Eppie M. Yiu

Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial.

BACKGROUND Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor function and is caused by the duplication of PMP22, the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A. METHODS This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2-16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, Number 12606000481572. FINDINGS 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1.7 m/s, 95% CI -0.1 to 3.4; p=0.06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events. INTERPRETATION 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached.

Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. Patients usually become wheelchair-bound by the age of 12 years, and die of cardiorespiratory complications in their late teens to early twenties. Advances in the management of DMD, including treatment with corticosteroids and the use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. The clinical features, investigations, and management of DMD are reviewed, as well as the latest in some of the novel therapies.

A New locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene

Hereditary motor and sensory disorders of the peripheral nerve form one of the most common groups of human genetic diseases collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis in a three generation kindred, we have mapped a new locus for X-linked dominant CMT to chromosome Xp22.11. A microsatellite scan of the X chromosome established significant linkage to several markers including DXS993 (Zmax = 3.16; θ = 0.05). Extended haplotype analysis refined the linkage region to a 1.43-Mb interval flanked by markers DXS7110 and DXS8027. Whole exome sequencing identified a missense mutation c.G473A (p.R158H) in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. The change localized within the 1.43-Mb linkage interval, segregated with the affected phenotype and was excluded in ethnically matched control chromosomes. PDK3 is one of the four isoenzymes regulating the pyruvate dehydrogenase complex (PDC), by reversible phosphorylation, and is a nuclear-coded protein located in the mitochondrial matrix. PDC catalyzes the oxidative decarboxylation of pyruvate to acetyl CoA and is a key enzyme linking glycolysis to the energy-producing Krebs cycle and lipogenic pathways. We found that the R158H mutation confers enzyme hyperactivity and binds with stronger affinity than the wild-type to the inner-lipoyl (L2) domain of the E2p chain of PDC. Our findings suggest a reduced pyruvate flux due to R158H mutant PDK3-mediated hyper-phosphorylation of the PDC as the underlying pathogenic cause of peripheral neuropathy. The results highlight an important causative link between peripheral nerve degeneration and an essential bioenergetic or biosynthetic pathway required for the maintenance of peripheral nerves.

Duchenne muscular dystrophy

Duchenne muscular dystrophy, an X‐linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non‐invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies.

Neurophysiologic abnormalities in children with Charcot-Marie-Tooth disease type 1A.

Abstract  Although Charcot‐Marie‐Tooth disease type 1A (CMT1A) initially manifests in the first decade, there are no large studies describing its neurophysiologic features in childhood. We report neurophysiologic findings in 80 children aged 2–16 years with CMT1A who underwent median motor and sensory nerve conduction studies. Neurophysiologic abnormalities were present in all children. Median motor nerve conduction velocity was invariably less than 33 m/s (mean 18.7 m/s, range 9.0–32.9 m/s), with conduction velocities significantly slower in children aged 7–16 years compared with children aged 6 years and below. All children had prolonged distal motor latencies (mean 7.3 ms, range 4.0–12.3 ms). The compound muscle action potential (CMAP) amplitude was reduced from an early age (mean 7.1 mV, range 2.1–13.5 mV), and its normal increase with age was attenuated. Median sensory responses were present in only seven children, all aged less than 9 years and with slowed sensory conduction. Neurophysiologic abnormalities are present in all children with CMT1A from the age of 2 years. Motor conduction slowing progresses through the first 6 years of life and thereafter remains stable. CMAP amplitude is reduced from an early age, and the normal physiologic increase with age is attenuated. Median sensory responses may be recorded in younger children, and their presence does not exclude the diagnosis of CMT1A.

Acute Transverse Myelitis and Acute Disseminated Encephalomyelitis in Childhood : Spectrum or Separate Entities?

The clinical and radiological features of childhood acute transverse myelitis are compared to those of acute disseminated encephalomyelitis with spinal cord involvement in 22 children with acute transverse myelitis and 12 children with acute disseminated encephalomyelitis with spinal cord involvement. Children with acute transverse myelitis were more likely to have a sensory level (55%) and areflexia. Sixty-eight percent of the children with acute transverse myelitis, and 92% of children with acute disseminated encephalomyelitis had longitudinally extensive transverse myelitis. Demyelination was more extensive in acute disseminated encephalomyelitis (mean 15.6 vertebral segments) than in acute transverse myelitis (mean 8.0 vertebral segments). The outcome was normal to good in 82% with acute transverse myelitis and in 100% with acute disseminated encephalomyelitis. Persistent bladder dysfunction was uncommon in both. Poor prognostic factors in acute transverse myelitis are flaccid paraparesis, respiratory failure, and age less than 6 months. These clinical and radiological differences suggest acute transverse myelitis and acute disseminated encephalomyelitis are separate entities.

KING-DENBOROUGH SYNDROME CAUSED BY A NOVEL MUTATION IN THE RYANODINE RECEPTOR GENE

Malignant hyperthermia (MH) is a rare pharmacogenetic syndrome characterized by muscle rigidity, respiratory and metabolic acidosis, and an elevation in body temperature after exposure to inhalational anesthetics. MH has been associated with a number of myopathies, including central core disease (CCD) and King-Denborough syndrome.1 King-Denborough syndrome is defined by a tendency to anesthetic-induced MH in children with proximal weakness and characteristic dysmorphic features.2 Mutations in the skeletal muscle calcium release channel ryanodine receptor ( RYR1 ) gene cause MH and CCD.1 We describe a girl with phenotypic features of King-Denborough syndrome and confirmed susceptibility to MH, in whom sequencing revealed a novel heterozygous A97G point mutation in exon 2 of RYR1. ### Case report. The patient was born at term after a pregnancy complicated by decreased fetal movements and breech presentation. Hypotonia and dysmorphism (bilateral ptosis, limited vertical gaze, a high-arched palate, prominent philtrum, and scaphocephaly) were noted at birth. She had early failure to thrive. Neurologic examination showed hypotonia with mild facial and proximal limb weakness and normal deep tendon reflexes. The father and paternal grandfather had congenital ptosis without other signs of neuromuscular disease. The mother and siblings were clinically unaffected. Electromyography (EMG) and serum …

Binaural speech processing in individuals with auditory neuropathy

Auditory neuropathy disrupts the neural representation of sound and may therefore impair processes contingent upon inter-aural integration. The aims of this study were to investigate binaural auditory processing in individuals with axonal (Friedreich ataxia) and demyelinating (Charcot-Marie-Tooth disease type 1A) auditory neuropathy and to evaluate the relationship between the degree of auditory deficit and overall clinical severity in patients with neuropathic disorders. Twenty-three subjects with genetically confirmed Friedreich ataxia and 12 subjects with Charcot-Marie-Tooth disease type 1A underwent psychophysical evaluation of basic auditory processing (intensity discrimination/temporal resolution) and binaural speech perception assessment using the Listening in Spatialized Noise test. Age, gender and hearing-level-matched controls were also tested. Speech perception in noise for individuals with auditory neuropathy was abnormal for each listening condition, but was particularly affected in circumstances where binaural processing might have improved perception through spatial segregation. Ability to use spatial cues was correlated with temporal resolution suggesting that the binaural-processing deficit was the result of disordered representation of timing cues in the left and right auditory nerves. Spatial processing was also related to overall disease severity (as measured by the Friedreich Ataxia Rating Scale and Charcot-Marie-Tooth Neuropathy Score) suggesting that the degree of neural dysfunction in the auditory system accurately reflects generalized neuropathic changes. Measures of binaural speech processing show promise for application in the neurology clinic. In individuals with auditory neuropathy due to both axonal and demyelinating mechanisms the assessment provides a measure of functional hearing ability, a biomarker capable of tracking the natural history of progressive disease and a potential means of evaluating the effectiveness of interventions.

A retrospective review of X-linked Charcot-Marie-Tooth disease in childhood

Objective: X-linked Charcot-Marie-Tooth disease (CMTX) is infrequently diagnosed in childhood, and its clinical and neurophysiologic features are not well-described. We reviewed clinical, neurophysiologic, and pathologic findings in 17 children with CMTX. Methods: This was a retrospective review of children with CMTX from 2 tertiary pediatric hospitals. The diagnosis of CMTX was based on an identifiable connexin 32 mutation (CMTX1) or a consistent pedigree and neurophysiologic features in children without a connexin 32 mutation (CMTX-other). Results: Six boys and 2 girls from 8 kindreds had CMTX1, and 8 boys and 1 girl from 5 kindreds had other forms of CMTX (CMTX-other). Fifteen children, including males and carrier females, were symptomatic from infancy or early childhood (younger than 5 years). In addition to the typical Charcot-Marie-Tooth disease clinical phenotype, some patients had delayed motor development, sensorineural hearing loss, tremor, pathologic fractures, or transient CNS disturbances. Eleven children underwent nerve conduction studies. Median nerve motor nerve conduction velocities were in the intermediate to normal range (30–54 m/s) in all children older than 2 years. Axon loss, reflected by low-amplitude compound muscle action potentials, was present in all patients. A pattern of X-linked dominant inheritance, with carrier females showing an abnormal neurologic or neurophysiologic examination, correlated with the presence of a connexin 32 mutation in all but 2 pedigrees. Conclusions: The clinical phenotype of CMTX is broader than previously reported. Onset in males and carrier females is most often in early childhood. Families with an X-linked dominant inheritance pattern are likely to have CMTX1.

Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia

Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% of affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease‐causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA.