In most cases, the infants with Infantile neuroaxonal dystrophy appear to grow normally until at about 6-18 months of age, when the symptoms start appearing. Infants may experience delay in achieving psychomotor development. Infantile neuroaxonal dystrophy may be classical or atypical.

Classical Infantile neuroaxonal dystrophy presents between 6 months to 3 years with psychomotor delay and developmental regression. It is characterized by truncal hypotonia progressing to tetraparesis. Dementia is also seen. Visual signs include strabismus, pendular nystagmus, uncoordinated eye movement, optic atrophy and failing vision. Seizure episodes may be seen.

The progression of disease is usually rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. During the end stages of disease, severe spasticity, progressive cognitive decline, and visual impairment result in a vegetative state [8]. Death occurs as a result of secondary illnesses such as aspiration pneumonia, associated with bulbar dysfunction. Many affected children do not survive beyond their first decade, but some survive into their teens or later.

Onset of atypical neuroaxonal dystrophy can be seen in early childhood or in late teens. Speech delay and neurobehavioral disturbance is seen. Progressive dystonia and dysarthia is seen. Visual disturbances are same as seen in classical neuroaxonal dystrophy like nystagmus, squints and gradually optic atrophy and ultimately loss of vision. Tetraparesis occurs late in disease. 

Neuropsychiatric disturbance include impulsivity, poor attention span, hyperactivity, and emotional liability. The disease progresses same like classical Infantile neuroaxonal dystrophy, leaving the child dependant [9].

• Poor Feeding

  […] swallowing Swallowing difficulties Swallowing difficulty [ more ] 0002015 Dystonia 0001332 EMG: chronic denervation signs 0003444 Emotional lability Emotional instability 0000712 Feeding difficulties Feeding problems Poor feeding [ more ] 0011968 Frontal [rarediseases.info.nih.gov]

• Hearing Impairment

  Physiotherapists, physical therapists, and special teachers for the visual and hearing impaired may help in providing relief. As mentioned above, prognosis is not very good. [cags.org.ae]

  As neurological deterioration progresses, affected children may also experience hearing impairment; progressive disorientation and loss of intellectual function (dementia); impaired response to touch (tactile stimulation); uncontrolled, rigid extensions [frostybabyblues.blogspot.com]

  impairment Deafness Hearing defect [ more ] 0000365 Hyperactivity More active than typical 0000752 Hyperreflexia Increased reflexes 0001347 Hypertonia 0001276 Impaired smooth pursuit 0007772 Impulsivity Impulsive 0100710 Intellectual disability Mental [rarediseases.info.nih.gov]

• Muscle Weakness

  Some patients may need assisted ventilation to treat respiratory muscle weakness and a pacemaker for cardiac abnormalities. [ninds.nih.gov]

  In addition, lack of muscle strength causes difficulty with feeding. This muscle weakness may also lead to problems that can cause frequent respiratory infections, such as pneumonia. [ivami.com]

  The first case was an 8 year old boy, with arrested motor and mental development, ataxia and muscle weakness. On physical examination there was horizontal and vertical nystagmus, optic disc atrophy, hypotonia; deep tendon reflexes were absent. [scinapse.io]

  Lack of muscle strength causes difficulty with feeding. Muscle weakness can also result in breathing problems that can lead to frequent infections, such as pneumonia. Seizures occur in some affected children. [ghr.nlm.nih.gov]

  Other symptoms of RSD include: Changes in your hair or nail growth, or skin’s texture Excess sweat in certain areas of your body Muscle weakness or spasms Stiff joints Trouble moving the injured area White, mottled, red, or blue skin Diagnosis Often, [webmd.com]

• Muscle Hypotonia

  A child who shows progressive motor and mental deterioration after the first year of life, who has pyramidal signs, marked muscle hypotonia, but no seizures, suggests to have infantile neuroaxonal dystrophy (INAD). [ncbi.nlm.nih.gov]

  The patient was a boy with negative family history who showed progressive neurologic symptoms (deviation of bulbi, muscle hypotonia and quadruplegia in flexion) soon after birth and died at 6 months of age. [semanticscholar.org]

• Psychomotor Retardation

  Axonic and synaptic changes in a case of psychomotor retardation: An electron microscopic study. J. Neuropath. exp. Neurol. 26, 179–199 (1967) Google Scholar Haberland, C., Brunngraber, E. G., Witting, L. [link.springer.com]

  O.: Axonic and synaptic changes in case of psychomotor retardation; an electron microscopic study. J. Neuropath. exp. Neurol. 26, 179–199 (1971) Google Scholar Ogata, J., Budzilovich, G. [springerlink.com]

  The broad spectrum is completed by a very heterogeneous group of patients with various degrees of epilepsy/behavioural difficulties/psychomotor retardation (four patients) and a mild phenotype in adults without overt neurological manifestations who have [nature.com]

• Dystonia

  In contrast, patients with dystonia-parkinsonism present with a parkinsonian movement disorder beginning at 15 to 30 years of age. [ncbi.nlm.nih.gov]

  Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism [moh-it.pure.elsevier.com]

  PLA2G6-related dystonia-parkinsonism The onset of PLA2G6-related dystonia-parkinsonism varies from childhood to second and third decade of life. [nbiadisorders.org]

• Dysarthria

  Tetraparesis occurs late in the disease and is not necessarily preceded by truncal hypotonia and patients are more likely to have progressive dystonia and dysarthria. Optic atrophy, nystagmus and seizures occur as in classic INAD. [orpha.net]

  Common muscle symptoms: -Involuntary muscle contractions (dystonia) -Poor articulation and speech (dysarthria) -Muscle tightness and weakness in both arms and legs -Reduced joint mobility due to muscle tightness -Overactive reflexes developing early disease [rarediseases.org]

  Other common features are dysarthria (difficulty pronouncing words), autonomic involvement and mild cerebral atrophy. Management Consider treating with dopaminergic agents. Consult a psychiatrist to treat neuropsychiatric symptoms. [nbiadisorders.org]

  In contrast to classic disease, extrapyramidal findings (i.e., dystonia and dysarthria) predominate in atypical NAD. Eye findings are similar to those seen in classic INAD. [ncbi.nlm.nih.gov]

• Pyramidal Tract Signs

  tract signs, marked hypotonia and early visual disturbances without epileptic seizures. [ncbi.nlm.nih.gov]

  The most common, classic form of the disease has its onset between six months to three years after an affected child's birth, when it presents with hypotonia progressing to spasticity, progressive psychomotor delay, and symmetric pyramidal tract signs [cags.org.ae]

  tract signs and spastic tetraplegia. [globalgenes.org]

  It is characterized by a progressive motor and mental deterioration, bilateral pyramidal tract signs, marked hypotonia, and early visual disturbances without epileptic seizures. [medigoo.com]

  The classic form begins before age three with hypotonia, progressive psychomotor delay and symmetric pyramidal tract signs (strabismus, nystagmus and optic atrophy). [scielo.mec.pt]

• Tremor

  To make matters worse, David and Glenda thought Katherine was beginning to exhibit a slight tremor and difficulty maintaining her balance. [parenting.blogs.nytimes.com]

  The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability. [ncbi.nlm.nih.gov]

  The main features are variable onset from childhood to young adulthood; parkinsonism (tremor, bradykinesia, rigidty, and impaired postural responses); dystonia; cognitive decline; neuropsychiatric (mental disorder due to disease of the nervous system) [nbiadisorders.org]

  Hyperreflexia Increased reflexes 0001347 Hypertonia 0001276 Impaired smooth pursuit 0007772 Impulsivity Impulsive 0100710 Intellectual disability Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ] 0001249 Intention tremor [rarediseases.info.nih.gov]

  Common symptoms include: -Tremors -Decreased muscle movement (hypokinesia) -Stiffness -Loss of balance -Walking difficulties: shuffling, freezing or getting stuck while walking -Involuntary muscles contractions and spasms (dystonia) – Poor articulation [rarediseases.org]

• Pendular Nystagmus

  Visual signs, including strabismus, pendular nystagmus, uncoordinated eye movements, optic atrophy and failing vision are generally early and prominent. Seizures occur in a minority. [orpha.net]

  Visual signs include strabismus, pendular nystagmus, uncoordinated eye movement, optic atrophy and failing vision. Seizure episodes may be seen. The progression of disease is usually rapid. [symptoma.com]

Workup should include a thorough neurological examination, a complete ophthalmic check up and a correct genetic consultation. A proper history should be taken to know the course of disease and time of onset. The age of the child should be considered. It along with the subjective and objective symptoms of the patient helps to come near the diagnosis.

• Brain MRI and ophthalmologic examination are recommended first as cerebellar atrophy and optic atrophy are strong clinical features. T2 weighted MRI of brain shows hypointense globus pallidus (indicating iron accumulation), cortical cerebellar hypointensities consistent with cerbellar gliosis, white matter abnormalities, thin vertically oriented corpus callosum. Seizures may present early or late in the disease course. EMG (Electromyogram) shows evidence of denervation. EEG (Electroencephalogram) shows fast rhythms. Visual Evoked Potential (VEP) is delayed with reduced amplitudes. Nerve Conduction Velocity (NCV) shows distal axonal type sensory motor neuropathy.
• Molecular genetic testing is done to find mutation of PLA2G6 gene. A blood sample is taken for the testing of PLA2G6 gene. If suspicion remains high, molecular genetic testing by sequence analysis is followed by deletion/duplication testing of PLA2G6 gene. This is recommended as the next step instead of invasive biopsy.
• If no mutation of PLA2G6 is found but the involving phenotype remains most consistent with Infantile neuroaxonal dystrophy OR atypical neuroaxonal dystrophy then Tissue Biopsy is done, to assess for axonal spheroid. The preferred tissues are conjunctiva, skin, rectum, other peripheral nerve. The piece of skin or conjunctiva was put under the microscope to look for the spheroid bodies. But there are other conditions which also have presence of spheroid bodies, so this along with clinical history plus the age of the patient are considered before coming to the diagnosis [10].

• High-Voltage Fast Rhythms

  The presence of high voltage, fast rhythms in the EEG and signs of denervation of an anterior horn-cell type at EMG, with normal nerve conduction velocities, is frequent additional evidence in favour of infantile neuroaxonal dystrophy. [ncbi.nlm.nih.gov]

The treatment of Infantile neuroaxonal dystrophy remains palliative to provide symptomatic relief to the patient. Every care should be taken to control the symptoms and give comfort to the child.

Pharmacologic treatment is given to control seizure and spasticity. Trial of oral or intrathecal baclofen is recommended for those having significant dystonia. Psychiatrists are brought in for the later stage when the patient has neuropsychiatric symptoms. Fiber supplements are given to treat constipation which is likely to be caused due to immobility. Gastric feeding tube or tracheostomy is done to prevent aspiration pneumonia.

Transdermal scopolamine patch to reduce the secretion in those with excessive drooling. Drugs to treat pain and infection are given if required. A physiotherapist can be engaged to guide and assist parents on positioning their affected children to provide better comfort. Specialized schooling is required. Some of the alternative therapies like cranial osteopathy and massage are found to give symptomatic relief.

There are no symptoms at birth, however as the child grows from 6 months to 2 years, the symptoms become apparent. The condition worsens with age. Over several years, the child becomes dependant wholly and eventually loses all learned skills and intellect. Death occurs by the age of 5-10 years. The prognosis is thus poor.

Infantile neuroaxonal dystrophy is caused by deposition of a substance called spheroid bodies (because of their appearance under microscope) in the axons of the nerves particularly those going to the muscles, skin and conjunctiva. It is not clear why these substances are deposited, but it is thought that the gene responsible for clearing the unwanted substance does not function properly.

Mutations in PLA2G6 gene are identified as the cause of the disease. However, some other gene is also thought to be responsible for it. Research for this is under progress [2] [3]. In some cases there is no mutation found and the cause remains a complete mystery.

It is a rare disease with the incidence of less than 1: 200,000. No gender or race predilection has been found owing to the exceedingly low number of cases.

PLA2G6 is the gene which has the instruction for making A2 phospholipase. It is involved in metabolism of phospholipids. Phospholipid metabolism is important to keep the cell membrane intact and function properly. A2 phospholipase produced from PLA2G6, regulates the level of phosphatidycholine which is found abundantly in cell membranes. Mutation in the PLA2G6 gene causes impairment in functioning of the enzyme and thus causes disturbance in maintaining the integrity of cell membrane leading to development of spheroid bodies in the nerve axon [4].

Due to the formation of such abnormal depositions in the parts of the brain, their function is hampered. The nerve endings going to different parts of body are affected due to presence of spheroid bodies particularly those going to muscles, skin and conjunctiva, thus gradually declining their function. It is also believed that there are abnormal amounts of iron deposited in the basal ganglia of the brain too [5] [6] [7].

Infantile neuroaxonal dystrophy is an inherited disorder and thus genetic counseling is done to determine the couple at risk of having affected child. Prenatal testing for Infantile neuroaxonal dystrophy is now usually possible if PLA2G6 gene is found in affected child.

Infantile neuroaxonal dystrophy (INAD) is a rare, hereditary disorder affecting the nervous system. It is seen in children between the ages of 6-18 months were they experience delay in acquiring motor and intellectual skills, have progressive loss of vision and reduction of physical and mental performance. It is also observed in late teenage when it is called atypical neuroaxonal dystrophy. In both the cases, the disease progresses towards death and symptomatic relief is the only treatment available.

It is an autosomal recessive disorder wherein both the parents are carrier of the disease and there are 25% chances of one of their kid having the disease. In the 1950’s, Dr Seitelberger described the disorder and it is still sometimes known as Seitelberger’s disease [1].

Infantile neuroaxonal dystrophy (INAD) is a rare inherited disease whereby both the parents are carrier and thus the chances of one of their child having Infantile neuroaxonal dystrophy is 25%. It is seen between the age of 6-18 months or it can also occur in late teenage.

The nerve endings responsible for carrying message to other parts of body are affected causing a progressive loss of vision and of physical and mental skills. Their muscles become weak and floppy and gradually very stiff. Eventually affected children loose their ability to move independently. Muscle strength decreases causing them difficulty in taking feeds and breathing thus making them prone to various infections causing pneumonia. Seizure may also occur in some patient. Eyes are affected causing rapid, involuntary eye movement, eyes that look in same direction and gradually loss of vision. Hearing loss may also occur. Children with this disorder loose their memory and eventually loose awareness of their surroundings.

The disease progresses rapidly and the child usually does not cross the decade. Diagnosis is done by doing MRI of brain, ophthalmic examination and genetic counseling. Management includes symptomatic relief.

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