Neuro / Head & Neck for Thursday, June 4th, 2026

History

6-day-old neonate with episodes of apnea associated with oxygen desaturation, with a maximum recorded decrease of 45% from baseline saturation.Video electroencephalogram (VEEG) and metabolic screening within normal parameters.

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Question

With these brain MRI findings (corpus callosum dysgenesis, periventricular cysts, diffuse cerebral atrophy) and the patient’s clinical presentation of respiratory difficulty and feeding difficulty, what is the most likely diagnosis?

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Correct answer

Pyruvate dehydrogenase deficiency

Discussion

Introduction:

Pyruvate dehydrogenase complex deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism.

Pyruvate dehydrogenase catalyzes the metabolic conversion of pyruvate into acetyl–coenzyme A (acetyl-CoA), one of the initial steps of the citric acid (tricarboxylic acid, TCA) cycle. This cycle is a fundamental biochemical process occurring in the mitochondrial matrix that generates energy from various metabolic substrates, including carbohydrates, fatty acids, and amino acids. Dysfunction of this cycle deprives the organism of energy.

Pyruvate, derived from carbohydrate metabolism, is not converted into acetyl-CoA. This results in decreased availability of the primary substrate required for the TCA cycle and leads to abnormal accumulation of lactate and alanine, which are alternative and metabolically inefficient end products of pyruvate metabolism.

The most common form is caused by mutations in the X-linked E1 alpha subunit gene (PDHA1); all other causes are due to alterations in autosomal recessive genes.

The incidence of PDCD is likely less than 1:50,000. It may be underdiagnosed, as the condition is potentially responsible for unexplained seizures, acidosis, and developmental delay in cases where enzymatic testing is not performed, as well as for unexplained Leigh syndrome with demonstrable central nervous system (CNS) pathology.

Clinical Presentation:

Individuals with neonatal- and infantile-onset PDCD typically die within the first few years of life. Later-onset disease in childhood is often, though not always, associated with survival into adulthood.

Nonspecific but common symptoms of metabolic disorders include:

• Poor feeding

• Lethargy

• Tachypnea

Nonspecific developmental signs include:

• Developmental delay

• Psychomotor delay

• Growth retardation

Progressive neurological symptoms of PDCD usually begin in infancy but may present at birth or later in childhood. Patients may exhibit:

• Poor acquisition or loss of motor milestones

• Hypotonia

• New-onset seizures

• Ataxia

• Abnormal eye movements

• Poor visual responsiveness

• Episodic or progressive dystonia

Diagnosis:

Elevated blood lactate and pyruvate levels, with or without lactic acidemia, suggest an inborn error of metabolism at the mitochondrial level.

Cerebrospinal fluid (CSF) also shows elevated lactate and pyruvate levels, even in the absence of elevated blood levels.

Targeted analysis for known PDCD-associated mutations is typically performed using mitochondrial gene panels. If the clinical presentation is unclear, whole-exome sequencing (WES) or whole-genome sequencing (WGS) may be indicated.

Structural abnormalities may be detected on prenatal ultrasound, including hydrocephalus, cystic lesions, and agenesis or dysgenesis of the corpus callosum, often evident before 10 weeks of gestation.

Brain MRI may reveal ventricular dilatation, cerebral atrophy, hydrocephalus, and partial or complete agenesis of the corpus callosum.

MRI in infants with progressive neurological symptoms may demonstrate symmetric cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum, or diffuse hypomyelination.

Individuals with E2 subunit deficiency may present with discrete lesions restricted to the globus pallidus.

Proton magnetic resonance spectroscopy (¹H-MRS) of the brain reveals elevated lactate levels. N-acetylaspartate (NAA) and choline levels are consistent with hypomyelination.

Treatment:

Cofactor supplementation with thiamine, carnitine, and lipoic acid constitutes standard therapy. Thiamine and lipoic acid are administered to optimize pyruvate dehydrogenase activity, while carnitine facilitates fatty acid transport into mitochondria and may enhance cellular ATP production.

Ketogenic diets (with restricted carbohydrate intake) have been used to control lactic acidosis and reduce seizures, ataxia, and sleep disturbances, and have been associated with more favorable developmental outcomes.

Differential diagnosis

Aicardi syndrome: Similar due to corpus callosum agenesis and early seizures, but distinguished by chorioretinal lacunae, female predominance, and absence of lactic acidosis. Imaging shows corpus callosum agenesis with colpocephaly and periventricular cysts.

Congenital CMV infection: Overlaps with developmental delay, seizures, and neurologic impairment, but differentiated by periventricular calcifications, hepatosplenomegaly, systemic findings, and virologic confirmation, without primary lactate elevation. MRI shows periventricular calcifications, ventriculomegaly, and polymicrogyria.

Vanishing white matter disease: Characterized by progressive neurologic decline and white matter involvement, often worsened by stress; lactate is normal or mildly elevated without marked metabolic acidosis. MRI shows progressive rarefaction and cystic degeneration of white matter (“vanishing” appearance), with relative cortical sparing early on.

PDCD: Characterized by persistent lactic acidosis with elevated pyruvate and alanine, without specific infectious or ocular findings. Imaging may show cerebral atrophy, ventriculomegaly, corpus callosum abnormalities, symmetric basal ganglia/brainstem lesions, and elevated brain lactate on MR spectroscopy.

References

• Pyruvate Dehydrogenase Deficiency (PDCD) Treatment & Management. Richard E Frye, Paul J Benke, Mary L Windle, Luis O Rohena. Jun 16, 2023
• Deficiencia del complejo piruvato deshidrogenasa: actualización del panorama clínico, metabólico y mutacional en una cohorte de pacientes portugueses. Hana Pavlu-Pereira ,María João Silva ,Cristina Florindo ,Sílvia Sequeira ,Ana Cristina Ferreira ,Sofía Duarte ,Ana Luísa Rodrigues ,Patrícia Janeiro ,Anabela Oliveira ,Daniel Gomes ,Anabela Bandeira ,Esmeralda Martins ,Roseli Gomes ,Sérgia Soares ,Isabel Tavares de Almeida ,João B. Vicente yIsabel Rivera. 22 de octubre, 2020
• Deficiencia del piruvato deshidrogenasa: con más fenotipos de los que creemos. Divahia García Martín, Natalia Martínez Córdoba, Eugenia Espinosa García. 26 de abril, 2022
• Pyruvate dehydrogenase complex deficiency masked by septic shock-induced lactic acidosis: a case report. Hao Zhou , Yin Wen , Hongguang Ding. May 24, 2024