Clinical characteristics.

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described:

• The most common phenotype presents in the neonatal period with severe encephalopathy and lactic acidosis and later manifests Leigh-like signs and symptoms. Those with presentation in the neonatal period typically have severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. Signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia.
• A second group of affected individuals present in infancy with developmental regression resulting in severe developmental delay.
• A third group of affected individuals have normal development with isolated paroxysmal dystonia that may be exacerbated by illness or exertion.

Across all three groups, T₂ hyperintensity in the basal ganglia is very common, and may affect any part of the basal ganglia.

Diagnosis/testing.

The diagnosis of ECHS1D is established in a proband by the identification of biallelic pathogenic variants in ECHS1 on molecular genetic testing or low short-chain enoyl-CoA hydratase (SCEH) activity using cultured skin fibroblasts.

Management.

Treatment of manifestations: Treatment of severe metabolic acidosis with bicarbonate therapy; hyperammonemia (which may be related to severe acidosis or low ATP from impaired aerobic oxidation) may be addressed by treatment of the metabolic acidosis and/or consideration of hemodialysis. Inadequate nutrition may require feeding therapy; placement of a feeding tube may be considered. Paroxysmal dystonia may respond to benzodiazepines, whereas chronic dystonia may require botulinum toxin injections. Treatment of dystonia with levodopa may also be considered. Standard treatment for seizures, cardiomyopathy, pulmonary hypertension, optic atrophy, sensorineural hearing loss, and developmental delay.

Surveillance: At least annual echocardiogram, dilated eye examination, and audiologic evaluation. Routine monitoring for neurologic symptoms and developmental issues. Assessment of acid/base status and blood lactate level with all illnesses or metabolic stressors.

Agents/circumstances to avoid: Mitochondrial toxins (i.e., valproic acid, prolonged propofol infusions); ketogenic diet.

Genetic counseling.

ECHS1 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% change of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the ECHS1 pathogenic variants in the family are known.

Suggestive Findings

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) should be suspected in individuals with clinical features of Leigh syndrome and/or exercise-induced dystonia who have supportive brain MRI and biochemical findings, including early-onset lactic acidosis.

Clinical features

• Neurologic
  • Developmental delay, often severe [Sakai et al 2015, Tetreault et al 2015, Huffnagel et al 2018, Aretini et al 2018]
  • Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [Ferdinandusse et al 2015, Haack et al 2015, Bedoyan et al 2017, Aretini et al 2018]
  • Dystonia (exercise induced) and/or choreoathetotic movements [Korenke et al 2016, Olgiati et al 2016, Mahajan et al 2017]
• Growth. Failure to thrive, which may present prenatally as intrauterine growth restriction and/or oligohydramnios in the most severe cases [Ganetzky et al 2016, Bedoyan et al 2017]
• Cardiorespiratory
  • Hypertrophic or dilated cardiomyopathy [Haack et al 2015, Ganetzky et al 2016, Nair et al 2016, Nouguès et al 2017]
  • Pulmonary hypertension [Ferdinandusse et al 2015]
• Ophthalmologic
  • Optic atrophy [Haack et al 2015, Aretini et al 2018]
  • Nystagmus [Tetreault et al 2015]
  • Glaucoma [Ferdinandusse et al 2015]
  • Strabismus [Aretini et al 2018]
  • Corneal clouding [Ganetzky et al 2016]
• Other
  • Sensorineural hearing loss [Haack et al 2015, Tetreault et al 2015]
  • Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [Haack et al 2015, Ganetzky et al 2016]

Brain MRI findings

• T₂ hyperintense signal in the basal ganglia (especially putamen and globus pallidus) [Ferdinandusse et al 2015, Haack et al 2015, Tetreault et al 2015, Korenke et al 2016]
• Cerebral atrophy [Ferdinandusse et al 2015, Huffnagel et al 2018]
• Agenesis or thinning of the corpus callosum [Ferdinandusse et al 2015, Haack et al 2015, Ganetzky et al 2016]
• High lactate with normal lactate to pyruvate ratio peak on MR-spectroscopy [Peters et al 2014, Haack et al 2015, Tetreault et al 2015]

Biochemical features

• Lactic acidosis. Pyruvate may be mildly elevated, elevated proportionally to the lactate, or normal [Ferdinandusse et al 2015, Sakai et al 2015, Ganetzky et al 2016, Bedoyan et al 2017].
• Abnormal urine organic acids, including elevations of:
  • 2-methyl-2,3-dihydoxybutyrate [Ferdinandusse et al 2015, Haack et al 2015, Bedoyan et al 2017]
  • Branched-chain ketoacids [Bedoyan et al 2017]
  • 3-hydroxyisovalerate [Huffnagel et al 2018]
  • 3-methylglutaconic acid, ketones, and lactate [Bedoyan et al 2017]
• Elevations of urine acryloyl-cysteamine, acryloyl-l-cysteamine, N-acetyl-acryloyl-cysteine, methacryl-cysteamine, methacryl-cysteamine, or N-acetyl-methacryl-l-cysteamine [Peters et al 2014, Peters et al 2015, Yamada et al 2015, Huffnagel et al 2018]
• While plasma acylcarnitine profile is often normal, slight elevations of C4 acylcarnitines may be seen [Ganetzky et al 2016, Nair et al 2016, Bedoyan et al 2017].
• If performed, muscle or fibroblast electron transport chain function (ETC) is typically normal, although mild decreases in complex I, III, IV, or multiple complexes, with residual activity above 30% of control function, can be seen [Haack et al 2015, Sakai et al 2015, Tetreault et al 2015, Bedoyan et al 2017, Aretini et al 2018, Fitzsimons et al 2018].

Note: Muscle biopsy is not required to make a diagnosis of ECHS1D.

Establishing the Diagnosis

The diagnosis of ECHS1D is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in ECHS1 on molecular genetic testing (see Table 1).

Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ECHS1D is broad, individuals with the distinctive biochemical findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with lactic acidosis, Leigh syndrome, and/or dystonia are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) has been reported in 40 individuals representing 31 families [Peters et al 2014, Ferdinandusse et al 2015, Haack et al 2015, Sakai et al 2015, Yamada et al 2015, Ganetzky et al 2016, Nair et al 2016, Olgiati et al 2016, Al Mutairi et al 2017, Balasubramaniam et al 2017, Bedoyan et al 2017, Mahajan et al 2017, Fitzsimons et al 2018]. ECHS1D represents a clinical spectrum in which several phenotypes have been described. The most common phenotype is presentation in the neonatal period with severe encephalopathy and lactic acidosis and later-onset Leigh-like signs and symptoms. A small number of affected individuals have normal development, exercise-induced dystonia, and basal ganglia abnormalities on MRI [Olgiati et al 2016, Mahajan et al 2017].

Age of onset is soon after birth in a majority of reported individuals (median age of onset: 1 day; range 1 day – 8 years, n=40); only five reported individuals have presented after the first year of life. In five affected individuals, prenatal signs (intrauterine growth restriction and/or oligohydramnios) were identified; two of those individuals were born prematurely [Ganetzky et al 2016, Nair et al 2016, Fitzsimons et al 2018].

Common clinical manifestations are summarized in Table 2 and discussed below.

Neurologic. Most affected individuals reported have presented with severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. In this scenario, signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia [Haack et al 2015, Ganetzky et al 2016, Nair et al 2016, Bedoyan et al 2017]. Affected individuals who survive the neonatal period typically have continued truncal hypotonia but develop limb spasticity. They tend to have severe static developmental delay.

A second group of affected individuals present in infancy (after the neonatal period up to age 24 months) with developmental regression [Tetreault et al 2015, Yamada et al 2015, Fitzsimons et al 2018], typically leading to severe developmental delay.

There have been two reports of individuals with isolated paroxysmal dystonia and otherwise normal development. In one report, two of three affected individuals were sibs, one of whom had learning disabilities [Olgiati et al 2016]. The other (unrelated) reported individual had attention deficit with hyperactivity disorder [Mahajan et al 2017].

Dystonia, or less commonly choreoathetosis and/or ataxia, is usually chronically present, but is exacerbated by illness or exertion [Tetreault et al 2015, Olgiati et al 2016].

Across all three phenotypes, T₂ hyperintensity in the basal ganglia is very common (88%) and may affect any part of the basal ganglia. This is seen even in those whose clinical presentation is limited to paroxysmal exercise-induced dystonia [Olgiati et al 2016, Mahajan et al 2017].

Growth. Most children with ECHS1 deficiency require enteral feeding tubes because of severe developmental delay and hypotonia. Dysphagia has been reported in three individuals, one of whom suffered aspiration events [Ferdinandusse et al 2015, Yamada et al 2015].

Cardiac. Cardiomyopathy may be dilated or hypertrophic. In two affected individuals, cardiac hypertrophy was transient [Ferdinandusse et al 2015, Fitzsimons et al 2018]. Three individuals with pulmonary hypertension have been reported [Ferdinandusse et al 2015, Nair et al 2016]. Two other individuals have had terminal bradycardiac arrhythmias in the setting of lactic acidosis. It is unclear whether this was as a result of a predisposition to arrhythmia or secondary to overwhelming metabolic acidosis [Ganetzky et al 2016, Al Mutairi et al 2017].

Sensorineural hearing loss. Hearing loss may be found incidentally by audiologic screening. Hearing loss may be mild and is often stable. Two affected individuals required hearing aids for severe hearing loss [Tetreault et al 2015, Aretini et al 2018].

Liver dysfunction. Hepatomegaly or hepatosplenomegaly has been seen in multiple infantile cases. Liver steatosis is often present in those who have had postmortem examinations. However, no individuals with clinically significant liver dysfunction have been reported [Ferdinandusse et al 2015, Ganetzky et al 2016, Bedoyan et al 2017, Fitzsimons et al 2018].

Biochemical and enzymatic features

• Lactate levels may be extremely high, causing metabolic acidosis as the primary clinical finding [Haack et al 2015, Ganetzky et al 2016, Nair et al 2016, Al Mutairi et al 2017, Bedoyan et al 2017]. However, in cases with onset after the neonatal period, lactic academia may be intermittent [Huffnagel et al 2018].
• Two affected individuals have had moderate hyperammonemia in the setting of profound neonatal metabolic stress, potentially related to their severe metabolic acidosis and/or low ATP secondary to impaired aerobic oxidation. Levels have been reported ranging from 150 to 800 µmol/L in cases with a concommittent pH < 7.1 [Ferdinandusse et al 2015, Nair et al 2016].
• Elevated creatine kinase (CK) levels (hyperCKemia) to about 3,000 IU/L in a critically ill newborn [Ferdinandusse et al 2015] and transient mild hypoglycemia [Olgiati et al 2016] have also been reported.
• In affected individuals, low pyruvate dehydrogenase complex (PDC) activity in cultured fibroblasts is noted in about 40% of cases [Bedoyan et al 2017]. Low PDC activity has also been noted in lymphocytes as well as liver and skeletal muscle [Ferdinandusse et al 2015, Bedoyan et al 2017].

Other manifestations. Variable dysmorphic facial features and structural anomalies have each been reported in a few affected individuals.

• Facial features are variable, but may include a long philtrum, similar to what is seen in individuals with pyruvate dehydrogenase deficiency [Ganetzky et al 2016, Balasubramaniam et al 2017].
• The only recurrent structural abnormality is thinning or absence of the corpus callosum [Ganetzky et al 2016, Bedoyan et al 2017, Fitzsimons et al 2018].
• The following have each been described in one affected individual:
  • Hypospadias [Ganetzky et al 2016]
  • Gastroschisis [Haack et al 2015]
  • Cutis laxa [Balasubramaniam et al 2017]
  • Hypertrichosis [Fitzsimons et al 2018]
  • Abnormal lung septation, multiple splenules, and a preauricular tag [Ganetzky et al 2016]

Prognosis. The prognosis of neonatal-onset ECHS1 deficiency is poor. Of the 18 reported neonatal cases, 16 (89%) are deceased, mostly within days to weeks of birth from overwhelming lactic acidosis, apnea, hypotension, or bradycardia. Of the 13 later-onset cases, five are deceased (38%), all in early childhood.

In contrast, those with the paroxysmal dystonia phenotype have been mildly affected with no reported deaths and relatively normal cognitive development. There is likely a broad spectrum between the infantile phenotype and the paroxysmal dystonia phenotype, as individuals with paroxysmal dystonia have been diagnosed after metabolic decompensation [Olgiati et al 2016] or stroke-like episodes [Authors, unpublished observation], but this is not yet clear.

Genotype-Phenotype Correlations

All affected individuals with the paroxysmal dystonia phenotype have been compound heterozygous for the pathogenic c.518C>T variant and a second pathogenic variant [Korenke et al 2016, Olgiati et al 2016, Mahajan et al 2017]. The c.518C>T variant, however, has not been identified in affected individuals with other, more severe clinical phenotypes [Bedoyan et al 2017].

Prevalence

ECHS1 deficiency is rare; the exact prevalence and incidence are unknown.

To date, 40 affected individuals representing 31 families from different ethnic backgrounds / geographic locations – including European, East Asian, French Canadian, and Middle Eastern – have been reported [Nair et al 2016]. No affected individuals of African heritage have yet been reported.

Additional data are required to determine if the c.538A>G (p.Thr180Ala) variant is a French Canadian founder variant [Sharpe & McKenzie 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D), the evaluations summarized in Table 4 (if they have not already been completed) are recommended.

Treatment of Manifestations

Management is best provided by a multidisciplinary team including specialists in clinical genetics / metabolism, neurology, nutrition, and developmental pediatrics. Other specialists, such as a cardiologist and an ophthalmologist, may be involved based on the associated complications. In those presenting in the neonatal period, involvement of a palliative care team is also essential to determine goals of care given the poor prognosis for this group. This should be especially considered for neonates with major structural abnormalities in whom surgical management is being considered.

No definite treatment is available to date; treatment is mainly supportive (see Table 5).

Other treatment considerations

• Anecdotal reports of treatment with N-aceylcysteine to detoxify the reactive metabolites of methacrylyl-CoA and acroyacryl-CoA are mixed.
• Valine restriction would be a rational biochemical approach; it has never been attempted.
• Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered [Parikh et al 2009].
  In one affected individual with paroxysmal exercise-induced dystonia, this "cocktail" produced a subjective improvement [Mahajan et al 2017].

Surveillance

Agents/Circumstances to Avoid

Mitochondrial toxins, such as valproic acid and prolonged propofol infusions, should be avoided [Parikh et al 2009].

The ketogenic diet may be poorly tolerated because of partially impaired fatty acid oxidation [Haack et al 2015]; one preliminary report suggests rapid disease progression following initiation of the ketogenic diet [Nouguès et al 2017] and in two other affected individuals, subjects perished within days of starting a ketogenic diet [Ferdinandusse et al 2015, Bedoyan et al 2017]. Therefore, ketogenic diet may not be effective to control lactic acidosis and may be harmful or even lethal – and thus should be avoided.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic younger sibs of an individual affected by the paroxysmal exercise-induced dystonia phenotype by molecular genetic testing of the ECHS1 pathogenic variants in the family in order to identify as early as possible those who would benefit from early initiation of exercise-guidance and dystonia-targeted therapies.

In an at-risk newborn, it is crucial to ensure metabolic stability by evaluating a lactic acid level and a blood gas. Urine organic acids and acylcarnitine profile may also be used as biochemical screening testing while waiting for molecular genetic testing results; they can have high specificity, but sensitivity may be low.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is inherited in an autosomal recessive manner.

Parents of a proband

• In most instances, the parents of an affected child are heterozygotes (i.e., carriers of one ECHS1 pathogenic variant).
• In rare cases, a proband has one de novo pathogenic variant and one pathogenic variant inherited from a carrier parent [Aretini et al 2018, Carlston et al 2019]; in these families, presumably only one parent is heterozygous for an ECHS1 pathogenic variant.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are carriers, 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.
• If only one parent is a carrier (i.e., the proband is compound heterozygous for an inherited pathogenic variant and a de novo pathogenic variant), each sib of the proband has a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier.
• Sibs who inherit two pathogenic variants will be affected. Sibs who inherit one pathogenic variant (heterozygotes) are expected to be asymptomatic. A sib who is heterozygous for an inherited pathogenic variant could be affected if the sib also has another de novo ECHS1 pathogenic variant on the other allele (i.e., in trans).

Offspring of a proband

• To date, individuals with the neonatal and infantile forms of ECHS1D are not known to reproduce.
• Each child of an individual with the paroxysmal dystonia form of ECHS1D has a 50% chance of inheriting the ECHS1 pathogenic variant.

Other family members. In general, each sib of the proband's parents is at a 50% risk of being a carrier of an ECHS1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ECHS1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the ECHS1 pathogenic variants have been identified in an affected family member, 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.

Molecular Pathogenesis

The mitochondrial short-chain enoyl-CoA hydratase (SCEH) has a primary function in the beta-oxidation of short-chain fats. However, the same enzyme also is involved in branched-chain amino acid metabolism, particularly valine metabolism [Peters et al 2014, Haack et al 2015]. The enoyl-CoA metabolites of valine catabolism that are the substrates of SCEH, methylacrylyl-CoA, and acryloyl-CoA are highly reactive intermediates [Haack et al 2015]. The most likely cause of the phenotype observed in this disorder is high concentrations of these toxic enoyl-CoA intermediates, which impair the function of pyruvate dehydrogenase complex (PDC) and the mitochondrial respiratory chain; however, the full mechanism(s) of this impairment are not yet fully elucidated [Ferdinandusse et al 2015, Bedoyan et al 2017]. Regardless of the exact mechanism, secondary deficiency of PDC is observed in about half of reported affected individuals. It is believed that PDC deficiency is an important contributor to the lactic acidosis [Bedoyan et al 2017].

Gene structure. ECHS1 has eight exons.

Pathogenic variants. The majority of reported variants have been missense. A variety of other loss-of-function pathogenic variants have also been reported, including a splice site pathogenic variant [Peters et al 2014], abrogation of the start codon [Sakai et al 2015], impairment of the mitochondrial targeting sequence [Ganetzky et al 2016], amino acid duplication [Haack et al 2015], and a frameshift pathogenic variant [Haack et al 2015]. With the exception of the recurrent c.518C>T pathogenic variant, all pathogenic variants reported to date have been private [Nair et al 2016].

Normal gene product. SCEH has 290 amino acids. The first 27 amino acids are the mitochondrial targeting sequence.

Abnormal gene product. ECHS1 pathogenic variants have loss of SCEH protein function [Bedoyan et al 2017].

Literature Cited

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Author Notes

Rebecca Ganetzky is an attending physician in the Mitochondrial Medicine Frontier Program at the Children's Hospital of Philadelphia. Her research is on mitochondrial ATP synthase deficiency. She has a special clinical interest in primary lactic acidosis.

Revision History

• 20 June 2019 (ma) Review posted live
• 9 April 2018 (rg) Original submission