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 anti-seizure medication (ASM). 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 ASM.
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.
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