AzTrials
AzTrials

Neuroaxonal Dystrophy, AtypicalATYPICPLA2G6NCT05440994

Phenotypic Description of Patients With Atypical Clinical Forms of PLA2G6 Mutations

An observational study of Neuroaxonal Dystrophy, Atypical, run by University Hospital, Clermont-Ferrand at 7 sites in France.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages Up to 18 years
Conditions the study is for
Neuroaxonal Dystrophy, Atypical
How many people
20 participants
Where
7 sitesFrance
Study dates
1 Jun 2022to 1 Dec 2022
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 18 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

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

Who may be able to join

  • 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

Who cannot join

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

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

France7 sites

  • CHU clermont-ferrand

    Clermont-Ferrand, 63000

  • CHU Grenoble

    Grenoble

  • HCL, Hôpital Femme, mère, enfant

    Lyon

  • CHU Montpellier

    Montpellier

  • APHP

    Paris

  • CHU Rennes

    Rennes

  • CHU Saint-Etienne

    Saint-Etienne

Other trials in France

About this study

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.

Read the 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
Keywords
PLA2G6, atypical infantile neuro-axonal dystrophy, progressive ataxia, Karak syndrome, pediatric parkinsonism, cerebello-spastic syndrome
Medical subject headings
NBIA2B, Karak Syndrome

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Birth term in gestational weeks

    quantitative feature, number of gestational weeks

    Measured: through study completion, an average of 9 months

  2. Age at sitting in months

    quantitative feature, age in months

    Measured: through study completion, an average of 9 months

  3. Age at walking in years and months

    quantitative feature, age in years and months

    Measured: through study completion, an average of 9 months

  4. Age at first language in years and months

    quantitative feature, age in years and months

    Measured: through study completion, an average of 9 months

  5. Acquisition of fine motor skills

    Qualitative feature, answer :Yes / No

    Measured: through study completion, an average of 9 months

  6. Autistic troubles

    Qualitative feature, answer :Yes / No

    Measured: through study completion, an average of 9 months

  7. Neurological regression

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type of regression (language, motor, social, hearing, visual)

    Measured: through study completion, an average of 9 months

  8. Progressivity of symptoms

    Qualitative feature, answer :Yes / No

    Measured: through study completion, an average of 9 months

  9. Axial hypotonia

    Qualitative feature, answer :Yes / No

    Measured: through study completion, an average of 9 months

  10. Movement disorders

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (dystonia, paroxysmal dyskinesia, parkinsonism, nystagmus, ataxia, other)

    Measured: through study completion, an average of 9 months

  11. Pyramidal signs

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (spasticity, Babinski, hyperreflexia, other)

    Measured: through study completion, an average of 9 months

  12. Intellectual deficiency

    Qualitative feature, answer :Yes / No Precision of severity (mild, moderate, severe, profound)

    Measured: through study completion, an average of 9 months

  13. Peripheral neurological signs

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (myopathy, neuropathy, areflexia, bulbar signs, other)

    Measured: through study completion, an average of 9 months

  14. Seizures

    Qualitative feature, answer :Yes / No Precision of age at onset

    Measured: through study completion, an average of 9 months

  15. Behavioral or mood disorders

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type

    Measured: through study completion, an average of 9 months

  16. Orthopaedic disorders

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (scoliosis, hip, ankle deformations, other)

    Measured: through study completion, an average of 9 months

  17. Sleep disorders

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type

    Measured: through study completion, an average of 9 months

  18. Gastro-intestinal disorders

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type

    Measured: through study completion, an average of 9 months

  19. Visual abnormalities

    Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (strabism, nystagmus, eye fundus abnormalities, other)

    Measured: through study completion, an average of 9 months

  20. 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)

    Measured: through study completion, an average of 9 months

  21. GMFCS

    GMFCS scoring from 1 to 5

    Measured: through study completion, an average of 9 months

Secondary outcomes (5)

  1. 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

    Measured: through study completion, an average of 9 months

  2. Electrophysiological findings

    Qualitative feature, answer : Yes / No Precision of type (abnormalities of EEG, abnormalities of electromyogram, abnormalities of evoked potentials)

    Measured: through study completion, an average of 9 months

  3. Pathophysiological findings

    Qualitative feature, answer : Yes / No Precision of type (abnormalities on cutaneous, muscular, nervous or other biopsies abnormalities on autopsy)

    Measured: through study completion, an average of 9 months

  4. 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

    Measured: through study completion, an average of 9 months

  5. Phenotype-genotype correlation

    Secondary analysis of phenotype-genotype correlation

    Measured: through study completion, an average of 9 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jul 2022
  2. Study start1 Jun 2022
  3. Primary completion1 Nov 2022 (estimated)
  4. Study completion1 Dec 2022 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Retrospective
Enrolment
20 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05440994
Sponsor's protocol ID
2021 SARRET ATYPIC-PLA2G6
Acronym
ATYPICPLA2G6
Status last verified
May 2022
First submitted
7 Jun 2022
Last updated
1 Jul 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

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.

    PubMed 26668131

  • 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.

    PubMed 30868093

  • 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.

    PubMed 27942883

  • 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.

    PubMed 21700586

  • 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.

    PubMed 20938027

  • 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.

    PubMed 18570303

  • 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.

    PubMed 33576074

  • 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.

    PubMed 30302010

  • 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.

    PubMed 28295203

  • 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.

    PubMed 31516627

  • 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.

    PubMed 24130795

  • 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.

    PubMed 25164370

  • 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.

    PubMed 24209433

  • 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.

    PubMed 24745848

Questions about this trial

What is this clinical trial studying?

An observational study of Neuroaxonal Dystrophy, Atypical, run by University Hospital, Clermont-Ferrand at 7 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 1 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Birth term in gestational weeks (time frame: through study completion, an average of 9 months). The study lists 21 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05440994, which also lists 19 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2022.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in