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].
