Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort

M. Romani, I. Kraoua, A. Micalizzi, H. Klaa, H. Benrhouma, C. Drissi, I. Turki, S. Castellana, T. Mazza, E. M. Valente, N. Gouider-Khouja

Research output: Contribution to journalArticle

Abstract

Background and purpose: Mutations in the PLA2G6 gene are causative of PLA2G6-associated neurodegeneration (PLAN), a spectrum of neurodegenerative conditions including infantile, childhood and adult onset forms. Methods: Seventeen North African patients with a clinical suspicion of infantile-onset PLAN underwent clinical, neurophysiological and neuroimaging examinations, and PLA2G6 sequencing. Haplotype analysis was performed to date the identified founder mutation. Results: All patients carried biallelic mutations in PLA2G6. Sixteen children had the commonest form of infantile-onset PLAN, with early onset of psychomotor regression, hypotonia, pyramidal and cerebellar signs, and abnormal ocular movements. The phenotype was highly homogeneous, with rapid development of severe spastic tetraparesis, cognitive impairment and optic atrophy. Neuroimaging showed cerebellar atrophy and claval hypertrophy to be the commonest and earliest signs, whilst cerebellar cortex hyperintensity and pallidal iron deposition were later findings. Motor or sensory-motor neuropathy and electroencephalogram fast rhythms were also frequent. Nine patients from six families shared the same founder mutation (p.V691del) which probably arose by the late seventeenth century. Only one patient fitted the diagnosis of the much rarer childhood-onset PLAN. Despite the early onset (18 months), clinical progression was slower, with behavioral disturbances and dystonia. Typical features of infantile-onset PLAN such as hypotonia, nystagmus/strabismus, optic atrophy, electroencephalogram fast rhythms and motor neuropathy were absent. Cerebellar atrophy, claval hypertrophy and pallidal hypointensity were evident at brain magnetic resonance imaging. This patient carried a missense variant predicted to be less deleterious. Conclusions: The PLAN-associated phenotypes and the challenges of diagnosing the childhood-onset form are delineated, and a common North African founder mutation is identifed.

Original languageEnglish
Pages (from-to)178-186
Number of pages9
JournalEuropean Journal of Neurology
Volume22
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

Fingerprint

Neuroaxonal Dystrophies
Mutation
Optic Atrophy
Muscle Hypotonia
Neuroimaging
Hypertrophy
Atrophy
Electroencephalography
Phenotype
Cerebellar Cortex
Muscle Spasticity
Dystonia
Strabismus
Dyskinesias
Eye Movements
Haplotypes
Iron
Magnetic Resonance Imaging
Brain

Keywords

  • Founder mutation
  • Infantile neuroaxonal dystrophy
  • NBIA
  • PLA2G6
  • PLAN

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Medicine(all)

Cite this

Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort. / Romani, M.; Kraoua, I.; Micalizzi, A.; Klaa, H.; Benrhouma, H.; Drissi, C.; Turki, I.; Castellana, S.; Mazza, T.; Valente, E. M.; Gouider-Khouja, N.

In: European Journal of Neurology, Vol. 22, No. 1, 01.01.2015, p. 178-186.

Research output: Contribution to journalArticle

Romani, M. ; Kraoua, I. ; Micalizzi, A. ; Klaa, H. ; Benrhouma, H. ; Drissi, C. ; Turki, I. ; Castellana, S. ; Mazza, T. ; Valente, E. M. ; Gouider-Khouja, N. / Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort. In: European Journal of Neurology. 2015 ; Vol. 22, No. 1. pp. 178-186.
@article{07494fdadd464f318b8bee3c6bf2acb1,
title = "Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort",
abstract = "Background and purpose: Mutations in the PLA2G6 gene are causative of PLA2G6-associated neurodegeneration (PLAN), a spectrum of neurodegenerative conditions including infantile, childhood and adult onset forms. Methods: Seventeen North African patients with a clinical suspicion of infantile-onset PLAN underwent clinical, neurophysiological and neuroimaging examinations, and PLA2G6 sequencing. Haplotype analysis was performed to date the identified founder mutation. Results: All patients carried biallelic mutations in PLA2G6. Sixteen children had the commonest form of infantile-onset PLAN, with early onset of psychomotor regression, hypotonia, pyramidal and cerebellar signs, and abnormal ocular movements. The phenotype was highly homogeneous, with rapid development of severe spastic tetraparesis, cognitive impairment and optic atrophy. Neuroimaging showed cerebellar atrophy and claval hypertrophy to be the commonest and earliest signs, whilst cerebellar cortex hyperintensity and pallidal iron deposition were later findings. Motor or sensory-motor neuropathy and electroencephalogram fast rhythms were also frequent. Nine patients from six families shared the same founder mutation (p.V691del) which probably arose by the late seventeenth century. Only one patient fitted the diagnosis of the much rarer childhood-onset PLAN. Despite the early onset (18 months), clinical progression was slower, with behavioral disturbances and dystonia. Typical features of infantile-onset PLAN such as hypotonia, nystagmus/strabismus, optic atrophy, electroencephalogram fast rhythms and motor neuropathy were absent. Cerebellar atrophy, claval hypertrophy and pallidal hypointensity were evident at brain magnetic resonance imaging. This patient carried a missense variant predicted to be less deleterious. Conclusions: The PLAN-associated phenotypes and the challenges of diagnosing the childhood-onset form are delineated, and a common North African founder mutation is identifed.",
keywords = "Founder mutation, Infantile neuroaxonal dystrophy, NBIA, PLA2G6, PLAN",
author = "M. Romani and I. Kraoua and A. Micalizzi and H. Klaa and H. Benrhouma and C. Drissi and I. Turki and S. Castellana and T. Mazza and Valente, {E. M.} and N. Gouider-Khouja",
year = "2015",
month = "1",
day = "1",
doi = "10.1111/ene.12552",
language = "English",
volume = "22",
pages = "178--186",
journal = "European Journal of Neurology",
issn = "1351-5101",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "1",

}

TY - JOUR

T1 - Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort

AU - Romani, M.

AU - Kraoua, I.

AU - Micalizzi, A.

AU - Klaa, H.

AU - Benrhouma, H.

AU - Drissi, C.

AU - Turki, I.

AU - Castellana, S.

AU - Mazza, T.

AU - Valente, E. M.

AU - Gouider-Khouja, N.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background and purpose: Mutations in the PLA2G6 gene are causative of PLA2G6-associated neurodegeneration (PLAN), a spectrum of neurodegenerative conditions including infantile, childhood and adult onset forms. Methods: Seventeen North African patients with a clinical suspicion of infantile-onset PLAN underwent clinical, neurophysiological and neuroimaging examinations, and PLA2G6 sequencing. Haplotype analysis was performed to date the identified founder mutation. Results: All patients carried biallelic mutations in PLA2G6. Sixteen children had the commonest form of infantile-onset PLAN, with early onset of psychomotor regression, hypotonia, pyramidal and cerebellar signs, and abnormal ocular movements. The phenotype was highly homogeneous, with rapid development of severe spastic tetraparesis, cognitive impairment and optic atrophy. Neuroimaging showed cerebellar atrophy and claval hypertrophy to be the commonest and earliest signs, whilst cerebellar cortex hyperintensity and pallidal iron deposition were later findings. Motor or sensory-motor neuropathy and electroencephalogram fast rhythms were also frequent. Nine patients from six families shared the same founder mutation (p.V691del) which probably arose by the late seventeenth century. Only one patient fitted the diagnosis of the much rarer childhood-onset PLAN. Despite the early onset (18 months), clinical progression was slower, with behavioral disturbances and dystonia. Typical features of infantile-onset PLAN such as hypotonia, nystagmus/strabismus, optic atrophy, electroencephalogram fast rhythms and motor neuropathy were absent. Cerebellar atrophy, claval hypertrophy and pallidal hypointensity were evident at brain magnetic resonance imaging. This patient carried a missense variant predicted to be less deleterious. Conclusions: The PLAN-associated phenotypes and the challenges of diagnosing the childhood-onset form are delineated, and a common North African founder mutation is identifed.

AB - Background and purpose: Mutations in the PLA2G6 gene are causative of PLA2G6-associated neurodegeneration (PLAN), a spectrum of neurodegenerative conditions including infantile, childhood and adult onset forms. Methods: Seventeen North African patients with a clinical suspicion of infantile-onset PLAN underwent clinical, neurophysiological and neuroimaging examinations, and PLA2G6 sequencing. Haplotype analysis was performed to date the identified founder mutation. Results: All patients carried biallelic mutations in PLA2G6. Sixteen children had the commonest form of infantile-onset PLAN, with early onset of psychomotor regression, hypotonia, pyramidal and cerebellar signs, and abnormal ocular movements. The phenotype was highly homogeneous, with rapid development of severe spastic tetraparesis, cognitive impairment and optic atrophy. Neuroimaging showed cerebellar atrophy and claval hypertrophy to be the commonest and earliest signs, whilst cerebellar cortex hyperintensity and pallidal iron deposition were later findings. Motor or sensory-motor neuropathy and electroencephalogram fast rhythms were also frequent. Nine patients from six families shared the same founder mutation (p.V691del) which probably arose by the late seventeenth century. Only one patient fitted the diagnosis of the much rarer childhood-onset PLAN. Despite the early onset (18 months), clinical progression was slower, with behavioral disturbances and dystonia. Typical features of infantile-onset PLAN such as hypotonia, nystagmus/strabismus, optic atrophy, electroencephalogram fast rhythms and motor neuropathy were absent. Cerebellar atrophy, claval hypertrophy and pallidal hypointensity were evident at brain magnetic resonance imaging. This patient carried a missense variant predicted to be less deleterious. Conclusions: The PLAN-associated phenotypes and the challenges of diagnosing the childhood-onset form are delineated, and a common North African founder mutation is identifed.

KW - Founder mutation

KW - Infantile neuroaxonal dystrophy

KW - NBIA

KW - PLA2G6

KW - PLAN

UR - http://www.scopus.com/inward/record.url?scp=84923013885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923013885&partnerID=8YFLogxK

U2 - 10.1111/ene.12552

DO - 10.1111/ene.12552

M3 - Article

C2 - 25164370

AN - SCOPUS:84923013885

VL - 22

SP - 178

EP - 186

JO - European Journal of Neurology

JF - European Journal of Neurology

SN - 1351-5101

IS - 1

ER -