3.1 Data collection
Out of 18 subjects enrolled, 10 children (56%) had a TYR gene alteration (OCA1), 7 (38%) an OCA2 gene deletion or mutation (OCA2) and 1 (6%) a SLC45A2 gene deletion (OCA4).
From the medical charts revision, pregnancy was uneventful in 16 (89%) cases while the mothers of 2 children (11%) suffered from gestational diabetes. Delivery was at term in 17 (94%) cases while a boy was born at 35 weeks of gestation. The mean birth weight was 3129.5 ± 426.0 grams (range: 2540-4000 grams). Perinatal was uneventful in all the sample.
Eight (44%) children appropriately acquired the gross (head control, sitting, walking) motor milestones, while 10 (56%) had different levels of delay: 5 (28%) presented with a delay in the head control, 5 (28%) in the sitting position, 4 (22%) in the walking, and 2 (11%) an overall delay. Specifically, the mean age of head control was 3.2 ± 1.2 months (range 2-6 months), sitting 7.5 ± 2.3 (range 5-12 months), walking 15.9 ± 4.2 (range: 10-24 months). Thumb finger was appropriately acquired in all the cases (mean age 12.5 ± 0.7 months, range12-14 months). Data on communication and language skills were collected in 16 children; the remaining two were infants (aged between 18-21 months) and have not yet achieved the vocabulary expansion. Six (38%) children were Late Talkers because they produced fewer than 50 words or no word combinations at 24 months of age. Four of these eventually met their same-age peers in language performance and therefore they can be considered Late Bloomers; the remaining two Late Talkers received a diagnosis of Language Disorder at age six because they showed impairments in both receptive and expressive language skills on specific neuropsychological test. More in general, canonical babbling was acquired at 8.2 ± 1.4 months (range 7-12 months), 1st word at 16.2 ± 5.4 (range 10-27 months), and >50 words at 30.1 ± 9.8 months (range 24-60 months).
The Developmental profile assessment evaluated in 16 children using GMDS-R (mean age at evaluation: 18.8 months ± 12.3, range 6-24) revealed normal scores on Developmental Quotient (DQ) in 7 cases (44%), borderline score in 5 (31%) and delayed score in 4 (25%). The analysis of each domain revealed borderline/delay scores as follow: Locomotor (3 borderline, 4 delay), Personal-Social (2 borderline, 6 delay), Hearing-Speech (2 borderline, 5 delay), Eye-Hand Coordination (2 borderline, 7 delay), Performance (3 borderline, 5 delay).
3.2 Direct assessment
Direct assessment was carried out at mean age of 84.5 months (SD 41.2; range 18-181 months). No abnormalities concerning cranial nerve, muscle strength, tone and bulk, reflexes and gait were detected.
From an ophthalmological perspective, all the 18 (100%) children presented refractive errors. Iris translucency and ocular fundus abnormalities characterized by hypopigmentation of retina and/or foveal hypoplasia were detected in 17 (94%) and 18 (100%) children, respectively. Eight children (44%) had photophobia and 16 (89%) an abnormal head position. As regards oculomotor functions, strabismus was observed in 14 (78%), nystagmus in 18 (100%), and alterations in fixation, smooth pursuit, and saccadic movements in 18 (100%), 17 (94%) and 13 (72%) children, respectively. The visual acuity was reduced in all the sample (100%), contrast sensitivity in 6 (33%) and visual field in 6 (33%). See table 1.
Table 1 - Neurovisual findings of the sample.
Sbj
|
Refr.
Errors
|
Ny
|
Strabismus
|
Fixation
|
Smooth
pursuit
|
Saccades
|
Visual acuity
|
Contr
Sens.
|
Visual
Field
|
1
|
As, H
|
Pend
|
Exo
|
A
|
A
|
A
|
0.2
|
1.25
|
N
|
2
|
As, M
|
Jerky
|
No
|
A
|
A
|
A
|
0.06
|
2.5
|
N
|
3
|
As, M
|
Pend
|
Eso
|
A
|
A
|
A
|
0.05
|
1.25
|
N
|
4
|
As, M
|
Pend
|
Eso
|
A
|
A
|
A
|
0.1
|
1.25
|
A
|
5
|
As, H
|
Pend
|
Exo
|
A
|
A
|
N
|
0.1
|
1.25
|
A
|
6
|
As, M
|
Pend
|
Eso
|
A
|
A
|
A
|
0.1
|
5
|
A
|
7
|
As, H
|
Pend
|
Exo
|
A
|
A
|
A
|
0.15
|
1.25
|
N
|
8
|
As, H
|
Pend
|
Eso
|
A
|
A
|
A
|
0.1
|
1.25
|
A
|
9
|
As, M
|
Mix
|
Eso
|
A
|
A
|
A
|
0.1
|
1.25
|
N
|
10
|
As, M
|
Jerky
|
Exo
|
A
|
A
|
A
|
0.05
|
1.25
|
N
|
11
|
As, M
|
Mix
|
Exo
|
A
|
A
|
N
|
0.15
|
1.25
|
A
|
12
|
As, H
|
Pend
|
Exo
|
A
|
A
|
A
|
0.3
|
1.25
|
N
|
13
|
As, H
|
Jerky
|
Eso
|
A
|
N
|
A
|
0.2
|
1.25
|
N
|
14
|
As
|
Pend
|
No
|
A
|
A
|
N
|
3.1*
|
1.25
|
N
|
15
|
As
|
Mix
|
No
|
A
|
A
|
A
|
4.7*
|
5
|
N
|
16
|
As, M
|
Mix
|
No
|
A
|
A
|
A
|
4.7*
|
5
|
N
|
17
|
As, M
|
Pend
|
Eso
|
A
|
A
|
N
|
3.1*
|
5
|
A
|
18
|
As, M
|
Pend
|
No
|
A
|
A
|
N
|
0.9*
|
100
|
N
|
Legend: Refr. Errors, refractive errors; Iris transl., iris translucency; Ny, nystagmus; Contr. Sens., contrast sensitivity; As, astigmatism; H, hypermetropia; M, myopia; A, altered: N, normal; Pend, pendular; Exo, exotropia: Eso, esotropia.
*values are reported in cyc/deg.
The cognitive evaluation, performed in 14 children, showed normal FSIQ in 11 children (79%), borderline score in 2 cases (14%) and deficient in 1 (7%). VIQ was normal in 11 (79%), borderline in 2 (14%) and delayed in 1 (7%) while PIQ was normal in 13 cases (93%) and borderline in one (7%). WMI and PSI evaluated in 11 children were impaired in 2 (18%, 1 borderline score and 1 delayed) and 7 (64%, 3 borderline score and 4 delayed) cases respectively. See table 2.
Table 2 - Cognitive profile.
Sbj
|
Intelligence quotient
|
FSIQ
|
VIQ
|
PIQ
|
WMI
|
PSI
|
1
|
93
|
96
|
102
|
82
|
97
|
2
|
94
|
104
|
100
|
100
|
74
|
3
|
93
|
96
|
102
|
-
|
-
|
4
|
86
|
112
|
82
|
100
|
65
|
5
|
82
|
80
|
98
|
73
|
51
|
6
|
66
|
47
|
91
|
-
|
-
|
7
|
84
|
74
|
100
|
91
|
88
|
8
|
94
|
108
|
93
|
97
|
79
|
9
|
112
|
130
|
95
|
124
|
82
|
10
|
94
|
126
|
100
|
91
|
53
|
11
|
106
|
118
|
108
|
115
|
82
|
12
|
121
|
126
|
130
|
109
|
88
|
13
|
91
|
108
|
111
|
88
|
107
|
14
|
95
|
100
|
90
|
-
|
-
|
Legend: Sbj, subject; WPSSI-III, Wechsler Preschool and Primary Scale of Intelligence III edition; WISC-IV, Wechsler Scales of Intelligence for Children IV edition; yrs, years; mo, months; FSIQ, full-scale intelligence quotient; VIQ, verbal intelligence quotient; PIQ, performance intelligence quotient; VCI, verbal comprehension index; PRI, perceptual reasoning index; WMI, working memory index; PSI, processing speed index. Values are reported in standard scores (mean 100, SD 15) and categorized as follow: more than -1DS, normal; between -1DS and -2DS, borderline; less than -2DS, delay.
Adaptive functioning was impaired in 3 children (17%), one of whom had difficulties in all the four VABS-II domains (communication, socialization, daily living skills and motor skills) while the remaining 2 showed delay scores only in communication and daily living skills. See Table 3.
At CBCL composite scales, 5 (28%) children had risk score in total problems, 6 (33%) in internalizing problems and 2 (11%) in externalizing problems. See Table 4. At CASD, 12 children (67%) showed one or more autistic-like features, even if none were in autism spectrum range (Table 3).
Table 3 - Adaptive functioning and behavioral aspects.
Sbj
|
Adaptive functioning (VABS), °p
|
Behavioral profile (CASD)
|
Total
|
COM
|
DLS
|
SOC
|
MS
|
SI
|
P
|
SS
|
C
|
M
|
AS
|
Total
|
1
|
98
|
91
|
99
|
92
|
-
|
0/5
|
0/4
|
0/10
|
0/5
|
0/4
|
0/2
|
0/30
|
2
|
25
|
12
|
9
|
79
|
-
|
0/5
|
0/4
|
1/10
|
1/5
|
0/4
|
0/2
|
2/30
|
3
|
14
|
12
|
55
|
25
|
3
|
2/5
|
0/4
|
1/10
|
1/5
|
0/4
|
1/2
|
5/30
|
4
|
73
|
66
|
87
|
50
|
-
|
0/5
|
0/4
|
0/10
|
1/5
|
0/4
|
0/2
|
1/30
|
5
|
3
|
1
|
3
|
23
|
-
|
0/5
|
0/4
|
2/10
|
0/5
|
0/4
|
0/2
|
2/30
|
6
|
0.2
|
0.5
|
2
|
3
|
0.1
|
0/5
|
0/4
|
0/10
|
0/5
|
0/4
|
0/2
|
0/30
|
7
|
21
|
27
|
30
|
14
|
-
|
0/5
|
0/4
|
1/10
|
0/5
|
0/4
|
0/2
|
1/30
|
8
|
25
|
42
|
30
|
18
|
-
|
0/5
|
0/4
|
1/10
|
0/5
|
0/4
|
1/2
|
2/30
|
9
|
70
|
79
|
70
|
53
|
-
|
1/5
|
1/4
|
2/10
|
1/5
|
1/4
|
0/2
|
6/30
|
10
|
12
|
14
|
19
|
37
|
5
|
0/5
|
0/4
|
0/10
|
0/5
|
0/4
|
0/2
|
0/30
|
11
|
98
|
91
|
99
|
92
|
-
|
0/5
|
0/4
|
0/10
|
0/5
|
0/4
|
0/2
|
0/30
|
12
|
21
|
18
|
5
|
66
|
-
|
0/5
|
0/4
|
0/10
|
0/5
|
0/4
|
0/2
|
0/30
|
13
|
96
|
87
|
99
|
104
|
98
|
0/5
|
2/4
|
3/10
|
0/5
|
1/4
|
1/2
|
7/30
|
14
|
42
|
58
|
19
|
39
|
61
|
0/5
|
0/4
|
1/10
|
0/5
|
0/4
|
0/2
|
1/30
|
15
|
45
|
21
|
87
|
47
|
25
|
0/5
|
0/4
|
1/10
|
0/5
|
0/4
|
0/2
|
1/30
|
16
|
37
|
32
|
45
|
23
|
58
|
0/5
|
0/4
|
0/10
|
0/5
|
0/4
|
0/2
|
0/30
|
17
|
32
|
53
|
14
|
61
|
23
|
0/5
|
0/4
|
1/10
|
0/5
|
0/4
|
0/2
|
1/30
|
18
|
5
|
3
|
5
|
7
|
27
|
0/5
|
1/4
|
0/10
|
0/5
|
2/4
|
1/2
|
4/30
|
Abbreviations: AS, problems with attention and safety; C, atypical communication, and development; CASD, checklist for autism spectrum disorder; COM, communication skills; DLS, daily living skills; M, mood; P, perseveration; Sbj, subjects; SI, problems with social interaction; SOC, socialization; SS, somatosensory disturbance; VABS II, Vineland Adaptive Behavior Scales II. VABS score: centile.
Table 4 - Child behavior checklist (CBCL) results.
|
Normal
|
Borderline
|
C. significant
|
CBCL 1½-5 and 6-18 composite scales (N=18)
Total problems
Internalizing problems
Externalizing problems
|
13 (72)
12 (66)
16 (90)
|
3 (17)
3 (17)
1 (5)
|
2 (11)
3 (17)
1 (5)
|
CBCL syndromes scales
CBCL 1½-5 (N=5)
Emotionally reactive
Anxious/depressed
Somatic complaint
Withdraw
Aggressive behavior
Attention problems
Sleep problems
CBCL 6-18 (N=13)
Anxious/depressed
Withdraw
Somatic complaint
Social problems
Though problems
Attention problems
Rule-breaking behavior
Aggressive behavior
|
4 (80)
4 (80)
5 (100)
5 (100)
5 (100)
4 (80)
5 (100)
10 (77)
10 (77)
12 (92)
12 (92)
13 (100)
11 (85)
13 (100)
13 (100)
|
0
1 (20)
0
0
0
0
0
3 (23)
2 (15)
0
1 (8)
0
2 (15)
0
0
|
1 (20)
0
0
0
0
1 (20)
0
0
1 (8)
1 (8)
0
0
0
0
0
|
Correlations between visual acuity and cognitive and behavioral features
Considering the cognitive level, we observed a statistically significant association between visual acuity and PIQ (p=0.001) and PSI (p=0.021). As regards adaptive functioning, statistical correlations were found between visual acuity and VABS-II total score (p=0.020), communication (p=0.020) and socialization (p=0.037) domains. No significant correlations were detected between visual acuity and emotional and behavioral difficulties at CBCL.