Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders

Fernández-Marmiesse, Ana; Morey, Marcos; Pineda, Merce; Eiris, Jesús; Couce, Maria Luz; Castro-Gago, Manuel; Fraga, Jose Maria; Lacerda, Lucia; Gouveia, Sofia; Pérez-Poyato, Maria Socorro; Armstrong, Judith; Castiñeiras, Daisy; Cocho, Jose A

doi:10.1186/1750-1172-9-59

Orphanet Journal of Rare Diseases

Table 3 Diagnostic suspicions and biochemical/histopathological tests for patients diagnosed using the NGS-LSD tool

From: Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders

PC	AO	AD	GD	NGS-LSD	Initial signs	Diagnostic suspicions	Biochemical-histopathology studies*	Other genetic studies*
P1	2Y	-	12Y	CLN5	Clumsiness, frequent falls, apraxic gait	CLN	VL; SBIOP + .	PPT1, TTP1
P2	4Y	-	7Y	CLN6	Clumsiness, myoclonic movements	GM2, GCL, MLD, Fabry, Schindler, MANSA, MANBA, MPS, CLN	EA: HEXA, HEXB, GLA, NAGA, MANBA, MAN2B1, MPS, GALC, ARSA, PPT1, TTP1	MFSD8
P3	3Y	-	16Y	CLN3	Language regression, school inattention, social isolation	CDG, GM1, GM2, GSL, Schindler, GSD II, III, CLN	VL; FC; SPA ; EA: GLB1, HEXB, CTSA, NAGA, GAA, AGL; SBIOP + .
P4	2Y	-	23Y	CLN7	Language delay, clumsiness	CLN	SBIOP +; EA: CLN2.	CLN1
P5	4Y	-	16Y	CLN3	Conduct disorder, attention deficit disorder	CLN	VL +; SBIOP, MBIOP, NBIOP + .	PPT1, TTP1, CLN3, CLN5, CLN8
P6	3Y	4Y	7Y	MLD	Leukodystrophy	Spastic paraparesia	EA: ARSA +
P7	1Y	-	9Y	GM1	Global developmental delay, gait instability	CDG; RCCD; INAD	MBI; NBIOP +; MBS; SPA; EA: HEXA, HEXB
P8	2Y	7Y	4Y	GM2	Language delay, conduct disorder	Unspecific global developmental delay, Neurodegenerative disease; CLN, GM2	SBIOP; MBS; EA: HEXA + .	Caryotype; Fragile X; Smith-Magenis
P9	2Y	-	14Y	GM2	Clumsiness, frequent falls	Ataxia, Attention deficit disorder	MBI	Caryotype; Fragile X; CGH-60 k array.
P10	3Y	9Y	12Y	GM1	Clumsiness, frequent falls, language delay	RS, MPSIII, GM1	MBS, U-GAGs; EA: GLB1+	Caryotype, Fragile-X, MECP2
P11	5Y	-	22Y	GM2	Learning problems, language difficulties	CLN	SBIOP	CLN3, CLN8
P12	13Y	-	18Y	NPC2^#	Clumsiness, short stature	MTDPS; RCCD; SCA; DRPLA	MBIOP; RCCFS; EA: muscular Coenzima Q10	mtADN(muscle); MTATP6; tRNALeu(UUR); SCA1,2,3,6,7,12,17; ATN1
P13	18 M	-	4Y	ML II,III	Growth delay, macrocephaly	MPS	U-GAGs	SHOX
P14	12 M	3Y	3Y	GM2	Psycomotor regression, language regression	RS, GM2	EA: HEXA +, HEXB	MECP2
P15	0 M	3 M	1Y	GM1	Hypotonia, hepatomegaly, cardiomyopathy, bony abnormalities	GSD II	EA: GAA
P16	9 M	2Y	2Y	MPSVI	Bilateral costal deformity, macrocephaly	AA, MPS	U-GAGs, Dermatan sulfate in urine, EA: ARSB
P17	0 M	-	2Y	ML II,III	Hypotonia, microcephaly, jaundice	MPS	MBS, U-OLG, U-GAGs	Caryotype; CGH array
P18	2 M	3Y	6Y	MPSII	Bilateral inguinal hernia	MPS	U-GAGs; EA: IDS +
P19	1Y	4Y	5Y	MPSI	Clubfoot, arthrogryposis, clawed hands	MPS	U-GAGs; EA: IDUA +, IDS, ARSB
P20	0 M	1Y	1Y	GM1	Hypotonia, severe psycomotor delay	GM1, GM2, GSL, ML I	MBS; VL; U-GAGs; EA: GBL1 +, HEXA, HEXB, CTSA, NEU1
P21	18 M	3Y	3Y	GM2	Unsteady gait, frequent falls	TORCH, Leukodystrophy	EA:
P22	2Y	-	6Y	CLN8	Cognitive regression, epilepsy	Lennox syndrome, CLN	PBIOP +
P23	3Y	-	9Y	CLN10	Psycomotor regression, dystonia, epilepsy	Neuroaxonal dystrophy, sphingolipidosis	MBIO	mtDNA
P24	3Y	5Y	23Y	MPSIIIB	Language delay, conduct disorder, learning disabilities, hypoacusia	MPS	Heparan sulfate +
P25	1Y	-	6Y	GM2AB	Developmental delay, regression	GM2, GSD II	EA: HEXA, HEXB, GAA (+); HPS GM2 +	GAA
P26	4Y	-	25Y^†	CLN8	Cognitive regression, epilepsy	CLN		CLN6

Abbreviations: PC Patient Code, AO Age of Onset (Y: years; M: months; ^†deceased), AD Age at Diagnosis, GD age at Genetic Diagnosis, NGS-LSD diagnosis reached with our NGS tool, CLN Neuronal Ceroid Lipofuscinosis, MLD metachromatic leukodystrophy, GM1 and 2 Gangliosidosis I and II, NPC2 Niemann-Pick disease, type C2, ML II III mucolipidosis III alpha/beta, MPS mucopolysaccharidosis, GM2AB Gangliosidosis type II, AB variant, MANSA Mannosidosis, alpha-, types I and II, MANBA mannosidosis beta, CDG congenital disorder of glycosylation, GSL galactosialidosis, GSD glycogen storage disease, GSD II Pompe disease, RCCD respiratory chain complex deficiency, INAD infantile neuroaxonal dystrophy, RS Rett syndrome, AA autoimmune arthritis, ML I sialidosis, TORCH Band-like calcification with simplified gyration and polymicrogyria, MBS metabolic study, SPA sialotransferrin profile analysis, VL vacuolated lymphocytes in peripheral blood, FC foam cells in bone marrow, RCCFS respiratory chain complex functional studies, GCL globoid cell leukodystrophy or Krabbe disease, SCA spinocerebellar ataxia, EA enzymatic assay, U-GAGs urinary glycosaminoglycan levels, U-OLG urinary oligosaccharides levels, SBIOP skin biopsy, MBIOP muscle biopsy, NBIOP nerve biopsy, HPS pathological study, mtDNA mithocondrial DNA deletions, depletion and punctual mutations, MTDPS mitochondrial depletion syndrome, CGH comparative genomic hybridization; ^#: not confirmed; *All results were negative unless indicated by a plus sign.

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ISSN: 1750-1172

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