Introduction:TPP1 variants have been identified as a causative agent of neuronal ceroid lipofuscinosis 2 disease, that ataxia is one of its clinical features. Therefore, here, molecular study of TPP1 variants is presented in an Iranian cohort and a novel pathogenic variant is described. Methods: This investigation was conducted as a cross-sectional study in a tertiary referral hospital, Children’s Medical Center, Pediatrics Center of Excellence. Clinical presentations and pedigrees were documented. Patients with cerebellar ataxia were enrolled in this study. Next-generation sequencing was applied to confirm the diagnosis. Segregation and bioinformatics analyses were also done for the variants using Sanger sequencing. Results: Forty-five patients were included in our study. The mean age of onset was 104 (+55.60) months (minimum = 31 months, maximum = 216 months). The majority of cases (73.3%) were born to consanguineous parents and only 1 patient (2.2%) had an affected sibling. Of the 45 patients, only 1 patient with a novel pathogenic variant (c.1425_1425+1delinsAT, p.A476Cfs*15) in the TPP1 gene was identified. Discussion: The main strength of current study is the relatively large sample size. Besides, a novel pathogenic variant could be important toward the diagnosis and management of this condition. With significant advances in various therapies, early diagnosis could improve the treatments using personalized-based medicine.

1.
Chang
X
,
Huang
Y
,
Meng
H
,
Jiang
Y
,
Wu
Y
,
Xiong
H
.
Clinical study in Chinese patients with late-infantile form neuronal ceroid lipofuscinoses
2012
;
34
:
739
45
.
2.
Chen
Z-R
,
Liu
D-T
,
Meng
H
,
Liu
L
,
Bian
W-J
,
Liu
X-R
.
Homozygous missense TPP1 mutation associated with mild late infantile neuronal ceroid lipofuscinosis and the genotype-phenotype correlation
.
Seizure
.
2019
;
69
:
180
5
.
3.
Cooper
DN
,
Ball
EV
,
Stenson
PD
,
Phillips
AD
,
Evans
K
,
Heywood
S
The human gene mutation database (HGMD®)
.
2020
.
4.
Davoudi-Dehaghani
E
,
Zeinali
S
,
Mahdieh
N
,
Shirkavand
A
,
Bagherian
H
,
Tabatabaiefar
MA
.
A transversion mutation in non-coding exon 3 of the TMC1 gene in two ethnically related Iranian deaf families from different geographical regions; evidence for founder effect
.
Int J Pediatr Otorhinolaryngol
.
2013
;
77
(
5
):
821
6
.
5.
Fogel
BL
,
Perlman
S
.
Clinical features and molecular genetics of autosomal recessive cerebellar ataxias
.
Lancet Neurol
.
2007
;
6
(
3
):
245
57
.
6.
Gardner
E
,
Bailey
M
,
Schulz
A
,
Aristorena
M
,
Miller
N
,
Mole
SE
.
Mutation update: review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease
.
Hum Mutat
.
2019
;
40
(
11
):
1924
38
.
7.
Goldberg-Stern
H
,
Halevi
A
,
Marom
D
,
Straussberg
R
,
Mimouni-Bloch
A
.
Late infantile neuronal ceroid lipofuscinosis: a new mutation in Arabs
.
Pediatr Neurol
.
2009
;
41
(
4
):
297
300
.
8.
Hofmann
SL
,
Atashband
A
,
Cho
SK
,
Das
AK
,
Gupta
P
,
Lu
J-Y
.
Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2)
.
Curr Mol Med
.
2002
;
2
(
5
):
423
37
.
9.
Ju
W
,
Zhong
R
,
Moore
S
,
Moroziewicz
D
,
Currie
J
,
Parfrey
P
.
Identification of novel CLN2 mutations shows Canadian specific NCL2 alleles
.
J Med Genet
.
2002
;
39
(
11
):
822
5
.
10.
Kida
E
,
Golabek
AA
,
Walus
M
,
Wujek
P
,
Kaczmarski
W
,
Wisniewski
KE
.
Distribution of tripeptidyl peptidase I in human tissues under normal and pathological conditions
.
J Neuropathol Exp Neurol
.
2001
;
60
(
3
):
280
92
.
11.
Kohan
R
,
Carabelos
MN
,
Xin
W
,
Sims
K
,
Guelbert
N
,
Cismondi
IA
.
Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America
.
Gene X
.
2013
;
516
(
1
):
114
21
.
12.
Kousi
M
,
Lehesjoki
AE
,
Mole
SEJH
.
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses
.
Hum Mutat
.
2012
;
33
(
1
):
42
63
.
13.
Kurachi
Y
,
Oka
A
,
Itoh
M
,
Mizuguchi
M
,
Hayashi
M
,
Takashima
S
.
Distribution and development of CLN2 protein, the late-infantile neuronal ceroid lipofuscinosis gene product
.
Acta Neuropathol
.
2001
;
102
(
1
):
20
6
.
14.
Lam
C-W
,
Poon
PM
,
Tong
S-F
,
Ko
C-HJA
.
Two novel CLN2 gene mutations in a Chinese patient with classical late-infantile neuronal ceroid lipofuscinosis
.
Am J Med Genet
.
2001
;
99
(
2
):
161
3
.
15.
Mahdieh
N
,
Mahmoudi
H
,
Ahmadzadeh
S
,
Bakhtiyari
S
.
GJB2 mutations in deaf population of Ilam (Western Iran): a different pattern of mutation distribution
.
Eur Arch Oto-Rhino-Laryngol
.
2016
;
273
(
5
):
1161
5
.
16.
Mazurkiewicz-Bełdzińska
M
,
Del Toro
M
,
Haliloğlu
G
,
Huidekoper
HH
,
Kravljanac
R
,
Mühlhausen
C
.
Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies
2021
1
8
.
17.
Mole
SE
,
Gardner
E
,
Schulz
A
,
Xin
WW
.
Molecular basis of CLN2 disease: a review and classification of TPP1 gene variants reported worldwide
.
Mol Genet Metabol
.
2018
123
2
S97
.
18.
Moore
S
,
Buckley
D
,
MacMillan
A
,
Marshall
H
,
Steele
L
,
Ray
P
.
The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland
.
Clin Genet
.
2008
;
74
(
3
):
213
22
.
19.
Miller
SA
,
Dykes
D
,
Polesky
H
.
A simple salting out procedure for extracting DNA from human nucleated cells
.
Nucleic Acids res
.
1988
;
16
(
3
):
1215
.
20.
Nickel
M
,
Jacoby
D
,
Lezius
S
,
Down
M
,
Simonati
A
,
Genter
F
.
Natural history of CLN2 disease: quantitative assessment of disease characteristics and rate of progression
.
Neuropediatrics
.
2016
47
S 01
FV04
03
.
21.
Nickel
M
,
Simonati
A
,
Jacoby
D
,
Lezius
S
,
Kilian
D
,
Van de Graaf
B
.
Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study
.
Lancet Child Adolesc Health
.
2018
;
2
(
8
):
582
90
.
22.
Perlman
SL
.
Symptomatic and disease-modifying therapy for the progressive ataxias
.
Neurologist
.
2004
;
10
(
5
):
275
89
.
23.
Rabbani
B
,
Mahdieh
N
,
Haghi Ashtiani
MT
,
Akbari
MT
,
Rabbani
A
.
Molecular diagnosis of congenital adrenal hyperplasia in Iran: focusing on CYP21A2 gene
.
Iran J Pediatr
.
2011
;
21
(
2
):
139
50
.
24.
Santorelli
FM
,
Garavaglia
B
,
Cardona
F
,
Nardocci
N
,
Dalla Bernardina
B
,
Sartori
S
Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy
.
2013
;
8
:
1
7
.
25.
Sleat
DE
,
Ding
L
,
Wang
S
,
Zhao
C
,
Wang
Y
,
Xin
W
.
Mass spectrometry-based protein profiling to determine the cause of lysosomal storage diseases of unknown etiology
.
Mol Cell Proteomics
.
2009
;
8
(
7
):
1708
18
.
26.
Sleat
DE
,
Gin
RM
,
Sohar
I
,
Wisniewski
K
,
Sklower-Brooks
S
,
Pullarkat
RK
.
Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder
.
Am J Hum Genet
.
1999
;
64
(
6
):
1511
23
.
27.
Sun
Y
,
Almomani
R
,
Breedveld
GJ
,
Santen
GW
,
Aten
E
,
Lefeber
DJ
.
Autosomal recessive spinocerebellar ataxia 7 (SCAR 7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN 2 disease)
.
Hum Mutat
.
2013
;
34
(
5
):
706
13
.
28.
Verma
J
,
Thomas
DC
,
Sharma
S
,
Jhingan
G
,
Saxena
R
,
Kohli
S
.
Inherited metabolic disorders: prenatal diagnosis of lysosomal storage disorders
.
Prenat Diagn
.
2015
;
35
(
11
):
1137
47
.
29.
Warrier
V
,
Vieira
M
,
Mole
SE
.
Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses
.
Biochim Biophys Acta
.
2013
;
1832
(
11
):
1827
30
.
30.
Zhong
N
,
Moroziewicz
DN
,
Ju
W
,
Jurkiewicz
A
,
Johnston
L
,
Wisniewski
KE
.
Heterogeneity of late-infantile neuronal ceroid lipofuscinosis
.
Genet Med
.
2000
;
2
(
6
):
312
8
.
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