Phenotypic Description of Patients With Atypical Clinical Forms of PLA2G6 Mutations

Study Overview
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Brief Summary
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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
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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

Official Title
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Phenotypic Description of Patients With Atypical Clinical Forms of PLA2G6 Mutations

Conditions
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Neuroaxonal Dystrophy, Atypical

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PLA2G6, atypical infantile neuro-axonal dystrophy, progressive ataxia, Karak syndrome, pediatric parkinsonism, cerebello-spastic syndrome