Idebenone treatment in paediatric and adult patients with Friedreich ataxia: Long-term follow-up

BACKGROUND: Antioxidant therapy is a new therapeutical approach for patients with Friedreich ataxia. AIMS: To assess the effectiveness of long-term idebenone treatment in Friedreich ataxia patients. METHODS: An open-labelled prospective study. Ten paediatric patients (age range 8-18 years) and 14 adults (age range 18-46 years) with genetic diagnosis of Friedreich ataxia were treated with idebenone (5-20mg/kg/day) for 3-5 years. Neurological evolution was evaluated using the International Cooperative Ataxia Rating Scale (ICARS), and cardiological outcomes using echocardiography. RESULTS: In paediatric patients, no significant differences were observed in ICARS scores and echocardiographic measurements when comparing baseline status and after 5 years of follow-up. Concerning adult cases, ICARS scores showed a significant increase in neurological dysfunctions during 3 years of therapy (Wilcoxon test, p=0.005), while echocardiographic measurements remained unchanged. CONCLUSIONS: Our results indicate that longer-term idebenone treatment prevented progression of cardiomyopathy in both paediatric and adult patients, whereas its stabilizing effect on neurological dysfunction was present only in the paediatric population, mainly before puberty. This suggests that the age at which idebenone treatment is initiated may be an important factor in the effectiveness of the therapy.     

Acute presentations of inherited metabolic disorders: investigation and initial management

Inborn errors of metabolism are individually rare, but so many have now been described that the general paediatrician will encounter one from time to time. For many, early treatment is important. Unfortunately, most that present acutely do so with non-specific symptoms and signs. It is therefore necessary to identify and investigate those at high risk. The most common problems are neurological (including coma, seizures and stroke-like episodes), hypoglycaemia, disorders of acid-base regulation, acute liver disease, rhabdomyolysis, cardiomyopathy and sudden collapse. Treatment should be started as soon as an inborn error is suspected. This review is a short, practical introduction and cannot cover all situations. If in doubt, consult your local specialist metabolic centre. Free, detailed instructions on the acute management of individual inborn errors of metabolism can be found on the British Inherited Metabolic Disease Group (BIMDG) Website: http://www.bimdg.org.uk/     

Downbeat nystagmus in two siblings with spinocerebellar ataxia type 6 (SCA 6)

We report two siblings with spinocerebellar ataxia type 6 (SCA 6), both showing downbeat nystagmus (DBN) as a predominant clinical feature. Familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA-2) and SCA 6 are allelic disorders, and interestingly, the occasional presence of DBN in EA-2 was reported. Our observations suggest that common molecular mechanisms might underlie DBN in FHM, EA-2 and SCA 6. Then, these disorders should be kept in mind in diagnosing patients with DBN.     

Nitrite,nitrate and cGMP in the cerebrospinal fluid in degenerative neurologic diseases

Summary To investigate whether nitric oxide (NO) plays a role in degenerative neurologic disease (DND), we measured nitrite, nitrate and cyclic GMP in cerebrospinal fluid (CSF) samples from patients with Parkinson's disease (PD), spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS). We found no significant change in CSF nitrite, nitrate or cyclic GMP in patients with any DND compared with control values. These results suggest that NO production is preserved in PD, SCA and ALS.     

The CSF-protein pattern in acute cerebellar ataxia of childhood and intracranial midline tumours

CSF-protein profiles of 25 children with acute cerebellar ataxia and of 39 children with intracranial midline tumours at diagnosis were examined by quantitative zone electrophoresis in agarose gel. The profiles were compared with those obtained from a control group of 86 cases, and those from 61 patients with aseptic meningitis and 40 children with bacterial meningitis. The data from the latter groups demonstrated the CSF-protein pattern of moderate or severe disturbance of the blood-CSF barrier (B-CSF-B), respectively. The children with acute cerebellar ataxia showed minor signs of a B-CSF-B impairment and no increase of -globulin. These findings point to a slight acute vascular lesion. CSF changes indicative of a moderate-to-severe dysfunction of the B-CSF-B occurred in the majority of the patients with cerebellar astrocytomas, pontine gliomas, tumours around the 3rd ventricle, and medulloblastomas. Therefore acute cerebellar ataxia can be differentiated from intracranial midline tumours in most cases by means of CSF-protein electrophoresis. A striking finding was that 12 out of 14 children with medulloblastomas revealed a marked increase of -globulin. Since in 5 of these cases oligoclonal -globulin could be detected, this finding means local immunoglobulin synthesis within the CNS. The marked increase of -globulin which almost exclusively occurred in association with medullo-blastomas allows their seperation from acute cerebellar ataxia and the other tumour groups. Quantitative agarose gel electrophoresis can be a complementary diagnostic test in children with acute ataxia and suspected of having a CNS infection, or in cases with a negative CT brain scan in which intracranial midline tumour is a likely possibility.     

GABA Levels in Cerebrospinal Fluid of Patients with Epilepsy

Abstract: The lumbar cerebrospinal fluid (CSF) γ-aminobutyric acid (GABA) levels were measured in 27 patients with epilepsy, another three epileptic patients with status epilepticus and three epileptic patients with chronic cerebellar ataxia. The mean lumbar CSF GABA levels of the 27 patients with epilepsy were not significantly different from those of normal controls. Six of these 27 patients who had daily partial complex and partial motor seizures showed significantly low CSF GABA levels as did the six other patients, three each with status epilepticus and chronic cerebellar ataxia. These findings suggest that some epileptic patients have impaired brain GABAergic neurons.     

Embryonic stem cell models of CAG repeat disease

Nine neurodegenerative disorders are caused by CAG/polyglutamine (polyQ) repeat expansions. The underlying molecular mechanisms responsible for disease specific neurodegeneration remain elusive. In vivo and in vitro models utilizing rodent tissues, immortalized human cell lines, and human post mortem samples have provided insight into disease mechanisms. Concern that cellular and molecular processes observed in these models may not faithfully reproduce human diseases or be useful to identify compounds of therapeutic utility has driven development of new disease models. In addition to their therapeutic potential, stem cells represent a renewable source of tissue that can be directed into neurons and glia and can be used to study neurodegenerative cascades from their inception. Neuronally differentiated human stem cells containing CAG repeat expansions have the potential to accurately replicate human CAG repeat diseases and may be a faithful predictor of which compounds will be of human benefit. As a first step in development of this type of model, we developed murine embryonic stem cell models to study the mechanisms of polyQ tract induced neuronal degeneration.     

Spinocerebellar ataxia type 20

Spinocerebellar ataxia type 20 (SCA20) was reported in 2004 in a single Australian Anglo-Celtic pedigree. The phenotype is distinctive, with palatal tremor, and hypermetric saccades, and early dentate (but not pallidal) calcification in the absence of abnormalities of calcium metabolism. Dysarthria, rather than gait ataxia, was the initial symptom in most, and was typically conjoined with dysphonia, clinically resembling adductor spasmodic dysphonia. The onset of these speech abnormalities was abrupt in some cases. MRI scanning showed mild to moderate pancerebellar atrophy with dentate calcification, with olivary pseudohypertrophy in some cases, in the absence of other brainstem or cerebral changes. Nerve conduction studies were normal. Progression appeared to be slow. SCA20 is probably rare, as despite the distinctive phenotype, only this one pedigree has been described. The locus mapped to the pericentromeric region of chromosome 11 with a LOD score of 4.47, and its candidate region overlaps that of SCA5. It seems probable that these two SCAs may be separate genetic entities, on the basis of their divergent clinical features, but formal proof awaits discovery of one or both responsible genes.     

Partial resistance of ataxin-2-containing olivary and pontine neurons to axotomy-induced degeneration

Spinocerebellar ataxia type 2 (SCA2) is caused by the expansion of a polyglutamine tract in ataxin-2, the SCA2 gene product. In spite of the identification of the genetic defect and the coded protein, the function of wild-type ataxin-2 has not been clarified. In order to identify the possible resistance of ataxin-2-containing neurons to degeneration, we investigated in this study the distribution and the characteristics of cell reaction to axotomy in ataxin-2-positive olivary and pontine neurons in a model of cerebellar damage represented by hemicerebellectomy. We also performed double immunofluorescence studies of ataxin-2 and purinergic receptors to characterize ataxin-2-positive surviving neurons. The present data demonstrated that after axotomy olivary and pontine ataxin-2-expressing neurons survived longer than the ataxin-2-negative cell population. Cell counting performed in the different olivary subdivisions failed to reveal any topographical prevalence in the distribution of ataxin-2-positive neurons. Therefore, the relative resistance to axotomy appears to be an intrinsic property of the ataxin-2 cell population. In addition, the capacity to modify the pattern of purinergic receptor expression in response to damage was present in only one subset of ataxin-2-positive surviving neurons. These data suggest that ataxin-2 is involved in resistance to degeneration phenomena which may be lost after mutation.     

Nitrous oxide inhalation as a cause of cervical myelopathy

Current evidence suggests that the incidence of recreational nitrous oxide inhalation is on the rise. Due to the possibility of clinically significant myelopathy, as well as potential response to treatment, it is important to consider this diagnosis when appropriate. We present a case of acquired ataxia and myelopathy due to nitrous oxide abuse and discuss diagnosis, pathophysiology, and response to treatment.