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What are Neurotransmitter Diseases?


"Neurotransmitter Disease” is an umbrella term for genetic disorders that affect the synthesis, metabolism and catabolism of neurotransmitters. These inborn errors of metabolism affect the central nervous system and if left untreated can lead to severely compromised neurological function. The symptoms of some neurotransmitter diseases can be completely treated whereas in other neurotransmitter diseases treatment can sometimes improve quality of life.



What is Succinic Semialdehyde Dehydrogenase Deficiency?


Succinic semialdehyde dehydrogenase deficiency (SSADH) is a rare

metabolic disorder characterized by lack of the enzyme involved in the

degradation of GABA, the major inhibitory neurotransmitter in the brain.

GABA controls the movements of humans, and when it is imbalanced,

major neurological abnormalities occur. In SSADH deficiency, neurotransmitters

are blocked from signaling one another correctly.


Due to the enzyme deficiency in SSADH patients, an unusual compound accumulates in the body, namely 4-hydroxybutyric acid (or gammahydroxybutyric acid; GHB). GHB is possibly a neurotransmitter like GABA, or at least at high concentrations it is likely a modulator of neurological activity in humans. GHB accumulation interferes with the patient’s, concentrate and process information in the brain.


What symptoms are associated with SSADH?


Symptoms associated with SSADH may be mild, moderate or severe and

often vary greatly from case to case. The symptoms of SSADH are caused

by the accumulation of GHB in the brain and include the following manifestations:

(*Defined as: common, > 70% of patients; frequent 30-70% of patients;

unusual, < 30% of patients)


Common manifestations
• Delayed gross motor development

• Delayed mental development

• Delayed fine motor skill development

• Delayed speech and language development

• Hypotonia


Frequent manifestations
• Seizures

• Hyporeflexia

• Ataxia

• Behavioral problems

• Hyperkinesis

Unusual manifestations
• Neonatal problems

• EEG abnormalities

• Psychoses

• MRI or CT abnormalities

• Oculomotor apraxia

• Microcephaly

• Macrocephaly

• Hyperreflexia

• Somnolence

• Autistic features

• Choreoathetosis

• Myopathy



What causes SSADH?


SSADH deficiency is inherited as an autosomal recessive trait. In recessive

disorders, the condition does not occur unless an individual inherits

the same defective gene for the same trait from each parent. A child

who receives one normal gene and one gene for the disease will be a

carrier but usually will not show symptoms. The risk of transmitting the

disease to the children of a couple, both of whom are carriers for a

recessive disorder, is 25 percent. 50 percent of their children risk being

carriers of the disease but generally will show no symptoms of the

disorder, 25 percent of their children may receive both normal genes,

one from each parent, and will be genetically normal for that trait. The

risk is the same for each pregnancy.


Who gets SSADH?


SSADH deficiency affects males and females in equal numbers. Approximately

350 cases of SSADH have been diagnosed throughout the world. However, it is believed that many SSADH patients are either undiagnosed or misdiagnosed.


How is SSADH diagnosed?


A diagnosis of SSADH deficiency is made based upon urine organic

profiling or blood amino acid analysis. For testing information contact K.

Michael Gibson PhD. or Phillip Pearl MD.  


K. Michael Gibson, PhD, FACMG
Professor and Section Head
Clinical Pharmacology / College of Pharmacy
Washington State University
Pullman, WA 99164-6510

Phillip L. Pearl, MD
Director of Epilepsy and Clinical Neurophysiology
Boston Children's Hospital
Harvard Medical School
Boston, MA 02115


How is SSADH treated?


Presently there is no known established and universally effective therapeutic

treatment for SSADH deficiency. In the longer term, medical

advancements made in gene therapy or stem cell transplantation may

provide an avenue to cure the disorder. In the shorter term, several

therapies have been tried or are currently being considered as listed



• Vigabitrin or Sabril - pharmacologically, the mode of action is an irreversible

inhibition of GABA-transaminase, leading to accumulation of

free and total GABA in the brain. The results of this therapy have

been encouraging in some patients, and of little to no value in others.

This medication has been suspended or avoided by some patients

due to the potential side effects.


• Lamotrigine - Pharmacologically, the mode of action is to inhibit the

release of excitatory amino acids, especially the major GABA precursor

glutamate, via inhibition of glutamic acid decarboxylase. Lamotrigine

has been successfully used and well tolerated in at lease one patient.


• NCS-382 antagonist - clinical trials on the use of this agent is pending.

In addition to the therapies listed above, several medications such as

prozac or Ritalin have been prescribed to assist in controlling behavioral

abnormalities. Extensive speech, physical and occupational therapy are

strongly encouraged.



Selected Reference

For a complete list of articles on SSADH, please refer to the Online

Mendelian Inheritance in Man (OMIM) which is linked below. Before

clicking, you will need to enter the following information at the OMIM site:

Key Words: “Succinic Semialdehyde Dehydrogenase Deficiency”

Access Listing: 271980

PDF/Printable Guide to Succinic Semialdehyde Dehydrogenase Deficiency