Leber's
Hereditary Optic Neuropathy
Clinical Manifestations of the 3460 Mutation Donald R.
Johns, MD; Kyle H. Smith, MD; Neil R. Miller,
\s=b\ Leber's hereditary optic neuropathy is associated with three different point mutations of mitochondrial DNA that appear to be pathogenetic for the disease. These mutations affect nucleotide positions 3460, 11778, and 15257. We reviewed the clinical characteristics of 12 visually symptomatic patients from nine families with the 3460 mutation and compared them with previously published characteristics of symptomatic patients with the 11778 mutation. The patients with the 3460 mutation were similar to the patients with the 11 778 mutation in most clinical parameters. However, the patients with the 3460 mutation had a higher incidence of visual recovery (20% vs 4%, P=.001), a higher percentage of pedigrees with more than one affected family member (78% vs 43%, P=.011), and a greater frequency of tobacco and alcohol abuse. The difference in visual prognosis between these two mutations and the need for modification of possible risk factors provide added significance to genetic testing for Leber's hereditary optic
neuropathy. (Arch Ophthalmol. 1992;110:1577-1581 ) eber's
hereditary optic neuropathy a maternally inherited disease characterized by acute or suba¬ cute loss of central vision primarily in -^
(LHON) is
males younger than 25 years. The sus¬ pected mitochondrial inheritance of this Accepted
for publication March 16, 1992. Departments of Neurology, The Johns Hopkins University School of Medicine (Dr Johns), and Ophthalmology, Wilmer Eye Institute (Drs Smith and Miller), Baltimore, Md. Reprint requests to Department of Neurology, The Johns Hopkins Hospital, Meyer 6-119, 600 N From the
Wolfe St, Baltimore, MD 21205 (Dr Johns).
MD
disease was confirmed in 1988 by Wal¬ lace et al,1 who identified a mitochon¬ drial DNA (mtDNA) point mutation at nucleotide position 11778 in the NADH dehydrogenase subunit 4 gene in nine pedigrees with a clinical diagnosis of LHON. The 11778 mutation has subse¬ quently been identified in 50% to 60% of all LHON pedigrees studied.25 A second etiologically important mu¬ tation was identified in three pedigrees without the 11778 mutation by Huoponen et al in 1991.6 This point mutation at nucleotide position 3460 converts an alanine into a threonine at codon 52 in subunit 1 of NADH dehydrogenase. It is readily detected by restriction en¬ zyme analysis, since the mutation abol¬ ishes a restriction site. The 3460 muta¬ tion has been identified in six additional independent pedigrees by Howell et al,7 and in nine pedigrees that one of us
(D.R.J.) reported previously.8
Another apparently pathogenetic mutation at nucleotide position 15 257 in the apocytochrome b gene was de¬ scribed recently by one of us (D.R.J.) and Neufeld9 and an independent group.10 This 15 257 mutation was iden¬ tified in 12 independent LHON
pedigrees.9,10
These three mutations (11778 [NADH dehydrogenase subunit 4 gene], 3460 [subunit 1 of NADH dehy¬
drogenase], and 15257 [apocytochrome gene]) each seem to be of primary pathogenetic significance, and together account for approximately 70% of all pedigrees with the LHON phenotype.9 b
Several other associated mutations have also been identified that may act synergistically to produce visual symptoms.911 Although the clinical
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/13/2015
characteristics of patients with LHON well documented before the avail¬ ability of genetic testing,1219 we now know that these clinical descriptions deal with a disease that is genetically heterogeneous. The only major study addressing the clinical characteristics of a genetically homogeneous LHON pop¬ ulation is that by Newman et al,5 which is a comprehensive review of the clini¬ cal data from 49 pedigrees with the 11778 mutation. The purpose of this ar¬ ticle is to clarify further the phenotypic expression of the 3460 mutation, and to compare these clinical findings with those of patients with the 11778 mutation. were
PATIENTS AND METHODS Patient Selection Molecular genetic analysis for the mtDNA mutations associated with LHON was performed on blood samples of pa¬ tients with acute visual loss that were sent to us from physicians throughout the United States and several foreign coun¬ tries. Samples from patients with other neurologic diseases and from healthy per¬ sons were used as controls.
Polymerase Chain Reaction and Restriction Enzyme Analysis The mtDNA region bracketing the 3460 mutation was amplified with the poly¬ merase chain reaction technique using a forward primer at positions 3346 through 3363 and a reverse primer at positions 3636 through 3650.8 We screened for the 3460 mutation by digestion of the poly¬ merase chain reaction product with the re¬ striction enzyme BsaHl (New England Biolabs, Beverly, Mass). The presence of the mutation was indicated by a single 304nucleotide band caused by the loss of the single BsaHl site. Verification of the 3460
Table 1.—Historical Characteristics of Patients With the 3460 Mutation Patient No.*/Sex/ Age at Onset, y 1.01/M/40 2.01/M/67 2.02/M/10 3.01/M/21 3.02/M/38 4.01/M/19 5.01/M/20 6.01/M/35 7.01 /F/13 8.01/M/17 8.02/M/31 9.01/M/36
Follow-up
Onset
Visual
Intervalf
Recovery
Simult Simult Simult 3 mo 5 mo Simult 2 mo 1 wk
No No Yes No
12 300 29
No No Yes
75 204 214
No No No Yes Yes
480 17 204 104
1 mo 1 mo
15 mo Simult
Period,
Family History
mo
Yes Yes Yes Yes Yes No Yes No Yes Yes Yes Yes
*Patient number Identifies the pedigree and a specific family member from that pedigree (eg, patient 3.02 refers to the second individual in pedigree 3). fOnset Interval represents the time from onset of visual symptoms In the first eye until onset of visual symptoms in the second eye; and simult, simultaneous loss of vision In each eye.
Table 2.—Environmental
Frequency Patient No. 1.01 2.01 2.02 3.01
Cigarettes
Exposures and Medical History
at the Time of Visual Loss
of Use* Alcohol
Other Medical/Environmental Untreated mild hypertension Uncontrolled severe hypertension None
Exposures
Hypertriglycerldemia (3.70 mmol/L), exposure
to toxic chemicals Diabetes mellitus, hypertriglyceridemla (83.7 mmol/L) exposure to smoke and toxic chemicals None None Drinking binge before symptoms None None
3.02
,
4.01 5.01 6.01 7.01 8.01 8.02 9.01
Frequent marijuana use ++ ++ Diabetes mellitus, hypertriglycerldemia (71.4 mmol/L) 'Prevalence among smokers and consumers of alcohol. For smokers, + represents 2 packs per day. For alcohol users, + represents occasional (social drinking) ++, moderate (dally alcohol consumption); and +++, heavy (alcoholic).
mutation in those patients who lost the BsaHl site was carried out by direct se¬ quence analysis.8 The restriction analysis of the other mtDNA mutations has been described elsewhere.9" The presence of heteroplasmy was determined by direct vi¬ sualization of the restriction digestion
pattern. Clinical Data Collection Pertinent clinical and historical data were collected for each symptomatic patient with LHON who tested positive for the 3460 mu¬ tation. We requested and reviewed copies of the medical records from each ophthalmolo¬ gist and neurologist involved in each pa¬ tient's care since the onset of visual symp¬ toms. Additional information was obtained, in some cases, through telephone conversa¬ tions with the patients, their family mem¬ bers, and their physicians. Statistical analy¬ sis was performed using the 2 test and Fisher's Exact Test.
RESULTS Genetic Information
We performed mtDNA analysis for the LHON mutations on at least one family member from 120 different ped¬ igrees with the LHON phenotype and on 410 normal and disease controls. Of these pedigrees, 68 (57%) harbor the 11778 mutation, nine (8%) have the 3460 mutation, and nine (8%) tested positive for the 15 257 mutation. None of the nine pedigrees with the 3460 mu¬ tation are positive for the 11778 or 15 257 mutation. Four of the pedigrees with the 3460 mutation have at least one of three secondary mutations associ¬ ated with LHON that one of us (D.R.J.) described previously,11 including three with the 13 708 mutation (pedigrees 4,7, and 9), one with the 4917 mutation
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/13/2015
(pedigree 2), and three that tested pos¬ itive for the 4216 mutation (pedigrees 2, 7, and 9). Two of the probands (5.01 and 6.01) are heteroplasmic. The test results
for all 410 controls were negative for the 3460 mutation. Historical Information
Clinical data
were
collected from 12
symptomatic patients from the nine pedigrees with the 3460 mutation (Ta¬ ble 1). Eleven (92%) of the 12 patients were male. However, investigation of the family history for each pedigree re¬ vealed another 11 maternal relatives with a history of bilateral optic neurop¬ athy. Thus, of 23 visually symptomatic persons from the nine pedigrees, 17 (74%) were male. All of the nine pedi¬ grees are white. None of the patients noted pain or other systemic or neuro¬ logic symptoms either at time of onset of visual loss or during progression of visual loss. The medical histories and known en¬ vironmental exposures of the 12 pa¬ tients are noted in Table 2. No patient had a history of significant neurologic disease. None of the patients had a his¬ tory of eye disease other than refractive errors, and none had a family history of other significant neurologic or ophthal¬ mologic disease. Patient 3.01 had worked in a boat manufacturing plant with occasional exposure to a variety of industrial chemicals. His uncle, patient 3.02, had worked as a firefighter where he had repeated job-related exposures to smoke and various noxious fumes and
chemicals, including xylene, toluene,
and methylethylketone. Seven patients (3.01, 3.02, 4.01, 5.01, 7.01, 8.01, and 8.02) were treated with various steroidal regimens, both oral and intravenous. Three patients (1.01, 2.01, and 7.01) received hydroxocobalamin injections, and one received oral thiamine hydrochloride and folate so¬ dium. No significant beneficial effect was noted for any treatment regimen. Patient 7.01, whose initial visual loss occurred at age 13 years, received in¬ tramuscular injections of hydroxocobalamin, niacin (nicotinic acid), and corti¬ sone acetate every other day for 6 months. Her visual acuity stabilized at 20/70 until further decline occurred 38 years later with no evidence of new oc¬ ular disease. Her brother and mother, who had lost vision to the counting fin¬ gers level at ages 14 and 28 years, respectively, had received no treatment.
Examination Information
The most important features of the ophthalmologic examination are re¬ corded in Table 3. Four patients expe-
Table 3.—Examination Patient No.
Eye
Initial Visual Acuity 20/200 20/200 5/200 20/200 20/80 20/50 CF
Findings* Final Visual
Poorest Visual Acuity 1/200 6/200 CF 1 ft CF 1 ft 1/200 8/200 CF CF CF CF 3/200 2/200 CF LP 20/200 20/100 CF5ft CF5ft CF 1 ft HM CF 20/200 CF 1 ft CF 1 ft
Disc
Appearance
Initial
Final
I
I
Acuity
OD 1/200 OS 6/200 OD CF 1 ft 2.01 OS CF 1 ft OD 20/20 2.02 OS 20/15 OD 10/200 3.01 OS CF 20/20 OD CF 20/50 3.02 OS CF 20/20 OD NA NA 4/200 4.01 OS NA 6/200 NA OD NA NA 20/200 5.01 OS NA LP NA OD 20/100 20/200 6.01 OS 20/100 20/100 OD 20/70 10/200 NA 7.01 OS 20/70 10/200 NA OD 20/200 CF 1 ft M, S M, S, P 1.01 OS HM CF 1 ft CF OD 20/25 1.02 OS 20/20 20/40 OD 20/70 20/25 S, M 9.01 OS 20/40 20/30 S, M "Initial visual acuity represents visual acuity when first examined by a physician after onset of visual symptoms; poorest visual acuity, poorest recorded visual acuity during follow-up; final visual acuity, visual acuity at most recent follow-up; OD, right eye; N, normal; P, optic disc pallor; OS, left eye; CF, counting fin¬ gers; S, swollen disc; M, peripapillary microangiopathy; NA, Information not available; LP, light perception; and HM, hand motions, the visual field for each patient was determined with Goldmann perimeter. 1.01
Table
4.—Summary of Clinical Characteristics:
Sex, M/F Mean Mean
(range) (range)
age at onset, y onset
Interval,
mot_ Mean (range) progression of visual loss, moi Poorest visual acuity
3460 vs 11 778 Mutation
3460 17/23 (74% male); 34/49 (69% male)* 29 (10-67) 2.3 (0-15); 5/12 (42%) simult 3.0
(0-12)
28 (8-60) 1.8 (0-9); 26/47 3.7
20/100 to light perception; 96%
Hereditary Optic Neuropathy
Clinical Manifestations of the 3460 Mutation Donald R.
Johns, MD; Kyle H. Smith, MD; Neil R. Miller,
\s=b\ Leber's hereditary optic neuropathy is associated with three different point mutations of mitochondrial DNA that appear to be pathogenetic for the disease. These mutations affect nucleotide positions 3460, 11778, and 15257. We reviewed the clinical characteristics of 12 visually symptomatic patients from nine families with the 3460 mutation and compared them with previously published characteristics of symptomatic patients with the 11778 mutation. The patients with the 3460 mutation were similar to the patients with the 11 778 mutation in most clinical parameters. However, the patients with the 3460 mutation had a higher incidence of visual recovery (20% vs 4%, P=.001), a higher percentage of pedigrees with more than one affected family member (78% vs 43%, P=.011), and a greater frequency of tobacco and alcohol abuse. The difference in visual prognosis between these two mutations and the need for modification of possible risk factors provide added significance to genetic testing for Leber's hereditary optic
neuropathy. (Arch Ophthalmol. 1992;110:1577-1581 ) eber's
hereditary optic neuropathy a maternally inherited disease characterized by acute or suba¬ cute loss of central vision primarily in -^
(LHON) is
males younger than 25 years. The sus¬ pected mitochondrial inheritance of this Accepted
for publication March 16, 1992. Departments of Neurology, The Johns Hopkins University School of Medicine (Dr Johns), and Ophthalmology, Wilmer Eye Institute (Drs Smith and Miller), Baltimore, Md. Reprint requests to Department of Neurology, The Johns Hopkins Hospital, Meyer 6-119, 600 N From the
Wolfe St, Baltimore, MD 21205 (Dr Johns).
MD
disease was confirmed in 1988 by Wal¬ lace et al,1 who identified a mitochon¬ drial DNA (mtDNA) point mutation at nucleotide position 11778 in the NADH dehydrogenase subunit 4 gene in nine pedigrees with a clinical diagnosis of LHON. The 11778 mutation has subse¬ quently been identified in 50% to 60% of all LHON pedigrees studied.25 A second etiologically important mu¬ tation was identified in three pedigrees without the 11778 mutation by Huoponen et al in 1991.6 This point mutation at nucleotide position 3460 converts an alanine into a threonine at codon 52 in subunit 1 of NADH dehydrogenase. It is readily detected by restriction en¬ zyme analysis, since the mutation abol¬ ishes a restriction site. The 3460 muta¬ tion has been identified in six additional independent pedigrees by Howell et al,7 and in nine pedigrees that one of us
(D.R.J.) reported previously.8
Another apparently pathogenetic mutation at nucleotide position 15 257 in the apocytochrome b gene was de¬ scribed recently by one of us (D.R.J.) and Neufeld9 and an independent group.10 This 15 257 mutation was iden¬ tified in 12 independent LHON
pedigrees.9,10
These three mutations (11778 [NADH dehydrogenase subunit 4 gene], 3460 [subunit 1 of NADH dehy¬
drogenase], and 15257 [apocytochrome gene]) each seem to be of primary pathogenetic significance, and together account for approximately 70% of all pedigrees with the LHON phenotype.9 b
Several other associated mutations have also been identified that may act synergistically to produce visual symptoms.911 Although the clinical
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/13/2015
characteristics of patients with LHON well documented before the avail¬ ability of genetic testing,1219 we now know that these clinical descriptions deal with a disease that is genetically heterogeneous. The only major study addressing the clinical characteristics of a genetically homogeneous LHON pop¬ ulation is that by Newman et al,5 which is a comprehensive review of the clini¬ cal data from 49 pedigrees with the 11778 mutation. The purpose of this ar¬ ticle is to clarify further the phenotypic expression of the 3460 mutation, and to compare these clinical findings with those of patients with the 11778 mutation. were
PATIENTS AND METHODS Patient Selection Molecular genetic analysis for the mtDNA mutations associated with LHON was performed on blood samples of pa¬ tients with acute visual loss that were sent to us from physicians throughout the United States and several foreign coun¬ tries. Samples from patients with other neurologic diseases and from healthy per¬ sons were used as controls.
Polymerase Chain Reaction and Restriction Enzyme Analysis The mtDNA region bracketing the 3460 mutation was amplified with the poly¬ merase chain reaction technique using a forward primer at positions 3346 through 3363 and a reverse primer at positions 3636 through 3650.8 We screened for the 3460 mutation by digestion of the poly¬ merase chain reaction product with the re¬ striction enzyme BsaHl (New England Biolabs, Beverly, Mass). The presence of the mutation was indicated by a single 304nucleotide band caused by the loss of the single BsaHl site. Verification of the 3460
Table 1.—Historical Characteristics of Patients With the 3460 Mutation Patient No.*/Sex/ Age at Onset, y 1.01/M/40 2.01/M/67 2.02/M/10 3.01/M/21 3.02/M/38 4.01/M/19 5.01/M/20 6.01/M/35 7.01 /F/13 8.01/M/17 8.02/M/31 9.01/M/36
Follow-up
Onset
Visual
Intervalf
Recovery
Simult Simult Simult 3 mo 5 mo Simult 2 mo 1 wk
No No Yes No
12 300 29
No No Yes
75 204 214
No No No Yes Yes
480 17 204 104
1 mo 1 mo
15 mo Simult
Period,
Family History
mo
Yes Yes Yes Yes Yes No Yes No Yes Yes Yes Yes
*Patient number Identifies the pedigree and a specific family member from that pedigree (eg, patient 3.02 refers to the second individual in pedigree 3). fOnset Interval represents the time from onset of visual symptoms In the first eye until onset of visual symptoms in the second eye; and simult, simultaneous loss of vision In each eye.
Table 2.—Environmental
Frequency Patient No. 1.01 2.01 2.02 3.01
Cigarettes
Exposures and Medical History
at the Time of Visual Loss
of Use* Alcohol
Other Medical/Environmental Untreated mild hypertension Uncontrolled severe hypertension None
Exposures
Hypertriglycerldemia (3.70 mmol/L), exposure
to toxic chemicals Diabetes mellitus, hypertriglyceridemla (83.7 mmol/L) exposure to smoke and toxic chemicals None None Drinking binge before symptoms None None
3.02
,
4.01 5.01 6.01 7.01 8.01 8.02 9.01
Frequent marijuana use ++ ++ Diabetes mellitus, hypertriglycerldemia (71.4 mmol/L) 'Prevalence among smokers and consumers of alcohol. For smokers, + represents 2 packs per day. For alcohol users, + represents occasional (social drinking) ++, moderate (dally alcohol consumption); and +++, heavy (alcoholic).
mutation in those patients who lost the BsaHl site was carried out by direct se¬ quence analysis.8 The restriction analysis of the other mtDNA mutations has been described elsewhere.9" The presence of heteroplasmy was determined by direct vi¬ sualization of the restriction digestion
pattern. Clinical Data Collection Pertinent clinical and historical data were collected for each symptomatic patient with LHON who tested positive for the 3460 mu¬ tation. We requested and reviewed copies of the medical records from each ophthalmolo¬ gist and neurologist involved in each pa¬ tient's care since the onset of visual symp¬ toms. Additional information was obtained, in some cases, through telephone conversa¬ tions with the patients, their family mem¬ bers, and their physicians. Statistical analy¬ sis was performed using the 2 test and Fisher's Exact Test.
RESULTS Genetic Information
We performed mtDNA analysis for the LHON mutations on at least one family member from 120 different ped¬ igrees with the LHON phenotype and on 410 normal and disease controls. Of these pedigrees, 68 (57%) harbor the 11778 mutation, nine (8%) have the 3460 mutation, and nine (8%) tested positive for the 15 257 mutation. None of the nine pedigrees with the 3460 mu¬ tation are positive for the 11778 or 15 257 mutation. Four of the pedigrees with the 3460 mutation have at least one of three secondary mutations associ¬ ated with LHON that one of us (D.R.J.) described previously,11 including three with the 13 708 mutation (pedigrees 4,7, and 9), one with the 4917 mutation
Downloaded From: http://archopht.jamanetwork.com/ by a Oakland University User on 06/13/2015
(pedigree 2), and three that tested pos¬ itive for the 4216 mutation (pedigrees 2, 7, and 9). Two of the probands (5.01 and 6.01) are heteroplasmic. The test results
for all 410 controls were negative for the 3460 mutation. Historical Information
Clinical data
were
collected from 12
symptomatic patients from the nine pedigrees with the 3460 mutation (Ta¬ ble 1). Eleven (92%) of the 12 patients were male. However, investigation of the family history for each pedigree re¬ vealed another 11 maternal relatives with a history of bilateral optic neurop¬ athy. Thus, of 23 visually symptomatic persons from the nine pedigrees, 17 (74%) were male. All of the nine pedi¬ grees are white. None of the patients noted pain or other systemic or neuro¬ logic symptoms either at time of onset of visual loss or during progression of visual loss. The medical histories and known en¬ vironmental exposures of the 12 pa¬ tients are noted in Table 2. No patient had a history of significant neurologic disease. None of the patients had a his¬ tory of eye disease other than refractive errors, and none had a family history of other significant neurologic or ophthal¬ mologic disease. Patient 3.01 had worked in a boat manufacturing plant with occasional exposure to a variety of industrial chemicals. His uncle, patient 3.02, had worked as a firefighter where he had repeated job-related exposures to smoke and various noxious fumes and
chemicals, including xylene, toluene,
and methylethylketone. Seven patients (3.01, 3.02, 4.01, 5.01, 7.01, 8.01, and 8.02) were treated with various steroidal regimens, both oral and intravenous. Three patients (1.01, 2.01, and 7.01) received hydroxocobalamin injections, and one received oral thiamine hydrochloride and folate so¬ dium. No significant beneficial effect was noted for any treatment regimen. Patient 7.01, whose initial visual loss occurred at age 13 years, received in¬ tramuscular injections of hydroxocobalamin, niacin (nicotinic acid), and corti¬ sone acetate every other day for 6 months. Her visual acuity stabilized at 20/70 until further decline occurred 38 years later with no evidence of new oc¬ ular disease. Her brother and mother, who had lost vision to the counting fin¬ gers level at ages 14 and 28 years, respectively, had received no treatment.
Examination Information
The most important features of the ophthalmologic examination are re¬ corded in Table 3. Four patients expe-
Table 3.—Examination Patient No.
Eye
Initial Visual Acuity 20/200 20/200 5/200 20/200 20/80 20/50 CF
Findings* Final Visual
Poorest Visual Acuity 1/200 6/200 CF 1 ft CF 1 ft 1/200 8/200 CF CF CF CF 3/200 2/200 CF LP 20/200 20/100 CF5ft CF5ft CF 1 ft HM CF 20/200 CF 1 ft CF 1 ft
Disc
Appearance
Initial
Final
I
I
Acuity
OD 1/200 OS 6/200 OD CF 1 ft 2.01 OS CF 1 ft OD 20/20 2.02 OS 20/15 OD 10/200 3.01 OS CF 20/20 OD CF 20/50 3.02 OS CF 20/20 OD NA NA 4/200 4.01 OS NA 6/200 NA OD NA NA 20/200 5.01 OS NA LP NA OD 20/100 20/200 6.01 OS 20/100 20/100 OD 20/70 10/200 NA 7.01 OS 20/70 10/200 NA OD 20/200 CF 1 ft M, S M, S, P 1.01 OS HM CF 1 ft CF OD 20/25 1.02 OS 20/20 20/40 OD 20/70 20/25 S, M 9.01 OS 20/40 20/30 S, M "Initial visual acuity represents visual acuity when first examined by a physician after onset of visual symptoms; poorest visual acuity, poorest recorded visual acuity during follow-up; final visual acuity, visual acuity at most recent follow-up; OD, right eye; N, normal; P, optic disc pallor; OS, left eye; CF, counting fin¬ gers; S, swollen disc; M, peripapillary microangiopathy; NA, Information not available; LP, light perception; and HM, hand motions, the visual field for each patient was determined with Goldmann perimeter. 1.01
Table
4.—Summary of Clinical Characteristics:
Sex, M/F Mean Mean
(range) (range)
age at onset, y onset
Interval,
mot_ Mean (range) progression of visual loss, moi Poorest visual acuity
3460 vs 11 778 Mutation
3460 17/23 (74% male); 34/49 (69% male)* 29 (10-67) 2.3 (0-15); 5/12 (42%) simult 3.0
(0-12)
28 (8-60) 1.8 (0-9); 26/47 3.7
20/100 to light perception; 96%
