Phenotypic Description of Patients With Atypical Clinical Forms of PLA2G6 Mutations

NCT ID: NCT05440994

Last Updated: 2022-07-01

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 20 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-06-01
• Study Completion Date: 2022-12-01

Brief 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. 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.

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

Conditions

Neuroaxonal Dystrophy, Atypical

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Eligibility Criteria

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

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Clermont-Ferrand

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Catherine Sarret

Role: STUDY_DIRECTOR

University Hospital, Clermont-Ferrand

Locations

CHU clermont-ferrand

Clermont-Ferrand, , France

CHU Grenoble

Grenoble, , France

HCL, Hôpital Femme, mère, enfant

Lyon, , France

CHU Montpellier

Montpellier, , France

APHP

Paris, , France

CHU Rennes

Rennes, , France

CHU Saint-Etienne

Saint-Etienne, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 30868093 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27942883 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21700586 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20938027 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18570303 (View on PubMed)

Gregory A, Kurian MA, Maher ER, Hogarth P, Hayflick SJ. PLA2G6-Associated Neurodegeneration. 2008 Jun 19 [updated 2017 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1675/

Reference Type: BACKGROUND

PMID: 20301718 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33576074 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30302010 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28295203 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31516627 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25164370 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24130795 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26668131 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24209433 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24745848 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18981035 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18443314 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17033970 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16783378 (View on PubMed)

Other Identifiers

2021 SARRET ATYPIC-PLA2G6

Identifier Type: -

Identifier Source: org_study_id