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Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency

Synonyms: ECHS1D, ECHS1 Deficiency, Mitochondrial Short-Chain Enoyl-CoA Hydratase Deficiency, SCEH Deficiency

, MD and , MS, MD.

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Estimated reading time: 21 minutes

Summary

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 diagnosis for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the ECHS1 pathogenic variants in the family are known.

Diagnosis

No consensus clinical diagnostic criteria for ECHS1 deficiency (ECHS1D) have been published.

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

Brain MRI findings

Biochemical features

• 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 variants in ECHS1 on molecular genetic testing (see Table 1).

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).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of ECHS1D, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of ECHS1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • A mitochondrial disease, Leigh syndrome, or lactic acidosis multigene panel that includes ECHS1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by early epileptic encephalopathy, Leigh Syndrome, or lactic acidosis, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic (particularly if only one pathogenic variant has been identified), an exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in ECHS1 Deficiency

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
ECHS1Sequence analysis 330/31
Gene-targeted deletion/duplication analysis 41/31 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

One affected individual had a larger deletion that included ECHS1 and adjacent genes [Aretini et al 2018].

Clinical Characteristics

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.

Table 2.

Common Clinical Manifestations of ECHS1 Deficiency

Clinical ManifestationFrequency
Neurologic 1Signal abnormalities in the basal ganglia28/32 (88%)
Developmental delay27/32 (84%)
Hypotonia21/30 (70%)
Dystonia15/29 (52%)
Seizures12/23 (52%)
Encephalopathy12/31 (39%)
Ataxia/choreoathetosis5/25 (20%)
GrowthFailure to thrive20/32 (62%)
Microcephaly7/30 (23%)
Intrauterine growth restriction5/27 (18%)
CardiovascularCardiomyopathy9/15 (60%)
Pulmonary hypertension3/14 (21%)
OphthalmologicNystagmus10/31 (32%)
Optic atrophy8/27 (30%)
Corneal clouding1/27 (4%)
OtherSensorineural hearing loss13/27 (48%)
Apnea7/37 (19%)
Liver steatosis &/or hepatomegaly5/6 (83%)
Biochemical/
Enzymatic
Lactic acidemia27/36 (75%)
Low PDC activity (in cultured fibroblasts)5/12 (42%)
1.

Neurologic manifestations were seen in all 40 individuals reported [Ganetzky et al 2016, Nair et al 2016, Fitzsimons et al 2018].

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 due to 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 due to 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

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

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].

Differential Diagnosis

Table 3.

Disorders to Consider in the Differential Diagnosis of ECHS1 Deficiency (ECHS1D)

DisorderGene(s)MOIClinical Features
Overlapping w/ECHS1DDistinguishing from ECHS1D
Pyruvate dehydrogenase complex (PDC) deficiency
(OMIM PS312170)
DLAT
LIAS
PDHA1
PDHB
PDHX
PDP1
AR
XL
  • Pyruvate dehydrogenase complex deficiency
  • Lactic acidosis
  • Elevated pyruvate
  • Normal lactate to pyruvate ratio
  • Long philtrum
  • Corpus callosum hypoplasia
  • May be a complete phenocopy 1
  • Individuals w/ECHS1 deficiency may have abnormal acylcarnitine profile or urine organic acids not typically seen in primary PDC deficiency.
3-hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD)
(OMIM 250620)
HIBCHAR
  • Lactic acidosis
  • Basal gangliar lesions
  • Elevated 2-methyl-2,3-dihydroxybutyrate
Organic acid abnormalities are typically more pronounced in HIBCH.
FBXL4-related encephalomyopathic mitochondrial DNA depletion syndromeFBXL4AR
  • Neonatal/primary lactic acidosis
  • Variable cardiomyopathy
  • FBXL4 deficiency typically has more striking hyperammonemia.
  • ATP synthase deficiency typically has more prominent 3-methylglutaconic aciduria.
  • ECHS1 deficiency may be suspected (rather than FBXL4 deficiency & TMEM70 deficiency) if 2-methyl-2,3-dihydroxybutyrate is present or if lactate-to-pyruvate ratio is normal.
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2
(OMIM 614052)
TMEM70
Mitochondrial complex I deficiency due to ACAD9 deficiency
(OMIM 611126)
ACAD9
Other Leigh syndromes (see Nuclear Gene-Encoded Leigh Syndrome Overview & Mitochondrial DNA-Associated Leigh Syndrome and NARP)>60 genesAR
mt
XL
  • T2 hyperintensity of the basal ganglia
  • Dystonia
  • Developmental regression
  • Lactic acidosis
ECHS1 may be clinically indistinguishable from other Leigh syndromes.
Paroxysmal exercise-induced dyskinesia & epilepsy (see Glucose Transporter Type 1 Deficiency Syndrome)SLC2A1AD
AR 2
Paroxysmal exercise-induced dystoniaNormal brain MRI
Paroxysmal kinesogenic dyskinesia (see PRRT2-Associated Paroxysmal Movement Disorders)PRRT2AD
AR 2
Paroxysmal dystonia (may be exercise induced)Normal brain MRI
Familial paroxysmal nonkinesigenic dyskinesiaPNKDAD
Pyruvate carboxylase deficiencyPCAR↑ lactate, pyruvate, & ammonia
  • More striking hyperammonemia
  • Ketonuria
  • Normal organic acids

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked

1.
2.

Autosomal recessive inheritance is rare.

Management

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 following evaluations are recommended if they have not already been completed:

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with ECHS1 Deficiency

System/ConcernEvaluationComment
NeurologicBrain MRI/MRS to evaluate for basal ganglia involvement & structural brain anomalies
Electroencephalogram to evaluate for epileptic encephalopathyIn those w/neonatal or infantile form
Growth/
Gastrointestinal
  • Nutritional evaluation
  • Swallowing assessment
  • Liver ultrasound to evaluate for hepatosplenomegaly
Nutritional & swallowing evaluations should be performed in all affected individuals, but liver ultrasound is only necessary in neonates.
CardiovascularEchocardiogram to evaluate for cardiomyopathy in those w/neonatal formMeasurement of pulmonary artery pressure is important to evaluate for pulmonary hypertension.
OphthalmologicDilated eye exam to evaluate for optic atrophy & other findingsIn all affected individuals
AudiologicAudiologic evaluation to evaluate for sensorineural hearing lossIn all affected individuals
BiochemicalLactate & blood gas to evaluate acid/base statusIn all affected individuals
  • Blood glucose level
  • Urine organic acids
For those presenting w/neonatal or infantile form
  • Blood ammonia level
  • Creatine kinase level
For those who present in neonatal period
OtherDevelopmental evaluationIn all affected individuals
Physical examination & consideration of imaging for possible structural anomaliesFor those presenting w/neonatal or infantile form
Consultation w/clinical geneticist &/or genetic counselor

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).

Table 5.

Treatment of Manifestations in Individuals with ECHS1 Deficiency

Manifestation/ConcernTreatmentComments
Dystonia (paroxysmal)BenzodiazepinesLevodopa has been tried w/out success in 1 affected individual; 1 nonetheless, trial of this low-risk, noninvasive therapy is probably reasonable.
Dystonia (chronic)Botulinum toxin injections
SeizuresStandard antiepileptic therapy
Inadequate nutritionNasogastric tube or gastrostomy tube; feeding therapy w/speech therapist
Cardiomyopathy or
pulmonary hypertension
Standard treatment per cardiologist
Optic atrophyLow-vision support for educational settingsN-acetylcysteine & vitamin C use may be considered, but evidence for benefit is limited.
Sensorineural hearing lossHearing aidsSee Hereditary Hearing Loss and Deafness Overview
AcidosisBicarbonate therapy for correctionSodium citrate & acetate are unlikely to provide sufficient buffering capacity in these children w/secondary impairment of the tricarboxylic acid cycle.
Hyperammonemia 2Correction of metabolic acidosisHigh-concentration dextrose would result in increased lacticemia & should be used with caution, if at all.
Consideration of hemodialysisIt is unknown if nitrogen scavengers would be of benefit.
1.
2.

The origin of the hyperammonemia is unclear. It may be secondary to metabolic acidosis, as it has only been observed in children with profound metabolic acidosis or due to low ATP secondary to impaired aerobic oxidation. Correction of acidosis is a reasonable first strategy.

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].

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.

Ages 5-21 years

  • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
  • Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:

  • Private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
  • In the US:
    • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
    • Families with limited income and resources may also qualify for supplemental security income for their child with a disability.

Surveillance

Table 6.

Recommended Surveillance for Individuals with ECHS1 Deficiency

EvaluationRecommended IntervalComments
Comprehensive neurologic examination & developmental assessmentDepending on symptomsRepeat MRI & EEG warranted only if symptoms concerning for new developments arise
Standard anthropometric monitoringW/routine pediatric follow up
Echocardiogram to monitor for cardiomyopathyAt least annuallyChildren w/cardiomyopathy noted on echocardiogram may need to be followed more closely.
Dilated eye exam to monitor for optic atrophy & other ophthalmologic findingsAt ages 6 mos & 12 mos, then annuallyChildren w/ophthalmologic anomalies detected may need to be followed more closely.
Audiologic evaluation for sensorineural hearing lossAt least annuallyChildren w/abnormal hearing screens may need to be followed more closely.
Sodium bicarbonate & lactate levels to monitor for acidosisW/all illnesses or metabolic stressorsChildren on chronic bicarbonate therapy also require routine monitoring of levels.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Parents of a proband

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 s/he 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 (Heterozygote) 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ECHS1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Neuro-Metabolic Disorders (ANMD)
    5223 Brookfield Lane
    Sylvania OH 43560-1809
    Phone: 419-885-1809; 419-885-1497
    Email: volk4olks@aol.com
  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
    Email: contact@metabolicsupportuk.org
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency (View All in OMIM)

602292ENOYL-CoA HYDRATASE, SHORT-CHAIN, 1, MITOCHONDRIAL; ECHS1
616277MITOCHONDRIAL SHORT-CHAIN ENOYL-CoA HYDRATASE 1 DEFICIENCY; ECHS1D

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].

Table 7.

Notable ECHS1 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.518C>Tp.Ala173ValNM_004092​.3
NP_004083​.3
c.538A>Gp.Thr180Ala

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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].

References

Literature Cited

  • Al Mutairi F, Shamseldin HE, Alfadhel M, Rodenburg RJ, Alkuraya FS. A lethal neonatal phenotype of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency. Clin Genet. 2017;91:629–33. [PubMed: 27905109]
  • Aretini P, Mazzanti CM, La Ferla M, Franceschi S, Lessi F, De Gregorio V, Nesti C, Valetto A, Bertini V, Toschi B, Battini R, Caligo MA. Next generation sequencing technologies for a successful diagnosis in a cold case of Leigh syndrome. BMC Neurol. 2018;18:99. [PMC free article: PMC6054728] [PubMed: 30029642]
  • Balasubramaniam S, Riley LG, Bratkovic D, Ketteridge D, Manton N, Cowley MJ, Gayevskiy V, Roscioli T, Mohamed M, Gardeitchik T, Morava E, Christodoulou J. Unique presentation of cutis laxa with Leigh-like syndrome due to ECHS1 deficiency. J Inherit Metab Dis. 2017;40:745–7. [PubMed: 28409271]
  • Bedoyan JK, Yang SP, Ferdinandusse S, Jack RM, Miron A, Grahame G, DeBrosse SD, Hoppel CL, Kerr DS, Wanders RJA. Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab. 2017;120:342–9. [PMC free article: PMC5382105] [PubMed: 28202214]
  • Carlston CM, Ferdinandusse S, Hobert JA, Mao R, Longo N. Extrapolation of variant phase in mitochondrial short-chain enoyl-CoA hydratase (ECHS1) deficiency. JIMD Rep. 2019;43:103–9. [PMC free article: PMC6323015] [PubMed: 29923089]
  • Ferdinandusse S, Friederich MW, Burlina A, Ruiter JP, Coughlin CR 2nd, Dishop MK, Gallagher RC, Bedoyan JK, Vaz FM, Waterham HR, Gowan K, Chatfield K, Bloom K, Bennett MJ, Elpeleg O, Van Hove JL, Wanders RJ. Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis. 2015;10:79. [PMC free article: PMC4474341] [PubMed: 26081110]
  • Fitzsimons PE, Alston CL, Bonnen PE, Hughes J, Crushell E, Geraghty MT, Tetreault M, O'Reilly P, Twomey E, Sheikh Y, Walsh R, Waterham HR, Ferdinandusse S, Wanders RJA, Taylor RW, Pitt JJ, Mayne PD. Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Am J Med Genet A. 2018;176:1115–27. [PMC free article: PMC5947294] [PubMed: 29575569]
  • Ganetzky RD, Bloom K, Ahrens-Nicklas R, Edmondson A, Deardorff MA, Bennett MJ, Ficicioglu C. ECHS1 deficiency as a cause of severe neonatal lactic acidosis. JIMD Rep. 2016;30:33–7. [PMC free article: PMC5110442] [PubMed: 26920905]
  • Haack TB, Jackson CB, Murayama K, Kremer LS, Schaller A, Kotzaeridou U, de Vries MC, Schottmann G, Santra S, Büchner B, et al. Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol. 2015;2:492–509. [PMC free article: PMC4435704] [PubMed: 26000322]
  • Huffnagel IC, Redeker EJW, Reneman L, Vaz FM, Ferdinandusse S, Poll-The BT. Mitochondrial encephalopathy and transient 3-methylglutaconic aciduria in ECHS1 deficiency: long-term follow-up. JIMD Rep. 2018;39:83–7. [PMC free article: PMC5953898] [PubMed: 28755360]
  • Korenke G, Nuoffer J-M, Alhaddad B, Mayr H, Prokisch H, Haack TB. Paroxysmal dyskinesia in ECHS1 defect with globus pallidus lesions. Neuropediatrics. 2016;47:PS01–10.
  • Mahajan A, Constantinou J, Sidiropoulos C. ECHS1 deficiency-associated paroxysmal exercise-induced dyskinesias: case presentation and initial benefit of intervention. J Neurol. 2017;264:185–7. [PubMed: 28039521]
  • Nair P, Hamzeh AR, Mohamed M, Malik EM, Al-Ali MT, Bastaki F. Novel ECHS1 mutation in an Emirati neonate with severe metabolic acidosis. Metab Brain Dis. 2016;31:1189–92. [PubMed: 27221955]
  • Nouguès MC, Guët A, Fazzio M, Danekova N, Valence S, Billette de Villemeur T, Garel C, Rodriguez D, Boutron A. Poor tolerance of ketogenic diet for suspicion of PDH deficiency: what about another diagnosis? Eur J Paediatr Neurol. 2017;21:e134.
  • Olgiati S, Skorvanek M, Quadri M, Minneboo M, Graafland J, Breedveld GJ, Bonte R, Ozgur Z, van den Hout MC, Schoonderwoerd K, et al. Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. Mov Disord. 2016;31:1041–8. [PubMed: 27090768]
  • Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, et al. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol. 2009;11:414–30. [PMC free article: PMC3561461] [PubMed: 19891905]
  • Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J, Yaplito-Lee J, Ferdinandusse S, Pitt J. ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain. 2014;137:2903–8. [PubMed: 25125611]
  • Peters H, Ferdinandusse S, Ruiter JP, Wanders RJ, Boneh A, Pitt J. Metabolite studies in HIBCH and ECHS1 defects: implications for screening. Mol Genet Metab. 2015;115:168–73. [PubMed: 26163321]
  • Sakai C, Yamaguchi S, Sasaki M, Miyamoto Y, Matsushima Y, Goto Y. ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat. 2015;36:232–9. [PubMed: 25393721]
  • Sharpe AJ, McKenzie M. Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency. Cells. 2018;7:E46. pii. [PMC free article: PMC6025059] [PubMed: 29882869]
  • Tetreault M, Fahiminiya S, Antonicka H, Mitchell GA, Geraghty MT, Lines M, Boycott KM, Shoubridge EA, Mitchell JJ, Michaud JL, Majewski J, et al. Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. Hum Genet. 2015;134:981–91. [PubMed: 26099313]
  • Yamada K, Aiba K, Kitaura Y, Kondo Y, Nomura N, Nakamura Y, Fukushi D, Murayama K, Shimomura Y, Pitt J, Yamaguchi S, Yokochi K, Wakamatsu N. Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion. J Med Genet. 2015;52:691–8. [PubMed: 26251176]

Chapter Notes

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
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