Correction to: Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

Due to a typesetting error the wrong Table 2 was used. The correct Table 2 is shown here.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

OBJECTIVES: To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. METHODS: We identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age-related reference ranges and to non-POLG patients presenting with status epilepticus. RESULTS: Forty-one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non-epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5-hydroxyindoleacetic acid levels. CONCLUSIONS: Children with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

Autosomal dominant SCN8A mutation with an unusually mild phenotype.

BACKGROUND: Mutations in SCN8A, coding for the voltage-gated sodium channel Nav 1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment, in particular early onset epileptic encephalopathy (EIEE) type 13. CASE REPORT: Here we report an infant and his father with early onset focal epileptic seizures but without cognitive or neurological impairment in whom next generation sequence analysis identified a heterozygous mutation (c.5630A > G, p. (Asn1877Ser)) in the SCN8A gene. This mutation, confirmed by Sanger sequence analysis, affects a highly conserved amino acid and in silico tools predicts that it may be pathogenic. The reported infant has a normal developmental profile at 16-month follow-up. His father also had normal development and has no cognitive impairment at 42 years. This is the second known SCN8A mutation associated with a phenotype of benign familial infantile epilepsy. Good seizure control was achieved in our patients with sodium channel blockers. CONCLUSION: Based on our proband and a recently described group of families with benign familial infantile epilepsy and SCN8A variant we suggest expanding testing to patients with infantile epilepsy and no cognitive impairment. In addition, the same SCN8A variant (c.5630A > G, p. (Asn1877Ser)) is also found in patients with epilepsy and developmental delay highlighting the phenotypic variability and the possible role of other protective genetic factors.

Muscle histology vs MRI in Duchenne muscular dystrophy.

OBJECTIVE: There are currently no effective treatments to halt the muscle breakdown in Duchenne muscular dystrophy (DMD), although genetic-based clinical trials are being piloted. Most of these trials have as an endpoint the restoration of dystrophin in muscle fibers, hence requiring sufficiently well-preserved muscle of recruited patients. The choice of the muscles to be studied and the role of noninvasive methods to assess muscle preservation therefore require further evaluation. METHODS: We studied the degree of muscle involvement in the lower leg muscles of 34 patients with DMD >8 years, using muscle MRI. In a subgroup of 15 patients we correlated the muscle MRI findings with the histology of open extensor digitorum brevis (EDB) muscle biopsies. Muscle MRI involvement was assigned using a scale 0-4 (normal-severe). RESULTS: In all patients we documented a gradient of involvement of the lower leg muscles: the posterior compartment (gastrocnemius > soleus) was most severely affected; the anterior compartment (tibialis anterior/posterior, popliteus, extensor digitorum longus) least affected. Muscle MRI showed EDB involvement that correlated with the patient's age (p = 0.055). We show a correlation between the MRI and EDB histopathologic changes, with MRI 3-4 grades associated with a more severe fibro-adipose tissue replacement. The EDB was sufficiently preserved for bulk and signal intensity in 18/22 wheelchair users aged 10-16.6 years. CONCLUSION: This study provides a detailed correlation between muscle histology and MRI changes in DMD and demonstrates the value of this imaging technique as a reliable tool for the selection of muscles in patients recruited into clinical trials.

Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia.

Congenital myopathy with fibre type disproportion (CFTD) has been associated with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. We report the clinico-pathological and electrophysiological features of 2 unrelated cases with heterozygous TPM3 mutation. Case 1 is a 19-year-old lady who presented with motor delay in infancy, respiratory failure in early teens requiring non-invasive ventilation despite being ambulant, ptosis, axial more than proximal weakness and scoliosis. Case 2 is a 7-year-old boy with hypotonia, feeding difficulties, motor delay and scoliosis, also requiring non-invasive ventilation while ambulant. Muscle biopsies in both cases showed fibre type disproportion. Muscle MRI (Case 1) showed mild uniformly increased interstitial tissue in and around the muscles. Sequencing of TPM3 in case 1 revealed a previously described heterozygous c.503G > A(pArg168His) missense variant in exon 5 and a novel heterozygous missense mutation c.521A > C(pGlu174Ala), also in exon 5, in case 2. A mild abnormality in the single fibre EMG was documented on electrophysiology in both cases. These cases highlight the neuromuscular transmission defect in CFTD secondary to TPM3 mutations.

Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7.

BACKGROUND: Mutations in the postsynaptic adaptor protein Dok-7 underlie congenital myasthenic syndrome (CMS) with a characteristic limb girdle pattern of muscle weakness. Patients usually do not respond to or worsen with the standard CMS treatments: cholinesterase inhibitors and 3,4-diaminopyridine. However, anecdotal reports suggest they may improve with ephedrine. METHODS: This was an open prospective follow-up study to determine muscle strength in response to ephedrine in Dok-7 CMS. Patients were first evaluated as inpatients for suitability for a trial of treatment with ephedrine. The response was assessed at 2 and 6 to 8 months follow-up clinic visits using a quantitative myasthenia gravis (severity) score (QMG) and mobility measures. RESULTS: Ten out of 12 of the cohort with DOK7 mutations tolerated ephedrine. We noted a progressive response to treatment over the 6 to 8 months assessment period with a significant improvement at the final QMG score (p = 0.009). Mobility scores also improved (p = 0.0006). Improvements in the subcomponents of the QMG score that measured proximal muscle function (those muscle groups most severely affected) were most marked, and in some cases were dramatic. All patients reported enhanced activities of daily living at 6-8 months. CONCLUSION: Ephedrine appears to be an effective treatment for Dok-7 CMS. It is well-tolerated by most patients and improvement in strength can be profound. Determining the long-term response and the most effective dosing regimen will require further research. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ephedrine given at doses between 15 and 90 mg/day improves muscle strength in patients with documented mutations in DOK7.

Childhood myasthenia: clinical subtypes and practical management.

In recent years, understanding of the pathogenesis and clinical presentation of distinct myasthenia subtypes has increased significantly. This article reviews the clinical manifestations of autoimmune myasthenia gravis (including myasthenia associated with anti-muscle-specific kinase antibodies), ocular myasthenia, and antibody negative myasthenia. The following treatments are examined: cholinesterase inhibitors, immunosuppressants, and thymectomy. Inherited congenital myasthenic syndromes (CMS) are now increasingly recognized, and most commonly present during childhood. This article outlines the presynaptic, synaptic basal lamina-associated, and postsynaptic classification of CMS and the clinical presentation and aetiology of individual syndromes. Relevant investigations and treatment options (including the role of pyridostigmine, 3,4-diaminopyridine, fluoxetine, and ephedrine) are discussed.

Neuroradiological aspects of subdural haemorrhages.

AIMS: To review the neuroimaging of a series of infants and young children admitted to hospital with subdural haemorrhage (SDH). METHODS: Neuroradiological investigations of 74 children under 2 years of age, from South Wales and southwest England, in whom an SDH or subdural effusion had been diagnosed between 1992 and 2001, were reviewed. Two paediatric neuroradiologists blinded to the original radiological report reviewed all the relevant images. RESULTS: Neuroradiological review of images identified radiological features which were highly suggestive of non-accidental head injury (NAHI). Interhemispheric haemorrhages and SDHs in multiple sites or of different densities were almost exclusively seen in NAHI. MRI was more sensitive in identifying SDHs of different signal characteristics, posterior and middle cranial fossa bleeds, and parenchymal changes in the brain. CT scans, if performed with suboptimal protocols, were likely to miss small subdural bleeds. CONCLUSIONS: Guidelines for neuroimaging in suspected NAHI are recommended. A radiologist with experience in NAHI should report or review these scans. The initial investigation should be CT, but MRI will also be necessary in most cases. Head CT should be an integral part of the skeletal survey in all infants less than 6 months of age referred for child protection investigation, and in children less than 2 years where child abuse is suspected and there are neurological signs, retinal haemorrhages, or fractures.

Topiramate in the treatment of myoclonic-astatic epilepsy in children: a retrospective hospital audit.

BACKGROUND: Myoclonic-Astatic Epilepsy (MAE) usually starts before five years of age and is associated with very frequent seizures and is highly resistant to treatment. AIM: To investigate the outcome of adjunctive topiramate (TPM) therapy in children with a diagnosis of MAE syndrome. SUBJECTS AND METHODS: In an outpatient setting, case notes of 27 children who received TPM were retrieved and analysed. RESULTS: Records of 6 children with MAE, who were experiencing 2-8 atonic seizures daily before starting TPM were studied. Improvement was noted after addition of TPM (mean dose at steady-state 7.4+/-2.5mg/kg/day) to the regimen of 1-3 anti-epileptic drugs they were receiving concurrently. All but one child improved following the titration period: one had 50-80% improvement in the frequency of atonic seizures and three had over 80% improvement. However, one child who showed over 80% improvement and was free of atonic seizures, later developed increased frequency of other seizure types. In one child there was no significant improvement. Improvement has been sustained for over 6 months in three patients and over 4 months in one; three have continued TPM. TPM was stopped in three patients (reduction in seizure control/no improvement). CONCLUSIONS: This study supports the efficacy of TPM in controlling atonic seizures in MAE and indicates that it should be considered as an add-on drug in the management of this 'difficult-to-treat' epileptic syndrome.

Isolated hypoglossal nerve palsy in a 14-year-old girl.

Isolated hypoglossal nerve palsy is rare, but occasionally it appears as the initial or solitary sign of an intracranial or extracranial space-occupying lesion or a vascular abnormality of the internal carotid artery. We present a 14-year-old girl who, following an upper respiratory tract infection, presented with isolated right hypoglossal nerve palsy. Anti-streptolysin O titre was increased to >1280 suggesting a preceding streptococcal infection. Magnetic resonance imaging of the brain did not show any intracranial or extracranial abnormality. She had a partial improvement at 3 months. This case emphasizes the value of recognizing the existence of benign self-limiting, post-infectious causes of isolated hypoglossal nerve palsies in children.

Gliomatosis cerebri in a 10-year-old girl masquerading as diffuse encephalomyelitis and spinal cord tumour.

Gliomatosis cerebri is the unifying term used when diffuse glial infiltration occurs throughout the cerebral hemispheres. The very few cases reported in children have presented with intractable epilepsy, corticospinal tract deficits, unilateral tremor, headaches, and developmental delay. Antemortem diagnosis is difficult because of the vagueness of the physical, radiological and pathological findings. Adult cases may simulate an acute diffuse encephalomyelitis and show postmortem evidence of a marked swelling of the spinal cord. Apparently benign intracranial hypertension with papilloedema has also been recorded. We report a 10-year-old girl who presented with a history and physical signs suggestive of benign intracranial hypertension. A diffuse encephalomyelopathy occurred, which was complicated by spinal cord swelling, followed by deterioration and death. Gliomatosis cerebri affecting the brain and spinal cord was found at postmortem examination.

Retinitis and dementia in a pregnant girl: an unusual case.

A 14-year-old pregnant Caucasian girl presented with a 1-week history of dementia. She had presented 1 year prior with acute unilateral visual impairment and was noted to have macular degeneration of presumed infective aetiology. This evolved to a pigmentary macular lesion. During the course of the current presentation she developed myoclonic jerks. An electroencephalogram revealed periodic spike and slow wave complexes at 1-2 second intervals. Blood and cerebrospinal fluid examination showed raised anti-measles IgG antibody titres. Intrathecal synthesis of anti-measles virus antibody was demonstrated unequivocally and a diagnosis of subacute sclerosing panencephalitis was made. A healthy male infant was delivered by elective caesarean section at 33 weeks' gestation. She continued to deteriorate clinically despite treatment with intraventricular alpha-interferon. She had not had primary immunization against measles.

Menkes kinky hair disease: an unusual case.

Menkes disease is a rare X-linked recessive disease of copper metabolism. Clinical manifestations begin in the first few months of life or even in the neonatal period. Hypothermia, hypotonia, poor weight gain, seizures and neurodevelopmental delay or regression are seen. Outcome is poor, with death occurring usually by 3 years of age. A characteristic facial appearance with steely hair suggest the diagnosis. Neuroimaging usually shows cortical atrophy, extra-axial fluid collections and progressive and extensive degeneration of grey matter with secondary demyelination. We describe an atypical, but biochemically proven case of Menkes disease with atypical clinical and radiological features. Our patient had a large head, atypical electron microscopy appearances of the hair and predominant diffuse white matter involvement on neuroimaging, but a low serum copper level and a high 64CU uptake in fibroblasts (89.5 ng/mg of protein) confirmed the diagnosis.

Subdural haemorrhages in infants: population based study.

OBJECTIVES: To identify the incidence, clinical outcome, and associated factors of subdural haemorrhage in children under 2 years of age, and to determine how such cases were investigated and how many were due to child abuse. DESIGN: Population based case series. SETTING: South Wales and south west England. SUBJECTS: Children under 2 years of age who had a subdural haemorrhage. We excluded neonates who developed subdural haemorrhage during their stay on a neonatal unit and infants who developed a subdural haemorrhage after infection or neurosurgical intervention. MAIN OUTCOME MEASURES: Incidence and clinical outcome of subdural haemorrhage in infants, the number of cases caused by child abuse, the investigations such children received, and associated risk factors. RESULTS: Thirty three children (23 boys and 10 girls) were haemorrhage. The incidence was 12.8/100 000 children/year (95% confidence interval 5.4 to 20.2). Twenty eight cases (85%) were under 1 year of age. The incidence of subdural haemorrhage in children under 1 year of age was 21.0/100 000 children/year and was therefore higher than in the older children. The clinical outcome was poor: nine infants died and 15 had profound disability. Only 22 infants had the basic investigations of a full blood count, coagulation screen, computed tomography or magnetic resonance imaging, skeletal survey or bone scan, and ophthalmological examination. In retrospect, 27 cases (82%) were highly suggestive of abuse. CONCLUSION: Subdural haemorrhage is common in infancy and carries a poor prognosis; three quarters of such infants die or have profound disability. Most cases are due to child abuse, but in a few the cause is unknown. Some children with subdural haemorrhage do not undergo appropriate investigations. We believe the clinical investigation of such children should include a full multidisciplinary social assessment, an ophthalmic examination, a skeletal survey supplemented with a bone scan or a skeletal survey repeated at around 10 days, a coagulation screen, and computed tomography or magentic resonance imaging. Previous physical abuse in an infant is a significant risk factor for subdural haemorrhage and must be taken seriously by child protection agencies.