Elsevier

Mitochondrion

Volume 8, Issue 3, June 2008, Pages 273-278
Mitochondrion

Mitochondrial diseases mimicking neurotransmitter defects

https://doi.org/10.1016/j.mito.2008.05.001Get rights and content

Abstract

Objectives

Mitochondrial disorders are clinically heterogeneous. We aimed to describe 5 patients who presented with a clinical picture suggestive of primary neurotransmitter defects but who finally fulfilled diagnostic criteria for mitochondrial disease.

Methods

We report detailed clinical features, brain magnetic resonance findings and biochemical studies, including cerebrospinal fluid (CSF) biogenic amine and pterin measurements, respiratory chain enzyme activity, and molecular studies.

Results

The 5 patients had a very early onset age (from 1 day to 3 months) and a severe clinical course. They all showed a clinical picture suggestive of infantile hypokinetic-rigid syndrome (hypokinesia, hypomimia, slowness of reactions, tremor), other abnormal movements (myoclonus, dystonia), axial hypotonia, limb hypertonia, feeding difficulties, and psychomotor delay. Abnormal CSF findings among the 4 patients without treatment included low levels of homovanillic acid (HVA) in 3 patients, with associated low 5-hydroxyindoleacetic acid (5-HIAA) concentrations in two of them. Absent or mild and transitory improvement was observed after treatment with l-dopa. A diagnosis of mitochondrial disorder was finally made due to the appearance of hyperlactacidemia, diverse respiratory chain defects, and multisystemic involvement.

Conclusions

Secondary neurotransmitter disturbances may occur in mitochondrial diseases. Differential diagnosis of hypokinetic-rigid syndrome presenting in infancy could also include paediatric mitochondrial disorders.

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.

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