Succinic Semialdehyde Dehydrogenase Deficiency

Succinic Semialdehyde Dehydrogenase Deficiency

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Succinic Semialdehyde Dehydrogenase Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • 4-Hydroxybutyric Aciduria
  • SSADH Deficiency

Disorder Subdivisions

  • None

General Discussion

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism that is inherited as an autosomal recessive trait. In individuals with the disorder, deficient activity of the SSADH enzyme disrupts the metabolism of gamma-aminobutyric acid (GABA). GABA is a natural chemical known as a "neurotransmitter" that serves to inhibit the electrical activities of nerve cells (inhibitory neurotransmitter). SSADH deficiency leads to abnormal accumulation of the compound succinic semialdehyde, which is reduced or converted to 4-hydroxybutyric acid, also known as GHB (gamma-hydroxybutyric acid). GHB is a natural compound that has a wide range of effects within the nervous system. The "hallmark" laboratory finding associated with SSADH deficiency is elevated levels of GHB in the urine (i.e., 4-hydroxybutyric or gamma-hydroxybutyric aciduria), the liquid portion of the blood (plasma), and the fluid that flows through the brain and spinal canal (cerebrospinal fluid [CSF]).



SSADH deficiency leads to various neurological and neuromuscular symptoms and findings. These abnormalities may be extremely variable from case to case, including among affected members of the same families (kindreds). However, most individuals with SSADH deficiency are affected by mild to severe mental retardation, delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), and delays in language and speech development. In addition, in some cases, initial findings may include diminished muscle tone (hypotonia), an impaired ability to coordinate voluntary movements (ataxia), and/or episodes of uncontrolled electrical activity in the brain (seizures). Some affected individuals may also have additional abnormalities, such as decreased reflex reactions (hyporeflexia); involuntary, rapid, rhythmic eye movements (nystagmus); increased muscular activity (hyperkinesis); and/or behavioral abnormalities.

Symptoms

In individuals with succinic semialdehyde dehydrogenase (SSADH) deficiency, the range, severity, and presentation of certain symptoms and findings may be variable, including among affected family members. In addition, such neurological and neuromuscular symptoms are often considered "nonspecific", meaning that they may be associated with any number of underlying disorders, potentially leading to difficulties with diagnosis. (For further information, pleasee see the "Standard Therapies: Diagnosis" section of this report below.) However, during childhood, most affected individuals appear to have some degree of psychomotor retardation--or delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (i.e., "developmental milestones").



According to reports in the medical literature, initial or "presenting" symptoms vary from case ot 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 (ataxia); episodes of uncontrolled electrical activity in the brain (seizures); and/or certain abnormalities during early infancy (neonatal abnormalities), including failure to cry or respond to certain visual stimuli. Although symptom onset is usually detected during infancy or childhood, the disorder sometimes has not been diagnosed until adulthood.



The language and speech abnormalities associated with SSADH deficiency may be extremely variable. For example, in severe cases, speech may be infrequent and consist of only a few words or simple phrases. However, others with the disorder may have normal speech and language development.



As mentioned above, ataxia or incoordination is sometimes an initial finding associated with SSADH deficiency. The ataxia is typically nonprogressive, may be confined to muscles of the trunk and the arms or legs (limbs), and tends to resolve with age.



Some individuals with SSADH deficiency may also develop additional neurological and neuromuscular symptoms. Such abnormalities may include decreased or absent reflex reactions (hyporeflexia or areflexia); abnormally increased muscular activity (hyperkinesis); and/or, less commonly, a movement disorder known as choreoathetosis. This condition is characterized by involuntary, rapid, jerky movements (chorea) occurring in association with relatively slow, sinuous, writhing motions (athetosis). Some affected individuals may also develop behavioral abnormalities, such as unusual irritability, easy agitation or frustration, increasingly aggressive behavior, or "autistic-like" behaviors. Teh latter may include impaired communication and social interaction, extreme withdrawal, and/or a tendency to engage in certain ritualistic behaviors or repeated body movements (e.g., frequent rocking).



Additional abnormalities have been reported in association with SSADH deficiency. For example, some individuals may be affected by unusual drowsiness (somnolence); psychotic behaviors, such as the perception of certain sounds, sights, or other sensations in the absence of external stimuli (hallucinations); and/or certain eye (locular) abnormalities. Ocular findings may include involuntary, rapid, rhythmic eye movements (nystagmus); and impaired ability to consciously coordinate movements of the eyeballs (oculomotor apraxia); and/or poor vision. Some cases have also been reported in which affected individuals ahve abnormalities of the skull and facial (craniofacial) area, including unusual smallness or largeness of the head (microcephaly or macrocephaly).



As mentioned above, nonprogressive ataxia associated with SSADH deficiency may tend to significantly improve with age. In addition, evidence suggests that there may be additional variations seen in associated symptoms. For example, whereas some younger individuals may tend to be affected by drowsiness (somnolence), older individuals may be mroe likely to develop abnormally increased activity (hyperactivity) or aggressive behaviors.

Causes

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism that is inherited as an autosomal recessive trait. "Metabolism" refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones (catabolism), usually with the release of energy, and processes in which complex substances are built up from simpler ones (anabolism), usually resulting in energy consumption. Inborn errors of metabolism result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body.



Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.



The parents of some individuals with SSADH deficiency have been closely related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.



A gene responsible for some cases of SSADH deficiency has been mapped to the short arm (p) of chromosome 6 (6p22). Researchers have identified a number of different changes (mutations) in the SSADH gene in individuals with the disorder. Evidence suggests that most affected families (kindreds) have had different mutations of the SSADH gene.



Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered.



In individuals with SSADH deficiency, impaired functioning of the SSADH enzyme results in disrupted metabolism of GABA (gamma-aminobutyric acid), an amino acid neurotransmitter. Amino acids are the chemical building blocks that form proteins in the body. Neurotransmitters modify or result in the transmission of nerve impulses from one nerve cell (neuron) to another, enabling neurons to communicate. More specifically, these natural chemicals either serve to trigger or inhibit the electrical activities of "targeted" neurons (i.e., excitatory or inhibitory neurons). GABA is the main inhibitory neurotransmitter in the brain.



SSADH deficiency leads to abnormal accumulation of the compound succinic semialdehyde, which is converted to 4-hydroxybutyric acid (4-HBA) or "GHB" (gamma-hydroxybutyric acid). Thus, individuals with SSADH deficiency have unusually elevated levels of GHB in urine, plasma, and cerebrospinal fluid. As mentioned above, GHB is a natural compound that has a wide range of effects within the nervous system (i.e., neurophysiologic effects). Although many researchers suspect that it acts as a neurotransmitter, its specific function in the brain remains unknown.



In the 1960s, GHB was developed by the pharmaceutical industry as an agent similar to GABA (analog). It was initially used as an anesthetic for children due to its sedative properties; however, such use resulted in adverse side effects. More recently, evidence suggests that GHB plays an important role in energy regulation and as a "protector" against tissue damage (e.g., during lack of adequate oxygen supply to tissues [hypoxia]). Its more current clinical uses include the treatment of a sleep disorder known as narcolepsy, alcohol-withdrawal syndrome, and difficult labor and delivery during childbirth.



Researchers indicate that certain effects potentially associated with the therapeutic use of GHB (i.e., pharmacologic effects) are similar to those seen in individuals with SSADH deficiency. These include diminished muscle tone (hypotonia), drowsiness (somnolence), and seizure-like activity. In addition, reports suggest that, in some affected individuals, there may be age-related decreases of GHB concentrations in bodily fluids, potentially leading to the symptom variations seen in some cases. For example, younger individuals with relatively high GHB concentrations in bodily fluids may tend to be affected by drowsiness. In contrast, in older individuals with lower GHB concentrations, symptoms may tend to include abnormally increased activity or aggressive behaviors. Based upon such findings, some investigators suggest that GHB may act on inhibitory nerve cell (neuron) receptors at high concentrations and excitatory receptors at low concentrations. (Receptors are specific sites on the surface of a neuron that bind with neurotransmitters.)



Further research is required to learn more about GHB's mode of action and to determine whether the neurological symptoms associated with SSADH deficiency result from increased accumulations of GHB, disturbances of GABA levels, a combination of both, or other abnormalities.

Affected Populations

SSADH deficiency appears to affect males and females relatively equally. Since the disorder was originally described in 1981 (C. Jakobs), over 300 cases of SSADH deficiency have been identified. According to one review published in 1997 reporting 23 affected individuals (from 20 families), the age at diagnosis ranged from three months to 25 years. Most affected individuals were of Turkish, American Caucasian, Indian, and Northern European descent. Additional nationalities were also noted, including Korean, Palestinian, Syrian, Pakistani, Saudi, Chinese, and Inuit descent.



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

Standard Therapies

Diagnosis

In some cases, a diagnosis of SSADH deficiency may be suggested before birth (prenatally) by specialized tests. These include studies that may detect increased concentrations of 4-ydroxybutyric acid (GHB) in fluid surrounding the developing fetus (amniotic fluid) and deficient activity of the SSADH enzyme in certain fetal cells obtained via amniocentesis or chorionic villus sampling (CVS). During amniocentesis, a sample of fluid that surrounds the fetus is removed and analyzed, whereas CVS involves the removal of tissue samples from a portion of the placenta.



The diagnosis is usually made after birth (postnatally) during infancy or childhood (or, in some cases, adulthood), 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 deficiency 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 deficiency 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 testing to confirm deficient activity of the SSADH enzyme in white blood cells (leukocytes) isolated from whole blood. (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.)



Physicians who are interested in obtaining information on testing for SSADH deficiency may wish to contact:



K. Michael Gibson, PhD, FACMG

Departments of Molecular and Medical Genetics and Pediatrics

Director, Biochemical Genetics Laboratory

Oregon Health Sciences University

2525 SW 3rd Avenue

Portland, OR 97201

Phone: (503) 494-2400

Fax: (503) 494-6922

E-mail: gibsonm@ohsu.edu



In some instances, other specialized tests may also be conducted to help detect or characterize certain abnormalities that may be associated with the disorder. Such testing may include computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or electroencephalography (EEG). During CT scanning, a computer and x-rays may be used to create a film showing cross-sectional images of the brain. In MRI, a magnetic field and radio waves may create detailed cross-sectional images of the brain. An EEG is conducted to record the brain's electrical impulses, potentially detecting brain wave patterns that are characteristic of certain types of seizure activity.



Treatment

The treatment of SSADH deficiency 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 pediatricians; physicians who specialize in the diagnosis and treatment of neurological disorders in children (pediatric neurologists); and/or other health care professionals.



In some affected individuals, treatment may include the use of certain medications to help prevent, reduce, or control seizures (anticonvulsants, e.g., carbamazepine, primidone, etc.) or to alleviate other symptoms potentially associated with the disorder. (For further information, please see the "Investigational Therapies" section of this report below.)



Early intervention may be important in ensuring that children with SSADH deficiency reach their potential. Special services that may be beneficial include physical therapy, special remedial education, speech therapy, and other medical, social, and/or vocational services.



Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.



Patients, families and physicians interested in obtaining clinical and/or therapeutics information on SSADH deficiency may wish to contact:



Phillip L. Pearl, MD

Associate Professor of Pediatrics and Neurology

Children's National Medical Center

The George Washington University School of Medicine

Washington, DC 20010-2970

Tel: 202-884-2120

e-mail: ppearl@cnmc.org

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Treatment of SSADH deficiency may include therapy with vigabatrin (Sabril), a medication that has been approved for use in several countries outside the United States, including Canada, Mexico, the United Kingdom, and Australia. However, to date, vigabatrin has not been approved for use by the U.S. Food and Drug Administration (FDA).

References

TEXTBOOKS

Pearl PL and Gibson KM. Succinic Semialdehyde Dehydrogenase Deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:499.



Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies, Inc.; 1996:86.



Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill Companies, Inc.; 1995:1360-1361.



Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:17-18.



REVIEW ARTICLES

Kuhara T. Diagnosis of inborn errors of metabolism using filter paper urine, urease treatment, isotope dilution and gas chromatography-mass spectometry. J Chromatogr B Biomed Sci Appl. 2001;758;3-25



Medina-Kauwe LK, Tobin AJ, De Meirleir L, et al. 4-Aminobutyrate aminotransferase (GABA-transaminase) deficiency. J Inherit Metab Dis. 1999;22:414-27.



Gibson KM, et al. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics. 1998;29:14-22.



JOURNAL ARTICLES

Pearl PL, et al., Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol. 2003;54:S73-80.



Gropman A, Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency. Ann Neurol. 2003;54:S66-72.



Gupta M, Greven R, Jansen EE, et al. Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (gamma hydroxybutyric aciduria). J Pharmacol ExpTher. 2002;302:180-87.



Hogema BM, Gupta M, Senephransiri H, et al. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet. 2001;29:212-16.



Hogema BM, Akaboshi S, Taylor M, et al. Prenatal diagnosis of succinic semialdehyde dehydrogenase deficiency: increased accuracy employing DNA, enzyme, and metabolic analyses. Mol Genet Metab. 2001;72:218-22.



Peters H, Cleary M, Boneh A. Succinic semialdehyde dehydrogenase deficiency in siblings: clinical heterogeneity and response to early treatment. J Inherit Metab Dis. 1999;22:198-199.



Gibson KM, Sweetman L, Kozich V, et al. Unusual enzyme findings in five patients with metabolic profiles suggestive of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). J Inherit Metab Dis. 1998;21:255-261.



Chambliss KL, Hinson DD, Trettel F, et al. Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). Am J Hum Genet. 1998;63:399-408.



Gibson KM, Doskey AE, Rabier D, et al. Differing clinical presentation of succinic semialdehyde dehydrogenase deficiency in adolescent siblings from Lifu Island, New Caledonia. J Inherit Metab Dis. 1997;20:370-374.



Gibson KM, Christensen E, Jakobs C, et al. The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics. 1997;99:567-574.



Trettel F, Malaspina P, Jodice C, et al. Human succinic semialdehyde dehydrogenase: molecular cloning and chromosomal localization. Adv Exp Med Biol. 1997;414:253-260.



Matern D, Lehnert W, Gibson KM, et al. Seizures in a boy with succinic semialdehyde dehydrogenase deficiency treated with vigabatrin (gamma-vinyl-GABA). J Inherit Metab Dis. 1996;19:313-318.



Peters H, Cleary M, Boneh A. Succinic semialdehyde dehydrogenase deficiency in siblings: clinical heterogeneity and response to early treatment. J Inherit Metab Dis. 1999;22:198-199.



Gibson KM, Hoffmann GF, Hodson AK, et al. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics. 1998;29:14-22.



Gibson KM, Sweetman L, Kozich V, et al. Unusual enzyme findings in five patients with metabolic profiles suggestive of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). J Inherit Metab Dis. 1998;21:255-261.



Chambliss KL, Hinson DD, Trettel F, et al. Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). Am J Hum Genet. 1998;63:399-408.



Gibson KM, Doskey AE, Rabier D, et al. Differing clinical presentation of succinic semialdehyde dehydrogenase deficiency in adolescent siblings from Lifu Island, New Caledonia. J Inherit Metab Dis. 1997;20:370-374.



Gibson KM, Christensen E, Jakobs C, et al. The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. Pediatrics. 1997;99:567-574.



Trettel F, Malaspina P, Jodice C, et al. Human succinic semialdehyde dehydrogenase: molecular cloning and chromosomal localization. Adv Exp Med Biol. 1997;414:253-260.



Matern D, Lehnert W, Gibson KM, et al. Seizures in a boy with succinic semialdehyde dehydrogenase deficiency treated with vigabatrin (gamma-vinyl-GABA). J Inherit Metab Dis. 1996;19:313-318.



Jakobs C, Ogier H, Rabier D, et al. Prenatal detection of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria) [letter]. Prenatal Diag. 1993;13:150.

Resources

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