Infantile neuroaxonal dystrophy

Ezgi Saylam MD (

Dr. Saylam University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.

)
Aravindhan Veerapandiyan MD (

Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.

)
AHM M Huq MD PhD, editor. (Dr. Huq of Wayne State University has no relevant financial relationships to disclose.)
Originally released April 15, 2019; expires April 15, 2022

This article includes discussion of infantile neuroaxonal dystrophy, INAD, and Seitelbelger disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Infantile neuroaxonal dystrophy, also as known as Seitelbelger disease, is a rare autosomal recessive neurodegenerative disorder that usually presents before 3 years of age with psychomotor regression. Clinical features include early truncal hypotonia followed by spastic quadriparesis, strabismus, nystagmus, cerebellar ataxia, and bulbar dysfunction. Nearly 80% of affected children have mutations in the PLA2G6 gene on chromosome 22q13.1. The disease has a rapid progressive course leading to severe spasticity, cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade.

Key points

 

(1) Infantile neuroaxonal dystrophy is a rare autosomal recessive neurodegenerative disorder with disease onset in the first 3 years of life.

 

(2) Clinical features include early psychomotor regression or delay, truncal hypotonia, progressive cognitive decline, and severe quadriparesis. Strabismus, optic neuritis, and nystagmus are also common.

 

(3) The disease has a rapid progression, culminating in death by 10 years of age.

 

(4) Mutations in the PLA2G6 gene have been identified in most individuals with infantile neuroaxonal dystrophy.

 

(5) Demonstration of PLA2G6 mutation may confirm the diagnosis in the setting of appropriate clinical features.

 

(6) Physicians should be aware of this condition while evaluating a patient with neurodevelopmental regression.

Historical note and terminology

Neuroaxonal dystrophy refers to a group of degenerative disorders that share the same pathologic axonal spheroids throughout the central nervous system. Infantile neuroaxonal dystrophy is a subgroup of neuroaxonal dystrophy that include axonal swellings in CNS and peripheral nerves. Spheroids can also be found in pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome), idiopathic neurodegeneration with brain iron accumulation and Schindler type (Gregory et al 2008).

The discovery of PLA2G6 gene mutations have expanded the classification, and it was found that 78% of patients with infantile neuroaxonal dystrophy have mutations in the PLA2G6 gene with a locus on chromosome 22q13.1 (Kurian et al 2008). Mutations in the PLA2G6 gene have also been detected in patients with idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. Now it appears that “PLA2G6-associated neurodegeneration (PLAN)” stands for a functional classification of mutation-positive patients to reflect the shared molecular etiology of the diseases, and it comprises a continuum of the phenotypes with overlapping clinical and radiological features: infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism. Infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation have very similar clinical phenotypes with widespread neurodegeneration that begins within the first 2 years of life. Brain iron accumulation can be seen in patients with infantile neuroaxonal dystrophy. Some individuals develop high levels of iron accumulation in the globus pallidus. PLA2G6-related dystonia-parkinsonism can present with bradykinetic movement disorder beginning at 15 to 30 years of age and have a different phenotype than infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation (Gregory et al 2017).

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