Ethylmalonic encephalopathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Ethylmalonic encephalopathy is an inherited disorder that affects several body systems, particularly the nervous system. Neurological signs and symptoms include delayed development and the loss of previously acquired skills (developmental regression), weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels (the vascular system) is also affected. Children with this disorder often develop rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy.

The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Ethylmalonic encephalopathy results from mutations in the ETHE1 gene. This gene provides instructions for making an enzyme that is active in mitochondria, which are the energy-producing centers in cells. The ETHE1 enzyme is part of a pathway that breaks down sulfide (H2S), a molecule that is critical at very low levels for normal cell functioning but is toxic at high levels. Excess sulfide interferes with numerous cell activities, including mitochondrial energy production.

Mutations in the ETHE1 gene lead to the production of a nonfunctional version of the enzyme or prevent any enzyme from being made. A shortage of functional ETHE1 enzyme prevents sulfide from being broken down, allowing this molecule to accumulate in cells. The buildup of sulfide interferes with the ability of mitochondria to produce energy and damages tissues and organs throughout the body. Researchers believe that the effects of excess sulfide in the brain, muscles, blood vessels, and lining of the intestines underlie most of the major features of ethylmalonic encephalopathy.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

About 70 individuals with this condition have been identified worldwide, mostly in Mediterranean and Arab populations. Although ethylmalonic encephalopathy appears to be very rare, researchers suggest that some cases have been misdiagnosed as other neurological disorders.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Encephalopathy · Very frequent (99-80%)

Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.

Ethylmalonic aciduria · Very frequent (99-80%)

The concentration of ethylmalonic acid in the urine, normalized for urine concentration, is above the upper limit of normal.

Abnormal basal ganglia MRI signal intensity · Frequent (79-30%)

A deviation from normal signal on magnetic resonance imaging (MRI) of the basal ganglia.

Abnormal pyramidal sign · Frequent (79-30%)

Functional neurological abnormalities related to dysfunction of the pyramidal tract.

Abnormality of extrapyramidal motor function · Frequent (79-30%)

A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).

Acrocyanosis · Frequent (79-30%)

Bluish discoloration of the skin of the hands or feet.

Ataxia · Frequent (79-30%)

Ataxia refers to impaired coordination of voluntary muscle movement. Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).

Developmental regression · Frequent (79-30%)

Loss of developmental skills, as manifested by loss of developmental milestones.

Diarrhea · Frequent (79-30%)

Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.

Failure to thrive · Frequent (79-30%)

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Generalized hypotonia · Frequent (79-30%)

Generalized muscular hypotonia (abnormally low muscle tone).

Intellectual disability · Frequent (79-30%)

The term intellectual disability or intellectual developmental disorder is used to describe significantly sub-average intellectual and adaptive functioning based on clinical assessment and as measured by individually administered, appropriately normed, standardized and validated tests of intellectual functioning and adaptive behavior, with onset during the developmental period from infancy through adolescence.

Lactic acidosis · Frequent (79-30%)

An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.

Neurodevelopmental delay · Frequent (79-30%)

Neurodevelopmental delay (NDD) refers to delays in the maturation of the brain and central nervous system; infants and young children with NDD may experience delays in the development of one or more skills including gross motor abilities, fine-motor coordination, language abilities and ability to solve increasingly complex problems.

Other findings in the same source

From: Orphanet

Additional reported features include Petechiae (Frequent (79-30%)); Retinal vascular tortuosity (Frequent (79-30%)); Seizure (Frequent (79-30%)); Abnormal brainstem MRI signal intensity (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Ethylmalonic encephalopathy is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Ethylmalonic encephalopathy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.