Succinic semialdehyde dehydrogenase deficiency
Encyclopedia
Succinic semialdehyde dehydrogenase deficiency (SSADHD), also known as 4-hydroxybutyric aciduria or gamma-hydroxybutyric aciduria, is a rare autosomal recessive
disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA
. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families
. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a patient that suffered from a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia
, hyporreflexia, seizures, and a nonprogressive ataxia
were frequent clinical features as well.
SSADH deficiency is caused by an enzyme deficiency in GABA
degradation. Under normal conditions, SSADH works with the enzyme GABA transaminase to convert GABA
to succinic acid
. Succinic acid can then be utilized for energy production via the Krebs cycle. However, because of the deficiency, the final intermediate of the GABA degradation pathway, succinic semialdehyde, accumulates and cannot be oxidized to succinic acid and is therefore reduced to gamma-hydroxybutyric acid
(GHB) by gamma-hydroxybutyric dehydrogenase. This causes elevations in GHB
and is believed to be the trademark of this disorder and cause for the neurological manifestations seen.
. The most constant features seen are developmental delay, hypotonia
, and mental retardation. Nearly half of patients seen manifest ataxia
, behavior problems, seizures, and hyporreflexia.
The age of onset ranges from newborn period to 25 years. Problems unique to neonates can include prematurity, lethargy, decreased sucking, respiratory difficulty and hypoglycemia
. Gastrointestinal symptoms have been seen primarily in this
population and are usually related to increased feeding.
Ocular
problems related to the disorder include strabismus
, nystagmus, retinitis, disc pallor, and oculomotor apraxia.
Nearly half of the patients with SSADH deficiency have seizures. These include absence, tonic clonic, and convulsive status epilepticus
. It is unclear whether decreased levels of GABA
or elevated levels of GHB
are responsible for these seizures but alterations in these neurotransmitters and their receptor binding or neurotransmitter transport is hypothesized to play a role in the pathogenesis of the seizures in this population.
SSADH deficiency is inherited in an autosomal recessive fashion. Such diseases are caused by an error in a single DNA gene. Because the disease is autosomal, the defective gene is found on an autosome
(chromosome 6), rather than the sex-linked 23rd chromosome. Being a recessive
disorder, the disease can only be inherited from both parents since the disorder can only occur when a person has two copies of the gene.
It is believed that the genetic basis for SSADH deficiency resides in the SSADH human ALDH5A1 gene which maps to chromosome 6p22. More than 47 disease-causing mutations have been identified for the disorder, all of which lead to absence of functional proteins through missense, nonsense
, or splicing
errors; no hotspots have been identified. Consanguinity is frequent; this suggests the occurrence of rare disease causing alleles in the general population.
is a major inhibitory neurotransmitter
in the central nervous system
. It modulates the activity of several neurotransmitters including dopamine
, serotonin
, and norepinephrine
. GABA
is synthesized in a single step from its precursor glutamate by glutamic acid decarboxylase. GABA
is metabolized by successive transamination
and oxidation to yield succinic semialdehyde
and succinic acid
respectively via the catalyzing effects of GABA transaminase. The succinic semialdehyde
can be converted into either succinic acid
by SSADH or to GHB
by the enzyme succinic semialdehyde reductase. The absence of SSADH leads to a 30-fold increase of GHB
and a 2-4 fold increase of GABA
in the brains of patients with SSADH deficiency as compared to normal brain concentrations of the compounds. Elevations of GHB
have been shown to induce spike and wave activity similar to that seen in generalized absence epilepsy
in animal models as well, which has motivated researchers to increase their knowledge on the relationship between GHB
and the neurological manifestations seen in SSADH deficiency.
GABA
acts via binding to its receptors which include the ligand gated ion channels, GABAA and GABAC and the G-protein couple receptors GABAB. The GABAB receptor has been found to be the most important of the three receptors for this disorder as it is vital in both GABA
and GHB
release. This receptor mediates the release through presynaptic effects through a voltage dependent inhibition of high voltage activation of calcium
channels. Many experiments have been able to show that it is the increased levels of both GABA
and GHB
that seem to alter the function of GABAB receptor, which may further play a role in the tonic-clonic seizures that are often seen in patients with the disorder.
In terms of intracellular signaling, GHB
inhibits mitogen activated protein (MAP) kinase action via the GABAB receptor mechanism. MAP kinase is imperative for numerous physiological changes including regulation of cell division
and differentiation, thus, down-regulation of this pathway may occur during the presence of too much GHB
as found in SSADH deficiency. In 2003, Ren and Mody et al. proved that repeated exposure of GHB
to MAP kinase affected myelin
expression. This is a critical finding since myelin
is the electrical and insulating phospholipid
layer that surrounds the axons of many neurons in the brain. Proper myelination is critical for carrying electrical signals, or data, from one nerve cell to the next. When myelin
becomes damaged, it can cause numerous neurological problems, many of which are seen in patients with SSADH deficiency. Thus, Ren and Mody’s work in the relationship between increased levels of GHB
and myelin
expression may further show the significance of this pathway in terms of the neurological deficits seen in SSADH deficiency.
Glutamine
metabolism may also play a role in the pathophysiology of SSADH deficiency. The major ionotropic glutamine receptors include the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainite receptor. High levels of GHB
have been shown to depress both the NMDA
and AMPA/kainite receptor mediated functions and may also alter glutamatergic excitatory synaptic transmission as well. Decreased glutamine
, coupled with elevated GABA
, has also suggested disruption of the glutamine-glutamate shuttle
which ultimately provides for astrocytic glutamine
as a precursor for neuronal glutamate and GABA
. This disruption has the potential to impair glutamate homeostasis and may lead to uncoupling of the normal balance between glutamatergic excitatory activity and GABAergic inhibition, and may be responsible for the convulsive seizures that are observed in this disorder.
Finally, additional mitochondrial processes may also be affected by SSADH deficiency. Succinate semialdehyde is considered a reactive carbonyl
and may lead to increased oxidative stress
. This stress is believed to contribute to the formation of free radicals in the brain tissue of animal models induced with SSADH deficiency, which further leads to secondary cell damage and death. Additionally, oxidative stress
may be responsible for loss of striatal dopamine
which may contribute to pathophysiology of the disease.
methodology to create a uniform absence of the SSADH enzyme activity as well as accumulations of GHB
and GABA
in tissues and physiological fluids. The mice are born at the expected Mendelian frequencies for an autosomal recessive disorder. Most of the models include distinctive neurological phenotypes and exhibit hypotonia
, truncal ataxia
, generalized tonic-clonic seizures associated with 100% mortality. The mice uniformly die at 3-4 postnatal
weeks. While this model is considered to be more severe than the phenotypes seen in humans, currently, it is the most highly regarded, valid, metabolic model to study potential therapeutic interventions for the disorder.
Studies have shown that alterations of both the GABAA receptor and the GABAB receptor early in the life of the Aldh5a1-/- mice can increase levels of GHB
and enhance GABA
release. Besides these effects, it has also been shown that “…a developmental down-regulation of GABAA receptor mediated neurotransmission in Aldh5a1-/- mice likely contributes to the progression of generalized convulsive seizures seen in mutant animals.” Other studies have confirmed the relationship between elevated levels of GHB
and MAP kinase in mutant animals contribute to profound myelin
abnormalities.
, and flurodeoxyglucose positron emission topography are just some of the neuroimaging modalities that have been used to diagnose patients with SSADH deficiency. On the basis of 29 previously published cases that had imaging results available, there were some common abnormalities found. These included increased T2-weighted signal abnormalities involving the globus pallidi bilaterally and symmetrically as well as the presence of subcortical white matter
. Similar abnormalities have been identified in the brainstem and cerebellar dentate nucleus
.
Signal intensity on a T2 image may be a result of edema
or an inflammatory response. Because this type of imaging is a water detecting sequence, any form of calcification or mineralization would also appear dark, thus explaining why accumulation of extra blood or fluid would appear bright on a T2 image. Another explanation for signal intensity may be demyelination since the globus pallidi are traversed by a number of myelinated axons, thus confirming Ren and Mody’s 2003 work proving that repeated exposure of GHB
to MAP kinase affected myelin
expression, thus causing the numerous neurological dysfunctions seen in SSADH deficiency patients. Ultimately, because the globus pallidus
is intimately linked with the basal ganglia
and thalamus
, it would be expected that some of the motor dysfunctions seen in SSADH patients such as ataxia
and hyporreflexia would be common.
analysis of the urine. Patients with SSADH deficiency will excrete high levels of GHB
but this can be difficult to measure since GHB
has high volatility and may be obscured on gas chromatography or mass spectrometry
studies by a high urea peak. Other GABA metabolites can also be identified in urine such as glycine
. Finally, succinic semialdehyde dehydrogenase levels can be measured in cultured leukocytes of the patient. This occurs due to the accumulation of 4,5-dihydroxyhexanoic acid which is normally undetectable in mammalian tissues but is characteristic of SSADH deficiency. This agent can eventually compromise the pathways of fatty acid
, glycine
, and pyruvate metabolism, and then become detectable in patients' leukocytes. Such enzyme levels can also be compared to non-affected parents and siblings.
via inhibition of GABA transaminase. Vigabatrin
is an irreversible inhibitor of GABA transaminases which leads to decreased levels of GHB
and elevation of GABA
. Clinical results after use are diverse, ranging from improved ataxia
and speech in some patients to worsening of symptoms in others. Lower doses (30–50 mg/kg per day) is associated with fewer side effects and greater improvement of clinical features at high doses of the therapeutic. Although vigabatrin
has not been consistently successful in patients with SSADH deficiency, it has shown enhanced survival of Aldh5a1-/- mice at very high doses.
has been used for the treatment of generalized and partial seizures in humans for both epilepsy
and bipolar disorder
. Valproate enhances GABA
synthesis and release leading to augmented GABAergic functions in some areas of the brain. Successful interventions with valproate have been noted, but no clinical trial
s have been conducted thus far.
However, Valproate is usually contraindicated as it may inhibit residual SSADH enzyme activity
(3-amino-propyl-(diethoxymethyl) phosphinic acid) has been used in Aldh5a1-/- mice with strong results. It has shown to reduce the frequency of absence seizures, though there have been some cases in which it worsened convulsive seizures.
(β-p-chlorophenyl-GABA) has some analgesic properties and has been traditionally used for spasticity. Its pharmacological effects primarily take place via presynaptic GABAB receptors in the spinal cord
, simultaneously releasing excitatory neurotransmitters onto motor neurons. Because the number and function of GABAB receptors has been shown to progressively diminish in Aldh5a1-/- mice, such a therapy may prove to be useful. However, no data on the efficacy of baclofen
on Aldh5a1-/- mice or human patients has been reported.
sulfur amino acid
that is found in high concentrations in human milk. It has been shown to have neuroprotective and neuromodulating properties. While it is an inhibitory neurotransmitter
, its ability to cross the blood brain barrier is limited. There is a lot of literature that indicates that taurine acts as antagonist at GABAA and GABAB receptors which may further enhance its ability to treat patients with SSADH deficiency, but further pharmacological studies are yet to be conducted to see if taurine could serve a therapeutic purpose.
Taurine has been successfully used in a single case open study in a child with SSADH deficiency; with resolving of brain lesions, and improvement in coordination and gait ( A.Saronwala, Anne Tournay, John J Gargus: Genetic inborn error of metabolism provides a unique window into molecular mechanisms underlying taurine therapy. Taurine in health and Disease ISBN 978-81-7895-520-9)
bodies serve as the primary energy source for the brain. In 2006, Henderson et al. showed that there is a therapeutic effect of maintaining a ketogenic diet
– a diet consisting of high fat
/low carbohydrate
meals – in children with epilepsy. Ketogenic diets have also been shown to have some neuroprotective effects in models of Parkinson's disease
and hypoxia
as well. In a recent study conducted at the Hospital for Sick Children in Canada in 2007, researchers found that a ketogenic diet
prolonged the lifespan of Aldh5a1-/- mice by greater than 300%, along with the normalization of ataxia
and some improvement in various seizure types seen in SSADH deficient murine models. These effects were in conjunction with “…a significant restoration of GABAergic synaptic
activity and region-specific restoration of GABAA receptor associated chloride channel
binding.” Ultimately, the data seen in the study indicated that a ketogenic diet
may work in its ability to restore GABAergic inhibition. But further studies on murine models need to be conducted, ultimately leading to the possibility of conducting a controlled study on humans afflicted with the disorder.
There is speculation that a ketogenic diet may be harmful for humans with SSADH deficiency as it may cause elevated levels of GHB in the bloodstream.
. Both have contributed significant efforts to finding appropriate therapies for SSADH deficiency and have specifically spent most of their recent efforts into understanding the efficacy of the ketogenic diet
for patients with SSADH deficiency. In addition, a lot of the research that was published in 2007 examined the pathogenesis for the disorder by examining the role of oxidative stress
on tissues in various cerebral structures of Aldh5a1-/- mice.
Ultimately, the metabolic pathway of SSADH deficiency is known, but how the enzyme
deficiency and accumulation of GABA
and GHB
contribute to the clinical phenotype
is not. For the future however, treatment strategies should focus on both decreasing the total production of GHB
and increasing the total concentration of GABA
and further assessing whether the effects of these changes influences the neurological manifestations seen in patients afflicted with SSADH deficiency.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families
Consanguinity
Consanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a patient that suffered from a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, hyporreflexia, seizures, and a nonprogressive ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
were frequent clinical features as well.
SSADH deficiency is caused by an enzyme deficiency in GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
degradation. Under normal conditions, SSADH works with the enzyme GABA transaminase to convert GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
to succinic acid
Succinic acid
Succinic acid is a dicarboxylic acid. Succinate plays a biochemical role in the citric acid cycle. The name derives from Latin succinum, meaning amber, from which the acid may be obtained....
. Succinic acid can then be utilized for energy production via the Krebs cycle. However, because of the deficiency, the final intermediate of the GABA degradation pathway, succinic semialdehyde, accumulates and cannot be oxidized to succinic acid and is therefore reduced to gamma-hydroxybutyric acid
Gamma-Hydroxybutyric acid
γ-Hydroxybutyric acid , also known as 4-hydroxybutanoic acid and sodium oxybate when used for medicinal purposes, is a naturally occurring substance found in the central nervous system, wine, beef, small citrus fruits, and almost all animals in small amounts. It is also categorized as an illegal...
(GHB) by gamma-hydroxybutyric dehydrogenase. This causes elevations in GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and is believed to be the trademark of this disorder and cause for the neurological manifestations seen.
Symptoms
The symptoms of SSADH deficiency fall into three primary categories: neurological, psychiatric, and ocularHuman eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
. The most constant features seen are developmental delay, hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, and mental retardation. Nearly half of patients seen manifest ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, behavior problems, seizures, and hyporreflexia.
The age of onset ranges from newborn period to 25 years. Problems unique to neonates can include prematurity, lethargy, decreased sucking, respiratory difficulty and hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
. Gastrointestinal symptoms have been seen primarily in this
population and are usually related to increased feeding.
Ocular
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
problems related to the disorder include strabismus
Strabismus
Strabismus is a condition in which the eyes are not properly aligned with each other. It typically involves a lack of coordination between the extraocular muscles, which prevents bringing the gaze of each eye to the same point in space and preventing proper binocular vision, which may adversely...
, nystagmus, retinitis, disc pallor, and oculomotor apraxia.
Nearly half of the patients with SSADH deficiency have seizures. These include absence, tonic clonic, and convulsive status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. It is unclear whether decreased levels of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
or elevated levels of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
are responsible for these seizures but alterations in these neurotransmitters and their receptor binding or neurotransmitter transport is hypothesized to play a role in the pathogenesis of the seizures in this population.
Genetics
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
(chromosome 6), rather than the sex-linked 23rd chromosome. Being a recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
disorder, the disease can only be inherited from both parents since the disorder can only occur when a person has two copies of the gene.
It is believed that the genetic basis for SSADH deficiency resides in the SSADH human ALDH5A1 gene which maps to chromosome 6p22. More than 47 disease-causing mutations have been identified for the disorder, all of which lead to absence of functional proteins through missense, nonsense
Nonsense
Nonsense is a communication, via speech, writing, or any other symbolic system, that lacks any coherent meaning. Sometimes in ordinary usage, nonsense is synonymous with absurdity or the ridiculous...
, or splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
errors; no hotspots have been identified. Consanguinity is frequent; this suggests the occurrence of rare disease causing alleles in the general population.
Mechanism
GABAGabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
is a major inhibitory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. It modulates the activity of several neurotransmitters including dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
. GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
is synthesized in a single step from its precursor glutamate by glutamic acid decarboxylase. GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
is metabolized by successive transamination
Transamination
There are two chemical reactions known as transamination . The first is the reaction between an amino acid and an alpha-keto acid...
and oxidation to yield succinic semialdehyde
Succinic semialdehyde
Succinic semialdehyde is a GABA analogue.-See also:* Succinic semialdehyde dehydrogenase deficiency* 4-aminobutyrate aminotransferase...
and succinic acid
Succinic acid
Succinic acid is a dicarboxylic acid. Succinate plays a biochemical role in the citric acid cycle. The name derives from Latin succinum, meaning amber, from which the acid may be obtained....
respectively via the catalyzing effects of GABA transaminase. The succinic semialdehyde
Succinic semialdehyde
Succinic semialdehyde is a GABA analogue.-See also:* Succinic semialdehyde dehydrogenase deficiency* 4-aminobutyrate aminotransferase...
can be converted into either succinic acid
Succinic acid
Succinic acid is a dicarboxylic acid. Succinate plays a biochemical role in the citric acid cycle. The name derives from Latin succinum, meaning amber, from which the acid may be obtained....
by SSADH or to GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
by the enzyme succinic semialdehyde reductase. The absence of SSADH leads to a 30-fold increase of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and a 2-4 fold increase of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
in the brains of patients with SSADH deficiency as compared to normal brain concentrations of the compounds. Elevations of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
have been shown to induce spike and wave activity similar to that seen in generalized absence epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
in animal models as well, which has motivated researchers to increase their knowledge on the relationship between GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and the neurological manifestations seen in SSADH deficiency.
GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
acts via binding to its receptors which include the ligand gated ion channels, GABAA and GABAC and the G-protein couple receptors GABAB. The GABAB receptor has been found to be the most important of the three receptors for this disorder as it is vital in both GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
release. This receptor mediates the release through presynaptic effects through a voltage dependent inhibition of high voltage activation of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
channels. Many experiments have been able to show that it is the increased levels of both GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
that seem to alter the function of GABAB receptor, which may further play a role in the tonic-clonic seizures that are often seen in patients with the disorder.
In terms of intracellular signaling, GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
inhibits mitogen activated protein (MAP) kinase action via the GABAB receptor mechanism. MAP kinase is imperative for numerous physiological changes including regulation of cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
and differentiation, thus, down-regulation of this pathway may occur during the presence of too much GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
as found in SSADH deficiency. In 2003, Ren and Mody et al. proved that repeated exposure of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
to MAP kinase affected myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
expression. This is a critical finding since myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
is the electrical and insulating phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
layer that surrounds the axons of many neurons in the brain. Proper myelination is critical for carrying electrical signals, or data, from one nerve cell to the next. When myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
becomes damaged, it can cause numerous neurological problems, many of which are seen in patients with SSADH deficiency. Thus, Ren and Mody’s work in the relationship between increased levels of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
expression may further show the significance of this pathway in terms of the neurological deficits seen in SSADH deficiency.
Glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
metabolism may also play a role in the pathophysiology of SSADH deficiency. The major ionotropic glutamine receptors include the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainite receptor. High levels of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
have been shown to depress both the NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
and AMPA/kainite receptor mediated functions and may also alter glutamatergic excitatory synaptic transmission as well. Decreased glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
, coupled with elevated GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
, has also suggested disruption of the glutamine-glutamate shuttle
Glutamate-glutamine cycle
In biochemistry, the glutamate-glutamine cycle is a sequence of events by which an adequate supply of the neurotransmitter glutamate is maintained in the central nervous system....
which ultimately provides for astrocytic glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
as a precursor for neuronal glutamate and GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
. This disruption has the potential to impair glutamate homeostasis and may lead to uncoupling of the normal balance between glutamatergic excitatory activity and GABAergic inhibition, and may be responsible for the convulsive seizures that are observed in this disorder.
Finally, additional mitochondrial processes may also be affected by SSADH deficiency. Succinate semialdehyde is considered a reactive carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
and may lead to increased oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. This stress is believed to contribute to the formation of free radicals in the brain tissue of animal models induced with SSADH deficiency, which further leads to secondary cell damage and death. Additionally, oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
may be responsible for loss of striatal dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
which may contribute to pathophysiology of the disease.
Animal Models Used to Understand SSADH Deficiency
Several scientists have developed murine models of SSADH (Aldh5a1-/-) by typical geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
methodology to create a uniform absence of the SSADH enzyme activity as well as accumulations of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
in tissues and physiological fluids. The mice are born at the expected Mendelian frequencies for an autosomal recessive disorder. Most of the models include distinctive neurological phenotypes and exhibit hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, truncal ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, generalized tonic-clonic seizures associated with 100% mortality. The mice uniformly die at 3-4 postnatal
Postnatal
Postnatal is the period beginning immediately after the birth of a child and extending for about six weeks. Another term would be postpartum period, as it refers to the mother...
weeks. While this model is considered to be more severe than the phenotypes seen in humans, currently, it is the most highly regarded, valid, metabolic model to study potential therapeutic interventions for the disorder.
Studies have shown that alterations of both the GABAA receptor and the GABAB receptor early in the life of the Aldh5a1-/- mice can increase levels of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and enhance GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
release. Besides these effects, it has also been shown that “…a developmental down-regulation of GABAA receptor mediated neurotransmission in Aldh5a1-/- mice likely contributes to the progression of generalized convulsive seizures seen in mutant animals.” Other studies have confirmed the relationship between elevated levels of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and MAP kinase in mutant animals contribute to profound myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
abnormalities.
Neuroimaging
Cranial computed topography, magnetic resonance imagingMagnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
, and flurodeoxyglucose positron emission topography are just some of the neuroimaging modalities that have been used to diagnose patients with SSADH deficiency. On the basis of 29 previously published cases that had imaging results available, there were some common abnormalities found. These included increased T2-weighted signal abnormalities involving the globus pallidi bilaterally and symmetrically as well as the presence of subcortical white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
. Similar abnormalities have been identified in the brainstem and cerebellar dentate nucleus
Dentate nucleus
The dentate nucleus is located within the deep white matter of each cerebellar hemisphere, and it is the largest single structure linking the cerebellum to the rest of the brain. It is the largest and most lateral, or farthest from the midline, of the four pairs of deep cerebellar nuclei, the...
.
Signal intensity on a T2 image may be a result of edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
or an inflammatory response. Because this type of imaging is a water detecting sequence, any form of calcification or mineralization would also appear dark, thus explaining why accumulation of extra blood or fluid would appear bright on a T2 image. Another explanation for signal intensity may be demyelination since the globus pallidi are traversed by a number of myelinated axons, thus confirming Ren and Mody’s 2003 work proving that repeated exposure of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
to MAP kinase affected myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
expression, thus causing the numerous neurological dysfunctions seen in SSADH deficiency patients. Ultimately, because the globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
is intimately linked with the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
and thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, it would be expected that some of the motor dysfunctions seen in SSADH patients such as ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
and hyporreflexia would be common.
Laboratory
Detection of the disorder is possible with an organic acidOrganic acid
An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group –COOH. Sulfonic acids, containing the group –SO2OH, are relatively stronger acids. The relative stability of the conjugate...
analysis of the urine. Patients with SSADH deficiency will excrete high levels of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
but this can be difficult to measure since GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
has high volatility and may be obscured on gas chromatography or mass spectrometry
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
studies by a high urea peak. Other GABA metabolites can also be identified in urine such as glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
. Finally, succinic semialdehyde dehydrogenase levels can be measured in cultured leukocytes of the patient. This occurs due to the accumulation of 4,5-dihydroxyhexanoic acid which is normally undetectable in mammalian tissues but is characteristic of SSADH deficiency. This agent can eventually compromise the pathways of fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
, glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
, and pyruvate metabolism, and then become detectable in patients' leukocytes. Such enzyme levels can also be compared to non-affected parents and siblings.
Treatments
A number of pharmacological treatments have been suggested or tested for efficacy on Aldh5a1-/- mice and/or humans. Below is a small sampling of the most common treatments though to be therapeutic to patients with SSADH deficiency. Unfortunately, there is very little data to support the benefit of the following treatments since few controlled studies have been conducted in patients.Vigabatrin
The most common therapeutic agent available for SSADH deficiency is one that reduces the levels of GHBGHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
via inhibition of GABA transaminase. Vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
is an irreversible inhibitor of GABA transaminases which leads to decreased levels of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and elevation of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
. Clinical results after use are diverse, ranging from improved ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
and speech in some patients to worsening of symptoms in others. Lower doses (30–50 mg/kg per day) is associated with fewer side effects and greater improvement of clinical features at high doses of the therapeutic. Although vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
has not been consistently successful in patients with SSADH deficiency, it has shown enhanced survival of Aldh5a1-/- mice at very high doses.
Sodium Valproate
Sodium valproateSodium valproate
Sodium valproate or valproate sodium is the sodium salt of valproic acid and is an anticonvulsant used in the treatment of epilepsy, anorexia nervosa, panic attack, anxiety disorder, posttraumatic stress disorder, migraine and bipolar disorder, as well as other psychiatric conditions requiring...
has been used for the treatment of generalized and partial seizures in humans for both epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
and bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. Valproate enhances GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
synthesis and release leading to augmented GABAergic functions in some areas of the brain. Successful interventions with valproate have been noted, but no clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s have been conducted thus far.
However, Valproate is usually contraindicated as it may inhibit residual SSADH enzyme activity
GABAB receptor antagonist: CGP-35348
The GABAB antagonist CGP-35348CGP-35348
CGP-35348 is a compound used in scientific research which acts as an antagonist at GABAB receptors....
(3-amino-propyl-(diethoxymethyl) phosphinic acid) has been used in Aldh5a1-/- mice with strong results. It has shown to reduce the frequency of absence seizures, though there have been some cases in which it worsened convulsive seizures.
GABAB agonist: Baclofen
BaclofenBaclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
(β-p-chlorophenyl-GABA) has some analgesic properties and has been traditionally used for spasticity. Its pharmacological effects primarily take place via presynaptic GABAB receptors in the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, simultaneously releasing excitatory neurotransmitters onto motor neurons. Because the number and function of GABAB receptors has been shown to progressively diminish in Aldh5a1-/- mice, such a therapy may prove to be useful. However, no data on the efficacy of baclofen
Baclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
on Aldh5a1-/- mice or human patients has been reported.
Taurine
Taurine is a non-proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
sulfur amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
that is found in high concentrations in human milk. It has been shown to have neuroprotective and neuromodulating properties. While it is an inhibitory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
, its ability to cross the blood brain barrier is limited. There is a lot of literature that indicates that taurine acts as antagonist at GABAA and GABAB receptors which may further enhance its ability to treat patients with SSADH deficiency, but further pharmacological studies are yet to be conducted to see if taurine could serve a therapeutic purpose.
Taurine has been successfully used in a single case open study in a child with SSADH deficiency; with resolving of brain lesions, and improvement in coordination and gait ( A.Saronwala, Anne Tournay, John J Gargus: Genetic inborn error of metabolism provides a unique window into molecular mechanisms underlying taurine therapy. Taurine in health and Disease ISBN 978-81-7895-520-9)
Ketogenic Diet
During prolonged periods of fasting, ketoneKetone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
bodies serve as the primary energy source for the brain. In 2006, Henderson et al. showed that there is a therapeutic effect of maintaining a ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
– a diet consisting of high fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
/low carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
meals – in children with epilepsy. Ketogenic diets have also been shown to have some neuroprotective effects in models of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
and hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
as well. In a recent study conducted at the Hospital for Sick Children in Canada in 2007, researchers found that a ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
prolonged the lifespan of Aldh5a1-/- mice by greater than 300%, along with the normalization of ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
and some improvement in various seizure types seen in SSADH deficient murine models. These effects were in conjunction with “…a significant restoration of GABAergic synaptic
Synaptic
Synaptic may refer to:*Synapse, part of the nervous system*Synapsis, the pairing of two homologous chromosomes*Synaptic , a Linux graphical package management program for APT See also...
activity and region-specific restoration of GABAA receptor associated chloride channel
Chloride channel
Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell...
binding.” Ultimately, the data seen in the study indicated that a ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
may work in its ability to restore GABAergic inhibition. But further studies on murine models need to be conducted, ultimately leading to the possibility of conducting a controlled study on humans afflicted with the disorder.
There is speculation that a ketogenic diet may be harmful for humans with SSADH deficiency as it may cause elevated levels of GHB in the bloodstream.
Other Interventions
Other therapeutic interventions include:- ethosuximideEthosuximideEthosuximide is a succinimide anticonvulsant, used mainly in absence seizures.-Approved:It is approved for absence seizures. Ethosuximide is considered the first choice drug for treating absence seizures in part because it lacks the idiosyncratic hepatotoxicity of the alternative anti-absence...
and other epileptic drugs - GHBGHBGHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
receptor antagonist NCS-382NCS-382NCS-382 is a moderately selective antagonist for the GHB receptor. It blocks the effects of GHB in animals and has both anti-sedative and anticonvulsant effects. It has been proposed as a treatment for GHB overdose in humans, as well as for the endogenous metabolic disorder succinic semialdehyde... - GABAA receptor modulators
- uridineUridineUridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....
- acamprosateAcamprosateAcamprosate, also known as N-acetyl homotaurine and by the brand name Campral, is a drug used for treating alcohol dependence.Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutamatergic...
- dopaminergic agents
- dextromethorphanDextromethorphanDextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
- glutamineGlutamineGlutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
- antioxidants
- LamotrigineLamotrigineLamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
The Future of SSADH Deficiency
While SSADH deficiency has been studied for nearly 25 years, knowledge of the disorder and its pathophysiology remains unclear. However, the progress that has been made with both murine and human models of the disorder have provided a lot of insights into how the disease manifests itself and what more can be done in terms of therapeutic interventions. Much of the current research into SSADH has been led by a dedicated team of physicians and scientists, including Phillip L. Pearl, MD of the Children’s National Medical Center at George Washington School of Medicine and K. Michael Gibson, PhD of the University of Pittsburgh School of MedicineUniversity of Pittsburgh School of Medicine
The University of Pittsburgh School of Medicine is a medical school located in Pittsburgh, Pennsylvania, USA. The School of Medicine is also known as Pitt Med, and is ranked as a “top medical school” by U.S. News & World Report in the publication's categories of research and primary care...
. Both have contributed significant efforts to finding appropriate therapies for SSADH deficiency and have specifically spent most of their recent efforts into understanding the efficacy of the ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
for patients with SSADH deficiency. In addition, a lot of the research that was published in 2007 examined the pathogenesis for the disorder by examining the role of oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
on tissues in various cerebral structures of Aldh5a1-/- mice.
Ultimately, the metabolic pathway of SSADH deficiency is known, but how the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
deficiency and accumulation of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
contribute to the clinical phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
is not. For the future however, treatment strategies should focus on both decreasing the total production of GHB
GHB
GHB may refer to:*gamma-Hydroxybutyric acid, a neuroprotective and depressant drug that is illegal in a number of countries*glycated hemoglobin, a form of hemoglobin created during its exposure to high plasma levels of glucose...
and increasing the total concentration of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and further assessing whether the effects of these changes influences the neurological manifestations seen in patients afflicted with SSADH deficiency.