Ethylmalonic Encephalopathy
Summary
Clinical characteristics.
Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder characterized by developmental delay / mild-to-severe intellectual disability; generalized infantile hypotonia that evolves into hypertonia, spasticity, and (in some instances) dystonia; generalized tonic-clonic seizures; and generalized microvascular damage (diffuse and spontaneous relapsing petechial purpura, hemorrhagic suffusions of mucosal surfaces, and chronic hemorrhagic diarrhea). Infants sometimes have frequent vomiting and loss of social interaction. Speech is delayed and in some instances absent. Swallowing difficulties and failure to thrive are common. Children may be unable to walk without support and may be wheelchair bound. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of children die in the first decade.
Diagnosis/testing.
The diagnosis of EE is suggested by clinical findings and the laboratory findings of increased blood lactate levels, C4- and C5-acylcarnitine esters, plasma thiosulphate, and urinary ethylmalonic acid.
The diagnosis is established by identification of biallelic pathogenic variants in ETHE1 on molecular genetic testing.
Management.
Treatment of manifestations: Multi-specialty care that includes child neurology, pediatrics, clinical genetics, nutrition, gastroenterology, pain management, and physical therapy can help with timely detection and treatment of the multiorgan dysfunction that characterizes EE. Treatment is primarily supportive including antispastic medications, muscle relaxants, and antiepileptic drugs (AEDs). Physical therapy early in the disease course can help prevent contractures. For severe diarrhea, it is important to maintain hydration and caloric intake. Tube feeding is often necessary.
Prevention of secondary complications: Prevention of infections that could be fatal.
Surveillance: Recommendations based on individual patient findings can include: monitoring of feeding and electrolyte status particularly in those with severe diarrhea; monitoring of seizures and response to AEDs.
Genetic counseling.
EE is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. No individuals diagnosed with EE have been known to reproduce. Once the ETHE1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Ethylmalonic encephalopathy (EE) should be suspected in an individual with the following clinical findings, preliminary laboratory findings, and brain MRI findings [Dionisi-Vici et al 2016].
Clinical findings
- Global neurologic impairment
- Early-onset progressive psychomotor regression
- Seizures
- Dystonia
- Diffuse microvasculature injury
- Petechiae and/or purpura
- Orthostatic acrocyanosis
- Hemorrhagic suffusions of mucosal surfaces
- Chronic hemorrhagic diarrhea
Preliminary laboratory findings
- Increased blood lactate levels (normal range: 6-22 mg/dL)
- Increased blood C4-acylcarnitine esters (normal range: <0.9 μmol/L) [Merinero et al 2006, Zafeiriou et al 2007] *
- Increased blood C5-acylcarnitine esters (normal range: <0.3 μmol/L) [Merinero et al 2006, Zafeiriou et al 2007] *
- Increased plasma thiosulphate (normal range: <4 μmol/L)
- Increased urinary ethylmalonic acid (normal range: <10 μmol/mmol creatinine) evaluated on spot urine [Merinero et al 2006, Zafeiriou et al 2007]
* More data are needed to define the range of C4/C5 acylcarnitine elevation in individuals with molecularly proven EE.
Newborn screening (NBS). Tandem mass spectroscopy can identify C4 elevation in a NBS dried blood spot; however, NBS for EE is not available in the US as there is no definitive treatment (see Therapies Under Investigation). Note: (1) NBS may be performed elsewhere in the world. (2) C4 elevation can also be found in primary short-chain acyl-CoA dehydrogenase (SCAD) deficiency [McHugh et al 2011]; an algorithm (pdf) from the American College of Medical Genetics can be used to distinguish the two disorders.
Brain MRI
- Symmetric patchy T2-weighted signals in the basal ganglia, periventricular white matter and dentate nuclei, brain stem, and cerebellar white matter. In some instances, cortical atrophy and diffuse leukoencephalopathy are present.
- Atypical neuroradiologic patterns were also reported [Grosso et al 2002, Heberle et al 2006].
Establishing the Diagnosis
The diagnosis of ethylmalonic encephalopathy is established in a proband with suggestive clinical and laboratory findings and identification of biallelic pathogenic variants in ETHE1 on molecular genetic testing (see Table 1).
Single-gene testing is the molecular genetic testing approach indicated. Sequence analysis of ETHE1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
Table 1.
Molecular Genetic Testing Used in Ethylmalonic Encephalopathy
| Gene 1 | Method | Proportion of Pathogenic Variants 2 in Probands Detectable by Method |
|---|---|---|
| ETHE1 | Sequence analysis 3 | 67/86 4 |
| Gene-targeted deletion/duplication analysis 5 | 19/86 4, 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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.
Tiranti et al [2006], Mineri et al [2008]
- 5.
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.
- 6.
Deletion of exon 4 and deletion of exons 1 to 7 have been detected frequently [Tiranti et al 2006, Mineri et al 2008].
Clinical Characteristics
Clinical Description
Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder, typically characterized by the following major manifestations: developmental delay, progressive neurologic involvement, seizures, and vascular damage. Findings usually appear in the first years of life, in some instances during metabolic stress such as infection or fever. Affected infants typically have severe neck, trunk, and limb hypotonia and loss of head control, sometimes associated with frequent vomiting and loss of social interaction. In addition, chronic diarrhea and failure to thrive are common.
Atypical findings have also been reported [Grosso et al 2002, Di Rocco et al 2006, Heberle et al 2006, Pigeon et al 2009].
Developmental delay, evident in early infancy, manifests later as intellectual disability that ranges from mild to severe. Speech difficulties are common; in some instances speech is absent.
Progressive neurologic involvement. Hypotonia evolves into spastic quadriparesis and eventually global neurologic impairment including pyramidal signs such as hypertonia and spasticity with increased deep tendon reflexes (in particular in the lower limbs) with paraparesis. Children may be unable to walk without support and in some instances are wheelchair bound. Difficulty in swallowing is common.
Dystonia, an extrapyramidal finding, generally involves the limbs and trunk.
Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of patients die in the early years, although some are still alive in the second decade of life.
Generalized seizures. Generalized tonic-clonic seizures are characterized by spasms of the neck, trunk, and arms that could evolve into status epilepticus with decreased level of consciousness.
Microvasculature injury is common and is characterized by diffuse and spontaneous relapsing petechial purpura, especially in the trunk and associated with "cutis marmorata" of the extremities.
Distal orthostatic acrocyanosis with edema of the extremities is often visible.
Hemorrhagic suffusions of mucosal surfaces and chronic hemorrhagic diarrhea are common manifestations.
Individuals with Atypical Findings
Of two affected individuals reported by Grosso et al [2002], one had chronic very slow neuromotor deterioration, ataxia, and dysarthria, and the other had acute neonatal onset with severe neuromotor retardation, severe generalized hypotonia, and intractable seizures.
In one individual with a molecularly confirmed diagnosis, the clinical findings suggested a connective tissue disorder (vascular fragility, joint hyperextensibility, and delayed motor development with normal cognitive development); urinary excretion of ethylmalonic acid was not abnormally increased during intercritical phases [Di Rocco et al 2006].
One individual who had the typical findings of EE also had hydronephrosis, undescended testes, mild tricuspid regurgitation, and mild dilatation of the pulmonary artery [Heberle et al 2006].
Monochorial twins had severe axial hypotonia without petechiae, orthostatic acrocyanosis, or chronic diarrhea. Other clinical findings differed markedly: one twin had an episode of coma at age three years followed by spastic quadriparesis and loss of language; the other had pyramidal involvement (mainly limited to the lower extremities) and spoke two languages [Pigeon et al 2009].
MR spectroscopy showed a lactate peak in one patient [Grosso et al 2004].
Neuropathologic findings in the brain of an infant age nine months showed widespread luminal microthrombi, acute microhemorrhages, and focal perivascular hemosiderin-laden macrophages, the latter being consistent with previous bleeding. These findings were consistent with both acute and chronic ischemic damage and corresponded with abnormal signal intensity lesions observed on repeat MRI [Giordano et al 2012].
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known to be associated with ETHE1 biallelic pathogenic variants.
Prevalence
The prevalence of ethylmalonic encephalopathy is unknown. More than 80 individuals with features consistent with EE and a molecularly confirmed diagnosis have been reported [Tiranti et al 2004, Tiranti et al 2006, Mineri et al 2008].
To date, families with EE have been from (or could be traced to) different regions of the Mediterranean basin or the Arabian Peninsula; parental consanguinity is common.
Differential Diagnosis
Ethylmalonic acid is a dicarboxylic organic acid produced by the carboxylation of butyrate. Ethylmalonic encephalopathy (EE) should be included in the differential diagnosis of other forms of persistent ethylmalonic aciduria, including the following:
- Defects of beta-oxidation of fatty acids with similar clinical findings (e.g., vomiting, diarrhea, difficulty with feeding, and developmental delay) such as short-chain acyl-CoA dehydrogenase (SCAD) deficiency and 3-hydroxyacyl-CoA dehydrogenase (HADH) deficiency (OMIM 231530). Petechiae, purpura, and orthostatic acrocyanosis are specific to EE [Burlina et al 1994].
- Defects of the mitochondrial electron-transfer flavoprotein pathway or glutaric aciduria type II
- Some forms of respiratory chain deficiency
Of note, brain vascular lesions appear to be a specific neuropathologic feature of EE, not seen in other forms of ethylmalonic aciduria or in disorders caused by primary respiratory chain defects such as Leigh syndrome [Giordano et al 2012, Tiranti & Zeviani 2013].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ethylmalonic encephalopathy (EE), the recommended evaluations following diagnosis (if not performed as part of the evaluation that led to the diagnosis) are as summarized in Table 2.
Table 2.
Recommended Evaluations Following Initial Diagnosis of Ethylmalonic Encephalopathy (EE)
| System/Concern | Evaluation | Comment |
|---|---|---|
| Neurologic | Neurologic evaluation | Particularly if medications are being used to treat spasticity &/or extrapyramidal movement disorders (e.g., dystonia) |
| Brain MRI | Indicated in any child w/EE w/seizures or spasticity who has not previously had a brain MRI | |
| EEG and video EEG | If seizures are suspected | |
| Gastrointestinal | Feeding evaluation & nutrition assessment | Referral to appropriate feeding therapist &/or nutritionist as indicated |
| Assessment for chronic diarrhea | Referral to gastroenterologist as needed | |
| Musculoskeletal | Orthopedic evaluation | Referral to orthopedist as needed |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Multi-specialty care that includes child neurology, pediatrics, clinical genetics, nutrition, gastroenterology, orthopedic, pain management, and physical therapy can help with timely detection and treatment of the multiorgan dysfunction that characterizes ethylmalonic encephalopathy. Treatment is primarily supportive including anti-spastic medications, muscle relaxants, and antiepileptic drugs. Physical therapy early in the disease course can help prevent contractures.
Table 3.
Treatment of Manifestations in Individuals with Ethylmalonic Encephalopathy
| Manifestation/ Concern | Treatment | Considerations/ Other |
|---|---|---|
| Spasticity | Antispastic medications | |
| Dystonia | Muscle relaxants | |
| Contractures | Physical therapy | |
| Seizures | Antiepileptic drugs | |
| Severe diarrhea | Maintain hydration & caloric intake | Tube feeding often necessary |
| Poor energy metabolism & oxidative stress | L-carnitine, riboflavin &/or coenzyme Q10 supplements (a cocktail of drugs generally used in mitochondrial disorders) & other vitamin therapies 1 |
- 1.
Gorman et al [2016]
Off-label compassionate use of N-acetylcysteine (NAC) in combination with metronidazole may be considered as they are the only drugs known to slow disease progression and improve the metabolic abnormalities of EE [Viscomi et al 2010, Kılıç et al 2017].
- N-acetylcysteine (NAC), a cell-permeable precursor of glutathione, is abundant in mitochondria where it can act as one of the physiologic acceptors of the sulfur atom of hydrogen sulfide (H2S), which has deficient clearance in persons with EE.
- Metronidazole is widely used to combat infections caused by anaerobic bacteria, and can reduce the sulfide-producing bacterial load in the large intestine.
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; 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, vocation/employment, 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.
Consideration of private supportive therapies based on the affected individual's needs is recommended. 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 (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures).
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
- For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox®, anti-parkinsonian medications, or orthopedic procedures.
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function (e.g., feeding, grooming, dressing, writing).
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication) for individuals who have expressive language difficulties.
Prevention of Secondary Complications
All affected individuals should receive routine immunizations; as well as annual immunizations for influenza.
Physicians must pay particular attention to the prevention of infections that could be fatal.
Surveillance
Surveillance should be individualized based on symptoms and organs affected.
Table 4.
Recommended Surveillance for Individuals with Ethylmalonic Encephalopathy
| System/Concern | Evaluation/Action | Frequency |
|---|---|---|
| Growth | Assess growth & monitor for failure to thrive. | At each visit |
| Gastrointestinal | Monitor feeding & electrolyte status, particularly in those w/severe diarrhea. | |
| Neurologic | Monitor for epileptic crisis; modify therapy according to clinical presentation &EEG findings. | Routine |
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
While clearance of circulating sulfide by a transplanted liver could be beneficial, to date only one instance of liver transplantation in EE has been reported [Dionisi-Vici et al 2016]. Although results were encouraging, follow up of this patient and experience with additional patients are necessary to determine therapeutic efficacy of liver transplantation in EE and possible relevance for national or state-mandated newborn screening, particularly in populations with relatively high prevalence of pathogenic variants.
Possible future treatments include AAV-mediated gene therapy [Di Meo et al 2012] or liver transplantation [Dionisi-Vici et al 2016].
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.