About the Disorder

Description

Succinic semialdehyde dehydrogenase deficiency (SSADH) is an ultra-rare neurometabolic disorder characterized by lack of one of two enzymes involved in the breakdown of GABA, the major inhibitory neurotransmitter in the brain.  GABA controls the movements of humans, and when it is imbalanced, major neurological abnormalities occur. With SSADH, neurotransmitters in neurons 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). The GHB accumulation may interfere with the patient’s ability to walk, speak, concentrate and process information. 

Since the disorder was originally described in 1981 by Cornelis Jakobs, PhD. over 200 cases of SSADH have been identified. SSADH appears to affect males and females equally.

However, due to the variability and nonspecific nature of associated symptoms, experts suggest that this disorder may be significantly underdiagnosed and/or misdiagnosed. As a result, it is difficult to determine the true frequency of SSADH in the general population.


Buzzi, Andrea et al. “Succinic semialdehyde dehydrogenase deficiency:
GABAB receptor-mediated function.” Brain research 1090 1 (2006): 15-22.

Symptoms

According to reports in the medical literature, initial or “presenting” symptoms vary from case to case. However, initial symptoms often include delays in achieving certain motor milestones (e.g., crawling, sitting unaided, walking without assistance); reduced muscle tone (hypotonia); and/or intellectual or language delays.

In some cases, additional presenting symptoms may be present, such as an impaired ability to coordinate voluntary movements; episodes of uncontrolled electrical activity in the brain or seizures; and/or certain abnormalities during early infancy, including failure to cry or respond to certain visual stimuli. Although symptom onset is usually detected during infancy or childhood, the disorder sometimes does not get diagnosed until later in life, and frequently not until adulthood.

Symptoms associated with SSADH may be mild, moderate or severe and often vary greatly from case to case even within the same family. The symptoms of SSADH are caused by the accumulation of GABA and 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
Sleep disturbance
Unusual Manifestations
Neonatal problems
EEG abnormalities
Psychoses
MRI or CT abnormalities
Oculomotor apraxia
Microcephaly
Macrocephaly
Hyperreflexia
Somnolence
Autistic features
Choreoathetosis
Myopathy

Genetics

SSADH is inherited as an autosomal recessive trait. In recessive trait disorders, the condition does not occur unless an individual inherits one copy of a defective gene for the same trait for SSADH from each parent. With each pregnancy the couple has a 25 chance of this happening.

Likewise, the couple has a 25 percent chance of their children receiving both normal genes for the trait from each parent and would have no symptoms and will not pass the disorder on to their children.

Additionally, the couple has a 50 percent chance of their children being a carrier of the disorder, but will have no SSADH symptoms that we are aware of.

Diagnoses

The diagnosis of SSADH is usually made after birth (postnatally) during infancy or childhood (or, in some cases, later in life), based upon a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests.

Due to the nonspecific nature and variability of associated symptoms, experts suggest that SSADH should be considered in any individuals with two or more features of intellectual, language, and motor delay and abnormally diminished muscle tone (hypotonia) of unknown cause (idiopathic).

Specialized testing to confirm a diagnosis of SSADH typically includes studies (i.e., quantitative organic acid analysis in an appropriate specialist laboratory) that may detect increased concentrations of 4-hydroxybutyric acid (4-HBA) in urine (i.e., 4-hydroxybutyric aciduria) and molecular genetic testing to confirm the abnormal gene from each parent in the patient.  (Note: As mentioned above, increased concentrations of 4-HBA may also be detected in plasma and cerebrospinal fluid. In addition, deficient SSADH activity has also been demonstrated in certain cells other than leukocytes.)

ALDH5A1 is the gene that codes for SSADH. Molecular genetic testing to identify bi-allelic mutations (abnormal changes found on both copies of a gene) or deletions in ALDH5A1 is used to make or confirm a diagnosis of SSADH. as noted above.  This testing is usually ordered by the patient’s pediatrician, primary care physician, neurologist or a genetic counselor and can be completed at a number of facilities around the world.  However, it is imperative that the testing facility specifically test for ALDH5A1.  Fortunately, diagnostic capabilities to identify SSADH via gene sequencing have been enhanced because a number of companies assess the sequence of this gene on panels of genes for idiopathic developmental delay, epilepsy, and other clinical features.

Treatment

The treatment of SSADH is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as a pediatrician or a primary care doctor, pediatric neurologist or adult neurologist who specialize in the diagnosis and treatment of neurological disorders and/or other health care professionals. Additionally, genetic counseling will be of benefit for affected individuals and their families.

In some affected individuals, treatment may include the use of certain medications to help prevent, reduce, or control seizures (anticonvulsants, e.g., carbamazepine, levetiracetam, etc.) or to alleviate other behavioral symptoms potentially associated with the disorder.

Early intervention is important in ensuring that patients with SSADH reach their potential. Special services that may be beneficial include physical therapy, speech therapy, occupational therapy, special remedial education, and other medical, social, and/or vocational services. There are a number of other therapies available depending on where you live and the needs of your patient.  Some examples are hippo therapy (horseback riding),  music therapy, sensory integration therapy, animal-assisted therapy, etc.


Click here to download the SSADH Parent Guide

Patients and families interested in obtaining information about the latest therapeutic and/or research information on SSADH may wish to contact:

SSADH Association
Carolyn Hoffman
498 Lillian Court
P.O. Box 180622
Delafield, WI 53018 USA
Phone: (262) 646-5133
choffmanwi@aol.com

Physicians interested in obtaining clinical and/or therapeutic information on SSADH may wish to contact:

Phillip L. Pearl, MD

Phillip L. Pearl, MD
Chief of Epilepsy and Clinical Neurophysiology
Boston Children’s Hospital
Harvard Medical School
300 Longwood Avenue,
Boston, MA 02115 USA
Phillip.Pearl@childrens.harvard.edu

Physicians interested in obtaining clinical research information on SSADH may wish to contact:

K. Michael Gibson, PhD, FACMG

Michael Gibson, PhD, FACMG
Professor of Pharmacotherapy
Washington State University
College of Pharmacy
Room 210C, Health Sciences Building
Spokane, WA 99202 USA
Mike.Gibson@wsu.edu