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!