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SSADH Research Projects

Natural History Study

Dr. Gibson was awarded $686,980 from a grant through the NIH to conduct a Natural History Study which will be of great value for future research and for the FDA drug approval process. The Natural History Study will aim to determine the natural evolution and the clinical presentation of SSADH with yearly neurological and neuropsychiatric assessments.

SSADH has a broad spectrum of symptoms and severity varies greatly among patients, even within the same family. Our hope is that the Natural History Study and the complimentary Biorepository will help to correlate clinical severity with prior-years predictor levels to better determine the natural evolution of SSADH.


We are close to the beginning of an NIH-funded study that will carry out a 5-year Natural History of SSADH (succinic semialdehyde dehydrogenase) deficiency. This study will include clinical data (imaging, electrophysiology, neuropsychiatric evaluation, etc) and biomarker data (blood, urine, CSF, saliva, DNA, etc).

Primary intake site for patients in the USA will be at Boston Children’s Hospital, under the direction of Dr. Phillip Pearl. It is likely that this site will only follow patients from the USA.

However, we hope to include cross-sectional and longitudinal data on patients seen around the world, in order to increase the power of this study. Our primary European partner is Dr. Thomas Opladen, University of Heidelberg, who is the Director of the iNTD (International Working Group on Disorders of Neurotransmitter Metabolism; https://intd-registry.org/).

We encourage you to consider enrollment of the iNTD. This would make the transfer of patient data between iNTD and our study facile, and benefit both sources.

The iNTD group already has 15 enrolled patients with SSADH deficiency. The easiest way to enroll is to contact Kathrin Jeltsch at the iNTD directly by email at: Kathrin.Jeltsch@med.uni-heidelberg.de

Please see the note below from Dr. Gibson regarding the Natural History Study.

I want to thank you again for your letters of support for this NIH grant application submitted by Drs. Jean-Baptiste Roullet and Mike Gibson (Washington State University) and his colleagues, Dr. Phillip Pearl, (Boston Children’s Hospital), Dr. Thomas Opladen (University Children’s Hospital, Heidelberg, Germany), Dr. Jeff Krischer (University of South Florida). They received over 50 letters of support, representing 58 patients with SSADH deficiency. Thanks to this overwhelming support, the NIH funded this project Aug. 1, 2018 for a period of 5 years.

To recap, this study plans to enroll and track more than 50 patients with SSADH deficiency over a period of 5 years. Some (approx. 25, USA patients only) will be followed at Boston Children’s Hospital, under the guidance of Dr. Pearl. The others will be recruited and followed by investigators of the International Working Group on Neurotransmitter Related Disorders (iNTD; https://intd-registry.org/) under Dr. Opladen’s guidance, and by several Metabolic experts throughout the world. The goal is to collect clinical observations and biospecimens (blood, urine, saliva, hair and stool, and others) to understand how the disease progresses over time and find better markers useful for early diagnosis (newborn screening) and therapeutic monitoring. USF Dr. Krischer, one of the world’s most recognized epidemiologist and statistician, will oversee data analysis.

At this time, the project is working on study approval via Ethics Board documents, a necessary step before any study activity, including enrollment, could begin. Thus, the research team does not realistically expect to enroll patients until early 2019. Nonetheless, I wanted to alert all of you to the eventual start of the study, hoping you will keep in mind the opportunity to participate and contribute to SSADHD research.

On a final and important note, enrollment in the study will require confirmed genetic SSADHD diagnosis. Some of you may not have such confirmation. Do not be concerned about this, as the Association and the researchers will help with mutation analysis, should you decide to participate in the study. Do not hesitate to contact me if you have questions about the study. I will personally keep you updated on study readiness and alert you as soon as the study team is ready to enroll!

1. Claudio Cinquemani (cinquemani@gmx.de)
2. Purificación Ríos Aroca (o.rios@deneu.org)
3. Mike Gibson (mike.gibson@wsu.edu) and Jean-Baptiste Roullet (j.roullet@wsu.edu)


$1.58 Million grant awarded to Mike Gibson, PhD. from the National Eye Institute 
Click here to read more about the grant.

Proposed Natural History Study of Patients with SSADH

Dr. Phil Pearl (Boston Children’s Hospital, USA), Mike Gibson PhD (Washington State University, USA) and Dr. Thomas Opladen (University Children’s Hospital, Heidelberg, Germany) are applying for a grant from the National Institutes of Health (NIH) in the United States to fund a Natural History Study of patients with Succinic Semialdehyde Dehydrogenase Deficiency (SSADH).

If this grant is approved it will allow the team to follow a cohort of approximately 20 patients over a specified period of time, with in-depth yearly appointments at a clinical intake center in the USA or Germany.  The purpose of the study would be to gain better knowledge of the disorder, help find effective treatments and to improve the quality of life for SSADH patients.

However at this time the SSADH Association has been asked to get signatures from SSADH families to show that we have an interest in being a part of the Natural History Study.  Your signature at this time would just help to emphasis our commitment to helping those with SSADH.

If you are interested in supporting this grant submission, please contact Carolyn Hoffman at choffmanwi@aol.com.



2016 Research Update 


$100,000 was awarded to K. Michael Gibson, PhD, FACMG at Washington State University to garner efficacy data over a two year period, in the SSADH deficient animal model to form the framework for the Investigational New Drug Application with the NIH for the use of compounds NCS-382 (GHB Antagonist) and HOCPCA.

This grant led to the success of a Small Business Technology Transfer (STTR) award from the National Institutes of Health (NIH) allowing for a Phase I Toxicology Study on NCS-382.  The goal is to complete this study by the fall of 2017. Pending results, we will then apply for a Phase II study potentially moving NCS-382 into a NIH clinical trial. 

$100,000 was awarded to Phil Pearl, MD & Robin Kleiman, PhD, to fund a one year research grant in conjunction with Boston Children’s Hospital and Harvard University. The objective of this project is to develop an in vitro disease model of SSADH Deficiency from patient iPSC lines differentiated into GABAergic neurons that will support phenotypic drug screening.

$10,000 was committed to kick off a Natural History Study with the US medical team of Phil Pearl, MD, (Boston Children's Hospital), Jean-Baptiste Roullet, PhD, and Mike Gibson, PhD, FACMG, (both from WSU), together with Evangeline Wassmer, PhD (UK), Thomas Opladen, MD, (Germany) and Garcia-Cazorla, PhD, (Spain) who will work with the SSADH Association on a grant proposal to support a multi-year (5+) and multi-site natural history study of SSADH patients. 

2016 NIH SGS-742 Trial Update
The initial goal of the NIH SGS-742 Medication Trial for SSADH patients that started in 2013 was designed to test a total of 22 patients.  However, struggling to meet that 22 patient goal, the NIH lowered the age restriction from 8 to 4 years of age in 2016.  The NIH also agreed to allow non-US patients to participate and extended the study through March of 2018. 

We are grateful to those who have participated in the trial and have gone to great measures to get the concessions in place with the NIH in hopes of having 22 patients complete the trail.  Please consider participating as this trial is not just imperative for this medication, but for all future NIH sponsored research opportunities for SSADH patients.

Understanding the critical importance of this effort, the SSADH Association has committed to financially support non-US patients and their caregivers to travel to the United States to complete the SGS-742 Medication Trial.  While the exact amount is not known at this time, an estimate of funds could be as high as $20,000Click here for details about the SGS trial from the NIH Website.

NIH Contact Information:
Tamika N. Mason [C]
Patient Care and Recruitment Specialist, Clinical Epilepsy Section
NINDS/NIH Building 10
10 Center Drive, Rm 7-5644 SW
Bethesda, MD 20892
Phone: 301-496-1923
Fax: 301-480-8383

Please contact Carolyn Hoffman by email at choffmanwi@aol.com if you are interested in being a part of the trial or if you have contacted the NIH and have not heard back.

Letter from K. M. Gibson, PhD, FACMG to SSADH patients requesting Hair Samples to measure the Gamma-Hydroxybutyrate (GHB) level.
Click here to review the letter.

Letter from K. M. Gibson, PhD, FACMG to SSADH families regarding the SGS-742 Medication Trial at the National Institutes of Health (NIH).
Click here to review the letter.


If you are have any questions, please contact:

Tamika N. Mason [C]
Patient Care and Recruitment Specialist, Clinical Epilepsy Section
NINDS/NIH Building 10
10 Center Drive, Rm 7-5644 SW
Bethesda, MD 20892
Phone: 301-496-1923
Fax: 301-480-8383

Click here to link to the NIH Web Site 


Urine Samples Requested

Cedric Wrenil, PhD., University of Applied Sciences, Switzerland, is looking into a new method to detect SSADH in urine for possible newborn screening options.  Please send a urine sample to him from your SSADH patient. 

Click here for shipping instructions.


Progress Report from Dr. Lakhani
National Institutes of Health awarded R21 Grant to Dr. Lakhani, the amount of $275,000 over the next two years to continue allowing him to focus on both mechanistic studies in yeast as well as work on mammalian cell studies for SSADH.  

Click here to read further details on Dr. Lakhani's Reserach

Research Notes from Family Meeting in Wisconsin
Mike Gibson, Ph.D at WSU meet with a group of SSADH families after the Chip for Charity Golf Outing in Wisconsin to discuss current SSADH Research.

Click here to read the notes from that meeting.

NIH Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
Recruiting Patients

Detailed Description:

Objective: To perform a clinical trial assessing the safety, tolerability and efficacy of the GABA(B) receptor antagonist SGS-742 in patients with SSADH deficiency.
Study Population: Twenty-two children and adults with SSADH deficiency.

Design: Double-blind, cross-over, phase II clinical trial. SGS-742 is a GABA (B) receptor antagonist that has shown to be safe and well-tolerated in clinical trials in adults with cognitive impairment. In addition, preliminary data in the SSADH knockout mouse model suggest efficacy in this specific syndrome. The primary outcome measure will be a change in the Auditory Comprehension subtest of the Neuropsychological Assessment Battery Language Module score; the secondary outcome measure will be a change in cortical excitation and inhibition measured by transcranial magnetic stimulation (TMS).

Additional evaluations will include neurological and neuropsychological examinations, magnetic resonance spectroscopy and CSF collection to measure GABA levels.

The trial will have a baseline phase in which each patient will undergo a neurological examination and a neuropsychological evaluation. During the subsequent treatment phase, patients will be randomized to SGS-742, supplied by IRIX Pharmaceuticals, 600 mg t.i.d. given orally, or placebo, each for 6 months. Patients will then have repeat TMS, neurological and neuropsychological evaluations, followed by cross-over to the alternate treatment arm, and re-evaluation after 6 months.

Outcome Measures: The primary outcome measures for drug efficacy will be TMS parameters of cortical excitation and inhibition. The secondary outcome measure will be performance on neuropsychological testing. The outcome measures for safety will include clinical examination and neuropsychological tests.

Click here to link to the NIH Web Site.

We are encouraging families to participate in the SGS-742 Trial.

If you are willing to be part of the study or want more information about what is involved, please contact:

Tamika N. Mason [C]
Patient Care and Recruitment Specialist, Clinical Epilepsy Section
NINDS/NIH Building 10
10 Center Drive, Rm 7-5644 SW
Bethesda, MD 20892
Phone: 301-496-1923
Fax: 301-480-8383

SSADH Association awards a $79,500 Research Grant to Ronak Lakhani, PhD
Dr. Ronak Lakhani at the University of California, San Diego, will continue his 2013 SSADH research through 2014. Dr. Lakhani submitted an application to determine if the induction of autophagy by Rapamycin would remove surplus organelles, thus reducing oxidative stress and restoring cellular homeostasis which may lead to potential treatments for SSADH deficiency.

These are the next steps that Dr. Lakhani will be working on:

1. Continue mechanistic studies for the GABA mitophagy/pexophagy project

2. Use qPCR to see if rapamycin can reduce oxidative stress markers in SSADH-deficient mice using RNA samples of WT mice and Aldh5a1-/- mice treated with rapamycin or vehicle alone.

3. Determine if other selective autophagy pathways are impacted in SSADH deficiency.

We are excited to have Dr. Lakhani continue his research in the hope of finding treatment for SSADH patients.


SSADH Association awards a $79,450 Fellowship Grant to Ronak Lakhani, PhD

Dr. Ronak Lakhani is a Post-Doctoral Fellow at the University of California, San Diego. In early 2013, Dr. Lakhani submitted an application for the SSADH Association to fund a project that may lead towards an eventual clinical trial to treat SSADH Deficiency.

After careful evaluation by several members of the SSADH Association’s Medical and Scientific Advisory Committee, the Board of Directors approved the funding of Dr. Lakhani’s project which is to a potential treatments for SSADH Deficiency.

SGS-742 Award Announcement
Testing of an experimental drug’s effectiveness on an inherited disorder with characteristics of autism and epilepsy has been funded by a $743,974 grant from the National Institutes of Health to K. Michael Gibson of the Washington State University professor.

NIH (National Institutes of Health) SSADH Study Authorized
Note from Dr. Phil Pearl  5/13/2012

We have at long last received approval from the NIH to begin studies of SSADH deficiency patients on taurine. This is a prelude to a study we anticipate in the not too, too distant future of SGS using the same biomarkers, now that the rights have been acquired by the NIH from the pharmaceutical company and we are working on approval to begin this experimental agent. We need to show we can meet recruitment goals with this first phase.

Please send an update with your child’s current age, weight, and whether he or she is taking taurine. If so, what brand (hopefully GNC, to keep this uniform) and what dose? Only patients age 12 and over can participate at this time, and this is currently limited to US citizens.

We will want to be sure your ABAS form is updated and we will then schedule you to be seen at the NIH to embark on a series of test procedures.

The protocol involves baseline testing and repeat following three months of taurine therapy at the target dose. The tests are:

·         Flumazenil-ligand brain PET (for patients > 18 years only)

·         Transcranial magnetic stimulation

·         MR spectroscopy for quantitation of GABA and related metabolites

·         CSF for quantitation of GABA and related metabolites

·         Neuropsychological evaluation

·         EEG

The tests will be done also at a 3 month interval “off” taurine, so it is fine to enter whether your child is currently on or off the taurine.

If you are interested in being involved in this study please email myself at ppearl@childrensnational.org and Danniele Provost at Provost@cnmc.org

Thank you.

Phillip L. Pearl, M.D.
Division Chief, Child Neurology
Children's National Medical Center
Professor of Pediatrics, Neurology, and Music
The George Washington University School of Medicine and Columbian College of Arts and Sciences
Washington, D.C.
Fax 202-476-5226
E-mail ppearl@childrensnational.org

National Institute of Health (NIH) Clinical Research Study
Protocol Number: 05-N-0224
Cortical Excitability in Succinic Semialdehyde Dehydrogenase Deficiency Patients

This study will measure brain excitability in patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, and in their parents.  SSADH is a rare inherited disease in which changes in certain brain chemicals affect brain cell activity.  Symptoms vary greatly among patients, and may include mental retardation, impaired ability to coordinate movements, and delay in language and speech development.  Other symptoms may include poor muscle tone, uncontrolled seizures and other neurological or behavioral abnormalities.  Test findings in patients and their parents will be compared with those of healthy normal volunteers.

The participants undergo the following:

Transcranial Magnetic Simulation (TMS)
Magnetic Resonance Imaging (MRI)
Electroencephalography (EEG)
Sleep study and Multiple Sleep Latency onset Testing (MSLT)
Nerve conduction studies

National Institute of Health (NIH) Clinical Research Study
Protocol Number: 05-N-0022
PET Imaging of GABA Receptors in Succinic Semialdehyde Dehydrogenase Deficiency

This study will use brain imaging to map brain cell receptors for a chemical called GABA, a chemical that inhibits the activities of nerve cells.  The study includes patients with succinic semialdehyde dehydrogenase deficiency, or SSADH (a disorder in which an enzyme deficiency disrupts GABA metabolism), their parents, and healthy volunteers.  SSADH deficiency causes various neurological and neuromuscular problems, including mild to severe mental retardation, delays in acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), delay in language and speech development, and other symptoms.

Patients undergo magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning.


SSADH Clinical Study Update

The study represents clinical protocols to assess the distribution and amount of GABA receptors, as well as neurophysiologic measures of cortical excitation versus inhibition in patients with SSADH deficiency. The study hypothesizes that chronic exposure to elevated GABA levels in the brain leads to down regulation of GABA receptors and subsequent reduction of GABA-mediated neuroinhibition.  The major objectives of this study are:

1) to measure binding and distribution of brain GABA receptor utilizing 11C-flumazenil PET scans in patients with SSADH deficiency compared with controls and obligate heterozygote carriers; and

2) to obtain measurable neurophysiologic parameters of cortical excitability and inhibition utilizing TMS in patients with SSADH deficiency compared with controls and obligate heterozygote carriers.

A database of approximately 100 patients with SSADH has been identified through the clinical population seen at Children's National Medical Center and the published literature. In addition, there is an ongoing study utilizing a questionnaire for systematic data collections and analysis. This has enabled entry of more comprehensive and reliable data on 57 patients enrolled to date. This work represents the first set of clinical studies of patients with SSADH beyond the collection of clinical and laboratory data to begin to characterize this disorder and its natural history. The information gathered from this study will also be utilized to develop biomarkers for clinical trials. SSADH Study. For more information or if you are interested in participating in the study please email them at michael.gibson@chp.com or ppearl@cnmc.org

Knockout SSADH Mouse Model

The use of transgenic mice has begun to revolutionize the study of human inborn errors of metabolism. Disruption of specific genes in mice enables a researcher to study the "human" counterpart disease in a model system (mouse) which produces rapidly. This approach has recently been applied to SSADH deficiency. In November of 1999, the first mice with genetically altered SSADH were born. These animals have a short life span, and manifest behavioral and gait abnormalities as seen in the human disease. In addition, seizures are a common finding, and may ultimately be the cause of death. These new knockout mice are the subject of intense investigation, and new therapeutic approaches are being attempted in them. The development of useful therapeutics will ultimately have important benefits to those with the human disease. This work is under the supervision of Dr. K. Michael Gibson, Associate Professor, Department of Molecular and Medical Genetics, Oregon Health Sciences University.Recently, Dr. Gibson was awarded a research grant through NIH to help support this important work.