PLA2G6-Associated Neurodegeneration

Overview:

PLA2G6 Associated Neurodegeneration (or simply PLAN) it's an extremely rare inherited
degenerative disorder of the nervous system which implies abnormalities of the nerve
endings, affecting movement, speech and cognition. There is actually a group of
neurodegenerative diseases, all caused by the mutation of the gene known as PLA2G6.
Sometimes they include brain iron accumulation, which cause progressive abnormal
involuntary movements and alterations in muscle tone, but the link between them is still
unknown.

Based on an individual’s age of onset and symptoms, their disease may be classified as one of
these three types of PLAN: INAD (Infantile Neuroaxonal dystrophy), aNAD (Atypical
neuroaxonal dystrophy), both affecting children, and PLA2G6-related dystonia-
parkinsonism, which is usually the adult-onset type.

Signs and symptoms:

Because there are many types of PLAN diseases, there are differences between each one of
them.

In children with INAD, the disease is slowing their development, causing ataxia, spastic
tetraparesis, delayed walking, psychomotor regression and visual abnormalities such as
strabismus or nystagmus. An EMG will provide the evidence of denervation and an EEG may
reveal abnormally high amplitude and fast activity of the brain.

In patients with aNAD, delayed speech and autistic features may be the first evidence of the
disease, with regression or slowed development of milestones.

The first symptoms seen in young adults with PLA2G6-related dystonia-parkinsonism are :

-Depression

-Personality changes

-Aggression

-Delusions

-Paranoia

In all of these cases, MRI indicates brain iron accumulation and cerebellar atrophy.
Causes:

This disease is caused by the mutation of the gene known as PLA 2G6. This gene encodes a
group 6 phospholipase A2, which is responsible for metabolising phospholipids. The
mutation of this gene cause an accumulation of lipids in the axons of the neurons, which will
contribute to the development of swellings called the spheroid bodies. This means that the
axonal transport is interrupted and explains the symptoms which I earlier discussed.

Risk factors and/or affected populations:

PLAN is an autosomal recessive disorder, which means that two copies of an abnormal gene
must be present in order for the disease to develop. So, it is normal that parents who are close
relatives (consanguineous) have a higher chance than unrelated parents to both carry the same
abnormal gene, which increases the risk to have children with a recessive genetic disorder.
But PLAN is so rare that the incidence and prevalence are not known with any certainty. It is
estimated to occur in about 1-2/million children.

Diagnosis:

The diagnosis is established by identification of the mutation in the PLA2G6 gene on

molecular genetic testing. Also, tissue biopsy can be considered if no PLA2G6 mutations are
identified but the evolving phenotype remains most consistent with INAD or aNAD. MRI,
EEG, EMG and sometimes microscopic examination can provide useful information about
the condition.

Complications:

Due to the fact that severe stiff muscles, progressive cognitive decline and vision loss have a
large impact on daily life, many children with INAD do not live beyond the age of 10, but
some do survive into their teens and early twenties. Death usually occurs due to secondary
problems, such as aspiration pneumonia, other infections or cardiorespiratory complications.

Treatment :

There is no cure for INAD and no treatment that can stop the progress of the disease.
Treatment is symptomatic and supportive. It is directed toward the specific symptoms that are
apparent in each individual. Currently, there are only palliative methods that can relieve
symptoms and prevent secondary complications.
Examples of actual cases:

Although death occurs usually between the age of 5 and 10 years, there is an interesting case
of a female child which lived past the age of 16. Parents were non-consanguineous and the
pregnancy was uneventful, except from a few episodes of minor bleeding. The early
development of motor and speech skills was reassuring. Concerns were first expressed at the
age of 3, when she developed an unsteady, broad-based gait. However, she commenced
mainstream education. At 10 years old she presented with 1 year history of gait deterioration,
poor balance, bilateral pes cavus deformity and left talipes equinovarus (Club foot).

Bilateral pes cavus deformity

Examination at 11 years demonstrated brisk upper limb reflexes and absent lower limb reflexes.
Features evolved over time, with deterioration in independent mobility secondary to increasing ataxia
and evolution of dystonic limb movements. At 16 years she acquired a rollator to facilitate
independence. Her speech is preserved, though intermittent dysarthria is reported.
References

https://www.sciencedirect.com/science/article/pii/S1096719214000961

https://www.ncbi.nlm.nih.gov/books/NBK1675/

https://rarediseases.org/rare-diseases/infantile-neuroaxonal-dystrophy/

https://www.frontiersin.org/articles/10.3389/fneur.2018.01100/full

https://www.sciencedirect.com/science/article/pii/B9780124051959000615