Alternating Hemiplegia of Childhood
(AHC) is a neurological disorder which triggers recurrent episodes
of weakness or paralysis on either side of the body as well as on both sides in
all those who are affected by it.
AHC is a complex disorder
which in addition to the above with few or many of the additional symptoms
mentioned below.
Essentially all AHC patients
also have manifestations of dystonia (abnormal muscle tone), nystagmus (rapid
movement of eyes), and many also have other abnormal limb movements, epilepsy,
postural and balance problems, cognitive delays, behavioural issues, and
delayed developmental milestones, difficulty in fine and gross motor skills, speech
and language impairment.
At molecular level, ATP1A3 gene encoding the alpha subunit of Na+/K+ -ATPase pump is implicated in AHC.
AHC is an ultra-rare disease
(affects 1 in 1,000,000 population) which is currently incurable. Little or no
treatment is available for AHC.
Definitions
Alternating hemiplegia:
This means the paralysis or weakness on one side of the body and shifts to
another side on the onset of next episode. Though it is not strictly
alternating every time, it mostly alternates.
Alternating Hemiplegia Childhood:
This means that the onset of AHC is generally in between birth to 18 months
old. The hemiplegic/quadriplegic attacks can vary greatly in duration and
generally cease completely with sleep. It is to be noted that there are adults
living with AHC, who started to have symptoms in their early childhood.
Cause and Diagnosis
Although the cause of AHC is
unknown, a number of different triggers have been identified in association
with episodes. Stress, infection and certain environmental triggers commonly
trigger episodes. Common environmental triggers include exposure to bright
lights, flashing lights, loud sounds, changes in temperature, excitement or
other strong emotions, or bath or pool water. However, attacks might occur
without any trigger as well.
Clinical diagnosis includes
understanding the pattern of episodes of the child correlating specific
symptoms. Most of the times, it is commonly misdiagnosed as epilepsy. DNA
sequencing as a confirmatory test can specifically look for mutation of ATP1A3.
In India very few cases have been reported or diagnosed so far.
What is ATP1A3
gene?
ATP1A3 gene (present in the DNA) encodes alpha-subunit protein of
the Na+/K+ -ATPase pump protein complex. This integral membrane protein, in
part, is responsible for establishing and maintaining electrochemical gradients
of sodium and potassium ions across the plasma membrane of neuronal cells.
In I971 researchers Simon
Virret and John C. Steeve first reported the occurrence of AHC. The cause
of the disease remained unknown till 2012 when it
was found that mutations of the ATP1A3 gene are the
cause in the majority of cases. Genes provide instruction for
creating protein that play key roles in the various functions of the
body, like development of brain cells, nerves, growth of limbs transport of Sodium,
potassium or calcium ions and their electrical charging to activate various
functions including higher functions of brain and other systems. Mutation of a
gene if it occurs, the protein production becomes faulty or absent or
inefficient and the resultant protein is unable to carry out its function
as needed in the cell. Depending on the function of particular
proteins, this can affect many organs of the body including the brain.
In AHC the ATP1Aa3 gene is mutated. In most cases
this mutation occurs at the time of egg or sperm production for that child
only and consequently in most of the case no other member of the
family is affected.
This type
of de-novo mutation is the usual cause of AHC, and it
is more common than the inherited type. ATP1A3 gene is responsible for
production of ATPase enzyme as explained above, which conducts
the sodium, potassium ions transport, across nerve cells and fibres
helping brain activity. If a mutation occurs, it causes a wide
variety of symptoms pertaining to the functions of brain and the heart
rhythm. In some AHC cases ATP1A3 mutation is not found and in these
cases other genes such as CACNA1, SLC2A1, ATP1A2 need
to be checked for possible mutations.
Developmental delay/cognitive challenges like Autism
Development delays including delays rolling
over, sitting, standing, walking and in the development social skills are seen
in AHC. They also have difficulty in speech and understanding. Some kids exhibit symptoms like repeating the
same sentence/question instead of reacting or answering the question. They are
often impulsive and hyperactive. However unlike children with autism they do
are usually engaging and even manipulative of their care takers and are able,
given the right conditions, to follow instructions.
Epilepsy/Seizures
Seizures or epilepsy would
mostly be the first diagnosis of kids with AHC as about 50% of them actually
have epilepsy. However almost all of them, even the ones who do not have
epilepsy, are initially misdiagnosed for epilepsy alone. The epilepsy could be
in the form of generalized or one sided stiffening (tonic) and or rhythmic
shaking (clonic) activity. It also can take the form of staring and
unresponsive seizures (complex partial seizures).
Behavioural problems
AHC is a genetic
congenital neurological disease with symptoms stating as early as
at birth and as a rule before the age of 18 months. The cardinal
symptoms are episodes of one sided paralysis that last minutes, hours or days
that often subside with sleep as well as episodes of total body paralysis and
of stiffening of different parts of the body or all the body that also last
minutes, hours or days. Development is delayed. Behavioral issues
like impulsivity, short temper, difficulty in communication, poor
concentration and learning problems often occur.
Movement problems like cerebral palsy
Kids with AHC have movement
problems like involuntary movement of limbs and body. Typically, a dance like
movement with hands clenched parallel to chest is seen while walking.
Some of them are unable to
walk or have involuntary movements in walking. They also exhibit exaggerated
reflexes when excited. Since the muscle tone is less and their motor control is
affected, they have difficulties in chewing and swallowing food. Difficulty in bowel control and hence
difficult to toilet train AHC patients during the early years can also occur.
Management and Treatment
As on now, there is not
specific treatment for AHC. However antiepileptic drugs are used in reducing
the frequency of the movement disorder episodes. Yet such drugs are not
effective in most cases.
Sleep can be very helpful
in recovering from episodes. Hence the Neurologist might prescribe such
medications to induce sleep such as chloral hydrate or benzodiazepines such as
Valium or Midazolam.
Management of AHC includes
keeping the child’s nutrition level in good state in order to improve the
development and improving the quality of life. Physiotherapy, occupationaltherapy,
speech-therapy, special education for learning disabilities can be given based
on the child’s development.
Future mainly depends on research
and clinical trials. As of now many countries in the world actively participate
in research of AHC.
Indian institutions such as
NIMHANS - Bengaluru, AIIMS - New Delhi have Paediatric Neurologists who are
familiar of AHC and its diagnosis and management. Duke AHC clinic of Duke University,
North Carolina, USA specializes in AHC.
Further Readings
1. Kalra V, Rathi S. Alternating Hemiplegia of
Childhood. Indian
pediatrics 1996; 33:233-6.
2. Heinzen EL, et al. De novo
mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat
Genet. 2012; 44: 1030–1034.
3. Kirshenbaum GS, Dawson N, Mullins JG, Johnston
TH, Drinkhill MJ, Edwards IJ, Fox SH, Pratt JA, Brotchie
JM, Roder JC, Clapcote SJ. Alternating Hemiplegia of
Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3
Missense Mutant Mice. PLoS One,2013; 8:e6014.
4. Alternating Hemiplegia of Childhood. Genetics Home Reference, National Institutes of Health, USA.
Alternating Hemiplegia of Childhood