Regression, Ataxia, and Nystagmus in a Toddler: Unraveling a Rare Neurodegenerative Disorder

ABSTRACT

Infantile neuroaxonal dystrophy (INAD) should be considered in any toddler presenting with psychomotor regression and cerebellar atrophy, even when basal ganglia iron deposition is absent on initial MRI. Molecular genetic testing of PLA2G6 is essential for definitive diagnosis, enabling accurate genetic counseling and timely multidisciplinary supportive care.

1. Introduction

PLA2G6‐associated neurodegeneration (PLAN) represents a spectrum of autosomal recessive neurodegenerative disorders caused by mutations in the PLA2G6 gene. This spectrum encompasses infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy, and adult‐onset PLA2G6‐related dystonia–parkinsonism. These disorders share pathological hallmarks of axonal spheroids and variable brain iron accumulation but differ in age of onset and clinical presentation. While the exact prevalence is unknown, it is estimated at 1:1,000,000 [1].

Classic INAD is the earliest and most severe phenotype within this spectrum, typically presenting during the first two years of life following an initial period of normal development. The clinical picture is characterized by progressive psychomotor regression, cerebellar dysfunction, hypotonia evolving to spasticity, and cognitive decline. Ophthalmological manifestations, including nystagmus, strabismus, and optic atrophy, are frequently observed. Neuroimaging characteristically demonstrates early cerebellar atrophy, while basal ganglia iron deposition may be absent in early disease stages [2, 3].

We report a child presenting with progressive neuroregression and cerebellar degeneration, in whom systematic clinical evaluation, neuroimaging, electrophysiological studies, and genetic analysis confirmed the diagnosis of infantile neuroaxonal dystrophy.

2. Case History

A 23‐month‐old girl, born to second‐degree consanguineous parents, was brought in with a history of progressive inability to walk unassisted since 15 months of age. She was the first child of healthy parents with an uneventful antenatal, perinatal, and neonatal history.

Early developmental milestones were appropriate for age: neck control at 3 months, unsupported sitting at 7 months, standing with support at 11 months, and walking with support by 12 months. Social and language development were satisfactory during infancy; she waved “bye‐bye” at 10 months and used meaningful words such as “mama” and “papa” by 12 months. The ability to follow simple commands and appropriately request food indicated intact receptive and expressive language skills.

After 12–15 months, developmental progress plateaued, followed by insidious deterioration. Further language acquisition ceased, and verbal output became less frequent. Although she continued to respond to her name and obey simple commands, responses were slower than previously, suggesting early cognitive slowing. Motor abilities declined gradually: she developed increasing unsteadiness while standing and subsequently lost the ability to ambulate even with support. Truncal ataxia was manifest as swaying and falling when seated. Fine motor regression was sequential, with loss of purposeful reaching and emergence of tremulous hand movements; dysmetria was evidenced by consistent overshooting or undershooting of objects during attempted grasping. Over the ensuing two to three months, truncal control further deteriorated, resulting in complete dependence for mobility.

For the preceding two months, parents had observed continuous, rapid eye movements that were persistent and non‐episodic. There was no history of seizures, acute encephalopathic episodes, choreoathetoid or dystonic movements, preceding febrile illness, behavioral change, or episodic neurological worsening. No features of metabolic or systemic illness—such as rash, jaundice, steatorrhoea, or feeding intolerance—were reported. Family history was non‐contributory.

On examination, she had microcephaly (head circumference 45.5 cm) and weight (8 kg) below the third centile for age. There were no neurocutaneous markers or dysmorphic facial features. Ophthalmological evaluation revealed rotatory and horizontal nystagmus. Neurological examination demonstrated axial hypotonia with impaired truncal control. Upper limb tone was increased, particularly at the elbows, while the lower limbs showed relative distal hypotonia with developing ankle contractures. Deep tendon reflexes were increased in the lower limbs, plantar responses were absent, and there was marked muscle wasting in all four limbs, with weakness more pronounced distally. Titubation was present, consistent with cerebellar involvement; detailed cerebellar assessment was limited by the extent of motor impairment.

3. Differential Diagnosis

The differential diagnosis for progressive cerebellar and cerebral degeneration in infancy included the following conditions:

Differential diagnosis	Features supporting the diagnosis	Features arguing against the diagnosis
Neurodegeneration with brain iron accumulation (NBIA) spectrum disorders	Progressive neuroregression with evolving pyramidal features	Absence of dystonia or other extrapyramidal manifestations; no characteristic basal ganglia signal abnormalities on MRI
Neuronal ceroid lipofuscinosis	Developmental regression with visual involvement	Absence of seizures and behavioral deterioration; no diffuse cortical or thalamic abnormalities on MRI
Pontocerebellar hypoplasia	Progressive cerebellar involvement	Preserved pontine architecture on MRI; cerebellar atrophy was progressive rather than congenital; documented normal early developmental milestones before regression
Mitochondrial disorders	Progressive neurodegeneration	No episodic encephalopathy or metabolic decompensation; absence of symmetric brainstem or basal ganglia lesions on MRI; normal metabolic investigations
Congenital disorders of glycosylation	Neurodevelopmental regression	No multisystem involvement, including dysmorphic features, hepatopathy, coagulopathy, or early‐onset failure to thrive
Ataxia‐telangiectasia	Progressive cerebellar ataxia	Absence of oculocutaneous telangiectasia, immunodeficiency, and recurrent infections
Infantile neuroaxonal dystrophy (final diagnosis)	Normal early development followed by regression at 12–15 months; progressive cerebellar vermian and hemispheric atrophy with preserved pontine architecture; subcortical white matter abnormalities; ophthalmological involvement; evolving pyramidal signs; sensory axonal neuropathy	Overall clinicoradiological and neurophysiological findings strongly supported the diagnosis and prompted confirmatory genetic testing.

4. Investigations

Routine laboratory evaluation, including complete blood count, liver and renal function tests, serum ammonia, arterial blood gas analysis, thyroid function, and vitamins B12 and D3, was within normal limits. Autoimmune workup (antinuclear antibodies, complement levels C3 and C4, lactate dehydrogenase) was unremarkable. Abdominal ultrasonography and two‐dimensional echocardiography showed no abnormalities.

Electroneuromyography demonstrated distal motor latencies, CMAP amplitudes, motor conduction velocities, and F wave latencies within normal limits in left median, ulnar, common peroneal, and posterior tibial nerves. No SNAP could be elicited from left median, ulnar, and radial superficial nerves. SNAP amplitude and sensory conduction velocity are within normal limits in left sural nerve. NCS findings are suggestive of sensory axonal neuropathy.

Brain MRI showed cerebellar hemispheric and vermian atrophy, evidenced by a reduced anteroposterior vermian diameter (below the third centile), prominence of the supravermian and basal cisterns, and relative enlargement of the fourth ventricle. The pontine protuberance was preserved with no evidence of hypoplasia, and dentate nucleus myelination was appropriate for age. A few T2/FLAIR hyperintensities were noted in the subcortical white matter, indicating cortical–subcortical involvement. Notably, no signal abnormality suggestive of basal ganglia iron deposition was identified. (Figures 1, 2, 3, 4).

FIGURE 1.

T2 axial brain shows severe cerebellar atrophy with prominent inter follial spaces, 4th ventricle and cerebellopontine cisterns. Dentate nucleus appears normal.

FIGURE 2.

T2 Coronal brain shows severe cerebellar atrophy with prominent inter follial spaces, 4th ventricle and cerebellopontine cisterns. Dentate nucleus appears normal.

FIGURE 3.

Flair axial brain shows hyper intense cerebellar cortex.

FIGURE 4.

T1 sagittal brain image shows decreased AP diameter of vermis with normal craniocaudal length. Pons and midbrain appears normal.

Clinical exome sequencing subsequently identified a homozygous pathogenic variant in PLA2G6 (c.370C>T; p.His124Tyr), confirming the diagnosis of INAD (NBIA type 2B).

5. Treatment

Management was primarily supportive; the child was commenced on nutritional supplements and enrolled in regular clinical follow‐up.

6. Conclusion and Results

This case highlights the importance of considering infantile neuroaxonal dystrophy in children presenting with early‐onset neuroregression and cerebellar atrophy. A structured clinical approach incorporating neuroimaging, electrophysiology, and molecular genetic testing is essential for accurate diagnosis. Early confirmation enables appropriate genetic counseling, informed prognostication, and timely multidisciplinary supportive care for affected families.

7. Discussion

PLA2G6‐associated neurodegeneration (PLAN) represents a heterogeneous group of autosomal recessive neurodegenerative disorders caused by mutations in the PLA2G6 gene, which encodes calcium‐independent phospholipase A2 (iPLA2β), an enzyme critical for membrane phospholipid remodeling and neuronal homeostasis. The clinical spectrum includes infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and adult‐onset dystonia–parkinsonism. Among these, INAD is the earliest and most severe phenotype, pathologically characterized by widespread axonal spheroids and progressive neuronal degeneration with variable basal ganglia iron deposition [4].

The natural history of INAD is well characterized, with symptom onset typically between 6 months and 3 years—most commonly around 12–22 months. The disease begins with imbalance and developmental delay, followed by progressive neuroregression affecting speech and gross motor function. Truncal hypotonia evolving to spasticity, ophthalmological manifestations (strabismus, nystagmus, optic atrophy), and eventual cognitive and bulbar decline are hallmark features. Seizures may occur at variable stages but are not universally present [5].

The clinical course of our patient closely mirrors this phenotype. Normal early development was followed by regression around 12–15 months, initially manifesting as gait instability and loss of supported ambulation, with subsequent decline in motor skills and language output. Neurological examination revealed truncal instability, dysmetria, titubation, axial hypotonia with evolving pyramidal signs, and persistent nystagmus—features consistent with the classical trajectory of INAD.

The PLA2G6 gene, located on chromosome 22q13, encodes iPLA2β. Dysfunction of this enzyme disrupts phospholipid homeostasis, leading to oxidative stress, mitochondrial dysfunction, and progressive neuronal injury, ultimately resulting in axonal degeneration—the key pathological hallmark of INAD. Most cases arise from homozygous or compound heterozygous mutations that impair catalytic activity, producing axonal spheroids predominantly in presynaptic terminals of both the central and peripheral nervous systems [6, 7, 8]. In our patient, genetic testing confirmed a homozygous missense mutation c.370C>T (p.His124Tyr) in exon 3 of PLA2G6.

Neuroimaging plays an important supportive role in diagnosis. The most characteristic MRI finding is diffuse cerebellar atrophy, predominantly involving the inferior vermis and posterior cerebellar hemispheres, often with widening of the cerebellar folia; T2/FLAIR hyperintensity of the cerebellar cortex may also be observed [9]. Cerebellar atrophy is among the earliest radiological features and may be evident at a very young age, whereas iron deposition in the globus pallidus and substantia nigra often becomes detectable only later in the disease course [10]. The neuroimaging findings in our patient were fully consistent with these established features.

Currently, no disease‐modifying therapy exists for INAD, and treatment centres on multidisciplinary supportive care encompassing physiotherapy, nutritional support, spasticity management, and treatment of associated complications including seizures, dysphagia, and respiratory difficulties. Genetic counseling is essential given the autosomal recessive inheritance pattern. Emerging therapeutic strategies, including gene replacement approaches targeting the PLA2G6 pathway, are under investigation in experimental models, though enzyme replacement therapy and gene therapy remain investigational [2].

Author Contributions

Agasthya Daggu: writing – original draft, writing – review and editing, data curation. Siddartha Reddy Gangapuram: validation, writing – review and editing, data curation. K. Venkataramana Reddy: conceptualization, supervision, writing – original draft, project administration, writing – review and editing. Sumanth Reddy Mudiyala: data curation, writing – original draft. Lakshya Nehal Samineni: writing – review and editing. M. Geethika: writing – original draft, data curation.

Funding

The authors have nothing to report.

Consent

Written informed consent has been obtained from the patient's guardian.

Data Availability Statement

All the relevant data have been included in the manuscript itself.