Mitochondrial diseases mimicking neurotransmitter defects
Introduction
Inborn errors of neurotransmitters are rare disorders, caused by a primary disturbance of neurotransmitter metabolism. Clinical manifestations include infantile parkinsonism, oculogyric crisis, psychomotor delay, neurovegetative dysfunction signs and non-specific neuroimaging findings (Garcia-Cazorla et al., 2005, García-Cazorla et al., 2007, Pearl et al., 2005). CSF study is essential for diagnosis, since metabolic studies in blood and urine are normal (Pearl et al., 2005).
Mitochondrial diseases are a heterogeneous group of disorders caused by mutations in both mitochondrial and nuclear genes controlling oxidative phosphorylation. Their clinical phenotypes are very diverse and the spectrum is still expanding (von Kleist-Retzow et al., 2003). Diagnosis is sometimes difficult to establish. This is particularly true when a final molecular characterization cannot be achieved. That is the reason why some consensus concerning diagnostic criteria for classifying patients as definite, probable and possible diagnosis (Bernier et al., 2002, Naviaux, 2004, Walker et al., 1996) needed to be attained.
Our aim was to describe 5 unrelated patients with the initial diagnostic hypothesis of primary biogenic amine deficiency, who eventually were found to fulfill definite diagnostic criteria for mitochondrial disease.
Section snippets
Case 1
This girl was born after normal pregnancy and delivery (birth weight (BW: 2700 g). Development up to 3 months of life was normal, followed by loss of cephalic control, limb tremor and feeding difficulties. At 5 months, bilateral palpebral ptosis, hypomimia, truncal hypotonia, lack of spontaneous movements, limb hypertonia, brisk tendon reflexes, hypersalivation and high amplitude limb tremor (spontaneous and triggered by tactile stimulus) were observed. A month later, she needed mechanical
Complementary exams
Tests were performed using standard procedures for lactate, pyruvate, ammonium and amino acids in plasma, organic acids, reducing substances, sulphite test and glycosaminoglycanes, creatine and guanidinoacetate in urine, isoelectric focusing pattern of transferring study, thyroid hormones, caeruloplasmine, copper, creatine kinase and karyotype. Brain MRI, electroretinogram, visual and acoustic evoked potentials, echocardiogram, electroencephalogram, electromyogram and nerve conduction studies
CSF analysis
CSF samples were obtained by lumbar puncture according to previously described protocols (Hyland et al., 1993, Ormazábal et al., 2005). Biogenic amine metabolites (HVA, 3-orthomethyldopa, 3-methoxy-4-hydroxyphenylglycol, 5-HIAA and 5-hydroxytryptophan) and pterins (neopterin and biopterin) were analysed by reverse phase high performance liquid chromatography with electrochemical and fluorescence detection (Ormazábal et al., 2005). Reference values were established in a control population where
Muscle biopsy studies
Quadriceps muscle biopsies were obtained for morphologic, biochemical and genetic investigations. The muscle was removed and frozen immediately, then tested in another center (Instituto de Bioquímica Clínica, Barcelona, Spain, and in patient 4, Hospital de Criancas Maria Pia, Porto, Portugal) at a later date. Muscle biopsies were taken and prepared according to standard procedures. Activities of NADH: cytochrome c oxidoreductase (complex I + CoQ + complex III), succinate: cytochrome c reductase
Results
Table 1, Table 2 show the main clinical, laboratory and imaging results.
Discussion
In this article we report 5 unrelated patients with definite diagnosis of mitochondrial disorder according to accepted criteria (Bernier et al., 2002), but whose initial clinical and biochemical CSF features were consistent with neurotransmitter deficiencies. In spite of these criteria, the absence of a genetic diagnosis should be considered as a limitation of this work. On the other hand, it is widely known that in the field of mitochondrial disorders, it is not always easy to establish a
Acknowledgments
This work was supported by FIS Grant PI051318 and CIBER-ER (ISC-III). S. Duarte is the recipient of a grant from the Portuguese Neurological Society.
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These authors contributed equally to this work.