addison in x-link adrenoleukodystrophy (x- ald): phenotype and genotype of 12 cases nguyen ngoc...
TRANSCRIPT
ADDISON IN X-LINK
ADRENOLEUKODYSTROPHY (X-
ALD): Phenotype and genotype of 12
cases
Nguyen Ngoc Khanh1, Vu Chi Dung1 , Shimozawa N2. , Bui Phuong Thao1, Can Thi Bich Ngoc1 , Nguyen Thi Hoan1 , Nguyen Phu Dat1, Le Thi Kim Ngoc1
1 Vietnam National Hospital of Pediatrics, Hanoi, Vietnam2 Division of Genomics Research Life Science Research Center, Department of Pediatrics, Gifu University School of Medicine, Gifu, Japan
BACKGROUND
• X-linked adrenoleukodystrophy (X-ALD):
peroxisomal disorder affecting adrenal cortex & central
nervous system.
• Rare disease: in males (USA): 1/21,000
• Symptoms: often in males
– Addison: hyperpigmentation, anxious.
– Progressive neurologic deficit: cognitive deficit, visual deficit,
hearing deficit, motor dysfunction…
– May be in females: often over 30 years old with increased deep
tendon reflexes and distal sensory changes in lower extremities…
BACKGROUND
• Variant phenotypes: 4 types: Cerebral inflammatory ALD, Adrenomyeloneuropathy: AMN, Addison – only, Asymtomatic.
• Broad phenotype: from childhood cerebral form characterized by rapid progression to a vegetative state or death within 1–2 years (31–35%), to slowly progressive adrenomyeloneuropathy (AMN) in adults (40–46%)
Moser HW et al. (2007) X-linked adrenoleukodystrophyNat Clin Pract Neurol 3: 140–151 doi:10.1038/ncpneuro0421
X-linked adrenoleukodystrophy phenotypes in males
THẢO LUẬN
Moser HW et al. (2007) X-linked adrenoleukodystrophyNat Clin Pract Neurol 3: 140–151 doi:10.1038/ncpneuro0421
BACKGROUND
• The gene that is defective in X-ALD was
mapped to Xq28 in 1981 & was isolated &
cloned in 1993.
• This gene is now referred to as ABCD1.
• It is composed of 10 exons, it codes for a
messenger RNA of 4.3 kb, & a protein of 745
amino acids that is now referred to as
adrenoleukodystrophy protein (ALDP).
BACKGROUND
• Definitive Diagnosis:– Plasma VLCFA profiles.– Mutations analysis of ABCD1 gene
AIMS
• To describe clinical, laboratory & cerebral MRI
characteristics of Vietnamese patients with X-
ALD
• To identify mutations of ABCD1 in these cases
PATIENTS & METHODS
• 12 cases from 10 unrelated families• Case series study• Clinical & imagine at NHP, Hanoi, Vietmam• Extraction of DNA from peripheral blood leukocyte
using standard procedures • VLCFA profile & mutation analysis of ABCD1 at
Gifu University, Japan
RESULTS
PHENOTYPE (1): onset – diagnosis: 0.25 – 11 yrs
Patient Family history
Age of onset of addison
(yrs)
Age of onset of neurologic symptoms (yrs)
Age of diagnosis
(yrs)
Time onset to diagnosis (yrs)
1 + 5 (-) until 11.5 10.5 4.5
2 (sibling of pt 1)
+ 4 7 9 5.0
3 - 1.7 (-) until 4.7 4.3 2.6
4* + 2 7 7 5.0
5* - (+) age NA 6 7.3
6 - No 9.5 9.75 0.25
RESULTS
PHENOTYPE (2): onset – diagnosis: 0.25 – 11 yrs
Patient Family history
Age of onset of addison
(yrs)
Age of onset of neurologic symptoms (yrs)
Age of diagnosis
(yrs)
Time onset to diagnosis (yrs)
7 - 1.7 (-) tới 4.3 tuổi 4.3 2.6
8 + 3 8.5 10.6 7.6
9 , brother of 8
+ 14 22 25 11
10 - - 5,5 6,3 0,8
11 + - 9 14,6 5,6
12 + 9 9,3 9,6 0,3
RESULTS Neurologic symptoms
Neurologic symptoms N
Cognitive deficit (poor learning,
neglect)
9/9
Attention deficit 9/9
Behaves deficit 7/9
Visual dysfunction 6/9
Hearing dysfunction 6/9
Speech difficulty 6/9
Motor dysfunction 6/9
RESULTSAdrenal function & Brain MRI
Patient Cortisol at 8 AM
(150-600 nmol/l)
ACTH
(7.2 – 63.3 pg/ml)
Brain MRI
1 50 398 Normal at 11 yrs
2 7 952 Marked loss of posterior white matter
3 4.6 2000 Normal at 4.7 yrs
4* 12 1134 Reduced density in white part in occipital areas
5* 123.8 1892 Marked loss of posterior white matter
RESULTSAdrenal function & Brain MRI (2)
Patient Cortisol at 8 AM
(150-600 nmol/l)
ACTH
(7.2 – 63.3 pg/ml)
Brain MRI
6 NA NA bilateral white matter lesions (Loes 14)
7 23 NA Normal at 4.3 yrs
8 45.9 10.8 White matter lesion (Loes 4)
9 NA NA NA
RESULTSAdrenal function & Brain MRI (3)
BN Cortisol 8 AM
(150-600 nmol/l)
ACTH
(7.2 – 63.3 pg/ml)
MRI Sọ não
10 284 8 Cerebral atrophy, billateral
white matter lesion in
thalamus, corpus callosum,
cerabellum (Loes: 16)
11 102 1,89 Bilateral white matter lesion
in periventricular, thalamus,
corpus callosum. (Loes: 12)
12 41,1 172 Bilateral white matter lesion
in periventricular, thalamus,
corpus callosum. (Loes: 10)
RESULTSVLCFA Profile (1)
Patient C24:0/C22:0
(1.05 ±0.16)
C25:0/C22:0
(0.024 ±0.006)
C26:0/C22:0
(0.012 ±0.005)
1 2.03 0.085 0.109
2 (sib of pt 1) 1.78 0.088 0.106
3 1.74 0.059 0.049
4* NA NA NA
5* 2.18 0.092 0.096
6 1.98 0.171
RESULTS
VLCFA Profile (2) Patient C24:0/C22:0
(1.05 ±0.16)
C25:0/C22:0
(0.024 ±0.006)
C26:0/C22:0
(0.012 ±0.005)
7 1.96 0.135
8 1.32 0.2 0.144
9 1.60 0.26 0.22
10 NA NA NA
11 NA NA NA
12 NA NA NA
RESULTSGenotype
Patient c.DNA Mutant protein
1 c.1628C>T p.Pro543Leu
2 (sib of pt 1) c.1628C>T p.Pro543Leu
3 c.1553G>A p.Arg518Gln
4* c.1202G>T p.Arg401Trp
5* c.1208T>A p.Met403Lys
*Novel mutation
RESULTSGenotype (2)
Patient c.DNA Mutant protein
6* deletion included between IVS1+505 and IVS2+1501, containing whole exon 2 (4243bp), plus insertion of 79bp from BAP31 and 8bp from unknown origin
7* IVS8+28-551bp del
8 c.1552 C>T p.Arg518Trp
9 (sibling of pt 8) c.1552 C>T p.Arg518Trp
9 different mutations including 4 *novel
RESULTSGenotype (3)
Patient c.DNA Mutant protein
10 c.46-53del insG
11 c.854G>C p.R285P
12 NA
9 different mutations including 4 *novel
CONCLUSION• Onset – diagnosis: 0.25 – 11 yrs• Addison in 9/12 cases; • progressive neurologic dysfunction in 9/12 cases • 6 cases: Addison + progressive neurologic
dysfunction• 3 cases: progressive neurologic dysfunction• 3 cases: Addison• Cognitive deficit, attention deficit were 1st
neurologic symptoms (9/9). Behave deficit, visual dysfunction, hearing dysfunction, motor dysfunction, speech difficulty were later.
Easy to misdiagnosis
CONCLUSION
• Low plasma cortisol & high ACTH levels in 7/7• Brain MRI: abnormal in 8/8 cases with neurologic
symptoms. 7/8 had Loes score >10, only 1 case 8 had Loes 4.
Brain MRI: important to decide HSCT Definitive diagnosis: • Increasing of plasma VLCFA in 8/8• Nine different mutations of ABCD1 including 4
novel ones• Same family & same genotype but without
neurologic symptoms in older boy (pt 1)
T.D.H (Pt1) 11.5 years oldT.Q.N (Pt2) 9 years old
Pt 1DOB: 1/1/2000HyperpigmentationNo neurologic symptomsp.543Pro>Leu
Pt 2DOB: 22/4/2002HyperpigmentationNeurologic symptomsp.543Pro>Leu
T.D.H (Pt1) 11.0 years oldT.Q.N (Pt2) 9 years old
ABCD1 ex6 c.1628C>T (p.543Pro>Leu)
H.D.M.T (Pt 3) 4.7 years old;
ABCD1 ex6 c.1553G>A p.518Arg>Gln
N.C.H
Novel mutation
c.1202G>T
(p.Arg401Trp)
Healthy
Carrierp.Arg401Trp
Died at 7 years of age
Died at 12 years of age
I
II
III
IV
Pt 4. Pedigree of N.C.H
N.C.H (pt 4)
Pt 6. Nguyen Van Q
Extent of deletion included between IVS1+505 and IVS2+1501, containing whole the exon 2 (4243bp), plus insertion of 79bp from BAP31 and 8bp from unknown origin
9.75 yrs.
From 9.5 yrs of age: pain of
legs, weakness, difficulties
of pronunciation, poor
hearing, poor vision, no
hyperpigmentation.
Trương Xuan H 11 yrs
c.1552 C>T (p.Arg518Trp)
p.Arg518Trp
p.Arg518Trp
Pt 8
C24:0/C22:0
0.00.20.40.60.81.01.21.41.61.8
3857 3860 3861 3769
C25:0/C22:0
0.00
0.05
0.10
0.15
0.20
0.25
0.30
3857 3860 3861 3769
C26:0/C22:0
0.00
0.05
0.10
0.15
0.20
0.25
3857 3860 3861 3769
Trương Xuan H 11 yrsVLCFA Profile
Pt 8
3857: ALD control; 3860: Pt 8; 3861: Pt 9; 3769 normal control
Thank you very much!