Goal 1.

Describe the clinical characteristics of primary PDCD.

Goal 2.

Review the genetic causes of primary PDCD.

Goal 3.

Review the differential diagnosis of primary PDCD.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of primary PDCD in a proband (when possible).

Goal 5.

Inform (when possible) medical management of primary PDCD based on genetic cause.

Goal 6.

Inform genetic risk assessment of family members of a proband with primary PDCD.

Features of Primary PDCD

Neurologic findings [DeBrosse et al 2012]

• Developmental delay (majority of individuals)
• Hypotonia, especially axial (majority of individuals)
• Epilepsy (occasional)
• Hypertonia, especially appendicular (occasional)
• Ataxia (occasional)
• Peripheral neuropathy (occasional) [Barnerias et al 2010]
• Dystonia – may be episodic, in response to fever, stress or exercise (occasional) [McWilliam et al 2010, Castiglioni et al 2015]
• Spasticity (occasional)
• Dyskinesia – may be paroxysmal exercise-induced (rare) [Friedman et al 2017]
• Hemiplegia or episodic limb paralysis (rare) [Sen et al 2021]

Facial features may include a long philtrum, thin upper lip, and low-set ears [De Meirleir et al 1993, Patel et al 2012].

Ophthalmologic findings [Patel et al 2012]

• Optic atrophy (rare)
• Nystagmus (rare)
• Ptosis (rare) or ophthalmoplegia [Sen et al 2021]
• Strabismus (rare)

Growth

• Intrauterine growth restriction
• Shortened long bones (rare)
• Primary or acquired microcephaly (majority of individuals)

Musculoskeletal findings include acquired hip dysplasia.

Psychiatric manifestations (e.g., auditory hallucinations, delusional thoughts) may develop in mildly affected individuals in adolescence and early adulthood [Author, unpublished observation].

Brain MRI findings [Ah Mew et al 2011, DeBrosse et al 2012]

• Cerebral atrophy (majority of individuals) [Patel et al 2012]
• Asymmetric ventriculomegaly (common)
• Dysgenesis or agenesis of the corpus callosum (common) [Barnerias et al 2010]
• T₂-weighted hyperintensities (occasional) typically involving the basal ganglia more than the brain stem and cerebellum [Patel et al 2012]
• Periventricular cysts and/or intraventricular septations (occasional)
• Hyporotation of the hippocampus (rare)

Laboratory features

• Elevated blood lactate with proportional elevation of pyruvate; normal lactate/pyruvate ratio (normal range 10-20). Peak pyruvate is typically >0.2 mmol/L [Clarke et al 2013]. Elevations of lactate and pyruvate may be intermittent and do not necessarily correlate with the severity of the clinical phenotype [Author, unpublished observation].
  Note: Pyruvate may appear artificially low in samples that are collected improperly (e.g., not drawn immediately into a perchloric acid tube, not drawn on ice, or drawn while using a tourniquet).
• Elevated plasma alanine and proline may also occur. Alanine-to-leucine and proline-to-leucine ratios are highly sensitive but not specific for primary PDCD [Bedoyan et al 2020].
• Elevated urine and CSF lactate and pyruvate
• Low pyruvate dehydrogenase complex (PDC) enzyme activity in cultured fibroblasts, lymphocytes, and/or skeletal muscle (activity levels may vary between tissues in an individual) [Shin et al 2017]. Note: The majority of primary PDCD is X-linked and PDHA1 related, and differential involvement of various tissues is common [Shin et al 2017].
• Additional laboratory features variably present in individuals with specific molecular causes of primary PDCD (See Table 1.)
• Positive newborn screen (limited availability to date). Pilot newborn screening for primary PDCD using dried blood spots to screen for ratio of alanine:leucine >4 and/or proline:leucine >3 was used to identify three neonates with PDCD and two additional neonates with other mitochondrial diseases. This screening had a 2.8% positive predictive value and an 80% sensitivity. Pilot newborn screening is ongoing in the state of Ohio [Bedoyan et al 2020].

Evaluations Following Initial Diagnosis

Treatment of Manifestations

There are no FDA-approved therapies for primary PDCD, thus, treatment recommendations are based on open-label case reports and small trials.

Ketogenic diet is the gold-standard therapy for individuals with primary PDCD [Bedoyan et al 2017, Shin et al 2017, Bedoyan et al 2020]. The underlying rationale for the ketogenic diet is that individuals with primary PDCD do not metabolize carbohydrates effectively. Therefore, carbohydrates may precipitate lactic acidosis. On the basis of this rationale and many open-label studies, high-fat, low-carbohydrate diets ("ketogenic diet”) are used [Sofou et al 2017]. Ketogenic diet has been shown to be particularly beneficial in decreasing seizures and improving ataxia, lactic acidosis, and sleep habits [Wexler et al 1997, Sofou et al 2017]. Half of individuals with primary PDCD-related epilepsy achieve epileptic remission within one year of starting a ketogenic diet; studies have also shown improvement of language, social, cognitive, and motor development on the ketogenic diet. The developmental benefit appears to be the most pronounced in individuals with relatively mild presentations, such as childhood-onset ataxia [Sofou et al 2017].

The recommended ratio varies from as low as a 1:1 fat-to-carbohydrate & protein ratio ("modified" ketogenic diet) to as high as a 4:1 ratio. There are no studies that definitively demonstrate the superiority of any particular ratio. The recommended amount of dietary fat can vary widely, from ~55% to 80%, with variable proportions of unsaturated and saturated fats. The best outcomes are associated with maintaining plasma or serum beta-hydroxybutyrate levels at about 3.0-3.5 mEq/L [Sofou et al 2017]. Tolerance of the ketogenic diet varies and treatment must be individualized.

Ketogenic diet is the most beneficial in individuals with a milder pre-treatment disease course, disease onset after the neonatal period, higher baseline developmental functioning, and absence of structural brain anomalies [Sofou et al 2017]; although the effect of early implementation of ketogenic diet such as in the neonatal period is not well understood or investigated because of the delayed diagnosis of individuals with PDCD. The most favorable developmental outcomes are associated with early implementation of the diet [Wexler et al 1997].

Thiamine (vitamin B₁) is routinely used in individuals with primary PDCD, at doses of 300-1000 mg/day divided in three doses, although only a minority of individuals have shown biochemical or neurologic response [Pastoris et al 1996, Sedel et al 2008, Barnerias et al 2010, Sofou et al 2017]. Genotype-phenotype correlation exists for thiamine responsiveness in primary PDCD, with missense variants – especially those in exon 3 or the thiamine pyrophosphate binding site of the E1-alpha subunit (PDHA1) – being the most amenable to treatment [Sedel et al 2008, Castiglioni et al 2015].

Therapies. For all individuals, physical therapy and occupational therapy are essential, with a goal of maintaining mobility for those with spasticity.

Other

• Lipoic acid. Lipoic acid supplementation is theoretically of benefit (and has very low toxicity). However, studies have suggested that exogenous lipoic acid, while beneficial as an antioxidant, is not utilized for mitochondrial lipoylation [Mayr et al 2014].
• N-acetylcysteine. As mitochondrial disorders (including primary PDCD) commonly have increased oxidative stress, antioxidant therapy may be considered. In particular, blood glutathione testing may reveal deficiency of the major cellular antioxidant defense system, glutathione, which may be responsive to N-acetylcysteine to boost endogenous glutathione production [Barcelos et al 2020].
• L-carnitine (if on ketogenic diet). Supplementation with L-carnitine (sugar free) is utilized to protect against secondary carnitine deficiency, which is associated with long-term use of ketogenic diet.

Surveillance

For individuals with primary PDCD, comprehensive neurologic examination and developmental assessment are recommended every six to 12 months to assess for new neurologic symptoms and epilepsy control. Repeat brain MRI and EEG are warranted only if new symptoms develop.

Individuals may require a physical medicine and rehabilitation specialist to guide their therapy and advise on the use of orthotic devices. Physical examination to assess for neuromuscular scoliosis and acquired hip dysplasia should be performed every six to 12 months, accompanied by radiographic imaging if there is clinical concern.

Annual ophthalmologic examination to assess for eye movement and ptosis is recommended.

Serum bicarbonate and lactate levels to monitor for acidosis should be performed as needed with illness and metabolic stressors, as well as with initiation of and modifications in ketogenic diet regimen.

Beta-hydroxybutyrate levels should be monitored routinely for children on the ketogenic diet, with a goal of maintenance above 3.0-3.5 mmol/L.

For individuals with pathogenic variants in DLD, liver monitoring includes physical examination and imaging to assess for liver size, as well as measurement of liver transaminases and synthetic liver function both routinely and when acutely ill. Like other mitochondrial hepatopathies, a theoretic risk exists of developing hepatocellular carcinoma – for which annual monitoring of alpha-fetoprotein and liver ultrasound may be considered; however, hepatocellular carcinoma has not been reported in DLD-related disease to date [Schady et al 2015]. See the GeneReview Dihydrolipoamide Dehydrogenase Deficiency for further guidance.

Therapies Under Investigation

Dichloroacetate (DCA) and phenylbutyrate both inhibit pyruvate dehydrogenase kinase 1 (PDK1), which is the major inhibitor of PDC. Inhibition of PDK1 results in enhanced residual PDC enzyme activity. DCA is reportedly a pan PDK inhibitor, although the inhibition varies among isoforms.

Clinical trials with DCA are ongoing (ClinicalTrials.gov NCT02616484). DCA may also reduce degradation of E1a. Therefore, it may have the most clinical efficacy in individuals with pathogenic variants that result in residual protein expression [Fouque et al 2003]. DCA has also shown in vitro promise in treating gain-of-function variants in PDK3, as expected [Perez-Siles et al 2020]. DCA dosing is titrated to the haplotype of the pharmacogenetic modifier gene, GSTZ1 [James et al 2017].

Phenylbutyrate has been shown in vitro to increase PDC enzyme activity in cell lines from individuals with DLAT, DLD, PDHA1, PDHB, PDHX, and PDP1 pathogenic variants, particularly in individuals with pathogenic variants associated with residual enzyme activity [Ferriero et al 2014].

Mode of Inheritance

PDHA1- and PDK3-related primary pyruvate dehydrogenase complex deficiency (PDCD) are inherited in an X-linked manner.

Unlike many X-linked disorders, an equal frequency of clinically affected males and females has been observed in PDHA1-related primary PDCD; however, affected females tend to have insertion/deletion pathogenic variants, while affected males are more likely to have missense pathogenic variants. Females with missense PDHA1 pathogenic variants are more likely to be asymptomatic [Lissens et al 2000].

Primary PDCD caused by pathogenic variants in DLAT, DLD, PDHB, PDHX, or PDP1 is inherited in an autosomal recessive manner.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor be hemizygous for the PDHA1 or PDK3 pathogenic variant; therefore, he does not require further evaluation or testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the mother may have somatic/germline mosaicism, or the affected male may have a de novo pathogenic variant (in which case the mother is not a heterozygote). About 60%-63% of males with PDHA1-related primary PDCD have the disorder as the result of a de novo pathogenic variant [Lissens et al 2000, Imbard et al 2011]. De novo PDK3 pathogenic variants have not been reported but are theoretically possible.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Parents of a female proband

• A female proband may have PDHA1-related primary PDCD as the result of a de novo pathogenic variant or she may have the disorder as the result of a PDHA1 pathogenic variant inherited from her mother or, theoretically, from her father (to date, there are no reports of paternal inheritance [Author, personal observation]). De novo PDHA1 pathogenic variants are more common in female probands than in male probands: about 85%-95% of females with PDHA1-related primary PDCD have the disorder as the result of a de novo pathogenic variant [Lissens et al 2000, Imbard et al 2011].
• To date, all reported female probands with PDK3-related primary PDCD whose parents have undergone molecular genetic testing have had the disorder as the result of an inherited PDK3 pathogenic variant. There are reports of both maternal and paternal transmission. De novo PDK3 pathogenic variants have not been reported but are theoretically possible.
• Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father either concurrently or subsequently if the mother’s testing is unrevealing) can help to determine if the pathogenic variant was inherited.

Sibs of a proband

• The risk to sibs of a male proband of inheriting a PDHA1 or PDK3 pathogenic variant depends on the genetic status of the mother: if the mother of the proband has a PDHA1 or PDK3 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
• The risk to sibs of a female proband of inheriting a PDHA1 or PDK3 pathogenic variant depends on the genetic status of the mother and the father.
  • If the mother of the proband has a PDHA1 or PDK3 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • If the father of the proband has a PDHA1 or PDK3 pathogenic variant, he will transmit it to all his daughters and none of his sons (paternal transmission of a PDHA1 pathogenic variant has not been reported to date [Author, personal observation]).
• The risk that a sib who inherits a PDHA1 or PDK3 pathogenic variant will have manifestations of the disorder cannot be fully predicted. The risk of manifestations is influenced by the sex of the sib, the sex of the proband, and, to an extent, the type of pathogenic variant segregating in the family (i.e., an insertion/deletion pathogenic variant or a missense pathogenic variant).
  • Sex of the sib. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and their clinical manifestations may range from asymptomatic to as severely affected as hemizygous males (see Clinical Characteristics).
  • Sex of the proband and type of pathogenic variant. As a result of the difference in pathogenic variants typically identified in male and female probands, it is difficult to fully predict what clinical manifestations may occur in a heterozygous or hemizygous sib who is a different sex from the proband. Theoretically, the female sibs of a male proband with a missense pathogenic variant may be asymptomatic or have milder manifestations than the proband, whereas an insertion/deletion pathogenic variant in a female proband may not be compatible with life in a hemizygous male fetus. Conclusive data regarding these possibilities are not available as there are few known families in which both male and female relatives are known to have a PDHA1 pathogenic variant (with the exception of male probands born to asymptomatic heterozygous mothers).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and the pathogenic variant cannot be detected in the leukocyte DNA of the mother (or, if the proband is female and the pathogenic variant cannot be detected in the leukocyte DNA of the mother or the father), the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Possible maternal germline mosaicism is suggested in a family described by Chun et al [1993] in which two female sibs were heterozygous for a PDHA1 pathogenic variant that was not identified in their mother, although their father was unable to be tested.

Offspring of a proband

• Affected males with PDHA1-related primary PDCD are not known to reproduce.
• Affected males with PDK3-related primary PDCD transmit the PDK3 pathogenic variant to all of their daughters and none of their sons.
• Females with a PDHA1 or PDK3 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. The severity of manifestations in offspring who inherit a PDHA1 or PDK3 pathogenic variant cannot be fully predicted and is influenced by several factors including the sex of the offspring (see Sibs of a proband).

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a primary PDCD-causing pathogenic variant, the parent's family members may be at risk.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one DLAT, DLD, PDHB, PDHX, or PDP1 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a primary PDCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a primary PDCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Intrafamilial clinical variability may be observed between sibs who inherit biallelic primary PDCD-causing pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with autosomal recessive primary PDCD are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a primary PDCD-causing pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the DLAT, DLD, PDHB, PDHX, or PDP1 pathogenic variants in the family.

Prenatal Testing and Preimplantation Genetic Testing

Once the primary PDCD-causing pathogenic variant(s) have been identified in an affected family member, molecular genetic prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Author Notes

All of the authors work together in the Mitochondrial Medicine Frontier Program at the Children's Hospital of Philadelphia, within the Division of Human Genetics in the Department of Pediatrics.

• Rebecca Ganetzky, MD (www.chop.edu/doctors/ganetzky-rebecca) is an Assistant Professor in the Department of Pediatrics at the University of Pennsylvania Perelman School of Medicine, attending physician, assistant director of the metabolic and advanced diagnostics laboratory, and PI of an active research laboratory focused on mitochondrial ATP synthase deficiency (www.research.chop.edu/ganetzky-laboratory); Dr Ganetzky has special clinical interest in primary lactic acidosis and PDCD. Contact email: ude.pohc@rkyztenag.
• Elizabeth M McCormick, MS, LGCC (www.chop.edu/clinical-staff/mccormick-elizabeth-m), is a Senior Genetic Counselor and research study coordinator. Contact email: ude.pohc@ekcimroccm.
• Marni J Falk, MD (www.chop.edu/doctors/falk-marni) is a Professor in the Department of Pediatrics at the University of Pennsylvania Perelman School of Medicine; founder, executive director, and attending physician in the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia (CHOP); and PI of an active translational research laboratory at CHOP focused on investigating the causes and global metabolic consequences of mitochondrial disease, as well as targeted therapies in cell and animal models (www.research.chop.edu/people/marni-j-falk). Contact email: ude.pohc@mklaf.

Acknowledgments

This work was funded in part by the Mitochondrial Medicine Frontier Program at Children's Hospital of Philadelphia and the National Institutes of Health (R35-GM134863, U24-HD093483, K08-DK113250). The content is solely the responsibility of the authors and does not necessarily represent the official views of the sponsors or the National Institutes of Health.

Revision History

• 17 June 2021 (sw) Review posted live
• 22 March 2021 (rg) Original submission

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