E Pagliano

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

Background The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. Methods We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). Results 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. Conclusions Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. Clinical trial registration ID number NCT01193075.

Sleep disorders in children with cerebral palsy: neurodevelopmental and behavioral correlates

OBJECTIVES We aimed to estimate the frequency of sleep disorders in children with cerebral palsy (CP) using the Sleep Disturbance Scale for Children (SDSC) and to evaluate the relations between sleep disorders and motor, cognitive, and behavioral problems. METHODS One hundred and sixty-five children with CP ages 6-16 years (mean age, 11years) were assessed using the SDSC, the Gross Motor Function Classification System (GMFCS), the Wechsler Intelligence Scale for Children and the Child Behavior Check List (CBCL) to assess sleep, motor, cognitive, and behavioral problems, respectively. RESULTS An abnormal total sleep score was found in 19% of children with CP; more than 40% of children had an abnormal score on at least one SDSC factor. The SDSC total score was significantly associated (P<.01) with mental retardation, epilepsy, CBCL scores, and level 5 on the GMFCS. CONCLUSIONS Our results confirm that sleep disorders are common in children with cerebral palsy. The relationship between motor and cognitive behavior and epilepsy should be further explored to better understand how these factors influence one another to identify effective treatments and to improve the well-being of the child.

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease

IMPORTANCE Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. OBJECTIVE To assess the variability of disease severity in a large cohort of children and adolescents with CMT. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. MAIN OUTCOMES AND MEASURES Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). RESULTS Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity. CONCLUSIONS AND RELEVANCE These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials.

Novel mutations in the GDAP1 gene in patients affected with early-onset axonal Charcot-Marie-Tooth type 4A

We report a detailed study of eight patients from four Italian families presenting with autosomal recessive axonal Charcot-Marie-Tooth disease (AR-CMT2), characterized by early-onset and progressive severe weakness of all limbs. Vocal cord paresis was present in two cases. Sural nerve biopsy performed in three patients showed a severe neuropathy characterized by a predominant axonal involvement. Five novel mutations (p.Gln99stop, p.Gln122Lys, p.Arg125stop, p.Val219Asp, p.Asn297Lys) and one previously reported mutation (p.Leu239Phe) were identified in GDAP1 gene. GDAP1 mutations should be considered both in recessive and sporadic cases of early-onset axonal CMT.

Sleep disturbances in preschool age children with cerebral palsy: a questionnaire study

OBJECTIVES The study aimed to analyze (i) the prevalence of sleep disorders in pre-school children with cerebral palsy (CP) using the Sleep Disturbance Scale for Children (SDSC), (ii) the possible association with motor, cognitive and behavioral problems, and (iii) the possible differences with typically developing children matched for age and gender. METHODS One-hundred children with CP (age range: 3-5 years, mean: 3.8 years) were assessed using the SDSC, the Gross Motor Function Classification System (GMFCS), the Wechsler Preschool and Primary Scale of Intelligence, and the Child Behaviour Check List (CBCL) to assess sleep, motor, cognitive, and behavioral problems, respectively. Further 100 healthy children matched for age and sex were assessed using the SDSC. RESULTS An abnormal total sleep score was found in 13% of children with CP while 35% had an abnormal score on at least one SDSC factor. SDSC total score was significantly associated with pathological internalizing scores on CBCL and active epilepsy on multivariate analysis. CP group reported higher significant median scores on SDSC total, parasomnias, and difficulty in initiating and maintaining sleep factors. CONCLUSIONS In pre-school children sleep disorders are more common in children with CP than in healthy control group and are often associated with epilepsy and behavioral problems.

Transitioning outcome measures: relationship between the CMTPedS and CMTNSv2 in children, adolescents, and young adults with Charcot‐Marie‐Tooth disease

Long‐term studies of Charcot‐Marie‐Tooth (CMT) disease across the entire lifespan require stable endpoints that measure the same underlying construct (e.g., disability). The aim of this study was to assess the relationship between the CMT Pediatric Scale (CMTPedS) and the adult CMT Neuropathy Score (CMTNSv2) in 203 children, adolescents, and young adults with CMT. There was a moderate curvilinear correlation between the CMTPedS and the CMTNSv2 (Spearmans rho ρ = 0.716, p < 0.0001), although there appears to be a floor effect of the CMTNSv2 in patients with a milder CMT phenotype. Univariate analyses indicate that the relationship between the CMTPedS and CMTNSv2 scores improves with worsening disease severity and advancing age. Although one universal scale throughout life would be ideal, our data supports the transition from the CMTPedS in childhood to the CMTNSv2 in adulthood as a continuum of measuring lifelong disability in patients with CMT.

Efficacy of oral pharmacological treatments in dyskinetic cerebral palsy: a systematic review

To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP).

Natural history of Charcot-Marie-Tooth disease during childhood

To determine the rate of disease progression in a longitudinal natural history study of children with Charcot‐Marie‐Tooth (CMT) disease.

Development, Reliability and Validity of the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS)

Development, reliability and validity of the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS) Joshua Burns, Richard Finkel, Tim Estilow, Andy Hiscock, Matilde Laura, Polly Swingle, Agnes Patzko, Allan Glanzman, Gyula Acsadi, Francesco Muntoni, Mary Reilly, Davide Pareyson, Isabella Moroni, Emanuela Pagliano, Sindhu Ramchandren, Kate Eichinger, Monique Ryan, Robert Ouvrier, Michael Shy, Rosemary Shy

Two single cases treated by a new pseudoelastic upper-limb orthosis for secondary dystonia of the young

The study proposes a new treatment for dystonia based on a dynamic wearable orthosis equipped with metallic materials of non-linear mechanical characteristics. Two boys with upper-limb dystonia were enrolled, as well as six healthy children. Fully-customised devices were made for the patients. They used the orthosis for one month and their performances were evaluated before and after the treatment. The assessment was done with clinical scales (Modified Ashworth Score, Melbourne Upper Limb Assessment, PedsQL), interviews and optoelectronic kinematic analysis. Normal kinematics was obtained from the healthy group for comparison. Kinematic analysis showed modifications in motor patterns for both patients, with increases in the ranges of motion of initially stiff segments, improvements in posture, emergence of multi-joint strategies. Clinical scales did not always show similar trends in the two cases. The changes in control strategies could be linked to the force field dynamically applied by the device and appear to be learnable. This interpretation will be further tested with larger groups and longer treatments.