**4.1. Pyruvate dehydrogenase (PDH) deficiency**

Pyruvate dehydrogenase is a multi-enzyme complex which catalyzes the conversion of pyruvate (the end product of glycolysis) into acetyl-coA- a substrate that can enter citric acid cycle (for production of ATP and energy equivalents). PDH is a six subunit complex composed of E1-pyruvate dehydrogenase, E2-dihydrolipoyl transacetylase and E3 dihydrolipoyl dehydrogenase, E3BP- E3 binding protein and two regulatory subunits pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphatase. Although several mutations in the PDH complex deficiency (such as point mutations, deletions, duplications) have been reported so far; deficiency in PDH E1-alpha subunit (abbreviated as PDHA1) is the most common type (51-53). PDH deficiencies due to mutations in other subunits of the PDH complex are comparatively rare. All mutations leading to PDH deficiency are X linked except, the one in regulatory units, which are autosomally recessive (54-57). Since PDH results in acetyl co-A formation, the most common clinical manifestation of PDH deficiency is severe lactic acidosis. Defects in energy metabolism can cause neurological deficits such as mental retardation, developmental delay as well as psychomotor retardation. Hypertonia/hypotonia, ataxia, motor dysfunction like spasticity are the more common symptoms observed (58). Structural anomalies (such as microcephaly, facial dysmorphism) and epilepsy (focal or generalized seizures- both have been reported) may develop *in utero*. Optic atrophy, nystagmus and strabismus are observed at ocular level whereas peripheral neuropathies such as in nerve conduction have also been reported.

Based on clinical case studies, PDH deficiencies have been classified into four typical neurological patterns (58-60):


Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology 101

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

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.

treatment in MSUD affected patients.

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

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 used to treat severe lactic acidosis to some extent.
