Gillespie’s Syndrome with Minor Cerebellar Involvementand No Intellectual Disability Associated with a NovelITPR1 Mutation: Report of a Case and Literature Review

Claudia Stendel Q1Q1Q11,2 Matias Wagner3,4 Guenther Rudolph5 Thomas Klopstock1,2,6

1Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-

University, Munich, Germany2GermanQ2Q2

Q2Center for Neurodegenerative Diseases (DZNE), Munich,

Germany3Helmholtz Center Munich, German Research Center for Environmental

Health, Institute of Neurogenomics, Neuherberg, Germany4 Institute of Human Genetics, Technische Universität München,

Munich, Germany5Department of Ophthalmology, University Eye Hospital, Ludwig-

Maximilians-University, Munich, Germany6Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

Neuropediatrics 2019;00:1–5.

Address for correspondence Claudia Stendel, MD, Department of

Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University,

Ziemssenstr. 1a, 80336 Munich, Germany

(e-mail: claudia.stendel@med.uni-muenchen.de).

Introduction

Gillespie’s syndrome (MIM 206700) is a rare inherited condi-

tion characterized by bilateral iris hypoplasia, congenital

muscle hypotonia, nonprogressive cerebellar ataxia, and

variable intellectual disability.1 Since the first description in

1965, less than 50 affected families have been reported

worldwide.2 Clinical diagnosis is usually made shortly after

birth due to a combination of fixed dilated pupils due to iris

hypoplasiaandmuscularhypotonia.3 In2016, thegeneticbasis

of Gillespie’s syndrome was unraveled when recessive and

dominant (de novo) variants in the inositol 1,4,5-trisphos-

phate receptor type 1 (ITPR1) gene were identified.4,5 ITPR1

encodes one of the three members of the inositol trisphos-

phate receptor (InsP3R) family that form large homo- and

heterotetrameric calcium release channels localized predomi-

nantly in membranes of endoplasmic reticulum calcium

stores.6 Variants in ITPR1 have been linked to several forms

of nonsyndromic spinocerebellar ataxia and atrophy.7,8

Here,we report a patientwith an unusuallymild phenotype,

caused by a novel heterozygous ITPR1 mutation and review

the genetic and clinical spectrum in genetically confirmed

Gillespie’s patients that were published in the literature to date.

Keywords

► ITPR1

► Gillespie’s syndrome

► ataxia

► cerebellar atrophy

► aniridia

► intellectual disability

Abstract Variants in the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene have been

recently identified as a cause of Gillespie’s syndrome, a rare inherited condition

characterized by bilateral iris hypoplasia, congenital muscle hypotonia, nonprogressive

cerebellar ataxia, and intellectual disability. Here, we describe the clinical and genetic

findings in a patient who presented with iris hypoplasia, mild gait ataxia, atrophy of the

anterior cerebellar vermis but no cognitive deficits. Whole-exome sequencing (WES)

uncovered a heterozygous ITPR1 p.Glu2094Lys missense variant, affecting a highly

conserved glutamic acid residue for which other amino acid substitutions have already

been reported in Gillespie’s syndrome patients. Our data expand both the phenotypic

and genetic spectrum associated with Gillespie’s syndrome and suggest a mutation

hotspot on Glu2094.

Claudia Stendel's ORCID is https://orcid.org/0000-0002-4234-

8393.

received

January 26, 2019

accepted after revision

May 29, 2019

© 2019 Georg Thieme Verlag KG

Stuttgart · New York

DOI https://doi.org/

10.1055/s-0039-1693150.

ISSN 0174-304X.

Short Communication 1

Case Report

The patient is the second child of healthy, nonconsanguineous

parentswithno familyhistoryofneurologicaloroculardisease.

At birth, he presented with fixed dilated pupils due to iris

hypoplasia. There was no perinatal hypotonia (Apgar’s score

10/10/10 at 1/5/10 minutes, respectivelyQ3Q3Q3). Motormilestones

were mildly delayed with independent walking at 2.5 years of

age. At age 1.5 years, mild intention tremor of both hands was

noted. Cognitive development was normal; he attended a

school for visually impaired children and graduated

fromsecondarymodern school. Asheexperiencednodisabling

neurological deficits in daily life, hewas not seen by a neurolo-

gist until age 22 years. Neurologic examination at age 22 years

revealed bilateral ptosis and dilated pupils with no reaction to

light. Visual impairment wasmild (visual acuity both eyes 0.8)

and he did not wear glasses in daily life. He had mild scoliosis

and thoracic kyphosis. There was no muscle wasting or weak-

ness. Muscle tone in the lower extremities was increased with

brisk deep tendon reflexes though plantar responses were

normal. He had mild ataxia on gait tests and was still able to

run. He also showedmoderate intention tremor of both hands.

Total scale for the assessment and rating of ataxia (SARA) score

was 6.5/40. He had normal cognition and was trained in office

communication. Montreal Cognitive Assessment (MoCA)

score at age 26 years was normal (28/30). Brain magnetic

resonance imaging (MRI) scan at age 22 years was reported

to be normal; however, nomid sagittal sectionswere aquisited

hampering evaluation of the cerebellar vermis. Follow-up

brain MRI at age 26 years confirmed normal volume of the

cerebellar hemispheres but revealed atrophy of the anterior

cerebellar vermis (►Fig. 1A, B). There were no periventricular

increased T2 white matter signals (►Fig. 1C). Anterior

segment optical coherence tomography (AS-OCT) revealed

symmetrically incomplete aniridia in the entire circumference

(►Fig. 1D, E).Configurationof thecorneaandanteriorchamber

was normal. Funduscopy was without any pathology (pink

optic disc, cup-to-disc ratio: 0.1). Based on neurological and

ophthalmologicalfindings, the tentativediagnosisofGillespie’s

syndrome was made and genetic testing was performed in

2015. Since ITPR1 mutations had not yet been assigned to

Gillespie’s syndrome at that time, we used whole-exome

sequencing (WES) to search for the genetic defect.

Methods

Written informed consent was obtained from the patient

for genetic testing and publication of genetic and clinical

data. WES of the DNA sample of the patient was performed

using a SureSelect Human All Exon 60 Mb V6 Kit (Agilent,

Santa Clara, California, United States) for enrichment and

sequencing was done on a HiSeq 4,000 engine (Illumina,

San Diego, California, United States). WES yielded 10.990 Gb

of sequence with 97.72% of the targeted region covered at

least 20xQ5Q5Q5. Variant prioritization was performed based on

an autosomal recessive pattern of inheritance (homozygous

or putative compound heterozygous variants with minor

allele frequency < 1%), as well as on an autosomal domi-

nant pattern of inheritance (heterozygous variants with a

minor allele frequency < 0.01%).

Results

No pathogenic mutation was identified in the PAX6, FOXC1,

and PITX2 genes, which are associatedwithmore than 90% of

cases of isolated aniridia.9 After publication of ITPR1 variants

in individuals with Gillespie’s syndrome,4,5 we reevaluated

WES results and observed a heterozygous ITPR1 missense

mutation, c.6280G > A (p.Glu2094Lys). The mutation was

not present in the unaffected mother. The father’s DNA

sample was not available for analysis. Based on molecular

data, the clinical diagnosis of autosomal dominant Gillespie’s

syndrome was confirmed.

Discussion

So far, 25 genetically confirmed patients with Gillespie’s

syndrome have been reported.10–14 In total, 12 mutations

have been identified, including dominant and recessive

variants. The mutations found in Gillespie’s syndrome are,

with one exception, localized either in the regulatory

domain or in the C-terminal transmembrane domain of

ITPR1 (►Fig. 1F). They act either through a dominant-

negative mechanism preventing the assembly of functional

homotetrameric structures or a loss-of-function mecha-

nism, generating prematurely truncated proteins.4,5 All

reported patients show partial aniridia, cerebellar ataxia,

variable cognitive impairment (usually mild to moderate),

and a motor delay, as none of themwalked before the age of

6 years (range: 6–16 years; ►Table 1). Nearby all show

additionally a cerebellar atrophy on brain scans (►Table 1).

The patient, we reported here, exhibited the typical ocular

characteristics (partial aniridia with iridolenticular strands)

that are an invariant feature of Gillespie’s syndrome. He

showed a normal intelligence and mild cerebellar involve-

ment. Although ITPR1mutations have been initially found in

cases with spinocerebellar ataxia, our observations suggest

that neurological and neuroradiological manifestations can

be minor. We speculate that extending ITPR1 mutation

screening to isolated iris hypoplasia caseswithoutmutations

in the PAX6, FOXC1, and PITX2 will increase the diagnostic

yield in these cohorts.

The ITPR1 variant in our case most likely occurred de

novo, either in one of the parental gametes or postzygoti-

cally in the patient. However, we cannot provide formal

evidence as no DNA sample could be obtained from the

reportedly healthy father. The pathogenic relevance of the

identified variant is supported by the observation that it

leads to a nonconservative exchange of a highly evolution-

arily conserved amino acid residue (►Fig. 1G) that has

already been targeted by different dominant mutations in

other cases with Gillespie’s syndrome (►Fig. 1F). Indeed,

the p.Glu2094Lys mutation reported here increases the

number of different variants affecting this residue to three,

confirming a mutation hot-spot and a critical role of

Glu2094 in protein function.

Neuropediatrics Vol. 00 No. 0/2019

Gillespie’s Syndrome and Novel ITPR1 Mutation Stendel et al.2

Fig. 1 Q4Q4Q4Brain MRI images, schematic representation of Gillespie’s variants in human ITPR1 and multiple sequence alignment. MRI, magnetic

resonance imaging. (A) Atrophy of the anterior cerebellar vermis (T1-weighted image). (B) Volume of the cerebellar hemispheres was normal

(T2-weighted image). (C) No increase of periventricular white matter signals were observed (T1-weighted image). (D, E) Anterior segment

optical coherence tomography revealed incomplete aniridia in the entire circumference of the left (D) and right (E) eye. Configuration of the

cornea and the anterior chamber appeared normal. (F) Schematic representation of human ITPR1 and its functional domains showing the

position of the mutations associated with Gillespie’s syndrome. The newly identified p.E2094K mutation and two other mutations affecting

residue 2094 are marked red. Amino acid numbering and domain positions are based on the 2743-amino acid isoform 2: Q14643–2, encoded by

the canonical transcript GenBank NM_001168272.1; ENST00000302640. (G) Multiple sequence alignment of ITPR1 protein regions surrounding

the p.E2094Q residue (red) in various species.

Neuropediatrics Vol. 00 No. 0/2019

Gillespie’s Syndrome and Novel ITPR1 Mutation Stendel et al. 3

ConclusionQ7Q7Q7

In conclusion, we describe a rare case of a patient with

genetically confirmed Gillespie’s syndrome without cogni-

tive impairment and minor cerebellar involvement harbor-

ing a novel ITPR1 mutation, expanding both, the phenotypic

and genotypic spectrum of ITPR1-associated diseases.

Conflict of Interest

The authors declare no conflict of interest.

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Table 1 Q6Q6Q6Clinical and genetic features of patients with genetically confirmed Gillespie’s syndrome

Reference,year

Sex Variant Bilateralirishypoplasia

Ataxia Hypotonia Age atwalking

Intellectualdisability

Cerebellaratrophyon MRI

McEntagartet al,4 2016

F c.6280G > C, p.E2094Q Y Y NR 8–9 y Y (mild) Y

F c.6281A > G, p.E2094G Y Y NR NA Y (mild) Y

F c.6281A > G, p.E2094G Y Y Y NA Y (mild) Y

M c.7786_7788delAAG, p.K2596del Y Y N 10 y Y (mild) Y

F c.7786_7788delAAG, p.K2596del Y Y Y NA (14 y) Y (mild) Y

F c.7786_7788delAAG, p.K2596del Y Y Y > 6y Y (mild) Y

F c.7786_7788delAAG, p.K2596del Y Y NR NR NR NR

M c.7615G > C, p.G2539R Y Y Y NA (40 y) Y (mild) Y

F c.7615G > A, p.G2539R y Y Y NR Y (moderate) Y

F c.7615G > C, p.G2539R Y Y Y 10 y Y (mild–moderate) Y

F c.7615G > C, p.G2539R Y Y Y NA (40 y) Y (severe) Y

F c.7615G > C, p.G2539R Y Y Y > 10y Y (severe) Y

M c.7615G > C, p.G2539R Y Y Y 7 y Y (mild) Y

Gerberet al,5 2016

F c.4771C > T, p.Q1591�,homozygous

Y Y Y NA (4.5 y) Y (severe) Y

F c.2281C > T, p.R761�,homozygous

Y Y Y NA (16 y) Y (mild) N (8 y)

F c.6465 þ 3A > T, p.G2135Vfs�;c.6763 þ 5G > T; p.A2254Vfs�

Y Y Y NA (7.5 y) Y (moderate) Y

F c.7786_7788delAAG, p.K2596del Y Y Y 16 y N Y

F c.7758T > G, p.F2586L Y Y Y NA (1.5 y) unevaluable Y

Denticiet al,10 2017

F c.7727A > T, p.N2576I Y Y Y 10y Y (moderate) Y

F c.7786_7788delAAG, p.K2596del Y Y Y NA (2 y) Y (mild) Y

Carvalhoet al,11 2018

M c.2952_2953insTATA; p.N984fs,homozygous

Y Y Y NA (4 y) Y Y

F c.2952_2953insTATA; p.N984fs,homozygous

Y Y Y NA (2 y) Y N (1 y)

Paganiniet al,12 2018

M c.278_279 þ 2delACGT;p.H93fs,homozygous

Y Y Y NA (9 y) Y (severe) Y

F c.278_279 þ 2delACGT;p.H93fs,homozygous

Y Y Y NA (6 y) Y (severe) Y

De Silvaet al,13 2018

F c.7786_7788delAAG, p.K2596del Y Y NR 9 y Y (mild) Y

Present study M c.6280G > A, p.E2094L Y Y (mild) N 2.5 y N N (22 y)

Abbreviations: F, female; M, male; MRI, magnetic resonance imaging; N, no; NA, not achieved; NR, not reported; Y, yes.

Neuropediatrics Vol. 00 No. 0/2019

Gillespie’s Syndrome and Novel ITPR1 Mutation Stendel et al.4

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Neuropediatrics Vol. 00 No. 0/2019

Gillespie’s Syndrome and Novel ITPR1 Mutation Stendel et al. 5

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