Wilson’s disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance

Table 1 Spectrum of mutations in the ATP7B gene of Lebanese patients with Wilson’s disease

Family	ID	Sex	Birth date	AD	Exon	Mutation(s)	Region of protein
U	P1	M	1966	7	7	Gly691Arg	TM2
	P2	M	1985	9	7	Gly691Arg	TM2
	P3	F	1986	131	7	Gly691Arg	TM2
	P4	F	1990	91	7	Gly691Arg	TM2
	P5	M	1996	31	7	Gly691Arg	TM2
	P6	M	NAV	32	7	Gly691Arg	TM2
	P7	M	NAV	72	7	Gly691Arg	TM2
	P8	M	NAV	122	7	Gly691Arg	TM2
	P9	F	NAV	NAV	7	Gly691Arg	TM2
Or	P10	F	1986	21	7/10	Gly691Arg/Val845Ser	TM2/Td
S	P11	F	1993	51	8	2299insC/2299insC	TM4
	P12	M	1973	12	8	2299insC/2299insC	TM4
	P13	F	1997	101	8	2299insC/2299insC	TM4
	P14	M	1980	16	8	2299insC/2299insC	TM4
	P15	M	2007	11	8	2299insC/2299insC	TM4
	P16	M	1981	16	8/13	2299insC/p.Ala1003Thr	TM4/Ch-TM6
	P17	F	1983	14	8/13	2299insC/p.Ala1003Thr	TM4/Ch-TM6
	P18	F	1993	12	8/13	2299insC/p.Ala1003Thr	TM4/Ch-TM6
	P19	F	1989	151	8/13	2299insC/p.Ala1003Thr	TM4/Ch-TM6
Ah	P20	M	1992	15	8	2299insC/2299insC	TM4
T	P21	F	1998	7	12	Trp939Cys	Td
	P22	M	2001	81	12	Trp939Cys	Td
	P23	M	2006	31	12	Trp939Cys	Td
B	P24	M	1992	13	12	Trp939Cys	Td
	P25	M	2002	53	12	Trp939Cys	Td
H	P26	F	1985	18	18	Asn1270Ser	ATP hinge
	P27	F	1987	181	18	Asn1270Ser	ATP hinge
	P28	F	1991	8	18	Asn1270Ser	ATP hinge
Ha	P29	F	1998	14	18	Asn1270Ser	ATP hinge
	P30	F	2002	11	18	Asn1270Ser	ATP hinge
Is	P31	M	1995	13	18	Asn1270Ser	ATP hinge
Z	P32	M	1990	15	18	Pro1273Leu	ATP hinge
	P33	M	2000	61	18	Pro1273Leu	ATP hinge
Ri	P34	M	2009	3	19	Arg1319stop	TM7
Sc	P35	M	1979	22	15/19	Thr1092Met/Arg1319stop	ATP loop/TM7
Gh	P36	M	1970	39	-	None identified	-

¹Screening;

²Died at age;

³Deceased. AD: Age at diagnosis; NAV: Not available.

Table 2 Phenotypic and genotypic profiles of Lebanese patients with Wilson’s disease

ID	Mutation(s)	GI manifestation(s)	Neurological manifestations	KF rings	Cp	Urinary Cu	Score
P1	Gly691Arg	Liver cirrhosis	Absent	Present	NAV	718.8	8
P2	Gly691Arg	Liver cirrhosis	Change in school performance	Present	0.11	1998	10
P3	Gly691Arg	Asymptomatic1	Absent	Absent	0.03	148.5	8
P4	Gly691Arg	Asymptomatic1	Absent	Absent	0.22	304	6
P5	Gly691Arg	Asymptomatic1	Absent	Absent	0.02	65.9	7
P6	Gly691Arg	NAV	NAV	NAV	NAV	NAV	4
P7	Gly691Arg	NAV	NAV	NAV	NAV	NAV	4
P8	Gly691Arg	NAV	NAV	NAV	NAV	NAV	4
P9	Gly691Arg	NAV	NAV	NAV	NAV	NAV	4
P10	Gly691Arg/Val845Ser	Liver cirrhosis	Suicidal attempts	Present	0.08	2184	12
P11	2299insC	Asymptomatic	Absent	Absent	0.04	99	7
P12	2299insC	Absent	Slurred speech, ataxia, tremors	Present	0.072	512	12
P13	2299insC	Asymptomatic	Absent	Absent	0.03	152.8	8
P14	2299insC	Absent	Choreoathetosis, tremors, rigidity	Present	0.423	2300	10
P15	2299insC	Asymptomatic	Absent	Absent	0.019	10	6
P16	2299insC/p.Ala1003Thr	Liver cirrhosis	Absent	Present	0.096	775	10
P17	2299insC/p.Ala1003Thr	Liver cirrhosis	Absent	Present	0.096	590	10
P18	2299insC/p.Ala1003Thr	Liver cirrhosis	Absent	Present	0.17	645	9
P19	2299insC/p.Ala1003Thr	Absent	Absent	Present	0.12	487	9
P20	2299insC	Liver cirrhosis	Absent	NAV	0.023	651	8
P21	Trp939Cys	Asymptomatic	Absent	Absent	0.02	77.6	7
P22	Trp939Cys	Asymptomatic	Absent	Absent	0.02	20	6
P23	Trp939Cys	Asymptomatic	Absent	Absent	0.02	41.5	6
P24	Trp939Cys	Liver cirrhosis, ascites	Jaw drooping, hypersalivation, slurred speech, narrow based gait, intention tremors	Present	0.021	744	12
P25	Trp939Cys	Liver cirrhosis, Hepatic encephalopathy, Hepatomegaly, Mild to moderate ascites	Absent	Absent	0.04	NAV	6
P26	Asn1270Ser	Liver cirrhosis	Psychiatric symptoms and suicidal attempts	Present	0.03	27.6	10
P27	Asn1270Ser	Liver cirrhosis	Absent	Present	0.03	65.1	9
P28	Asn1270Ser	Ascites, liver cirrhosis	Absent	Present	0.04	55	9
P29	Asn1270Ser	Transaminitis	Neurodevelopmental	Present	0.078	171	11
P30	Asn1270Ser	Asymptomatic	Absent	Absent	0.03	116	8
P31	Asn1270Ser	Chronic liver parenchymal disease	Dysarthria and left-sided dystonia	Present	0.029	402.3	12
P32	Pro1273Leu	Ascites, Liver cirrhosis, Hepatic encephalopathy	Absent	Present	0.17	1041.1	9
P33	Pro1273Leu	Asymptomatic	Absent	Absent	0.19	89.7	6
P34	Arg1319stop	Asymptomatic	Delay in speech	Absent	0.02	92	8
P35	Thr1092Met/Arg1319stop	Chronic liver disease and early portal hypertension	Clenching of mandible, left side dystonia, sialorrhea, dysarthia, head tremors	Present	0.025	199	12
P36	None identified	Absent	Drooling, dysathria, difficulty concentrating, dysphagia	Present	0.085	NAV	6

¹Developed later. Normal range: Serum ceruloplasmin: 0.2 to 0.6 g/L; Urine copper: 15 to 50 μg/24 h. Score = Ferrenci Score of diagnosis. 2 or less: Very unlikely; 3: Possible, more tests needed; 4 or more: Established[4]. Cp: Ceruloplasmin (g/L); KF: Keiser-Fleischer; NAV: Not available; Urinary Cu: 24-h urine copper (μg/24 h).

Table 3 Identified polymorphisms in the ATP7B gene of Lebanese patients with Wilson’s disease

Polymorphism	Asp96Gly	Ser406Ala	Val456Leu	Lys832Arg	Arg952Lys	Ala1003 Ala	Val1140Ala	Ser1166Ser
Exon	2	2	3	10	12	13	16	16
Base change	GAC → GGC	TCT → GCT	GTG → CTG	AAG → AGG	AGA → AAA	GCG → GCA	GTC → GCC	AGC → AGT
Domain	Cu1-4	Cu4 binding	Cu4/Cu5	Td	Tm5	ATP binding/Tm6	ATP loop	ATP loop
Family
U				HM	HM		HM
Or		HM	HM	HM	HM		HM
S
P1, P2, P31, P41, P59				HM	HM		HM
P7, P8				HT	HT		HT
P3, P4					HM		HM
AH			HM	HM	HM		HM
TF				HM	HM	HM	HM	HM
B				HM	HM	HM	HM
H		HM	HM	HM	HM		HM
Ha								HM
Is			HM	HM	HM		HM
Z		HM	HM	HM	HM		HM
Ri	HM			HM			HM
Sc			HT	HM	HM		HM
Gh		HM	HM	HM	HM		HM
Ah			HM	HM	HM		HM

Table 4 Lebanese vs regional Arab and non-European Wilson’s disease patients: Genotype-phenotype

	Lebanon	Egypt	Iran	Turkey	Saudi Arabia	Oman
Number of patients	36	198	88	46	1521	14
Number of families	13	135	-	46	53	1
% Homozygosity	83%	68.4% - 85.7%	NAV	NAV	50%-53%	NAV
% Consanguinity	75%	39.5% - 78.9%	NAV	NAV	36.6%-88.8%	NAV
% Hepatic manifestation	28%	45.5% - 84.2%	65.20%	43.50%	25%-54.9%	0%
% Neurologic manifestation	12.50%	4.2%-15.8%	4.30%	34.80%	0%-25%	21.40%
% Mixed manifestation	21.80%	0%-20.9%	21.70%	21.70%	19.6%-55.6%	0%
% Asymptomatic	37%	0%-35.1%	-	0%	30.35%	78.60%
% KF rings	58%	26.3%-69.2%	65.20%	67.40%	50.7%-59%	NAV
Mutation
E2		Glu396stop
E3				Gly457stop
E4-6	No common mutations identified
E7	Gly691Arg			Gly691Arg
E8	2299insC	c. 2304-5insC	Trp779Gly	Gly710Ser	Ser744Pro
		Cys703Tyr		Pro767Arg
E9	No common or frequent mutations identified
E10	Val845Ser	Val845Ser	Val845Ser	Val845Ser
E11	No common or frequent mutations identified
E12	Trp939Cys
E13	Ala1003Thr		3061-1G>A sp	Ala1003Thr		Deletion of E13
E14		Thr1076Ile
		His1069Gln	His1069Gln	His1069Gln
E15	Thr1092Met	His1126fs	Ile1102Thr
E16-17	No common or frequent mutations identified
E18	Asn1270Ser	Asn1270Ser	Asn1270Ser	Asn1270Ser
	Pro1273Leu	Pro1273Leu
		IVS18-2A>G
E19	Arg1319stop	Arg1319stop		Arg1319stop
E20					Gly1341Ser
E21					Gln1399Arg
Ref.	Barada et al[13,30]	Abdelghaffar et al[12,22]	Dastsooz et al[27]	Simsek Papur et al[25]	Al Jumah et al[18]	Al-Tobi et al[29]
					Al Fadda et al[19]
	Usta et al[6,14]	El-Karaksy et al[23]	Zali et al[28]	Loudianos et al[26]	Majumdar et al[20,21]
		El-Mougy et al[24]

¹152 patients described in articles from Saudi Arabia, of which 5 patients were from yemen and syria.