**4.2. Branched Chain Alpha Ketoacid dehydrogenase (BCKDH) complex Deficiency – Maple syrup urine disease (MSUD)**

Another important dehydrogenase deficiency leading to an inborn error in metabolism is that in the branched chain alpha ketoacid dehydrogenase (BCKDH) complex (61;62). This complex is similar to PDH complex, and autosomal recessive mutations in the different subunits of the complex have been reported for this disease. In this disorder, accumulation of branched chain amino acids (BCAAs like isoleucine, leucine and valine) and branched chain alpha ketoacids (BCKAs) (with maple syrup odor to the urine) is observed along with neurological deficits and developmental disorders. Based on the characteristic manifestations and level of neurological complications, this disease is classified into the following five forms:


Thus, all these forms of IEM are caused due to varying degree of deficiency in the enzyme activity leading to varying levels of neurological complication. Treatment is initiated by high calories leucine free diet rich with BCAA-free formulas and an optimum supplementation of isoleucine and valine. Hemodialysis or hemofiltration may be used to remove deposited BCAAs and BCKAs from the body. During acute MSUD, brain edema and hyponatremia can also occur but can be immediately treated by administration of mannitol or diuretic drugs. In adolescents and adults, it can lead to depression, anxiety. However, the burden of these pathologies can be decreased by treatment with appropriate standard drugs such as psychostimulants or antianxiety drugs. Although no direct drug is used to treat MSUD, recent studies have shown the role of phenylbutyrate in increasing BCKDH activity, reducing levels of BCAAs and BCKAs and causing relief in MSUD patients (63). However, careful monitoring and routine biochemical testing is key in appropriate treatment in MSUD affected patients.

### **4.3. Succinic semialdehyde dehydrogenase (SSD) deficiency**

100 Dehydrogenases

dystonia.

following five forms:

iii. A chronic relapsing ataxia with prolonged survival

used to treat severe lactic acidosis to some extent.

**Deficiency – Maple syrup urine disease (MSUD)** 

iv. Static encephalopathy, cerebral palsy like motor deficits associated with paroxysmal

Alkali (such as sodium bicarbonate) administration to neutralize severe lactic acidosis and provide immediate temporary relief has been reported to treat acute episodes of severe acidosis. Chronic treatment strategies for PDH deficiency on the other hand, include incorporation of ketogenic diet consisting of high fat, low carbohydrate and low protein. High doses of thiamine can be beneficial in treating thiamine responsive PDH deficiency. Dichloroacetate (DCA) can reduce the inhibition of PDHc phosphorylation and thus can be

Another important dehydrogenase deficiency leading to an inborn error in metabolism is that in the branched chain alpha ketoacid dehydrogenase (BCKDH) complex (61;62). This complex is similar to PDH complex, and autosomal recessive mutations in the different subunits of the complex have been reported for this disease. In this disorder, accumulation of branched chain amino acids (BCAAs like isoleucine, leucine and valine) and branched chain alpha ketoacids (BCKAs) (with maple syrup odor to the urine) is observed along with neurological deficits and developmental disorders. Based on the characteristic manifestations and level of neurological complications, this disease is classified into the

i. Classical MSUD: This is the most common type of MSUD with early symptoms in neonates. Neonates born normal, within 3-7 days of birth show symptoms such as lethargy, weight loss, metabolic dearrangement, encephalopathy with hypotonia and

iii. Intermittent MSUD: Episodic ataxia, semicoma, elevated BCAAs and BCKAs occur after episodes of infection or acute illness. Cognitive functions may be affected only in case of

iv. Thiamine responsive MSUD: Mutation in E2 protein of the BCKDH complex results in reduced affinity of cofactor thiamine pyrophosphate (TPP), thus this form of disorder can be treated with thiamine substitution. Reduced activity of the complex results in

v. E3-deficient MSUD: Combined deficiency of E3 subunit (common component of all three mitochondrial multi enzyme complexes - BCKDH, pyruvate dehydrogenase complex and alpha ketoglutarate dehydrogenase) results in elevated lactate, pyruvate

Thus, all these forms of IEM are caused due to varying degree of deficiency in the enzyme activity leading to varying levels of neurological complication. Treatment is initiated by high calories leucine free diet rich with BCAA-free formulas and an optimum

hypertonia. It is characterized by seizures, coma and even death if not treated. ii. Intermediate MSUD: This type shows mild but persistent ketoacidosis and

developmental delay with 3-30% less dehydrogenase activity.

and alpha ketoglutarate along with BCAAs and BCKAs.

repeated episodes of acute illness.

hyperaminoacidemia.

**4.2. Branched Chain Alpha Ketoacid dehydrogenase (BCKDH) complex** 

SSD deficiency is an autosomal recessive disorder of γ-hydroxybutyric acid (GABA) metabolism. In human brain, GABA is the most important inhibitory neurotransmitter. Oxidative conversion of succinate semialdehyde to succinic acid is impaired in this deficiency. This leads to production of γ-hydroxybutyrate (GHB) (see **Figure 5**). ALDH5A1 is the only gene associated with this deficiency. Mild developmental delay, psychomotor retardation, hypotonia, ataxia are observed along with extrapyramidal symptoms such as dystonia, choreoathetosis and myoclonus. More than 50% of affected individuals develop seizures (64-67). Neuroimaging screening generally reveals hyper intensities in globus pallidus, sub cortical white matter, cerebellar dentate nucleus and brain stem (68). Accumulation of γ-amino butyric acid (GABA) and GHB are considered positive indicators for this disease which can be confirmed by testing of SSD enzyme activity in leucocytes.

**Figure 5.** SSD deficiency: In the absence of SSD, transamination of γ-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (γ-hydroxybutyrate [GHB]). SSADH deficiency leads to significant accumulation of GHB and GABA.

Current therapies are mostly symptomatic, directed at seizure treatment and amelioration of neurobehavioral symptoms. Antiepileptic drugs such as carbamazepine and anti-anxiety drugs may be administered in conjunction with physical and occupational therapy. Early attempts to use Vigabtrin (GABA transaminase inhibitor) did not meet the therapeutic expectations (69).

Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology 103

**5. Aging: The role of dehydrogenases in metabolic and mitochondrial** 

Aging or growing old is defined as a time related loss and decline in certain morphological, anatomical and functional features of body in comparison to its previous state. Beginning as a maturation process from childhood to young adulthood, it assumes the characteristic of decline through middle and late ages. Accumulation of molecular, cellular, or organ level damage leads to higher vulnerability of disease and eventually death. There have been numerous theories and hypothesis for causes of aging but it is still under investigation and discussion. "The Free Radical Theory of aging (ROS generation), shortening of telomerase, DNA methylation and epigenetics are few main ones. Important to us is the "The Free Radical Theory of aging since it is closely associated with mitochondria, and linked DHOs (78-81).

Broadly, both genetic as well as external environmental factors can be responsible for promoting the age associated decline in functionalities (82). Oxidative stress and dietary restrictions can influence the genes externally. "Oxygen derived species", "Reactive nitrogen species" and "Reactive aldehydic species" can cause changes at cellular level ensuing damage to our natural defense mechanisms affecting repair and elimination processes in the body. In totality, irregularities in function, oxidative changes and the piled up cellular damages can lead to homoeostatic imbalance which finally result in aging as well as agerelated diseases. "The Free Radical Theory of aging" suggests generation of superoxide radical, hydrogen peroxide and hydroxyl radical as a side reaction to the electron transport chain at mitochondrial membrane (83). These free radicals can cause enzyme inactivation to different extent with different mechanisms (see **Figure 6**). Studies show that mitochondrial enzymes are resistant to hydrogen peroxide free radical but are fairly affected by hydroxyl free radical. On the other hand oxygen free radical by itself can cause significant oxidative damage with respect to inactivation of mitochondrial enzymes like NADH dehydrogenase,

succinate dehydrogenase, NADH oxidase, succinate oxidase and ATPase 2.

accumulation of toxic metabolites in the body.

**dehydrogenases** 

Link between aging and various dehydrogenase enzymes is based on the energy demand of our body which involves the participation of different dehydrogenases for production of ATP at cellular level (as elaborated in the earlier section of energy metabolism). Several dehydrogenases involved in energy metabolism can exhibit altered activity or complete inactivation with aging. This can result in hampering energy production as well as

**6. Metabolic dysfunction and its link to Alzheimer's disease: The role of** 

Alzheimer's disease is the most common form of dementia characterized by loss of memory, cognitive decline and change in perception and behavior. Pathological hallmarks include accumulation of amyloid beta protein (Aβ) and resulting plaque formation (a cleavage protein of amyloid precursor protein-APP) and formation of neurofibrillary tangles (due to hyper phosphorylation of microtubule associated protein of neurons in the brain). Genetic

**dysfunction** 
