant cause
`ofvisual loss to people from all over the world."4
`In the United States an estimated 200,000 to 300,000
`people have macular degenerations withjuvenile onset
`or onset in later life. Figure 1A illustrates the fundus of
`a patient with ajuvenile form of macular degeneration;
`depigmentation of the pigment epithelium and white
`deposits are present in the macula. These patients
`usually have severely reduced central vision with
`preserved peripheral vision. Some 50,000 to 100,000
`people in this country have degenerative retinal
`diseases grouped under
`the heading of
`retinitis
`pigmentosa. Figure 18 shows the fundus of a patient
`with a moderately advanced stage of retinitis pig-
`mentosa; characteristic intraretinal pigment deposits
`in a bone spicule configuration are distributed around
`the midperiphery. These patients characteristically
`have night blindness and decreased peripheral vision
`in the early stages; eventually, almost all will lose
`central vision as well. Patients with retinitis pigmentosa
`can now be detected in early life on the basis of an
`
`From the Barman-Gund Laboratory for the Study of Retinal
`Degenerations, Harvard Medical School, Massachusetts Eye and
`Ear Infirmary. Boston, Massachusetts.
`Supported in part by Specialized Research Center Grant
`EYO2OI4 from the National Eye lnstitutc and in part bythe National
`Retinitis Pigmentosa Foundation. Baltimore, Maryland, and the
`George Gund Foundation. Cleveland, Ohio.
`Presented at the Symposium on Nutrition, Pharmacology, and
`Vision sponsored by the Committee on Vision, National Research
`Council, National Academy of Sciences, Washington, DC.
`November 16—17, [981.
`Reprint requests: Eliot L. Berson, MD, Berman-Gund Labora-
`tory, Massachusetts Eye and Ear Infirmary, 243 Charles Street.
`Boston. MA 02114.
`
`abnormal electroretinogram (ERG) at a time when
`minimal, if any, abnormalities are visible on ophthal-
`moscopic examinationf’6 Macular degenerations and
`retinitis pigmentosa,
`taken together, account
`for
`approximately 30% of the legal blindness in the United
`States. The problem is magnified further when we
`consider that no treatments are known for practically
`all types.
`Outside of the United States xerophthalmia is a
`major cause of blindness in 73 countries and terri-
`tories.7 The term xerophthalmia or dry eyes is now
`applied to all of the ocular manifestations of vitamin A
`deficiency, including conjunctiva] and corneal xerosis,
`Bitot’s spots, corneal ulcerations, keratomalacia,
`corneal scarring, night blindness, and retinal degenera-
`tion."’9 In the mid-19605 the annual
`incidence of
`blindness due to xerophthalmia was estimated to be
`100,000 people; this estimate was based on a global
`survey sponsored by the World Health Organization10
`together with an intensive investigation in Jordan.” A
`recent survey in Indonesia with projections to the
`whole of Asia (Table I) has led to an estimate that as
`many as 250,000 people become blind each year while
`millions suffer from partial signs of vitamin A
`deficiency.7 Severe vitamin A deficiency is associated
`with a mortality rate that may be as high as 60% in
`children under 5 years of age. Vitamin A deficiency is
`not the sole cause of death as protein—energy malnu-
`trition and infection are often present.7’”"3
`Treatment of night blindness with diet appears to
`have originated with the ancient Egyptians who
`recommended the eating ofliver forthis affliction.” In
`1917 the factor in liver that can cure nutritionally
`induced night blindness was identified as “fat soluble
`
`0275-004X/82/0400/0236/$1.90 © The Ophthalmic Communications Society
`
`236
`
`

`

`NUTRITION AND RETINAL DEGENERATION 0 BERSON
`
`237
`
`PRECURSOR: All-trans-[B—Carotene
`
`
`
`li-cis
`
`7
`\ 9\
`
`11
`\13
`fiR
`
`ISOMERIC FORMS:
`All-trans
`
`ll
`7
`\ 9\ \ 13\
`
`Fl
`
`W R
`
`etinol: R = CHZOH
`
`Retinal: R = CHO
`
`Retinoic Acid: R —- COOH
`Fig. 2. Structures of B-carotene, retinol (vitamin A). retinaldchyde
`(retinal). and retinoic acid.
`
`A,"15 later called vitamin A. The chemical structure of
`carotene was determined in l93016 and that ofvitamin
`A, or
`retinol,
`in
`l93l,l7 thereby clarifying the
`relationship between vitamin A in animals and the
`provitamin A, carotene,
`in plants. Vitamin A is
`important not only for vision but also for reproduc-
`tion, growth,
`the maintenance of differentiated
`epithelia, and mucous secretion. It participates in
`glycoprotein synthesism‘lg and appears to influence
`DNA and RNA synthesis20 but the exact mechanisms
`of action by which it subserves all of its biologic
`functions remain to be clarified.
`
`Through research largely conducted in the past 15
`years, we now know that vitamin A can be used in the
`treatment ofa hereditary disease involving the retina,
`namely the Bassen—Kornzweig syndrome. We also
`have discovered that dietary deficiency of taurine can
`result in a retinal degeneration in animals. Treatment
`trials with special diets are being conducted to
`determine whether lowering of plasma ornithine in
`gyrate atrophy or serum phytanic acid in Refsum’s
`disease will alter the course ofthe retinal degenerations
`in these human diseases. The purpose of the present
`report is to provide an overview of some of the recent
`advances made in our understanding of these retinal
`degenerations.
`
`Vitamin A and the Bassen-Kornzweig Syndrome
`
`Major natural sources of vitamin A (eg, retinol) in
`the diet include ,B-carotene, which is found in yellow
`and green leafy vegetables, and long-chain retinyl
`esters, which are found in animal tissues.[3-carotene is
`converted to retinol primarily in the intestinal mucosa.
`B-carotene 15,15’ deoxigenase catalyzes the cleavage
`of B-carotene at the central double bond (Fig. 2),
`
`Fig. 1. Top. Fundus photograph from an 18-year-old man with
`juvenile macular degeneration and bottom, a 44-year-old man with
`retinitis pigmentosa. Patient (top) has best-corrected vision of
`20/200 with intact peripheral vision: patient (bottom) has 20/20
`with night blindness and substantial
`loss of peripheral vision.
`Photograph (top)
`includes left disc and macula; photograph
`(bottom) shows right disc and nasal midperiphery.
`
`Table 1. Estimations of Annual Incidence of
`Xerophthalmia in Asia Based on Indonesian Data"
`
`Ocular
`Sign
`
`Indonesia
`Corneal
`Noncorneal
`
`Annual
`Incidence
`Preschool
`
`Population
`at Risk
`
`Cases
`Per Year
`
`4/1,000
`104/1 ,000
`
`12 million
`12 million
`
`48,000
`1.250.000
`
`Asia
`Corneal xerophthalmia. annually: 500,000; about
`250,000 go blind
`Noncorneal. annually18—9 million
`‘From the International Vitamin A Consultative Group
`(IVACG).7
`
`

`

`238
`
`Lymph
`and
`Blood
`
`L(9:38"r
`
`Blood
`
`Target
`Cell
`
`RETINA 0 1982 0 VOLUME 2 0 NUMBER 4
`
`
`
`
` MembianeAcceptor‘
`
`Photoreceptor
`Outer
`Segments
`
`,
`
`Fig. 4. Pathway of vitamin A transport from plasma to photo-
`receptor outcr segments. A designates vitamin A; RBP, retinol-
`binding protein; CRBI’, eytosol retinol binding protein; N, nucleus.
`(From Chader G. Retinoids in ocular tissues: binding proteins.
`transport and mechanism of action. In: McDevitt DS, ed. Cell
`Biology ofthe Eye. New York: Academic Press, I982, 377—433.
`
`specific cell surface receptors (Fig. 4) for the RBI3'.25’26
`The vitamin A so delivered enters the target cell, eg,
`the pigment epithelium, where it may become as-
`sociated with an intracellular eytosol retinol-binding
`protein (designated CRPB, Fig. 4).27 In the pigment
`epithelium, vitamin A is esterified and again stored
`primarily as the palmitateffl’29 Upon demand it
`is
`hydrolyzed and transported to the photoreceptor
`outer segments apparently bound to one or more
`
`r‘ho opsin (498 MM)
`
`pr‘e - 7umirhodop5/n (543m/4)
`
`>-14o °c.
`
`7um/‘rhodops/nf497m/u)
`
`>—40°C.
`
`metarhodopsin I (478m/A)
`
`HM, >-I5°c,
`
`met‘arhodopsin II (380 net/.4)
`
`H20 >O°C.
`
`
`
`[Fe/'5retinal+opsin
`
`oil-trons retinal {387mg}
`+
`opsin
`Fig. 5. Stages in the bleaching of rhodopsin. Photochemical
`reactions are denoted by wavy lines, thermal (dark) reactions by
`straight
`lines. Reactions arrested at designated temperatures.
`Absorption maxima in parentheses. (From Matthews RG, Hubbard
`R, Brown PK, Wald G, Tautomcric forms of metarhodopsin. J Gen
`Physiol
`l963-l964:47:2|5—220. by copyright permission of The
`Rockefeller University Press).
`
`— \_l *— Diet
`
`Retinol (NW3KQOEQ
`
`Rou h
`
`A A Kidney
`
`
`
`
` *
`
`.
`A ”Action
`
`
`
`Fig. 3. Vitamin A transport to a model target cell. A designates
`vitamin A; RBP, rctinol-binding protein; A-RPB, holo-RBP; PA.
`prealbumin: ER. endoplasmic reticulum; N. nucleus.
`(From
`Chadcr G. Retinoids in ocular tissues: binding proteins. transport
`and mechanism ofaction. In: McDevitt DS. ed. Cell Biology ofthe
`Eye. New York: Academic Press, 1982, 377-433.)
`
`yielding two molecules of retinaldehyde (eg, retinal)
`and then retinaldehyde is
`reduced to retinol by
`retinaldehyde reductase. Dietary retinyl esters are
`hydrolyzed in the intestine, and the resulting retinol is
`then absorbed into the mucosa] cells. In the mucosa]
`
`cells retinol (designated as A in Fig. 3), either newly
`absorbed or newly synthesized from carotene, is re-
`esterified mainly as the palmitate, complexed with
`other lipids and proteins in the form of chylomicra,
`and transported via the lymph and blood to the liver.
`Chylomicra are removed from the circulation almost
`entirely by the liver.“ After uptake of the chylomicra
`retinyl esters, hydrolysis and re—esterification occurs in
`the liver, and the resulting retinyl esters, mainly retinyl
`palmitate, are stored in association with lipid droplets,
`either in the hepatic parenchymal cells or in “fat-
`storing cells,” sometimes referred to as Ito cells.22
`From these liver stores, vitamin A is mobilized as the
`free alcohol, retinol, bound to a specific retinol-
`binding protein (RBP)23 and secreted as holo-RBP
`(designated as A-RBP in Fig. 3). The secreted complex
`of vitamin A and retinol—binding protein then forms a
`H molar complex with prealbumin (designated PA)
`in the plasma. The REP-prealbumin complex serves to
`reduce glomerular filtration and renal catabolism of
`RBP. Vitamin A mobilization from the liver is highly
`regulated by factors that control the rates of RBP
`production and secretion by the liver.24 Delivery of
`vitamin A to peripheral tissues appears to involve
`
`

`

`NUTRITION AND RETINAL DEGENERATION 0 BERSON
`
`239
`
`Fig. 6. Retinal histology ofruts raised on vitamin A-free diets and supplemented with vitamin A (A) or retinoic acid (B, C.and D). In contrast to
`normal structure(A). rats raised on vitamin A-frce diets and supplemented with retinoic acid show less intensely stained outer segments at two
`months (B), almost complete disappearance of outer segments with loss ofabout halfthe inner segments and visual cell nuclei at six months (C).
`and disappearance of visual cells except for one irregular row of visual cell nuclei at ten months (D). Other parts ofthe retina and pigment
`epithelium appear normal. (From DowlingJE. Gibbons 1R. The effect ofvitamin A deficiency on the fine structure ofthe retina. ln: Smelser G.
`ed. The Structure of the Eye. New York: Academic Press, l96l;89).
`
`proteins.2°’3° Along the way, oxidation and isomeriza-
`tion convert vitamin A to lI-cis retinaldehyde.
`Binding is thought to occur between I l-cis retinalde-
`hyde and the lysine in opsin at position 53 from the
`C-terminus by a Schiff-base linkage between the
`aldehyde group and the epsilon-amino group of
`lysine.”32 Light results in isomerization of ll-cis
`retinaldehyde to all-trans retinaldehyde and opsin
`through a series of intermediates (Fig. 5)33 and results
`
`in visual excitation34 by mechanisms still to be defined
`completely.
`Vitamin A supports growth and the visual cycle
`while vitamin A acid or retinoic acid supports growth
`but does not support the visual cycle. Photoreeeptors
`of weanling rats fed a vitamin A-free diet supple-
`mented with retinoic acid show the effects ofvitamin A
`
`deprivation within two months. Figure 6A shows the
`normal control retina of a rat raised on a vitamin
`
`Fig. 7. Recovery from vitamin A deficiency. ln a typical experiment litter mates were raised on vitamin A-frec diets for about six montltstone
`rat was supplemented wth vitamin A (A), the other two with retinoic acid. Sixteen days prior to the end of the experiment the recovery animal
`was fed a large dose of vitamin A (500 pg) and then periodically fed further vitamin A for l6 days (C). while the defictent animal (B) was
`continued on retinoic acid. For description ofhistology see text. (From DowlingJE. Gibbons IR. The effect of vitamin A deficiency on the fine
`structure of the retina. In: Smelser G. The Structure ofthe Eye, New York: Academic Press, l96l;95).
`
`

`

`240
`
`RETINA 0 1982 0 VOLUME 2 0 NUMBER 4
`
`A-free diet supplemented with vitamin A. In contrast,
`rats raised on a vitamin A-free diet supplemented with
`retinoic acid show changes in the outer segments at
`about
`two months (Fig. 6B) and loss of outer
`segments, inner segments, and about half the photo-
`receptor nuclei at about six months (Fig. 6C). At ten
`months (Fig. 6D) the photoreceptors have disappeared
`except for one row ofnuclei. In rats on vitamin A-free
`diets plus retinoic acid, the level of rhodopsin declines
`to 5—10% of normal after two months, while the
`concentration of the visual protein opsin decreases
`more slowly, with 50% remaining after two months.
`Loss of ERG function and loss of outer segments
`precede loss of photoreceptor cells, and this provides
`
`an opportunity for therapeutic intervention. In fact,
`reversal offunction and structure can be achieved with
`
`refeeding vitamin A in early stages. Figure 7 illustrates
`the retina of a control rat (A), that of a vitamin
`A-deficient
`rat at six months with loss of outer
`
`segments and half the photoreceptors (B), and the
`retina ofa rat depleted for about six months and then
`given vitamin A for 16 days (C). No increase in the
`thickness of the outer nuclear layer occurs (Fig. 7C
`compared with Fig. 7B), but new outer segments
`(Fig. 7C) with normal length and width regenerate
`within 16 days.”‘36
`Light is required to produce this sequence of events
`as vitamin A-deficient rats supplemented with retinoic
`
`Fig. 8. Representative sections from
`midpcripheral retina of vitamin A-
`depleted l3-lined ground squirrel
`keptin cyclicdimillumination(0.l—
`IO ft-C) for45 weeks (top)and from
`midperipheral retina of vitamin A-
`depleted l3-lined ground squirrel
`kcptincycliedimillumination(0.l—
`10 l't-C) for 38 weeks and then cyclic
`moderate illumination (SO—500 ft-
`C)
`for eight weeks. The upper
`section appears normal whereas the
`lower section shows abnormal de-
`posits at the photo-receptor pigment
`epithelial cell interface that extend
`into inner segment
`layer. Largest
`deposit is 20 X 40 a (From Berson
`EL. Experimental and therapeutic
`aspects of photic damage to the
`retina.
`Invest Ophthalmol 1973;
`12:37).
`
`

`

`NUTRITION AND RETINAL DEGENERATION 0 BERSON
`
`241
`
`acid and maintained in darkness do not show
`
`the rats are
`photoreceptor cell degeneration until
`placed in cyclic light.37-3“ In the vitamin A—deficient,
`lB-lined ground squirrel supplemented with retinoic
`acid, the retinal structure appears relativelyintaet if
`the squirrel is maintained in very dim cyclic light for
`about one year (Fig. 8, top).39 Exposure of some of
`these animals to brighter cyclic light for a few weeks
`(Fig. 8, bottom) results in scattered white lesions at
`the photoreceptor-pigment epithelial cell interface,”
`some ofwhich are visible with the ophthalmoscope as
`scattered white deposits (Fig. 9, left, in contrast to a
`control, Fig. 9, right). These fundus abnormalities
`resemble the scattered white deposits reported in
`vitamin A deficiency in man. In the vitamin A-de-
`ficient rat, rod degeneration precedes cone degenera-
`tion.m Photoreceptor loss is accelerated in vitamin
`A~depleted rats that are also vitamin E-deficient;
`weanling rats on diets adequate or deficient
`in A
`and/or E show greatest
`loss of photoreceptor cell
`nuclei at 35 weeks if they are both A- and E-deficient
`(Fig. 10).“1
`With the above as background, we can better
`understand the pathogenesis and treatment of the
`retinal degeneration in the Bassen-Kornzweig syn-
`
`Fig. 9. Representative fundus photographs of vitamin A-depleted
`ill-lined ground squirrel kept in cyclic dim illumination (0.1—l0
`ft-C) for 38 weeks and then cyclic moderate illumination (50—500
`ft-C) for eight weeks (left), and of a vitamin A—depleted 13—lined
`ground squirrel kept in cyclic dim illumination (0.1-10 ft-C) for 45
`weeks (right). Fundus lesions (left) resemble multiple white deposits
`reported in the fundus in human vitamin A deficiency. See Figure 8
`for retinal histology.
`
`Fig. 10. Representative sections of rat retina for each diet group at
`35 weeks showing changes in the outer nuclear laycr(ONL). the rod
`outer segments (ROS). and the pigment epithelium (PE). (From
`Robison WC. Kuwabara T. Bieri JG. Invest Ophthalmol Vis Sci
`I980zl911033).
`
`drome. In 1950 Bassen and Kornzweig described an
`18-year-old girl, born of first cousins, who had a
`malabsorption syndrome, a generalized retinal de-
`generation, a diffuse neuromuscular disease similar to
`Friedreich’s ataxia, and a peculiar crenation ofthe red
`blood cells, now called acanthocytosis.42'“ In 1958
`low cholesterol was observed.45 Soon thereafter, an
`absence of low-density plasma lipoproteins or so-
`called B~lipoproteins was found, and the term A-Beta-
`Lipoproteinemia was assigned to this disorder.“'48
`More recently, other classes of lipoproteins have also
`been found to be abnormal.“9 In the Bassen—Kornzweig
`syndrome the patient can assimilate fat
`into the
`intestinal mucosa, but a defect exists in its removal
`from this site because of the lack of chylomicra.50 An
`intestinal biopsy from a patient (Fig. 11, right) shows
`diagnostic findings of normal-sized villi filled with
`lipid droplets that are essentially triglycerides; this
`contrasts with a normal intestinal biopsy (Fig. 11,
`left)“ It appears that the liver and then the retina
`become depleted of vitamin A in this condition.
`Abnormal ERGs have been reported in a 15-month-
`old child52 and a 6-year-old patient53 in whom the
`fundi were still normal. The original ease described by
`Bassen and Kornzweig showed multiple white dots in
`the early stages, but by age 31, the patient developed
`multiple areas of pigment epithelial cell atrophy. In
`other cases, the typical intraretinal pigment that we
`associate with retinitis pigmentosa has been noted in
`the retinal periphery.”
`The role of vitamin A deprivation in causing the
`retinal degeneration in this syndrome is supported by
`the observation that large doses of vitamin A have led
`to return of dark adaptation thresholds and ERG
`responses to normal in two patients with the early
`
`

`

`242
`
`RETINA 0 1982 I VOLUME 2 0 NUMBER 4
`
`that vitamin A deficiency in the retina is not the
`problem. In most types of retinitis pigmentosa, the
`ERGs become not only reduced in amplitude but also
`substantially delayed in their temporal aspects (Fig.
`l4).5’(’“’5 For example, cone—isolated responses to white
`30 cps flicker are so delayed for the dominant with
`reduced penetrance and the autosomal recessive and
`X-chromosome-linked forms that the stimulus (noted
`by the vertical lines in Fig. 14, column 3) elicits the
`next but one response.
`In contrast, patients with
`vitamin A deficiency, night blindness, and chronic
`alcoholism with cirrhosis ofthe liver do not show these
`
`profound delays either prior to treatment or during
`stages of recovery on vitamin A therapy (Fig. 15,
`column 3).“6 Moreover, during stages of recovery these
`patients report normal cone thresholds with elevated
`rod thresholds in the central retina and the opposite in
`the periphery“ possibly due to rod/cone rivalry for
`vitamin A“; this central night blindness with normal
`rod function in the periphery, seen in the vitamin
`A-deficient patient with chronic alcoholism, has not
`been observed in human retinitis pigmentosa.
`Fundus reflectometry measurements in a vitamin
`A-deficient patient with intestinal malabsorption lead
`us to the same conclusion."8 Figure 16 demonstrates
`changes in psychophysical rod thresholds as a function
`of percent rhodopsin in the dark-adapted retina as
`measured with fundus reflectometry for a vitamin
`A-deficient patient (open circle) and patients with
`retinitis pigmentosa (solid symbols). The dashed line
`shows the linear relationship between log threshold
`
`MM\
`
`WM
`
`. M
`x
`
`J
`
`Fig. 12. Full—fields ERGs to a red (top) and a blue (middle) light,
`equal for rod vision, and a brighter white stimulus (bottom) from a
`patient with hereditary abetalipoproteinemia (dark adapted).
`Responses in the left column were obtained before vitamin A
`therapy. those in the middle column at six hours. and those on the
`right at 24 hours after vitamin A therapy. Two to three responses to
`the same stimulus are superimposed. The arrows indicate an
`exclusively cone response. The light stimulus begins with each trace.
`The calibration (lower right) signifies 0.06 mv vertically and 60 msec
`horizontally. (From Gouras P, Carr RE. Gunkel RD. Retinitis
`pigmentosa in abetalipoproteinemia: effects of vitamin A. Invest
`Ophthalmol 19711101790.
`
`Fig. 11. Photomicrographs of epithelial villi obtained by pcroral
`biopsy of the small intestine and stained with hematoxylin-cosin.
`The 1ch photograph shows upper villous tip from a normal subject
`with the cytoplasm being a homogeneous color. The right
`photograph shows upper villous tip from a patient with abetalipo-
`proteincmia; the cytoplasm of the intestinal epithelial cells appears
`foamy and vacuolatcd because of the presence of unstained lipid.
`(From Carr RE. Abetalipoprotcincmia and the eye. in: Bergsma D.
`Bron AJ. Cotlier E. eds. The Eye and lnborn Errors of Metabolism.
`Birth Defects: Original Article Series. New York: Alan R. Liss. lne..
`[9762381)
`
`stages”54 (Fig. 12). More advanced cases have not
`responded, but in one such casein which the retina was
`examined after the death of the patient, widespread
`loss of photoreceptor cells was observed.” Whether or
`not vitamin A therapy can maintain retinal function
`over the long term is still open to question as patients
`have been reported in whom vitamin A levels have
`been restored to normal and yet the retinal degenera-
`tion has appeared to progress.”57 Moreover, plasma
`levels of vitamin E have been reported as low in
`untreated patients.”—60 Therefore, vitamin E therapy
`has also been advocated to prevent the progression of
`this retinal degeneration59’fil’62
`As in vitamin A-deficient animals, patients with
`retinitis pigmentosa have shown remaining photo-
`receptors with shortened or absent outer segments.
`Foveal cones from a postmortem donor eye from a
`24—year—old man with X-chromosome—linked retinitis
`pigmentosa have only a few outer segments with the
`inner segments apposed to the pigment epithelium
`(Fig. 13); remaining rods in the periphery were also
`shortened. Trials with large doses of vitamin A given
`orally"3 or intramuscularly64 have been unsuccessful;
`but one might question whether patients with retinitis
`pigmentosa can transport vitamin A normally from
`the plasma across the pigment epithelium to the
`photoreceptors.
`Careful comparison of the retinal malfunction in
`early retinitis pigmentosa with that in vitamin A-
`deficient patients with chronic alcoholism suggests
`
`

`

`NUTRITION AND RETINAL DEGENERATION 0 BERSON
`
`243
`
`Fig. 13. Cones in the central fovca
`from post-mortem donor eye with
`sex-linked retinitis pigmentosa have
`enlarged inner segments (15) and
`distorted remnants of outer seg-
`ments (OS). Autophagic vacuoles
`(arrows) are seen in the perinuclear
`cytoplasm. Pigment epithelial cells
`contain large numbers ofmelanoly-
`sosomes ( l). lysosomes (2), and few
`free melanin granules. Apical pro-
`trusions of these cells extend be-
`tween cone inner segments. Horizon-
`tal bar (lower right) is 5 it M. (From
`Slamier RB. Berson EL. Klein R,
`Meyers S. Sex-linked retinitis pig-
`mentosa: ultrastruclure of photo-
`receptors and pigment epithelium.
`Invest Ophthalmol Vis Sci 1979;
`182MB.)
`
`and bleached rhodopsin, while the continuous curve is
`the relationship expected if threshold is determined by
`the probability of quantal absorption. The rod
`thresholds of retinitis pigmentosa patients approxi—
`mate closely the continuous curve showing that their
`rods appear to be functioning normally for the amount
`of visual pigment they have. For the same reduction in
`visual pigment concentration, the patient with vitamin
`
`A deficiency (open circle) shows an elevation in
`psychophysically determined threshold that is several
`orders of magnitude higher than that observed for
`patients with retinitis pigmentosa (solid symbols).
`Early in vitamin A deficiency, rod outer segments are
`depleted of retinaldehyde as if by bleaching with light,
`while the rods of patients with retinitis pigmentosa
`behave as if they have lost the entire visual pigment
`
`

`

`244
`
`RETINA 0 1982 0 VOLUME 2 0 NUMBER 4
`
`LRGs In EARLY RETINITIS PIGMENTOSA (RP)
`
`Blue
`
`White
`
`White(30cp~ .
`
`Normal
`
`complete)
`
`Dominant RP
`
`(We
`
`KNOW
`
`1
`
`Dominant RP
`
`(reduced) 5 E
`
`Sex linked RP E l i
`
`It
`
`Auto Rec RP
`
`2 W};95“"
`
`Fig. 14. ERG responses from a normal subject and four patients
`with retinitis pigmentosa (ages l3, l4, l4. and 9). Responses were
`obtained after45 minutes ofdark adaptation to single flashes ofblue
`light (left column) and white light (middle column). Responses
`(right column) were obtained to 30 cps white light. Calibration
`symbol (lower right corner) signifies 50 mscc horizontally and IOO
`microvolts vertically. Rod b-wave implicit
`times in column 1
`(normal range 7| — IOB mscc) and cone implicit times (normal range
`25—32 mscc) in column 3 are designated with arrows. (From Berson
`EL. Retinitis pigmentosa and allied diseases: clectrophysiologic
`findings. Trans Am Acad Ophthalmol Otolaryngol 1976;81:659.)
`
`molecule (ie, opsin plus retinaldehyde). Although one
`cannot exclude a deficiency of a binding site for a
`carrier protein for vitamin A in the outer segments in
`patients with retinitis pigmentosa69 or some intrinsic
`defect
`involving vitamin A or
`its derivatives in
`photoreceptor cells,
`the available evidence would
`suggest
`that, with the exception of the Bassen-
`Kornzweig syndrome, patients with early stages of
`retinitis pigmentosa do not have a local deficiency of
`vitamin A in the retina.
`
`
`
`Fig. 16. Change in log threshold as a function of the percent
`rhodopsin present in the dark-adapted retina as determined by
`fundus reflectomctry. Threshold elevation is relative to a mean
`absolute value of—‘4.02 log scot td-sec; l00% rhodopsin refers to a
`measured density ofO. l3 units. Threshold values that lie above the
`cone threshold line show that visual sensitivity was mcasureable but
`that it was subserved by the cone mechanism. Large filled circles are
`for four subjects of this study. Small filled circles are data from
`Highman and Wealc (Highman VH, Weale RA. AmJ Ophthalmol
`19731752822) rcplottcd on this scale of coordinates. Open circle is
`data point from a vitamin-A deficient subject. Continuous curve
`and dashed line: see text. (From Ripps H, Britt KP. Weale RA.
`Rhodopsin and visual threshold in retinitis pigmentosa.
`Invest
`Ophthalmol Vis Sci 1978;l7:738.)
`
`Normal
`
`:J11
`
`\\
`
`E\
`
`[M‘UWJ
`
`E
`2
`1
`Patient
`Pre Vitamin A S
`
`:
`1
`I
`i
`
`2* :W WII I I I
`
`I
`I
`
`
`
`_
`
`Vitamin A
`7 days
`
`i
`I
`l
`i
`l
`Z
`:
`;>‘§: 23;.“{‘A W‘N
`5
`E
`I
`H
`i‘
`I
`
`Vitamin A
`13 days
`
`I:
`
`‘-.
`
`I:
`-___/’\
`:
`3
`3
`.
`3
`E
`Mum
`Vitamin A
`f
`i
`WUVW
`27 (lays A N \ \LWWJ;
`
`|
`-
`.
`(KW
`
`\KX
`“
`\
`
`Fig. 15. Full-field ERGs fora normal person and fora patientwith
`chronic alcoholism. before and during vitamin A therapy.
`in
`response to single flashcs of a dim blue (A < 470 nm) light (left
`column) and white (16 X 10’ ft-Lamberts) light (middle column)
`after dark adaptation for 45 minutes and in response to white light
`(l6 X 10’ ft-Lamberts) flickering at 30 cps (right column). Two or
`three consecutive responses to the same stimulus are superimposed.
`The vertical lines denote stimulus onset. (From Sandberg MA.
`Rosen JB, Berson EL. Cone and rod function in vitamin A
`deficiency with chronic alcoholism and in retinitis pigmentosa.
`Published with permission from Am J Ophthalmol 1977;84:660.
`Copyright by The Ophthalmic Publishing Company.)
`
`/
`,
`
`4.50A
`
`4.18-
`‘ I
`
`ELEVATION
`LOGTHRESHOLD
`
`too
`
`50
`PERCENT RHODOPSIN
`
`0
`
`

`

`NUTRITION AND RETlNAL DEGENERATION 0 BERSON
`
`245
`
`Methionine
`
`Serine
`
`Taurine and Retinal Degeneration
`
`CH3-S-CH2-CH-COOH
`
`I
`I
`CHerH-COOH
`
`NHZ /OH NH:
`
`Cysteine
`
`HS-CHZ- CH - COOH
`
`NH2
`¢
`i decarboxylase
`
`Taurine
`0
`
`OH '8' GHQ-CH2
`II
`I
`
`NH2
`O
`Fig. 17. Taurine synthesis in liver: simplified scheme. (From
`Schmidt SY, Berson EL, Hayes KC. Retinal degeneration in the
`taurine-deficient cat. Trans Am Acad Ophthalmol Otolaryngol
`1976;81:687.)
`
`Taurine (Fig. 17) is present in meat, seafood, fish,
`and human breast milk. It was long referred to as an
`end product of sulfur amino acid metabolism but now
`is recognized: as important in several organ systems
`including the heart, brain, and skeletal muscle.”—72
`The livers from man, monkey, and cat have extremely
`low activities of cysteine-sulfinic acid decarboxylase,
`thus limiting endogenous taurine biosynthesis. More-
`over, taurine is in high concentrations in the retinas of
`all species so far studied including man.”76
`Within the past ten years taurine deficiency has been
`shown to lead to retinal degeneration in the cat."'79
`Cats with this degeneration develop a small hyper-
`reflexive area in the center of the area centralis (Fig.
`188) in contrast with a normal control (Fig. 18A). In
`more advanced stages, the white lesion can be seen to
`enlarge as shown in Figures 18C and D. Stages of
`degeneration (B, C, and D) seen in the veterinarian’s
`office“ can be simulated in the laboratory by feeding
`eats a taurine-free diet with casein as the only source of
`protein or by feeding a synthetic diet containing all
`amino acids except taurine.“l Cats fed taurine-free
`diets show a gradual fall in ERG amplitudes that can
`
`Fig. 18. Representative fundus photographs of posterior pole of normal cat fed taurine-containing chow diet (A) and those of cats fed a
`taurine-free casein diet (B, C, D). Progressive stages of degeneration are shown in B, C, and D. (From Schmidt SY, Berson EL, Hayes KC.
`Retinal degeneration in the taurine-deficient cat. Trans Am Acad Ophthalmol Otolaryngol 1976;81:689.)
`
`

`

`246
`
`RETlNA O 1982 0 VOLUME 2 0 NUMBER 4
`
`23 WEEKS
`
`CHOW- NORMAL
`
`CASEIN
`
`,o.........
`
`CASEIN +METHIONINE
`
`W WWW we,”
`
`Fig. 19. Representative full-
`field ERG responses from
`cats fed chow, a casein diet
`alone. or
`a
`casein diet
`supplemented with either
`methionine.
`cysteine.
`or
`taurine for 23 weeks. Re-
`sponses were obtained to
`single flashes of white light
`(30 x 10’ ft.-L) in the dark—
`adapted state (left column),
`to 40 cps flickering white
`light
`stimuli
`(middle col-
`umn). and to single flashes
`ofwhitc light in the presence
`of
`full-field white back-
`ground (right column). Re-
`sponses in middle and right
`columns represent computer
`summation of 256 and l28
`sweeps,respectively. Normal
`range (mean i SD)
`for
`response amplitudes
`from
`cats fed chow were 400uV:
`65 pV (left column), 8.2 ,uV
`i 1.9 [1V (middle column),
`and l3.0pVi 3.0 uV (right
`column). Normal
`range
`(mean i SD) for cone b-
`wave implicit
`times
`from
`cats fed chow was 22.0 msee
`i l.5 msec. Calibration
`symbol (lower right corner)
`represents vertically 50 pV
`for the left column. ZpV for
`the middle column. and 4 [JV for the right column and horizontally 20 msec for all tracings. Stimulus onset is the vertical hatched lines for left
`and right columns and the vertical shock artifacts for the middle column. Cone implicit times are designated by horizontal arrows in the middle
`column. (From Berson EL. Hayes KC. Rabin AR, Schmidt SY, Watson G. Retinal degeneration in cats fed casein: ll supplementation with
`methionine, cysteine or taurine. Invest Ophthalmol 1976;15:54.)
`
`CASEIN +CY$TEINE
`
`m ‘./V‘-va‘v‘
`
`iJ\.. we.
`
`CASEIN +TAURINE
`
`J
`
`(viii/i
`
`IIxx
`I.
`
`l
`
`_l
`
`be correlated with a fall
`
`in retinal taurine concen-
`
`trations prior to photoreceptor cell death as measured
`by retinal DNA concentrations“ or as monitored by
`histologic studies.82 At a time when taurine-deficient
`cats show the first visible abnormality, namely a small
`hyper~reflexive area in the center of the area centralis,
`the full-field ERG is usually very small or nondeteet-
`able, indicating that the retinal malfunction extends
`far beyond the visible lesion. Supplementation of a
`taurine-free casein diet with the precursors of taurine,
`namely methionine or cysteine, does not preserve
`retinal
`function, whereas supplementation of the
`casein diet with taurine preserves normal ERGs
`comparable to those re