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Infantile Neuroaxonal Dystrophy

PLAN

Infantile neuroaxonal dystrophy (INAD) is a rare inherited, progressive neurodegenerative disease.


Presentation

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].

Fishing
  • These children showed remarkable dysmorphism in the face which included prominent forehead, strabismus, small nose, fish mouth (boy), micrognathia, and large and low-settled ears.[ncbi.nlm.nih.gov]
Muscle Hypotonia
  • Abstract 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]
  • .: 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]
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]
Spastic Paraplegia
  • CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain 2009 ; 132 : 1589 – 600.. The emerging role of group VI calcium-independent phospholipase A2 n releasing docosahexaenoic acid from brain phospholipids.[brain.oxfordjournals.org]
Loss of Gait
  • Abstract A 21-month-old boy with a family history of parental consanguinity and two siblings having died of a progressive neurological disorder was investigated for a neurometabolic disease because of recent loss of gait and lack of intellectual progress[ncbi.nlm.nih.gov]

Workup

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]
Cytoplasmic Inclusion Bodies
  • Independent of axonal changes, a few endoneurial and Schwann cells showed cytoplasmic inclusion bodies composed of structures similar to those seen in the spheroids.[ncbi.nlm.nih.gov]

Treatment

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.

Prognosis

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.

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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.

Summary

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].

Patient Information

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.

References

Article

  1. Schneider SA, Hardy  J, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation (NBIA): An update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Mov. Disord. 2012 27: 42–53..
  2. Morgan NV, Westaway SK, Morton JE, Gregory A, et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006 Jul;38(7):752-4.
  3. Hayflick SJ. Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Semin Pediatr Neurol. 2006 Sep;13(3):182-5.
  4. Khateeb S, Flusser H, Ofir R, Shelef I, et al. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet. 2006 Nov;79(5):942-8.
  5. Kurian MA, Morgan NV, MacPherson L, Foster K, et al. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008 Apr 29;70(18):1623-9.
  6. McNeill A, Chinnery PF. Neurodegeneration with brain iron accumulation. Handb Clin Neurol. 2011;100:161-72.
  7. Mubaidin A, Roberts E, Hampshire D, Dehyyat M, et al. Karak syndrome: a novel degenerative disorder of the basal ganglia and cerebellum. J Med Genet. 2003;40:543–6.
  8. Nardocci N, Zorzi G, Farina L, Binelli S, et al. Infantile neuroaxonal dystrophy: clinical spectrum and diagnostic criteria. Neurology. 1999;52:1472–8.
  9. Balsinde J, Balboa MA. Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells. Cell Signal. 2005;17:1052–62.
  10. Bakker HD, de Sonnaville ML, Vreken P, Abeling NG, et al. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: no association with neuroaxonal dystrophy? Eur J Hum Genet. 2001;9:91–6.

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Last updated: 2018-06-21 18:30