Comprehensive article on Genotype-Phenotype Correlations in 187 subjects

Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry
Louis Viollet, Gustavo Glusman, Kelley J. Murphy, Tara M. Newcomb, Sandra P. Reyna, Matthew Sweney, Benjamin Nelson, Frederick Andermann, Eva Andermann, Gyula Acsadi, Richard L. Barbano, Candida Brown, Mary E. Brunkow, Harry T. Chugani, Sarah R. Cheyette, Abigail Collins, Suzanne D. DeBrosse, David Galas, Jennifer Friedman, Lee Hood, Chad Huff, Lynn B. Jorde, Mary D. King, Bernie LaSalle, Richard J. Leventer, Aga J. Lewelt, Mylynda B. Massart, Mario R. Mérida II, Louis J. Ptáček, Jared C. Roach, Robert S. Rust, Francis Renault, Terry D. Sanger, Marcio A. Sotero de Menezes, Rachel Tennyson, Peter Uldall, Yue Zhang, Mary Zupanc, Winnie Xin, Kenneth Silver, Kathryn J. Swoboda

journal.pone.0127045.t001

To read the article click HERE

A functional correlate of severity in alternating hemiplegia of childhood

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“Alternating Hemiplegia of Childhood (AHC) can present in a mild or severe manner. Some patients are able to live close to normal lives with the help of family members, while others are wheelchair bound and completely dependent. The disease is caused by mutations in an ion transporting protein in the brain that normally helps to maintain brain excitability. The pump removes sodium ions from neurons, and replaces with potassium ions, sometimes allowing hydrogen ions to pass through the pump and into the neuron because of their small size. Scientists have found a correlation between what mutation a patient has and how severely affected the patient is. In this study, researchers sought to determine how one mutation might be causing a more severe outcome than another. They focused on the three most common mutations (D801N, G947R, and E815K). They found that each of these mutations impaired the pumps ability to function almost equally. Scientists then worked to determine if the presence of one mutated copy of the gene could impair the function of the good copy. They found just that, that one bad copy had a dominant negative effect on the pump’s function, regardless of which mutation it was. Finally, researchers investigated whether the rate at which hydrogen ions passed through was different between the mutations. Only in the case of the E815K mutation, the mutation correlated with the most severe AHC presentation, the rate was significantly decreased. A decrease in hydrogen ions in the neuron can increase seizure susceptibility. This study provides the first insight into how mutations may be associated with disease severity.”
(Translated to “layman´s terms by Cure AHC”)

For the whole article click HERE

Rare Toolkits from Global Genes

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RARE Toolkits provide individuals with usable information on a variety of topics related to living with and/or advocating for rare disease patients. RARE Toolkits are being created in collaboration with key rare disease stakeholders that have developed a vast array of subject matter expertise and believe in the importance of sharing these best practices. RARE Toolkits are interactive and will continue to evolve as advocates share additional best practices around specific topics.

More on Rare Toolkits HERE

Today is RARE DISEASE DAY

Today rare families all around the world celebrate RARE DISEASE DAY

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Rare Disease Day takes place on the last day of February each year.

The main objective of Rare Disease Day is to raise awareness amongst the general public and decision-makers about rare diseases and their impact on patients’ lives.

The campaign targets primarily the general public and also seeks to raise awareness amongst policy makers, public authorities, industry representatives, researchers, health professionals and anyone who has a genuine interest in rare diseases.

Since Rare Disease Day was first launched by EURORDIS and its Council of National Alliances in 2008, thousands of events have taken place throughout the world reaching hundreds of thousands of people and resulting in a great deal of media coverage.

The political momentum resulting from Rare Disease Day also serves advocacy purposes. It has notably contributed to the advancement of national plans and policies for rare diseases in a number of countries.

Even though the campaign started as a European event, it has progressively become a world phenomenon, with the USA joining in 2009, and participation in a record-breaking 84 countries around the world in 2014. We hope many more will join in 2015. Some countries have decided to raise rare disease awareness further, for example, Spain declared 2013 as the National Year for Rare Diseases.

Our objective is for the World Health Organization to recognise the last day of February as the official Rare Disease Day and to raise increasing awareness for Rare Diseases worldwide.

HAPPY INTERNATIONAL AHC DAY

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Today we celebrate the International AHC day, today we raise awareness on Alternating Hemiplegia of Childhood in order to speed up research process and ultimately to find a treatment for AHC.

3 years ago scientists discovered the mutated gene ATP1A3 that is the cause AHC for the majority of AHC champions.

AHC has been called by neurologist “The most complex disorder known to man”

If scientists discover what triggers the AHC episodes then we are also discovering basic functions of other much more common disorders that will eventually help millions of people all over the world.

To help us find a treatment for AHC will not just help our AHC champions but also millions of people with other disorders, perhaps someone in YOUR family……

WHAT IS AHC?

AHC is short for Alternating Hemiplegia of Childhood. Plegia refers to forms of paralysis of the body and or limbs, Hemi adds the scale of half the entire body to it and Alternating indicates that the forms of paralysis may change from one side of the body to the other. Childhood means that the disease is most often diagnosed during childhood.
AHC is a very rare neurological disorder with only about 800 diagnosed patients worldwide.

Alternating hemiplegia of Childhood is a condition that causes transient weakness of either, or both, sides of the body. The attacks may alternate or sometimes overlap, that is the second side is affected before the first recovers. Attacks start in the first eighteen months of life but the earliest episodes are often unusual irregular eye movements. The attacks last from less than an hour, which is unusual, to several days. When the attacks are prolonged the manifestations are not apparent during sleep or for the first fifteen to twenty minutes on waking when they then return. This is a very characteristic finding and when there are bilateral attacks, this may allow feeding and drinking to occur in that short clear period after waking. The episodes of hemiplegia are not epileptic in nature but epileptic seizures also occur in about half of those affected and require separate anti-epileptic drug treatment.

WHAT TRIGGERS AHC EPISODES?
All children and young adults are different and have different triggers. Some common ones are as follows:-
Water – bathing and swimming.
Anxiety.
Excitement.
Changes in temperature.
Bright lights and loud noises.
Childhood illnesses and infections.
Tiredness and lack of sleep.

What causes AHC?
A de novo mutation in ATP1A3 causes the episodes for 80% of the AHC individuals but other mutated genes cause the episodes for the remaining 20%.
Diagnoses can be confirmed by exome sequencing in majority of cases.

What’s the treatment?
The treatment most commonly used is Flunarizine (a calcium channel blocker). Other drugs have not been found to be consistently helpful. Management is complex because of the multiple impairments and episodic deterioration. Bilateral attacks (those that occur on both sides of the body) may pose hazards for nutrition, hydration and breathing.
As each child is so different with this condition a treatment or medication that works for one will not necessarily work for another.

Knock-in mouse model of alternating hemiplegia of childhood

Knock-in mouse model of alternating hemiplegia of childhood: Behavioral and electrophysiologic characterization

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Summary

Objectives

Mutations in the ATP1α3 subunit of the neuronal Na+/K+-ATPase are thought to be responsible for seizures, hemiplegias, and other symptoms of alternating hemiplegia of childhood (AHC). However, the mechanisms through which ATP1A3 mutations mediate their pathophysiologic consequences are not yet understood. The following hypotheses were investigated: (1) Our novel knock-in mouse carrying the most common heterozygous mutation causing AHC (D801N) will exhibit the manifestations of the human condition and display predisposition to seizures; and (2) the underlying pathophysiology in this mouse model involves increased excitability in response to electrical stimulation of Schaffer collaterals and abnormal predisposition to spreading depression (SD).

Methods

We generated the D801N mutant mouse (Mashlool, Mashl+/−) and compared mutant and wild-type (WT) littermates. Behavioral tests, amygdala kindling, flurothyl-induced seizure threshold, spontaneous recurrent seizures (SRS), and other paroxysmal activities were compared between groups. In vitro electrophysiologic slice experiments on hippocampus were performed to assess predisposition to hyperexcitability and SD.

Results

Mutant mice manifested a distinctive phenotype similar to that of humans with AHC. They had abnormal impulsivity, memory, gait, motor coordination, tremor, motor control, endogenous nociceptive response, paroxysmal hemiplegias, diplegias, dystonias, and SRS, as well as predisposition to kindling, to flurothyl-induced seizures, and to sudden unexpected death. Hippocampal slices of mutants, in contrast to WT animals, showed hyperexcitable responses to 1 Hz pulse-trains of electrical stimuli delivered to the Schaffer collaterals and had significantly longer duration of K+-induced SD responses.

Significance

Our model reproduces the major characteristics of human AHC, and indicates that ATP1α3 dysfunction results in abnormal short-term plasticity with increased excitability (potential mechanism for seizures) and a predisposition to more severe SD responses (potential mechanism for hemiplegias). This model of the human condition should help in understanding the molecular pathways underlying these phenotypes and may lead to identification of novel therapeutic strategies of ATP1α3 related disorders and seizures.

 

For the whole article click HERE