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.

Determinants of reduced health-related quality of life in pediatric inherited neuropathies.

OBJECTIVE: We have shown that health-related quality of life (QOL) in children with inherited neuropathies (Charcot-Marie-Tooth disease [CMT]) is significantly reduced compared to population norms, thus establishing its utility as an outcome measure in therapeutic trials. However, the Australian ascorbic acid trial in children with CMT type 1A (CMT1A) identified no change in QOL scores despite a trend toward improvement in nerve conduction velocities in the treated group. The objective of this study was to identify clinical, electrophysiologic, and functional correlates of QOL in children with CMT1A, to guide future investigations of strategies to improve QOL and reduce disability in these patients. METHODS: In this cross-sectional study, a series of multivariate regression models were developed to determine whether QOL scores could be explained by demographic and symptom data, standardized measures of gross motor function, foot/ankle and hand/finger involvement, electrophysiology, and gait characteristics in 70 children aged 5-16 years with CMT1A. RESULTS: Independent determinants of reduced QOL in children with CMT1A, from strongest to weakest, were leg cramps, hand tremor, short step length, reduced long jump distance, ankle inflexibility, poor agility and endurance, advancing age, and foot drop. Many of the standardized clinical and electrophysiologic measures used as endpoints in clinical trials of CMT correlated poorly with QOL. CONCLUSION: QOL is negatively affected by CMT1A in children. Multivariate modeling suggests that interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility might have a substantial effect on QOL in children with CMT1A.

Autosomal dominant congenital spinal muscular atrophy--a possible developmental deficiency of motor neurones?

We describe a kindred with an unusual congenital lower motor neuron disorder with significant but static muscle weakness predominantly affecting the lower limbs. The proband had talipes equinovarus and congenital hip contractures and did not walk until 19 months of age. Lower-extremity predominant, primarily proximal weakness was identified on assessment at three years. Over a 20 year follow-up there has been no clinical progression. The proband has a four-year-old daughter with very similar clinical findings. Electromyography and muscle biopsy suggest reduced numbers of giant normal duration motor units with little evidence of denervation or reinnervation. Dominant congenital spinal muscular atrophy predominantly affecting the lower limbs is rarely described. It is possible that the disorder is due to a congenital deficiency of motor neurons.

Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations.

OBJECTIVE: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations. METHODS: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined. RESULTS: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations. CONCLUSION: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.

Interventions for the prevention and treatment of pes cavus.

BACKGROUND: People with pes cavus frequently suffer foot pain, which can lead to significant disability. Despite anecdotal reports, rigorous scientific investigation of this condition and how best to manage it is lacking. OBJECTIVES: To assess the effects of interventions for the prevention and treatment of pes cavus. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (April 2007), MEDLINE (January 1966 to April 2007), EMBASE (January 1980 to April 2007), CINAHL (January 1982 to April 2007), AMED (January 1985 to April 2007), all EBM Reviews (January 1991 to April 2007), SPORTdiscuss (January 1830 to April 2007) and reference lists of articles. We also contacted known experts in the field to identify additional published or unpublished data. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials of interventions for the treatment of pes cavus. We also included trials aimed at preventing or correcting the cavus foot deformity. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed trial quality and extracted data. MAIN RESULTS: Only one trial (custom-made foot orthoses) fully met the inclusion criteria. Two additional cross-over trials (off-the-shelf foot orthoses and footwear) were also included. Both studies assessed secondary biomechanical outcomes less than three-months after randomisation. Data used in the three studies could not be pooled due to heterogeneity of diagnostic groups and outcome measures. The one trial that fully met the inclusion criteria investigated the treatment of cavus foot pain in 154 adults over a three month period. The trial showed a significant reduction in the level of foot pain, measured using the validated 100-point Foot Health Status Questionnaire, with custom-made foot orthoses versus sham orthoses (WMD 10.90; 95% CI 3.21 to 18.59). Furthermore, a significant improvement in foot function measured with the same questionnaire was reported with custom-made foot orthoses (WMD 11.00; 95% CI 3.35 to 18.65). There was also an increase in physical functioning of the Medical Outcomes Short Form - 36 (WMD 9.50; 95% CI 4.07 to 14.93). There was no difference in reported adverse events following the allocation of custom-made (9%) or sham foot orthoses (15%) (RR 0.61; 95% CI 0.26 to 1.48). AUTHORS' CONCLUSIONS: In one randomised controlled trial, custom-made foot orthoses were significantly more beneficial than sham orthoses for treating chronic musculoskeletal foot pain associated with pes cavus in a variety of clinical populations. There is no evidence for any other type of intervention for the treatment or prevention of foot pain in people with a cavus foot type.

The expanding phenotype of laminin alpha2 chain (merosin) abnormalities: case series and review.

Initial reports of patients with laminin alpha2 chain (merosin) deficiency had a relatively homogeneous phenotype, with classical congenital muscular dystrophy (CMD) characterised by severe muscle weakness, inability to achieve independent ambulation, markedly raised creatine kinase, and characteristic white matter hypodensity on cerebral magnetic resonance imaging. We report a series of five patients with laminin alpha2 deficiency, only one of whom has this severe classical CMD phenotype, and review published reports to characterise the expanded phenotype of laminin alpha2 deficiency, as illustrated by this case series. While classical congenital muscular dystrophy with white matter abnormality is the commonest phenotype associated with laminin alpha2 deficiency, 12% of reported cases have later onset, slowly progressive weakness more accurately designated limb-girdle muscular dystrophy. In addition, the following clinical features are reported with increased frequency: mental retardation (~6%), seizures (~8%), subclinical cardiac involvement (3-35%), and neuronal migration defects (4%). At least 25% of patients achieve independent ambulation. Notably, three patients with laminin alpha2 deficiency were asymptomatic, 10 patients had normal MRI (four with LAMA2 mutations reported), and between 10-20% of cases had maximum recorded creatine kinase of less than 1000 U/l. LAMA2 mutations have been identified in 25% of cases. Sixty eight percent of these have the classical congenital muscular dystrophy, but this figure is likely to be affected by ascertainment bias. We conclude that all dystrophic muscle biopsies, regardless of clinical phenotype, should be studied with antibodies to laminin alpha2. In addition, the use of multiple antibodies to different regions of laminin alpha2 may increase the diagnostic yield and provide some correlation with severity of clinical phenotype.

Anterior horn cell disease and olivopontocerebellar hypoplasia.

To date, fewer than 30 cases of anterior horn cell disease with associated olivopontocerebellar hypoplasia have been reported. We describe five patients and review the literature on this uncommon disorder. In addition to a syndrome of progressive spinal muscular atrophy similar to that seen in Werdnig-Hoffmann disease, this disorder is characterised by hypoplasia of the olivary nuclei, pons, and cerebellum. Additional clinical features may include dysmorphism, abnormal eye movements, stridor, congenital joint contractures, and enlarged kidneys. Pontocerebellar hypoplasia may be associated with posterior fossa cystic malformations, cerebral atrophy, and a demyelinating neuropathy.

Childhood chronic inflammatory demyelinating polyneuropathy: clinical course and long-term outcome.

We reviewed the clinical history, electrophysiologic and pathologic findings, and response to therapy of 16 children with chronic inflammatory demyelinating polyneuropathy. The majority presented with lower limb weakness. Sensory loss was uncommon. The illness was monophasic in seven children, relapsing in six, and three had a slowly progressive course. All patients were treated with immunosuppressive agents. In 11, the initial treatment was prednisolone. All had at least a short-term response but five went on to develop a relapsing course. Intravenous immunoglobulin was the initial treatment in four patients. Three responded rapidly, with treatment being stopped after a maximum of 5 months. In resistant chronic inflammatory demyelinating neuropathy, in addition to prednisolone and immunoglobulin, plasma exchange, azathioprine, cyclosporine, methotrexate, cyclophosphamide and pulse methylprednisolone were tried at different times in different patients. On serial neurophysiologic testing slowing of nerve conduction persisted for long periods after clinical recovery. Follow-up was for an average of 10 years. When last seen 14 patients were asymptomatic, two having mild residual deficits. Childhood chronic inflammatory demyelinating neuropathy responds to conventional treatment and generally has a favourable long-term outcome.

Clinical syndromes associated with tomacula or myelin swellings in sural nerve biopsies.

OBJECTIVES: To describe the neuropathological features of clinical syndromes associated with tomacula or focal myelin swellings in sural nerve biospies and to discuss possible common aetiopathological pathways leading to their formation in this group of neuropathies. METHODS: Fifty two patients with sural nerve biopsies reported to show tomacula or focal myelin swellings were reviewed, light and electron microscopy were performed, and tomacula were analysed on teased fibre studies. Molecular genetic studies were performed on those patients who were available for genetic testing. RESULTS: Thirty seven patients were diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), four with hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1), four with HMSN with myelin outfolding (CMT4B), three with IgM paraproteinemic neuropathy, three with chronic inflammatory demyelinating polyneuropathy (CIDP), and one with HMSN III (CMT3). CONCLUSIONS: Most of these syndromes were shown to be related to genetic or immunological defects of myelin components such as peripheral myelin protein 22 (PMP22), myelin protein zero (P0), or myelin associated glycoprotein (MAG). These proteins share the HNK-1 epitope which has been implicated in cell adhesion processes. Impaired myelin maintenance may therefore contribute to the formation of tomacula and subsequent demyelination.

Influenza A encephalitis with movement disorder.

Influenza A is an uncommon but well-recognized cause of viral encephalitis in childhood, occurring most commonly during community influenza outbreaks. The authors report four cases of influenza A encephalitis that occurred during an Australian epidemic in 1997-1998. Choreoathetosis during the acute phase of infection or basal ganglia involvement on neuroimaging was observed in three of the four patients. These findings in pediatric encephalitis are suggestive of influenza A infection and may guide investigation and early diagnosis.

A novel syndrome of episodic muscle weakness maps to xp22.3.

We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular musculature, as well as the trunk and limbs, and resolve spontaneously over a period of weeks to months. Younger members of the family are normal between episodes but during relapses show generalized weakness, ptosis, and fluctuations in strength. In some cases, fatigability can be demonstrated. The proband has late-onset chronic weakness and fatigability. The clinical phenotype has features suggestive both of the congenital myasthenic syndromes and of ion-channel disorders such as the periodic paralyses. We have localized the responsible gene to chromosome Xp22.3, with a maximum two-point LOD score of 4. 52 at a recombination fraction of.0, between OACA2 and DXS9985.

Drug therapy in juvenile dermatomyositis: follow-up study.

A series of 33 patients with juvenile dermatomyositis was reviewed in terms of their prognosis in relation to their drug therapy. This retrospective study was intended to help clarify the use of various therapies in this rare, heterogeneous disease from our hospital's experience in the last 24 years. The results confirmed that oral corticosteroids should remain the undisputed first line of treatment. For more refractory, chronic patients, the results suggest that azathioprine should be the favored drug of first choice (in addition to corticosteroids). There may be a role for cyclosporine as a "rescue" treatment, but this needs to be further defined.

X-linked Dystonia-Deafness syndrome.

We report a family with early-onset deafness and progressive dystonia exclusively involving males over two successive generations. There is also evidence of cognitive impairment and corticospinal tract involvement. The pedigree suggests an X-linked inheritance. A similar family was originally described by Scribanu and Kennedy. Tranebjaerg et al. have recently reported two other families with linkage to Xq22 and also proposed a novel X-linked candidate gene. These findings support the existence of a distinct neurodegenerative syndrome principally characterized by early-onset deafness and progressive dystonia. Neuropathology of one case showed a mosaic pattern of neuronal loss and gliosis in the caudate and putamen suggesting that this pattern is not restricted to XDP or Lubag.

Charcot-Marie-Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and connexin32 mutations (CMTX1).

The two most common subtypes of Charcot-Marie-Tooth (CMT) disease are CMT1A and CMTX1. To determine whether these different genetic entities display different morphological phenotypes we compared sural nerve biopsies of CMT1A patients due to PMP22 duplication with biopsies of CMTX1 patients with proven Connexin32 mutations. In CMT1A nerve biopsies we found a severe reduction in myelinated fiber density, hypermyelination as well as demyelination, and a high percentage of onion bulb formations. CMTX1 nerve biopsies showed significant differences: a higher myelinated fiber density, thinner myelin sheaths, more cluster formations, and only few onion bulb formations. Teased fibers studies in CMT1A patients showed features of demyelination and/or remyelination in almost all fibers. In contrast, teased fibers of CMTX1 patients were uniformly thinly myelinated with 5-10% active axonal degeneration and 15% segmental demyelination. Median nerve motor conduction velocities were significantly faster in CMTX1 patients (31.6+/-5.5 m/s) than in CMT1A patients (18.2+/-6.9 m/s). The possible roles of PMP22 and Connexin32 in the pathogenesis of CMT are discussed.

Clinical and neurophysiological features of tick paralysis.

The clinical and neurophysiological findings in six Australian children with generalized tick paralysis are described. Paralysis is usually caused by the mature female of the species Ixodes holocyclus. It most frequently occurs in the spring and summer months but can be seen at any time of year. Children aged 1-5 years are most commonly affected. The tick is usually found in the scalp, often behind the ear. The typical presentation is a prodrome followed by the development of an unsteady gait, and then ascending, symmetrical, flaccid paralysis. Early cranial nerve involvement is a feature, particularly the presence of both internal and external ophthalmoplegia. In contrast to the experience with North American ticks, worsening of paralysis in the 24-48 h following tick removal is common and the child must be carefully observed over this period. Death from respiratory failure was relatively common in the first half of the century and tick paralysis remains a potentially fatal condition. Respiratory support may be required for > 1 week but full recovery occurs. This is slow with several weeks passing before the child can walk unaided. Anti-toxin has a role in the treatment of seriously ill children but there is a high incidence of acute allergy and serum sickness. Neurophysiological studies reveal low-amplitude compound muscle action potentials with normal motor conduction velocities, normal sensory studies and normal response to repetitive stimulation. The biochemical structure of the toxin of I. holocyclus has not been fully characterized but there are many clinical, neurophysiological and experimental similarities to botulinum toxin.

Vestibular abnormalities in charge association.

We report the vestibular abnormalities in 5 patients with the CHARGE association (Coloboma, Heart disease, Atresia of choanae, Retarded growth and development and/or central nervous system anomalies, Genital hypoplasia, and Ear anomalies). All patients had absent vestibular function as indicated by absent vestibulo-ocular reflexes and severe imbalance on simultaneous deprivation of proprioception and vision, as well as delayed motor development. All 6 semicircular canals were aplastic in each of the patients. While cochlear function was severely reduced in 6 of the 10 ears, it was absent only in 3 ears and was actually intact below 3 kHz in 1 ear. All 10 bony cochleas were present on computed tomography, and although 7 appeared abnormal, 3 appeared normal. This study confirms that absence of the bony semicircular canals in the presence of a bony cochlea is a characteristic finding in CHARGE association. It also demonstrates that these disproportionate structural abnormalities are reflected in the functional abnormalities: absent vestibular function with preservation of some cochlear function.

Hereditary neuropathies in children: the contribution of the new genetics.

Although the prevalence of the hereditary motor and sensory neuropathies in childhood is not clearly established and the age of presentation may overlap the arbitrary boundary between pediatric and adult neurology, the recent explosion of genetic information regarding these conditions has completely altered our understanding and classification of these diseases. The current status of our understanding of the molecular basis of the hereditary neuropathies which might present in childhood is reviewed. The impact of this information on our concepts of the mechanisms operative in the production of the clinical signs and symptoms in these diseases is discussed.