Phenotypic Description of Patients With Atypical Clinical Forms of PLA2G6 Mutations (ATYPICPLA2G6)

Mutations in the PLA2G6 gene are well known in the classical phenotype called infantile neuro-axonal dystrophy (INAD), a severe neurodegenerative disease starting in infancy with homogeneous clinical, radiological, electrophysiological and pathophysiological features, with early death. Other clinical forms in pediatric patients called atypic INAD have been described in some patients. Expansion of high-throughput sequencing in the last decades has lead to identify mutations in the PLA2G6 gene in pediatric patients with late-onset phenotypes associating progressive ataxia, spastic paraplegia, cognitive regression and/or dystonia / parkinsonism. A high variability in radiological and electrophysiological findings is also described. Less than twenty patients with a pediatric onset have been reported with an atypical INAD. Very poor data are available on management and therapeutic options in these patients and global prognostic is not known. This multicentric retrospective study will record clinical, radiological, electrophysiological and pathophysiological data in pediatric patients with genetically confirmed atypical INAD. Management, therapeutics and evolution of the disease will also be recorded.

Study Overview

• Status: Enrolling by invitation
• Conditions: Neuroaxonal Dystrophy, Atypical

Detailed Description

Patients with biallelic mutations in PLA2G6 with an atypic INAD starting before 18 years will be recruited after a collaboration call of neuropaediatricians in France. After family consent, a retrospective collection of data will be performed using REDCap® digital questionnaire performed by the practitioner who follows / followed each patient.

Genetical, clinical, radiological, electrophysiological, pathophysiological outcomes will be anonymously recorded. Therapeutics proposed to patients, potential complications of the disease or treatments, age of premature death will also be recorded.

Data will be computed numerically and analysed in the Clermont-Ferrand center. A descriptive analysis will be proposed as the expected number of patients affected by this rare disease varies from 10 to 30. Median []interquartiles], means [standard deviation] and percentages will be calculated for quantitative data.

Collected data will include :

• general information :

  • centre number
  • Patient (First letter last name, first letter first name)
  • Investigator name
  • Patient age
  • Patient sex
  • Age at clinical onset
  • Patient alive or deceased
  • Age when deceased
  • Ethnic origin
  • Consanguinity

• Clinical data :

  • Birth term
  • Age at sitting
  • Age at walking
  • Age at first language
  • Acquisition of fine motor skills
  • Autistic troubles
  • motor regression and age
  • Loss of walking and age
  • Language regression and age
  • Social skill regression and age
  • Vision loss and age
  • Hearing loss and age
  • Progressivity of symptoms
  • Axial hypotonia
  • Ataxia
  • Dystonia
  • Parkinsonism
  • Other paroxysmic movements
  • Spasticity
  • Hyperreflexia
  • Hyporeflexia /areflexia
  • Babinski sign
  • Peripheral neuropathy
  • Muscular atrophy
  • Bulbar signs
  • Dysarthria
  • Nystagmus
  • Strabism
  • Seizures
  • Intellectual deficiency and severity
  • Specific learning disabilities
  • Behavioral troubles
  • Mood disorders
  • Scoliosis
  • Other orthopedic abnormalities
  • Sleep disturbance or Sleep apnea syndrome
  • Gastro-intestinal troubles
  • Other symptoms
  • Patient still ambulant or not
  • Gross Motor Function Classification Score (GMFCS from 1 to 5)
  • Schooling modalities
  • Eye fundus abnormalities

• Genetic data :

  - Name of mutation 1 / mutation 2 in PLA2G6

• Radiological data :

  • Iron deposits
  • White matter abnormalities
  • Cerebellar atrophy
  • Optic nerve atrophy
  • Brainstem atrophy
  • Cortical-subcortical atrophy
  • Splenium verticalization
  • Other abnormalities of corpus callosum
  • Clava hypertrophy
  • Other abnormalities

• Electrophysiological data :

  • abnormalities of EEG
  • abnormalities of electromyogram
  • Other results of evoked potentials

• Pathophysiological data:

  • Results of potential cutaneous, muscular, nervous or other biopsies
  • Results of potential autopsy in case of deceased patients

• Therapeutical data :

  • Type of feeding (oral, tube..)
  • Ventilatory support
  • Baclofen
  • Botulinic toxin
  • L-dopa
  • Trihexyphenidyl
  • Tetrabenazine
  • Antiepileptic drugs (names)
  • neuropathic analgesic
  • Treatment os swallowing
  • Mitochondrial cocktail or other vitamins
  • Treatment of sleep disorders
  • Orthopedic or other surgery
  • Other symptomatic treatment
  • Treatment leading to aggravation
  • Treatment leading to improvement

• Study Type: Observational
• Enrollment (Anticipated): 20

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63000
    • Chu Clermont-Ferrand
  • Grenoble, France
    • CHU Grenoble
  • Lyon, France
    • HCL, Hôpital Femme, mère, enfant
  • Montpellier, France
    • CHU Montpellier
  • Paris, France
    • APHP
  • Rennes, France
    • Chu Rennes
  • Saint-Étienne, France
    • CHU Saint-Etienne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients will be recruited from a French retrospective cohort on invitation to neuropaeditricians exercing in French pediatric hospital.

Description

Inclusion Criteria:

• Children with atypical neuroaxonal dystrophy under 18 years at disease-onset
• with 2 deleterious mutations in the PLA2G6 gene
• alive or deceased
• Non-opposition of parents to participate to the retrospective study

Exclusion Criteria:

• Classical form of infantile neuroaxonal dystrophy
• Neuro-axonal dystrophy with adult-onset
• Opposition of parents to participate to the retrospective study

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Birth term in gestational weeks	quantitative feature, number of gestational weeks	through study completion, an average of 9 months
Age at sitting in months	quantitative feature, age in months	through study completion, an average of 9 months
Age at walking in years and months	quantitative feature, age in years and months	through study completion, an average of 9 months
Age at first language in years and months	quantitative feature, age in years and months	through study completion, an average of 9 months
Acquisition of fine motor skills	Qualitative feature, answer :Yes / No	through study completion, an average of 9 months
Autistic troubles	Qualitative feature, answer :Yes / No	through study completion, an average of 9 months
Neurological regression	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type of regression (language, motor, social, hearing, visual)	through study completion, an average of 9 months
Progressivity of symptoms	Qualitative feature, answer :Yes / No	through study completion, an average of 9 months
Axial hypotonia	Qualitative feature, answer :Yes / No	through study completion, an average of 9 months
Movement disorders	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (dystonia, paroxysmal dyskinesia, parkinsonism, nystagmus, ataxia, other)	through study completion, an average of 9 months
Pyramidal signs	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (spasticity, Babinski, hyperreflexia, other)	through study completion, an average of 9 months
Intellectual deficiency	Qualitative feature, answer :Yes / No Precision of severity (mild, moderate, severe, profound)	through study completion, an average of 9 months
Peripheral neurological signs	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (myopathy, neuropathy, areflexia, bulbar signs, other)	through study completion, an average of 9 months
Seizures	Qualitative feature, answer :Yes / No Precision of age at onset	through study completion, an average of 9 months
Behavioral or mood disorders	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type	through study completion, an average of 9 months
Orthopaedic disorders	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (scoliosis, hip, ankle deformations, other)	through study completion, an average of 9 months
Sleep disorders	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type	through study completion, an average of 9 months
Gastro-intestinal disorders	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type	through study completion, an average of 9 months
Visual abnormalities	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (strabism, nystagmus, eye fundus abnormalities, other)	through study completion, an average of 9 months
Radiological abnormalities	Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (Iron deposits, White matter abnormalities, Cerebellar atrophy, Optic nerve atrophy, Brainstem atrophy, Cortical-subcortical atrophy, Splenium verticalization, Other abnormalities of corpus callosum, Clava hypertrophy, Other)	through study completion, an average of 9 months
GMFCS	GMFCS scoring from 1 to 5	through study completion, an average of 9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mutations in PLA2G6	Qualitative feature, answer Yes / No Precision of the name of mutation 1 / name of mutation 2 in the PLA2G6 gene for each patient	through study completion, an average of 9 months
Electrophysiological findings	Qualitative feature, answer : Yes / No Precision of type (abnormalities of EEG, abnormalities of electromyogram, abnormalities of evoked potentials)	through study completion, an average of 9 months
Pathophysiological findings	Qualitative feature, answer : Yes / No Precision of type (abnormalities on cutaneous, muscular, nervous or other biopsies abnormalities on autopsy)	through study completion, an average of 9 months
Therapeutics	Qualitative feature, answer Yes / No Precision of type and age at onset (feeding tube / Ventilatory support / Baclofen / Botulinic toxin/ L-dopa/ Trihexyphenidyl/ Tetrabenazine / Antiepileptic drugs / Neuropathic analgesic / Treatment of swallowing / Mitochondrial cocktail or other vitamins / Treatment of sleep disorders / Orthopedic or other surgery / Other) Precision of aggravation / improvement	through study completion, an average of 9 months
Phenotype-genotype correlation	Secondary analysis of phenotype-genotype correlation	through study completion, an average of 9 months

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand
• Investigators: Study Director: Catherine Sarret, University Hospital, Clermont-Ferrand

Publications and helpful links

General Publications

• Davids M, Kane MS, He M, Wolfe LA, Li X, Raihan MA, Chao KR, Bone WP, Boerkoel CF, Gahl WA, Toro C. Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration. J Med Genet. 2016 Mar;53(3):180-9. doi: 10.1136/jmedgenet-2015-103338. Epub 2015 Dec 14.
• Erro R, Balint B, Kurian MA, Brugger F, Picillo M, Barone P, Bhatia KP, Pellecchia MT. Early Ataxia and Subsequent Parkinsonism: PLA2G6 Mutations Cause a Continuum Rather Than Three Discrete Phenotypes. Mov Disord Clin Pract. 2016 Mar 31;4(1):125-128. doi: 10.1002/mdc3.12319. eCollection 2017 Jan-Feb.
• Yamashita C, Funayama M, Li Y, Yoshino H, Yamada H, Seino Y, Tomiyama H, Hattori N. Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism. J Neural Transm (Vienna). 2017 Apr;124(4):431-435. doi: 10.1007/s00702-016-1658-7. Epub 2016 Dec 9.
• Shi CH, Tang BS, Wang L, Lv ZY, Wang J, Luo LZ, Shen L, Jiang H, Yan XX, Pan Q, Xia K, Guo JF. PLA2G6 gene mutation in autosomal recessive early-onset parkinsonism in a Chinese cohort. Neurology. 2011 Jul 5;77(1):75-81. doi: 10.1212/WNL.0b013e318221acd3. Epub 2011 Jun 22.
• Yoshino H, Tomiyama H, Tachibana N, Ogaki K, Li Y, Funayama M, Hashimoto T, Takashima S, Hattori N. Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism. Neurology. 2010 Oct 12;75(15):1356-61. doi: 10.1212/WNL.0b013e3181f73649.
• Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, Wood NW, Hardy J, Houlden H, Singleton A, Schneider SA. Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol. 2009 Jan;65(1):19-23. doi: 10.1002/ana.21415.
• McMillan HJ, Marshall AE, Venkateswaran S, Hartley T, Warman-Chardon J, Ramani AK, Marshall CR, Michaud J, Boycott KM, Dyment DA, Kernohan KD. Whole genome sequencing reveals biallelic PLA2G6 mutations in siblings with cerebellar atrophy and cap myopathy. Clin Genet. 2021 May;99(5):746-748. doi: 10.1111/cge.13935. Epub 2021 Feb 11. No abstract available.
• Koh K, Ichinose Y, Ishiura H, Nan H, Mitsui J, Takahashi J, Sato W, Itoh Y, Hoshino K, Tsuji S, Takiyama Y; Japan Spastic Paraplegia Research Consotium. PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia. J Hum Genet. 2019 Jan;64(1):55-59. doi: 10.1038/s10038-018-0519-7. Epub 2018 Oct 9. Erratum In: J Hum Genet. 2018 Nov 9;:
• Ozes B, Karagoz N, Schule R, Rebelo A, Sobrido MJ, Harmuth F, Synofzik M, Pascual SIP, Colak M, Ciftci-Kavaklioglu B, Kara B, Ordonez-Ugalde A, Quintans B, Gonzalez MA, Soysal A, Zuchner S, Battaloglu E. PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia. Clin Genet. 2017 Nov;92(5):534-539. doi: 10.1111/cge.13008. Epub 2017 Apr 19.
• Jain S, Bhasin H, Romani M, Valente EM, Sharma S. Atypical Childhood-onset Neuroaxonal Dystrophy in an Indian Girl. J Pediatr Neurosci. 2019 Apr-Jun;14(2):90-93. doi: 10.4103/jpn.JPN_91_18.
• Salih MA, Mundwiller E, Khan AO, AlDrees A, Elmalik SA, Hassan HH, Al-Owain M, Alkhalidi HM, Katona I, Kabiraj MM, Chrast R, Kentab AY, Alzaidan H, Rodenburg RJ, Bosley TM, Weis J, Koenig M, Stevanin G, Azzedine H. New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations. PLoS One. 2013 Oct 9;8(10):e76831. doi: 10.1371/journal.pone.0076831. eCollection 2013. Erratum In: PLoS One. 2013;8(11). doi:10.1371/annotation/cb01a74a-3330-4412-8040-2a94842420ed.
• Gregory A, Kurian MA, Maher ER, et al. PLA2G6-Associated Neurodegeneration. 2008 [Updated 2017]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.
• Romani M, Kraoua I, Micalizzi A, Klaa H, Benrhouma H, Drissi C, Turki I, Castellana S, Mazza T, Valente EM, Gouider-Khouja N. Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort. Eur J Neurol. 2015 Jan;22(1):178-86. doi: 10.1111/ene.12552. Epub 2014 Aug 27.
• Kurian MA, Hayflick SJ. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. Int Rev Neurobiol. 2013;110:49-71. doi: 10.1016/B978-0-12-410502-7.00003-X.
• Illingworth MA, Meyer E, Chong WK, Manzur AY, Carr LJ, Younis R, Hardy C, McDonald F, Childs AM, Stewart B, Warren D, Kneen R, King MD, Hayflick SJ, Kurian MA. PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. Mol Genet Metab. 2014 Jun;112(2):183-9. doi: 10.1016/j.ymgme.2014.03.008. Epub 2014 Mar 29.
• Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet. 2009 Feb;46(2):73-80. doi: 10.1136/jmg.2008.061929. Epub 2008 Nov 3.
• Kurian MA, Morgan NV, MacPherson L, Foster K, Peake D, Gupta R, Philip SG, Hendriksz C, Morton JE, Kingston HM, Rosser EM, Wassmer E, Gissen P, Maher ER. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008 Apr 29;70(18):1623-9. doi: 10.1212/01.wnl.0000310986.48286.8e.
• Khateeb S, Flusser H, Ofir R, Shelef I, Narkis G, Vardi G, Shorer Z, Levy R, Galil A, Elbedour K, Birk OS. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet. 2006 Nov;79(5):942-8. doi: 10.1086/508572. Epub 2006 Sep 19.
• Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S, Cangul H, Coryell J, Canham N, Nardocci N, Zorzi G, Pasha S, Rodriguez D, Desguerre I, Mubaidin A, Bertini E, Trembath RC, Simonati A, Schanen C, Johnson CA, Levinson B, Woods CG, Wilmot B, Kramer P, Gitschier J, Maher ER, Hayflick SJ. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006 Jul;38(7):752-4. doi: 10.1038/ng1826. Epub 2006 Jun 18. Erratum In: Nat Genet. 2006 Aug;38(8):957.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Anticipated): November 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: June 7, 2022
• First Submitted That Met QC Criteria: June 29, 2022
• First Posted (Actual): July 1, 2022

Study Record Updates

• Last Update Posted (Actual): July 1, 2022
• Last Update Submitted That Met QC Criteria: June 29, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: PLA2G6; atypical infantile neuro-axonal dystrophy; progressive ataxia; Karak syndrome; pediatric parkinsonism; cerebello-spastic syndrome
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroaxonal Dystrophies
• Other Study ID Numbers: 2021 SARRET ATYPIC-PLA2G6

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No