Infantile neuroaxonal dystrophy

Neurogenetic Disorders

Updated 04.28.2024
Released 04.15.2019
Expires For CME 04.28.2027

Infantile neuroaxonal dystrophy

Authors: Aravindhan Veerapandiyan MD, Ezgi Saylam MD

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Editor: AHM M Huq MD PhD

Infantile neuroaxonal dystrophy

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Introduction

Overview

Infantile neuroaxonal dystrophy, also as known as Seitelbelger disease, is an autosomal recessive neurodegenerative disorder. It is classified under the umbrella term of PLA2G6-associated neurodegeneration (PLAN) along with atypical neuroaxonal dystrophy (atypical INAD) and PLA2G6-related dystonia-parkinsonism. Symptoms usually present between 6 months and 3 years of age with psychomotor regression. Prior to onset of symptoms, patients develop normally. Clinical features include early truncal hypotonia followed by spastic quadriparesis, strabismus, nystagmus, and cerebellar ataxia. Severe muscle weakness can lead to bulbar dysfunction and difficulties in breathing and feeding. Seizures may occur in a minority. Bilateral symmetric iron deposition in globus pallidus and cerebellar atrophy are characteristic imaging findings. Genetic testing is the key element for the diagnosis and disease classification. 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. Atypical neuroaxonal dystrophy may start in early childhood.
	(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. Progression is slower in atypical neuroaxonal dystrophy.
	(4) Mutations in the PLA2G6 gene have been identified in most individuals with infantile neuroaxonal dystrophy. Demonstration of the PLA2G6 mutation may confirm the diagnosis in the setting of appropriate clinical features.
	(5) Treatment is symptomatic and supportive. A multidisciplinary approach is recommended to increase quality of life.
	(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), idiopathic neurodegeneration with brain iron accumulation and Schindler type (10).

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 (19). 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 (05) and have a different phenotype than infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation (09). Enhanced molecular diagnostic methodologies such as whole exome sequencing, and targeted gene panel testing lead to continued identification of PLA2G6 mutations expanding the clinical spectrum. Wang and colleagues described a neuroaxonal dystrophy case with hearing impairment in 2018 (27). Tan and colleagues and Li and colleagues described new pathogenic heterozygous variations of PLA2G6 gene (11; 20).

Clinical manifestations

Prognosis and complications

Typical age of onset of the disease is between 6 months and 3 years of age. The presenting symptoms of infantile neuroaxonal dystrophy are related to involvement of peripheral and central nervous systems. Symptoms include psychomotor regression, rapidly progressive hypotonia, hyperreflexia, and quadriparesis. In a study that included 18 patients with infantile neuroaxonal dystrophy, gross motor regression was the most common presenting symptom (07). Other clinical features include ataxia or gait instability, strabismus, nystagmus, and seizures. Truncal hypotonia is noted early in the disease course, which progresses over time to spastic tetraparesis with symmetric pyramidal tract signs. Similarly, strabismus and nystagmus can be earlier visual manifestations, but most individuals eventually develop optic atrophy (09). Epileptic seizures are rare but can occur during progression of the disease as a later symptom (24; 29). Bulbar symptoms, such as dysphagia, dysarthria and dysphonia, can be seen and increase the mortality and morbidity in these patients. Autonomic nervous system involvement can be manifested as constipation, cold extremities, and fluctuations in core body temperatures. Skeletal deformities, cerebellar atrophy, and elevations of serum aspartate aminotransferase and lactate dehydrogenase are also noted (03). Hearing impairment was also detected in approximately 28% of patients with infantile neuroaxonal dystrophy in one study (07). In another cohort, abnormal hearing test results were noted in 77% of patients (08). Disease progression is rapid. Patients can eventually end up in a vegetative state due to progressive motor and cognitive deterioration, severe spasticity, and visual impairment. Most patients do not survive beyond age 10 years. Mortality is typically due to complications associated with bulbar dysfunction. Classical neuroaxonal dystrophy, which is a part of PLA2G6-associated neurodegeneration is the severe end of the spectrum. Atypical neuroaxonal dystrophy is much rarer. Disease usually starts in early childhood (between 2 and 6 years) but can be as late as late teens. As a result of slower progression, affected patients may manifest with gait problems, progressive dystonia, dysarthria, speech regression, and neurobehavioral disturbances such as hyperactivity, emotional lability, and impulsivity (10; 15). Tetraparesis may occur as a late manifestation, but truncal hypotonia is much rarer. Slower disease course may resemble static encephalopathy; however, neurologic deterioration may start between 7 and 12 years of age (19). The early signs of disease may include speech impairment and loss of gross motor milestones. With disease progression, loss of fine motor skills and bulbar dysfunction can be seen.

To date, there is no standardized clinical tool assessing the severity of infantile neuroaxonal dystrophy. Atwal and colleagues developed a clinical assessment tool called Infantile Neuroaxonal Dystrophy Rating Scale (INAD RS) to monitor disease progression by evaluating gross motor skills, fine motor skills, bulbar function, ocular function, temporo-frontal function, and autonomic nervous system function (04). They demonstrated a significant correlation between scores and disease severity. INAD RS was first utilized to assess the disease severity in a cohort study. It showed that 60% of the maximum potential loss occurred within 6 months of symptom onset (07).

Clinical vignette

A 2-year-old Hispanic boy, born full-term after a normal pregnancy and delivery, presented to our clinic with motor regression and speech delay. Motor milestones were initially attained on time. He had head control at 2 months, sat unassisted at 6 months, pulled to stand at 10 months, and was walking without support at 12 months of age. He was able to climb stairs. He lost his ability to walk without support by 15 months of age but continued to cruise until 18 months of age. By 2 years of age, at the time of presentation, he could no longer cruise or crawl but could sit with minimal support for a limited time. Speech development was also normal initially. He was cooing at 2 to 3 months of age and babbling by 3 to 4 months of age. At 9 months of age, he had three words (mama, dada, and papa). His speech did not progress further. At time of evaluation, he could not point, wave, or otherwise communicate his needs to his parents. However, he could recognize his parents and smile responsively. His weight, length, and head circumference were 5th, 60th, and 50th percentile for the age, respectively.

Neurologic examination was significant for bilateral esotropia on primary gaze, restricted upgaze, lower facial diplegia, severe hypotonia, mild quadriparesis, and truncal ataxia. Musculoskeletal examination revealed a thoracic scoliosis. Remainder of his physical examination was within normal limits. The following tests were within normal limits: complete and differential blood counts; renal, liver, and thyroid function; serum lactate, pyruvate, ammonia, creatine kinase, vitamin B12, folate, iron, lead, carcinoembryonic antigen, alpha-fetoprotein, amino acids, acyl carnitine profile, and transferrin isoform assay for congenital disorders of glycosylation and cerebrospinal fluid cell counts, protein, glucose, lactate, and pyruvate. MRI of brain with and without gadolinium showed cerebellar atrophy. Chromosomal analysis and microarray were normal. Whole exome sequencing revealed a homozygous mutation c.1019_1025del7 causing a protein change of p.G340fsX24 in exon 7 of the PLA2G6 gene. Testing of his asymptomatic parents revealed that they were heterozygous carriers of the alteration. Parents were known to be distant cousins from the same small town (26).

Differential diagnosis

Early diagnosis of typical infantile neuroaxonal dystrophy can be challenging because the initial symptoms of psychomotor regression and delay can be observed in many other conditions. While evaluating a child for possible infantile neuroaxonal dystrophy, it is important to consider other disorders associated with PLA2G6 gene. Infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism are together called as PLA2G6-associated neurodegeneration.

In atypical neuroaxonal dystrophy, disease onset is generally in early childhood but can be as late as teenage years. Spastic tetraparesis noted in later stages is rarely preceded by hypotonia. Predominant extrapyramidal findings, gait instability, and ataxia can be seen. Behavioral manifestations, such as impulsivity, poor attention span, hyperactivity, and emotional lability are common. The disease course is quite static in early childhood, and deterioration is typically seen between 7 and 12 years of age. In PLA2G6-related dystonia-parkinsonism, affected individuals consistently develop dystonia and parkinsonism in their late teens to early twenties. Presenting symptoms include personality changes, aggression, delusions, stuttering, clumsiness, and dyslexia. Dystonia is most common in the hands and feet. Commonly seen Parkinsonism features are bradykinesia, resting tremor, rigidity, and postural instability.

Neuroimaging shows cerebellar atrophy in patients with infantile neuroaxonal dystrophy. A wide range of diagnoses associated with cerebellar atrophy should be considered while evaluation a child with neurodevelopmental regression and cerebellar atrophy. This includes, but is not limited to, ataxia telangiectasia, neuronal ceroid lipofuscinoses, GM2 gangliosidosis, congenital disorders of glycosylation, vanishing white matter disease, and mitochondrial disorders. Thorough history and examination along with investigations will help with etiological delineation. Approximately half of the patients with infantile neuroaxonal dystrophy have abnormal iron accumulation in the basal ganglia. Neurodegeneration with brain iron accumulation should be considered in the differential diagnosis of infantile neuroaxonal dystrophy. Elevated aspartate aminotransferase to alanine aminotransferase ratio and elevated lactate dehydrogenase in the appropriate clinical setting should raise the suspicion for infantile neuroaxonal dystrophy (18). Eye-of-the-tiger sign (abnormal low T2 signal on MRI due to accumulation of iron in the globus pallidus) is typically seen in pantothenate kinase-associated neurodegeneration (13) and not in infantile neuroaxonal dystrophy.

Another genetically related disorder to be considered in the differential diagnosis is Schindler disease. Schindler disease was originally reported in siblings with early-onset, rapidly progressive psychomotor regression, evidence of axonal spheroids, and deficiency of alpha-N-acetylgalactosaminidase (alpha-NAGA). Reports suggest that the pathogenic variants in PLA2G6 may be causative in a subset of patients with Schindler disease that have early onset neurodegenerative phenotype due to the proximity of PLA2G6 to NAGA gene in chromosome 22 (28).

Some studies have revealed compound heterozygous mutations in the PLA2G6 gene in a particular form of hereditary spastic paraplegia with early-onset spastic paraplegia, cognitive impairment, and cerebellar ataxia. Hereditary spastic paraplegia should be considered in the differential diagnosis of infantile neuroaxonal dystrophy (17).

Acquired etiologies, such as infections, increased intracranial pressure, chronic lead poisoning, hypothyroidism, subacute sclerosing panencephalitis, autism, and epileptic syndromes with regression, such as Landau Kleffner syndrome, should also be considered.

Diagnostic workup

Prior to the widespread availability of genetic testing, diagnosis was made with tissue biopsy, often from skin and conjunctiva, demonstrating spheroid bodies in axonal endings. However, with recent advances, the diagnostic approach is curtailed from invasive tissue biopsies to molecular genetic testing The diagnosis is established by identification of biallelic pathogenic variants in PLA2G6 by single gene testing, panel testing that includes PLA2G6 and other genes of interests, or whole exome sequencing. If the genetic testing did not identify any pathogenic variants and the phenotype is highly consistent with infantile neuroaxonal dystrophy, biopsy can be considered to assess for dystrophic axons or axonal spheroids. The most commonly used tissues to examine nerve structure under electron microscopy include conjunctiva, skin, rectum, muscle, or peripheral nerve. Membranotubular profiles, mitochondrial aggregates, and increased axonal diameter can be visualized under electron microscope in the dystrophic axons. Patients may need multiple biopsies as axonal spheroids accumulate over time (09).

Neuroimaging (MRI brain) findings in infantile neuroaxonal dystrophy include cerebellar atrophy, T2 hypointense globus pallidus (indicating iron accumulation), T2 hyperintensities in cerebellum suggesting gliosis and white matter, and thinning of corpus callosum (14; 02). Among these features, cerebellar atrophy is the most common finding in infantile neuroaxonal dystrophy and correlated with the phenotype severity (06), and along with vermian atrophy, it can be a key feature of infantile neuroaxonal dystrophy cerebral hypomyelination was also noted (07). Neurophysiological findings that can be seen in infantile neuroaxonal dystrophy include axonal motor/sensorimotor neuropathy and evidence of denervation in nerve conduction studies and electromyogram, respectively; fast rhythms in electroencephalogram; and delayed visual-evoked potential with reduced amplitude. Laboratory investigations may show elevated aspartate aminotransferase to alanine aminotransferase ratio and elevated lactate dehydrogenase. Extensive testing in blood, serum, plasma, cerebrospinal fluid, and urine may be required to exclude certain conditions to be considered in the differential diagnosis.

References

01: Adams D, Midei M, Dastgir J, et al. Treatment of infantile neuroaxonal dystrophy with RT001: a di-deuterated ethyl ester of linoleic acid: report of two cases. JIMD Rep 2020;54(1):54-60. PMID 32685351
02: Al-Maawali A, Yoon G, Feigenbaum AS, et al. Validation of the finding of hypertrophy of the clavain infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis. Neuroradiology 2016;58(10):1035-42. PMID 27516098
03: Altuame FD, Foskett G, Atwal PS, et al. The natural history of infantile neuroaxonal dystrophy. Orphanet J Rare Dis 2020;15(1):109. PMID 32357911
04: Atwal PS, Midei M, Adams D, Fay A, Heerinckx F, Milner P. The infantile neuroaxonal dystrophy rating scale (INAD-RS). Orphanet J Rare Dis 2020;15(1):195. PMID 32727524
05: Chu YT, Lin HY, Chen PL, Lin CH. Genotype-phenotype correlations of adult-onset PLA2G6-associated neurodegeneration: case series and literature review. BMC Neurol 2020;20(1):101. PMID 32183746
06: Darling A, Aguilera-Albesa S, Tello CA, et al. PLA2G6-associated neurodegeneration: new insights into brain abnormalities and disease progression. Parkinsonism Relat Disord 2019;61:179-86. PMID 30340910
07: Dehnavi AZ, Bemanalizadeh M, Kahani SM, et al. Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients. Orphanet J Rare Dis 2023;18(1):177. Erratum in: Orphanet J Rare Dis 2023;18(1):190. PMID 37403138
08: Ganesan P, Sankaran P, Kothandaraman PP. A rare case of hearing impairment due to cerebello-pontine angle lesion: trigeminal schwannoma. J Int Adv Otol 2015;11(2):170-2. PMID 26381011
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13: Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003;348(1):33-40. PMID 12510040
14: Illingworth MA, Meyer E, Chong WK, et al. 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;112(2):183-9. PMID 24745848
15: Jain S, Bhasin H, Romani M, Valente EM, Sharma S. Atypical childhood-onset neuroaxonal dystrophy in an Indian girl. J Pediatr Neurosci 2019;14(2):90-3. PMID 31516627
16: Khateeb S, Flusser H, Ofir R, et al. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet 2006;79(5):942-8. PMID 17033970
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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Aravindhan Veerapandiyan MD

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

Dr. Saylam University of Nationwide Children's Hospital in Columbus, Ohio has no relevant financial relationships to disclose.
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Editor

AHM M Huq MD PhD

Dr. Huq of Wayne State University has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: 0 month to 5 years
Sex preponderance: Female = male
Heredity: Autosomal recessive
Population groups selectively affected: None
Occupation groups selectively affected: None

ICD & OMIM codes

ICD: Infantile neuroaxonal dystrophy: G23.0
OMIM: Neurodegeneration with brain iron accumulation: #256600

Phospholipases A2: 603604

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Infantile neuroaxonal dystrophy

Associated Disorders

Atypical neuroaxonal dystrophy
PLAG26 associated dystonia parkinsonism

Differential Diagnosis

ataxia telangiectasia
neuronal ceroid lipofuscinoses
GM2 gangliosidosis
congenital disorders of glycosylation
vanishing white matter disease
- mitochondrial disorders
- neurodegeneration with brain iron accumulation
- Schindler disease
- Infection
- increased intracranial pressure
- chronic lead poisoning
- hypothyroidism
- subacute sclerosing panencephalitis
- autism
- epileptic syndromes with regression
- Landau Kleffner syndrome
- hereditary spastic paraplegia

Also Relevant

Childhood movement disorders
Molecular diagnosis of neurogenetic disorders
Neurodegeneration with brain iron accumulation

Clinical Categories

Neurogenetic Disorders

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Infantile neuroaxonal dystrophy

Infantile neuroaxonal dystrophy

Infantile neuroaxonal dystrophy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Patient Profile

ICD & OMIM codes

This is an article preview.
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to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Infantile neuroaxonal dystrophy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

This is an article preview.
Start a Free Account
to access the full version.