This issue contains a most interesting and comprehensive case report by D. Zafeiriou
and co-authors [13] on one of the very rare inborn errors of metabolism - ethylmalonic encephalopathy
(EE). Since the first description in 1991 by Burlina et al. [3] only about 35 patients, mostly of Mediterranean descent, have been described. Knowledge
on very rare inborn errors of metabolism may not only contribute to our every day
clear-up rate of unexplained cases, but may also improve our understanding of the
molecular pathomechanisms involved in CNS disease. The delineation of ethylmalonic
encephalopathy has been intriguing and despite the identification of the underlying
gene defect by Tiranti et al. in 2004 [10], the molecular mechanisms are only partly understood today.
EE is characterized by an early onset progressive encephalopathy and vasculopathy
with chronic diarrhea, recurrent petechiae and orthostatic acrocyanosis, leading to
death in early infancy or childhood. Although the combination of these clinical features
seems to be fairly constant, there is variability in the disease onset and severity,
recognized with the number of reports published. In some patients there may be a period
of near normal early psychomotor development, while others have complete lack of motor
development and social interaction. Diarrhea in EE usually starts after weaning and
frequent watery stools have led to failure to thrive in some cases. Petechiae may
occur spontaneously or with intercurrent illness and are easily provoked by minimal
pressure. Diarrhea and petechiae may precede the onset of neurological symptoms and
some patients have undergone extended hematological or gastrointestinal work-up before
the developmental delay had become more prominent [4]
[6]. Patients affected by EE all suffer from some degree of muscle hypotonia followed
by spasticity and dystonia [6]
[7]
[9] but independent walking may be achieved in milder cases [9]. In those cases with a milder course, cognitive function seems to be initially well
preserved, while the more severe cases show profound mental retardation and early-onset
seizures. Episodes of metabolic decompensation with severe metabolic acidosis as well
as severe nephrotic syndrome have been observed in single patients [1]. Cranial MRI is always abnormal but per se unspecific with bilateral signal changes
in the basal ganglia, and white matter involvement with brain atrophy in the more
progressed state. Chiari I malformation and tethered cord have been described in two
siblings [9] but direct association with the primary defect needs proof in further cases.
Lactic acid elevation and excretion of ethylmalonic acid have been detected as biochemical
markers in the first Italian patients [3], but in some patients these have recently been recognized to be of intermittent
occurrence along with metabolic decompensation only [4]
[8]. As outlined in the case report by Zafeiriou, the excretion of ethylmalonic acid
is non-specific and can also be seen in other inborn errors of metabolism affecting
energy production. Nevertheless, the presence of diarrhea and recurrent petechiae
clearly distinguish this disorder from phenotypes described in short-chain acyl CoA
dehydrogenase deficiency and multiple acyl CoA dehydrogenase deficiency. The source
of ethylmalonic acid as well as the accompanying elevation of plasma C4 and C5 acylcarnitine and acylglycine fractions observed in EE are still unclear. It has
been noted early that some patients with EE have mild reduction of their cytochrome
C oxidase activity in muscle tissue [5], but again, no correlation to the excretion of ethylmalonic acid could be established.
In order to promote the activity of enzymes involved in the beta-oxidation of fatty
acids and in mitochondrial function, Yoon et al. had undertaken a cofactor trial with
riboflavine, coenzyme Q and carnitine in three patients with EE with some clinical
improvement, especially with respect to diarrhea, while no consistent change of the
laboratory abnormalities could be observed [12].
In 2004 the underlying molecular defect of EE has been detected by Tiranti and co-workers
[10]. In a first step a chromosomal region spanning about 130 genes was identified on
chromosome 19q13 by homozygosity mapping. Considering the clinical and biochemical
findings, genes related to mitochondrial function were then selected within this region
by a so-called neighborhood index. This index reflects the similarity of proteins
targeted to mitochondria on an RNA level. The gene finally identified as the ethylmalonic
encephalopathy ETHE1 gene had previously been found overexpressed in human hepatoma
cell cultures and highlights the role of mitochondrial dysfunction not only in inborn
errors of metabolism but also in carcinogenesis. Loss of function mutations as well
as missense mutations of the ETHE1 gene have since been described in EE patients.
The propositus described in the case report by Zafeiriou, corresponds to the severe
spectrum described in EE. Regarding the clinical, neuroradiological and biochemical
findings observed in EE, some patients (especially with intermittent excretion of
ethylmalonic acid) may be misdiagnosed as Leighs disease. Aicardi Goutières syndrome
may be another differential diagnosis with respect to early onset encephalopathy associated
with vasculopathy and acrocyanosis, but in those patients basal ganglia changes represent
calcifications, white matter changes are more marked and elevated interferon in CSF
would serve as a diagnostic marker. The diagnosis of EE may be extremely difficult
before the onset of neurological symptoms but entering the search terms “diarrhea
and petechiae” into PubMed would bring up 6 citations out of 87 with this differential
diagnosis. The biochemical findings in Zafeiriou's patient diagnosed with EE are typical
in the degree of ethylmalonic acid excretion, less so with the isolated elevation
of the C4 but normal C5 fraction of the acylcarnitines, but authors have clearly ruled out SCAD deficiency
by enzymology and molecular analysis of the SCAD gene. Analysis of the respiratory
chain in muscle of this patient revealed normal activity of cytochrome C oxidase,
while complex II was found to be mildly decreased. The fact that abnormalities of
the respiratory chain enzymes are only found in some EE patients, point towards indirect
effects by secondary impairement of respiratory chain enzymes, possibly caused by
toxic effects of the ethylmalonic acid [2].
The clinical and neuroradiological findings along with the lactic acidosis observed
in EE could well be in line with a mitochondrial disorder. The actual hypothesis for
the function of the ETHE1 protein is that it acts as a thioesterase on an as yet unknown
substrate involved in a novel mitochondrial pathway [11]. It has to be proven if early diagnosis and cofactor treatment can alter the course
of this devastating disease.
