Pyruvate Dehydrogenase Complex Deficiency Clinical Presentation

The presentation and progression of pyruvate dehydrogenase complex (PDC) deficiency (PDCD) widely varies.^{[2, 3]}

Nonspecific but common symptoms of metabolic illnesses include the following:

• Poor feeding
• Lethargy
• Rapid breathing (ie, tachypnea)

Developmental nonspecific signs of metabolic disease include the following:

• Mental delays
• Psychomotor delays
• Growth retardation

Progressive neurologic symptoms of pyruvate dehydrogenase complex deficiency usually start in infancy but may be evident at birth or in later childhood. The following are signs of poor neurological development or degenerative lesions:

• Poor acquisition or loss of motor milestones
• Poor muscle tone
• New onset seizures
• Periods of incoordination (ie, ataxia)
• Abnormal eye movements
• Poor response to visual stimuli
• Episodic dystonia: This is associated with a deficiency of the E2 subunit, whereas progressive dystonia appears to be associated with a deficiency in the E1-alpha subunit.

Early childhood-onset pyruvate dehydrogenase complex deficiency typically presents with intermittent periods of incoordination, especially during mild illnesses.

The following respiratory symptoms are consistent with neurological disease and severe lactic acidosis:

• Apnea
• Dyspnea
• Respiratory depression

An acute form resembling Guillain-Barré syndrome with limb weakness has recently been described.

Low Apgar scores and small for gestational age are nonspecific signs of prenatal onset. With poor feeding and lethargy out of proportion to a mild viral illness, consider metabolic disturbances, especially after bacterial infection has been ruled out.

Neurologic

Hypotonia, ataxia, choreoathetosis, and progressive encephalopathy are found in children with lactic acidosis.

Loss of cortical material can result in a positive Babinski reflex, absent deep tendon reflexes, tremors, or spastic diplegia or quadriplegia.

Prenatal or postnatal microcephaly may be found.

Ophthalmological examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary responses, and blindness.

Seizures vary in type from clonic-tonic to infantile spasms.

Episodic or progressive dystonia

Respiratory

Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.

Dysmorphology

A characteristic but uncommon dysmorphology has been described for infantile-onset pyruvate dehydrogenase complex deficiency. Features include narrow forehead, frontal bossing, wide nasal bridge, long philtrum, and anteverted nostrils. Structural brain lesions have also been reported.

In addition, a case of X-component deficiency has been described with trigonocephaly, supranasal lipoma, hypertelorism, thin upper lip, bilateral epicanthus, upward slant of the eyes, high palate, and pectus excavatum.

The intramitochondrial pyruvate dehydrogenase complex is composed of 3 basic substrate-processing enzymes: a protein X and 2 regulatory enzymes. Thiamine pyrophosphate and lipoic acid are important pyruvate dehydrogenase complex cofactors. Dysfunction in all 3 substrate-processing enzymes, as well as protein X and thiamine dependence of the E1 alpha enzyme, has been described; however, dysfunction of the E1 alpha enzyme subunit is most common.

The E1 alpha subunit gene is located at Xp22.2-p22.1. More than 90 mutations of the E1 alpha enzyme subunit impair either polypeptide stability or catalytic efficiency.

The gene for the E1 beta enzyme subunit of the pyruvate dehydrogenase complex has been mapped to 3p13-q23; an isolated deficiency in E1 beta enzyme subunit has recently been documented.

A thiamine triphosphate synthesis inhibitor may cause pyruvate dehydrogenase complex E1 enzyme thiamine dependence in some patients who present with Leigh syndrome.

Recently a post-translational modification in which EGFR-PTK-mediated tyrosine-phosphorylation of the E1ss protein led to enhanced ubiquitination followed by proteasome-mediated degradation has been described.^[4]

A deficiency of lipoic acid, the E2 enzyme cofactor, has been described.

A deficiency of the E2 enzyme has been described.

The gene for the X protein of the pyruvate dehydrogenase complex is located at 11p13 and has an autosomal recessive inheritance. Eleven cases of pyruvate dehydrogenase complex X protein deficiency have been documented.

The E3 enzyme is mapped to 7q31-32 and has an autosomal recessive inheritance. The E3 enzyme is also active in the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes.