Journal Article

The natural history of infantile neuroaxonal dystrophy

Milner, Peter, Hamad, Muddathir, Atwal, Paldeep S., Endemann, Sarah, Altuame, Fadie D., Foskett, Gretchen, Salih, Mustafa A., Alkuraya, Fowzan S., Midei, Mark, Hashem, Mais, Al-Muhaizea, Mohammad

2020

Overview

Background Infantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6 , which encodes a calcium-independent phospholipase A2. Objective We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings. Materials and methods We comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6 -associated neurodegeneration (PLAN) and a clinical history consistent with INAD. Results In our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern ( p  = 0.04), initial loss of language ( p  = 0.001), initial loss of fine motor skills ( p  = 0.009), and initial loss of bulbar skills ( p  = 0.007). Conclusion INAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Age / Analysis / Atrophy / Calcium / Cerebellum / Children / Clinical trials / Development and progression / Dystrophy / Families & family life / Family medical history / Gait / Gastrointestinal diseases / Health care industry / Human Genetics / Hypoxia / INAD / INAD protein / Infantile neuroaxonal dystrophy / Laboratories / Magnetic resonance imaging / Medical records / Medical research / Medical schools / Medicine / Medicine & Public Health / Molecular genetics / Motor skill / Natural history / Nervous system / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neurophysiology / Nystagmus / Patients / Pharmacology/Toxicology / Phospholipase A2 / Phospholipases / Rare diseases / Rare neurological diseases / Seizures / Siblings / Statistical analysis / Strabismus