Clinical manifestations

Presentation and course

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. 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 (07). Epileptic seizures are rare but can occur during progression of the disease as a later symptom (21; 26). 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). 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 (08; 13). 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 (17). 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 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.

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 3 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 (23).

Biological basis

Etiology and pathogenesis

Association of PLA2G6 gene mutations and infantile neuroaxonal dystrophy was first described in 2006 (14). Numerous further studies have established the association of mutations in PLA2G6 gene located on chromosome 22q13.1 with infantile neuroaxonal dystrophy (23). PLA2G6 encodes the group VI calcium independent phospholipase protein (iPLA2-VI) that is critical in cell membrane homeostasis and maintaining membrane integrity. Defects in iPLA2-VI can lead to structural abnormalities that may underlie the axonal pathology observed in infantile neuroaxonal dystrophy (20). Pathological hallmarks include marked neuroaxonal dystrophy, severe cerebellar atrophy, and degeneration of the lateral corticospinal tracts (23). Prior to the widespread availability of genetic testing, diagnosis was made with tissue biopsy, often from skin and conjunctiva, demonstrating axonal swelling and spheroid bodies (21).

Epidemiology

The prevalence of infantile neuroaxonal dystrophy is not known. It is believed to be a rare disorder; specific incidence is unknown. The prevalence for PLA2G6-associated neurodegeneration as a group is estimated to be about 1 in 1,000,000 in the general population (07).

Prevention

When a sibling is affected and carrier status is identified, a prenatal diagnosis can be obtained. The first successful preimplantation genetic diagnosis was reported in February 2020 (10). For parents at risk, preimplantation genetic diagnosis may be an option for pregnancy with embryo unlikely to develop the condition.

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 (16). 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 (11) 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 (25).

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 (15).

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 (07).

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 (12; 02). Among these features, cerebellar atrophy is the most common finding in infantile neuroaxonal dystrophy and correlated with the phenotype severity (06). Neurophysiological findings that can be seen in infantile neuroaxonal dystrophy include axonal 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.

Management

Outcomes

There is no available definitive cure for infantile neuroaxonal dystrophy. Treatment is mainly symptomatic and supportive. Long-term management is primarily palliative and includes treatment of spasticity, seizures, drooling, constipation, and neuropsychiatric symptoms. G-tube or tracheostomy should be used as needed to prevent aspiration pneumonia. Proactive rehabilitation with physical therapy, occupational therapy, and orthopedic management early in the disease course may prevent contractures. Core body temperature fluctuations can be monitored. Periodic evaluation of swallowing, hearing, and vision can be considered. Age-appropriate dose of docosahexaenoic acid supplementation can be recommended in these patients as docosahexaenoic acid can reverse selective iPLA2-beta (protein encoded by PLAG26) inhibition (19).

An open-label study to assess the efficacy and safety of encapsulated di-deutero synthetic homologue of linoleic acid ethyl ester in patients with infantile neuroaxonal dystrophy (01) and an interventional study of novel off-label use of desipramine in these patients are ongoing (clinicaltrials.gov). Studies, including gene replacement therapy and the utilization of pharmacological chaperons to improve the function of mutant PLA2G6, are still in preparation.

Special considerations

Pregnancy

There has been no reported infantile neuroaxonal dystrophy case with pregnancy.

Anesthesia

Sedation and anesthesia should be provided at a tertiary care center with respiratory, neurology, and anesthesia providers familiar with infantile neuroaxonal dystrophy available. Similar to other neurodegenerative disorders, difficult intubation and poor respiratory status are primary concerns. Awake intubation may be challenging due to cognitive impairment (22).