Neuroaxonal Dystrophy, Atypical
Conditions
Keywords
PLA2G6, atypical infantile neuro-axonal dystrophy, progressive ataxia, Karak syndrome, pediatric parkinsonism, cerebello-spastic syndrome
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
Interventions
None listed
Sponsors
University Hospital, Clermont-Ferrand
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GMFCS | through study completion, an average of 9 months | GMFCS scoring from 1 to 5 |
| Orthopaedic disorders | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (scoliosis, hip, ankle deformations, other) |
| Sleep disorders | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type |
| Gastro-intestinal disorders | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type |
| Visual abnormalities | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (strabism, nystagmus, eye fundus abnormalities, other) |
| Radiological abnormalities | through study completion, an average of 9 months | 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) |
| Birth term in gestational weeks | through study completion, an average of 9 months | quantitative feature, number of gestational weeks |
| Age at sitting in months | through study completion, an average of 9 months | quantitative feature, age in months |
| Age at walking in years and months | through study completion, an average of 9 months | quantitative feature, age in years and months |
| Age at first language in years and months | through study completion, an average of 9 months | quantitative feature, age in years and months |
| Acquisition of fine motor skills | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No |
| Autistic troubles | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No |
| Neurological regression | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type of regression (language, motor, social, hearing, visual) |
| Progressivity of symptoms | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No |
| Axial hypotonia | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No |
| Movement disorders | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (dystonia, paroxysmal dyskinesia, parkinsonism, nystagmus, ataxia, other) |
| Pyramidal signs | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (spasticity, Babinski, hyperreflexia, other) |
| Intellectual deficiency | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of severity (mild, moderate, severe, profound) |
| Peripheral neurological signs | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type (myopathy, neuropathy, areflexia, bulbar signs, other) |
| Seizures | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset |
| Behavioral or mood disorders | through study completion, an average of 9 months | Qualitative feature, answer :Yes / No Precision of age at onset Precision of type |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Electrophysiological findings | through study completion, an average of 9 months | Qualitative feature, answer : Yes / No Precision of type (abnormalities of EEG, abnormalities of electromyogram, abnormalities of evoked potentials) |
| Pathophysiological findings | through study completion, an average of 9 months | Qualitative feature, answer : Yes / No Precision of type (abnormalities on cutaneous, muscular, nervous or other biopsies abnormalities on autopsy) |
| Therapeutics | through study completion, an average of 9 months | 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 |
| Phenotype-genotype correlation | through study completion, an average of 9 months | Secondary analysis of phenotype-genotype correlation |
| Mutations in PLA2G6 | through study completion, an average of 9 months | Qualitative feature, answer Yes / No Precision of the name of mutation 1 / name of mutation 2 in the PLA2G6 gene for each patient |
Countries
France
Outcome results
None listed