Analysis of fatal outcomes of patients with mucopolysaccharidosis type II according to the Russian mucopolysaccharidosis registry

Table 1 Clinical characteristics of 20 Russian mucopolysaccharidosis II patients who died between 2016-2022 years

ID	Height at birth, cm	1st-year psychomotor delay	Delayed mental and speech	Intellectual disability: 5-12 / > 12 year	Hydrocephalus	Epilepsy	Swallow disorders	Independent walking 5-12 / > 12 year	Hurler pheno-type	Cardio-myopathy	Myxomatous valve degeneration	Respiratory disorders	Tracheostomy	Carpal tunnel syndrome
46	49	No	Yes	No/no	Yes	No	No	Yes/yes	Yes	Yes	Yes	0	0	0
58	N/A	N/A	N/A	N/A/N/A	N/A	N/A	No	N/A/N/A	Yes	N/A	N/A	N/A	N/A	N/A
65	52	No	Yes	Mod/profound	Yes	Yes	Yes	Yes/no	Yes	Yes	Yes	Yes	0	Yes
71	57	Yes	No	No/no	N/A	N/A	N/A	Yes/yes	Yes	N/A	N/A	Yes	N/A	N/A
72	N/A	Yes	Yes	No/no	N/A	Yes	Yes	Yes/no	Yes	No	Yes	Yes	0	0
92	52	No	Yes	No/N/A	Yes	Yes	Yes	No/N/A	Yes	No	Yes	Yes	0	Yes
93	51	No	Yes	Profound/profound	No	Yes	Yes	No/no	Yes	No	Yes	Yes	Yes	Yes
96	52	No	Yes	Severe/severe	No	Yes	Yes	Yes/no	Yes	Yes	Yes	0	0	Yes
104	N/A	Yes	Yes	No/no	Yes	No	Yes	No/no	Yes	Yes	Yes	1	0	N/A
106	50	Yes	Yes	No/not significant	No	N/A	N/A	N/A/N/A	Yes	No	Yes	N/A	N/A	N/A
109	57	Yes	Yes	Moderate/severe	Yes	Yes	Yes	Yes/no	Yes	No	Yes	Yes	0	Yes
110	N/A	No	No	No/no	Yes	No	No	Yes/yes	Yes	No	Yes	Yes	0	Yes
111	57	Yes	Yes	Not significant/profound	Yes	Yes	Yes	Yes/no	Yes	Yes	Yes	Yes	0	Yes
113	51	N/A	N/A	N/A/N/A	N/A	N/A	N/A	N/A/N/A	Yes	N/A	N/A	N/A	N/A	N/A
116	55	Yes	Yes	Severe/N/A	Yes	N	Yes	N/A/N/A	Yes	Yes	Yes	1	0	1
120	N/A	No	No	No/no	N/A	N/A	N/A	Yes/no	N/A	N/A	N/A	N/A	N/A	N/A
124	56	Yes	Yes	No/severe	Yes	No	Yes	Yes/yes	Yes	Yes	Yes	Yes	0	0
144	N/A	No	Yes	No/N/A	Yes	No	No	Yes/N/A	Yes	N/A	N/A	Yes	0	Yes
147	54	No	No	No/no	No	No	No	Yes/yes	Yes	Yes	Yes	Yes	Yes	Yes
149	51	Yes	Yes	Moderate/profound	Yes	Yes	Yes	Yes/no	Yes	Yes	Yes	Yes	Yes	Yes

Table 2 Comparison of disease’s features in alive/dead mucopolysaccharidosis type II patients, n (%)

Parameter	Total n = 160	Alive n = 140	Median (IQR); min-max	Dead n = 20	Median (IQR); min-max		P value
General information
Age at last observation1	160	140	10.7 (5.9; 15.9); 0.7-46.4	20	16.5 (12.5; 21); 9.0-43		0.001
Birth weight, kg	91	83	3.4 (3.2; 3.9); 1.5-4.7	8	3.9 (3.4; 4.3); 3.3-4.5		0.062
Height at birth, cm	117	103	53 (51; 54); 40-60	14	52 (51; 56); 49-57		0.609
Age of first symptom, years	128	112	1.0 (0; 2); 0-19.0	16	1.0 (0; 2); 0-8		0.982
Age at diagnosis, years	145	125	3.0 (2; 5); 0-32	20	5.0 (4; 7); 2-38		0.0006
Ever received ERT	152	133	118 (88.7)	19	16 (84.2)		0.569
Age of start ERT, years	117	101	5.0 (3; 9); 0-43	16	7.5 (6.5; 11.5); 4-39		0.004
Pathogenic SNP	118	102	59 (57.8)	13	8 (61.5)		0.532
Likely pathogenic SNP			34 (33.3)		5 (38.5)
VUS SNP			9 (8.8)		0 (0)
Neurology
Patients with a neuronopathic form	98/148	130	85 (65.4)	18	13 (72.2)		0.565
Psychomotor development delay (up to 1 year)	148	130	54 (41.5)	18	9 (50.0)		0.496
Delayed mental and speech development (1-3 years)	147	129	85 (65.9)	18	14 (77.8)		0.314
Intellectual disability: From mild to profound (5-12 years)	128	110	69 (62.7)	18	13 (72.2)		0.648
Intellectual disability: From mild to profound (after 12 years)	84	69	40 (58.0)	15	15 (66.7)		0.546
Hydrocephalus	131	116	18 (41.4)	15	11 (73.3)		0.019
Bypass surgery	133	119	0 (0)	14	1 (7.1)		0.003
Epilepsy	134	119	12 (10.1)	15	8 (53.3)		0.000009
Swallowing disorder	129	113	26 (23.0)	16	11 (68.8)		0.0002
Impossible independent walking (5-12 years)	136	120	12 (10.0)	16	2 (12.5)		0.757
Impossible independent walking (after 12 years)	82	68	15 (22.1)	14	8 (57.1)		0.002
Carpal tunnel syndrome	114	100	58 (58.0)	14	11 (78.6)		0.140
Somatic symptoms
Hurler phenotype	142	123	118 (95.9)	19	19 (100)	0.371
Hepatosplenomegaly	139	121	113 (93.4)	18	18 (100)	0.261
Hearing loss	126	113	76 (67.3)	13	12 (92.3)	0.062
Respiratory disorders	135	119	47 (39.5)	16	14 (87.5)	0.001
Tracheostomy	136	121	2 (1.7)	15	3 (20.0)	0.0004
Any hernias	136	118	98 (83.0)	18	18 (100)	0.059
Orthopedic problems
Any orthopedic features	140	121	119 (98.4)	19	19 (100)	0.573
Spinal involvement	132	117	76 (65.0)	15	13 (86.7)	0.091
Chest deformity	139	123	67 (54.5)	16	11 (68.8)	0.279
Cardiac disorders
Cardiac disorders (cardiomyopathy + myxomatous valve disease)	132	116	89 (76.7)	16	16 (100)	0.031
Cardiomyopathy	131	115	34 (29.3)	15	9 (60.0)	0.017
Myxomatous valve disease	130	115	78 (67.8)	15	15 (100)	0.009

¹For died patients – age of the death; IQR: Interquartile range (Q1; Q3); ERT: Enzyme replacement therapy; VUS: Variant of unknow significance; SNP: Single nucleotide polymorphism.

Table 3 Epidemiology characteristic of 20 Russian mucopolysaccharidosis type II patients who died between 2016-2022

ID	Year of the death	Death age, year	Cause of death	SNP/Rearrangements	Protein	Exon/9	Type of nucleotide change	Significance of variant	Normalized enzyme activity, %	Age of first symptoms, year	Age of diagnosis, year	ERT	Age of start ERT, year	MPS form, mild/severe
46	2020	18	CVF	c.253G > A	p.Ala85Thr	3	ms	Pathogenic	N/A	2	8	Yes	10	Mild
58	2019	10	Pneumonia	c.1295G > A	p.Cys432Tyr	9	ms	LP	N/A	0	5	Yes	6	N/A
65	2020	21	MPS	c.196C > T	p.Gln66Ter	2	ns	Pathogenic	15	0	5	Yes	13	Severe
71	2016	21	Acute CVF	c.257C > T	p.Pro86 Leu	3	ms	LP	7.6	N/A	6	No	N/A	Mild
72	2020	14	Acute CVF	c.1403G > A	p.Arg468Gln	9	ms	Pathogenic	N/A	N/A	4	Yes	4	Severe
92	2021	11	N/A	c.133G > T	p.Asp45Tyr	2	ms	LP	3.8	1	5	Yes	7	Severe
93	2019	20	RF, renal failure	c.395C > G	p.Ser132Trp	3	ms	LP	0.1	2	4	Yes	11	Severe
96	2022	13	CVF, dilated cardiomyopathy	c.262C > T	p.Arg88Cys	3	ms	Pathogenic	0	0	3	Yes	5	Severe
104	2019	15	Pneumonia	N/A	N/A	N/A	N/A	N/A	0	3	5	Yes	7	Severe
106	2020	13	N/A	Recombination between intron 7 of the IDS gene and the distal part of exon 3 of the IDSP1 pseudogene, with deletion of exons 1-3 of the IDS gene	N/A	N/A	N/A	Pathogenic	0	2	2	Yes	7	Severe
109	2022	20	CVF	Recombination between intron 7 of the IDS gene and the distal part of exon 3 of the IDSP1 pseudogene, without deletion	N/A	N/A	N/A	Pathogenic	9.1	1	11	Yes	12	Severe
110	2018	43	Chronic obstructive pulmonary disease. Pneumonia	c.1037C > T	p.Ala346Val	8	ms	LP	0	N/A	20	No	N/A	Mild
111	2022	22	MPS	c.133delG	p.Asp45Metfs*15	2	ms	Pathogenic	NA	1	5	Yes	11	Severe
113	2017	15	CVF	Recombination between intron 7 of the IDS gene and the distal part of exon 3 of the IDSP1 pseudogene, without deletion	N/A	N/A	N/A	Pathogenic	0.43	2	3	N/A	N/A	N/A
116	2018	10	CVF	N/A	N/A	N/A	N/A	N/A	0.01	0	6	Yes	6	Severe
120	2017	41	CVF	N/A	N/A	N/A	N/A	N/A	1.8	8	38	Yes	39	Mild
124	2022	18	Viral infection	c.1340T > A	p.Leu447Term	9	ns	Pathogenic	0	5	6	Yes	8	Severe
144	2018	9	N/A	Del exon 1-7	N/A	N/A	N/A	Pathogenic	0.002		4	No		Severe
147	2016	21	RF	c.1034G > C	p.Trp345Ser	8	ms	Pathogenic	0.66	1	11	Yes	17	Mild
149	2017	12	RF	c.1006G > C	p.Gly336Arg	7	ms	Pathogenic	0.42	0	5	Yes	7	Severe

CVF: Cardiovascular failure; ERT: Enzyme replacement therapy; N/A: Not applicable; LP: Likely pathogenic; ms: Missense; ns: Nonsense; MPS: Mucopolysaccharidosis; RF: Respiratory failure; SNP: Single nucleotide polymorphism.

Table 4 The main predictors of the fatal outcomes (univariant analysis) in patients with mucopolysaccharidosis type II

MPS type II feature	Sensitivity	Specificity	OR (95%CI)	P value
Diagnosis age > 4 years	70.0	72.8	6.3 (2.2; 17.6)	0.0002
ERT age > 5 years	87.5	59.4	10.2 (2.2; 47.5)	0.0005
Birth weight > 3.88 kg	62.5	72.3	4.4 (0.96; 19.7)	0.042
Age > 13 years	75.0	65.0	5.6 (1.9; 16.2)	0.0006
Hydrocephalus	73.3	58.6	3.9 (1.2; 13.0)	0.019
Epilepsia	53.3	89.9	10.2 (3.1; 33.1)	0.000009
Swallowing disturbances	68.8	77.9	7.4 (2.3; 23.1)	0.0002
Impossible to walk after 12 years	61.5	77.9	5.7 (1.6; 19.9)	0,002
Heart disease	100.0	23.3	-	0.031
Cardiomyopathy	60.0	70.7	3.6 (1.2; 11.0)	0.017
Myxomatous valve disease	100.0	32.3	-	0.009
Deafness	92.3	32.7	5.8 (0.7; 46.7)	0.062
Respiratory disorders	87.5	60.2	10.6 (2.3; 48.7)	0.001
Apnoe at the diagnosis	54.5	73.6	3.4 (0.92; 12.3)	0.057
Apnoe at the last visit	77.8	70.2	8.3 (1.6; 42.6)	0.004
Obstructive disease	72.7	66.3	5.2 (1.3; 21.2)	0.012
Hernias	100.0	16.9	-	0.059

ERT: Enzyme replacement therapy; MPS: Mucopolysaccharidosis; OR: Odds ratio.

Table 5 The predictors of the fatal outcome in mucopolysaccharidosis type II patients according to Cox-regression analysis

Predictors	SE	HR (95%CI)	P value
Psychomotor development delay (up to 1 year)	0.26	3.4 (1.2; 9.3)	0.019
Delayed mental and speech development (1-3 years)	0.33	5.7 (1.8; 17.9)	0.003
Hydrocephalus	0.30	3.3 (1.03; 10.4)	0.044
Epilepsia	0.28	4.4 (1.5; 12.8)	0.008
Swallow disorders	0.29	5.1 (1.6; 16.7)	0.006
Impossible walking at age < 12 years	0.40	4.9 (1.01; 23.3)	0.049
Impossible walking at the age > 12 years	0.31	9.4 (2.8; 31.3)	0.0003
Respiratory disorders	0.38	5.7 (1.3; 25.6)	0.023
Tracheostomia	0.33	4.7 (1.3; 16.7)	0.022
Neuronopathic form	0.27	4.1 (1.4; 11.9)	0.01

SE: Standard error; HR: Hazard ratio.