Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Natural history of ankle function during gait in youth with Charcot-Marie-Tooth disease types 1 and 2.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) can cause progressive muscle weakness and contracture, leading to gait abnormalities such as increased and delayed peak ankle dorsiflexion and reduced ankle power generation in terminal stance. Understanding strength loss on ankle function during gait is important for interpreting treatment outcomes and evaluating new therapies designed to improve gait. RESEARCH QUESTION: Do ankle kinematics and kinetics vary as a function of age, disease progression with associated loss of muscle strength and CMT type in youth with CMT types 1 and 2? METHODS: A prospective convenience sample of 45 participants with CMT1 and 2, ages 7-22 years, underwent comprehensive gait analysis. Seventeen patients underwent repeat analyses totaling 67 tests. Generalized mixed effects linear modeling was used to compare CMT1 versus CMT2 and to examine the effects of age on ankle strength, range of motion, kinematics, and kinetics within each CMT type. RESULTS: Plantarflexor and dorsiflexor strength were less in CMT2 compared with CMT1 (p ≤ 0.05), while peak dorsiflexion in terminal stance (TST) was greater (p = 0.02). Peak plantarflexion moment and power generation were also less in CMT2 (p ≤ 0.02). In CMT1, peak dorsiflexion in TST increased with age through 13 years (p = 0.004); then plateaued in the normal range (p = 0.73). Peak ankle angle in mid-swing was closely related to the angle in TST (p < 0.001) following a similar pattern with age. In CMT2, no significant associations were observed between age, peak dorsiflexion in TST, and peak ankle angle in mid-swing (p ≥ 0.19). There were no consistent trends with age for individual patients with repeat tests. SIGNIFICANCE: The heterogeneity of joint level impairments and gait kinematics and kinetics point to the importance of having an in-depth understanding of gait at the individual patient level using comprehensive gait analysis including valid and reliable strength measures.

Stance and swing phase ankle phenotypes in youth with Charcot-Marie-Tooth type 1: An evaluation using comprehensive gait analysis techniques.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) results in muscle weakness and contracture leading to a wide variety of gait issues including atypical ankle kinematics in both stance and swing. Knowledge of the stance and swing phase kinematic patterns for CMT type 1 (CMT1), the most common CMT type, will improve our understanding of expected gait outcomes and treatment needs to improve gait function. RESEARCH QUESTION: What are the stance/swing phase ankle phenotypes in CMT1? METHODS: A prospective convenience sample of 25 participants with CMT1, ages 7-19 years, underwent comprehensive gait analysis following standard procedures. Ankle phenotypes based on peak ankle dorsiflexion in terminal stance and mid-swing were defined and compared using linear mixed models. RESULTS: Patients with CMT1 presented with three stance phase ankle phenotypes: 21 limbs (42 %) with reduced (mean 5°, SD 2°), 19 limbs (38 %) with typical (mean 11°, SD 1°) and 10 limbs (20 %) with excessive (mean 15°, SD 2°) peak dorsiflexion in terminal stance (p < 0.05). There were two swing phase phenotypes: 19 limbs (38 %) with typical (mean -1.7°, SD 1.5°) and 31 limbs (62 %) with excessive (mean -5.6°, SD 1.4°) plantarflexion in mid-swing (p < 0.002). Eleven patients (44 %) had ankles that were classified into different stance groups, and 9 patients (36 %) had ankles that were classified into different swing groups. The most common combination of stance/swing ankle phenotypes was decreased dorsiflexion in terminal stance with increased plantarflexion in mid-swing (16 sides, 32 %). SIGNIFICANCE: This study shows that youth with CMT1 have multiple combinations of combined ankle kinematics for stance and swing. The ankle phenotypes identified in this study reflect contributions of both dorsi/plantarflexor weakness and plantarflexor contracture, which require different treatment approaches. Comprehensive gait analysis can distinguish between multiple ankle phenotypes to assist in determining the most appropriate treatment to improve gait for individual patients.

The impact of orthoses on gait in children with Charcot-Marie-Tooth disease.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) results in distal muscle weakness that leads to gait difficulties in both the stance and swing phases, thus limiting function in the community. A primary purpose of ankle foot orthoses (AFOs) is to improve gait function; however, little is known about what AFOs are prescribed and how they benefit children with CMT. RESEARCH QUESTION: To determine the impact of previously prescribed AFOs on gait in children with CMT using comprehensive gait analysis techniques. METHODS: We examined strength, passive range of motion and gait (kinematics, kinetics and temporal-spatial) for barefoot and AFO walking on 15 children with a diagnosis of CMT. Participants used their prescribed AFOs, the design of which varied depending on the patient. Comparisons between barefoot and AFO walking were completed for selected ankle, knee and hip kinematics and kinetics and temporal-spatial parameters. Subgroups were also evaluated based upon specific ankle kinematics relevant to AFO prescription. RESULTS: AFOs resulted in increased walking velocity (0.91, SD 0.31 to 1.13, SD 0.23 m/sec, p = 0.001) and improved ankle kinematics (dorsiflexion in mid-swing: -11, SD 10 to 0, SD 5 degrees, p = 0.0001) and kinetics (peak plantar flexor moment in stance: 0.71, SD 0.30 to 0.85, SD 0.29 Nm/kg, p = 0.001). In patients with increased equinus in swing, AFOs resulted in improved ankle kinematics. In patients with increased dorsiflexion in terminal stance, AFOs did not provide the support that was needed to improve gait function. SIGNIFICANCE: AFOs enhance gait function in children with CMT by improving walking velocity and selected ankle kinematics and kinetics. It is important that the AFO design be aligned with the patient's specific joint level impairment and associated gait dysfunction. Comprehensive gait analysis techniques can measure differences between barefoot and AFO function and help to clarify the most appropriate AFO prescription for an individual child.

Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study.

INTRODUCTION: The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies. METHODS: Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study. RESULTS: Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level. DISCUSSION: Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.

Medical management of muscle weakness in Duchenne muscular dystrophy.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens. METHODS: A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach. RESULTS: Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid. DISCUSSION: The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects.

Changes in walking velocity and stride parameters with age in children with Charcot-Marie-Tooth disease.

The purpose of this study is to assess how Charcot-Marie-Tooth disease, a group of inherited peripheral neuropathies that result in distal weakness, affects walking velocity over time in comparison to age-matched controls. Comprehensive gait analysis of 57 children (mean age 12.0, SD 3.7 years) compared to 76 age-matched controls (mean age 10.1, SD 3.4 years) demonstrated slower walking velocity (p<0.001) due to both shorter stride length (p<0.001) and diminished cadence (p=0.01). There was higher walking velocity (p<0.001), stride length (p=0.002) and cadence (p<0.001) in patients with dorsiflexor strength ≥3 and higher walking velocity (p=0.001) and cadence (p=0.03) in patients plantar flexor strength ≥4. Analysis of Charcot-Marie-Tooth type 1 and type 2 subgroups showed that walking velocity increased significantly with age in controls (p=0.001) but did not increase in children with either subtype (p>0.54). Stride length increased significantly with age in all groups (p<0.001) but at a slower rate in type 1 and 2 compared to controls. These differences contributed to increasing deficits in walking velocity and stride length with age in type 1 and 2 in comparison to controls, with deficits appearing earlier in type 2. Since the slower walking velocity in children with Charcot-Marie-Tooth disease is primarily due to short stride length, treatments that enable improved stride length, such as plantar flexor strengthening and bracing, may improve walking velocity and associated gait function.

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores.

OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9). CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.

Comparison of gait patterns and functional measures between Charcot-Marie-Tooth disease type I and II in children to young adults.

INTRODUCTION: Charcot-Marie-Tooth (CMT) disease is an inherited peripheral neuropathy that causes progressive distal extremity nerve degeneration and muscle atrophy which can negatively impact function, gait and quality of life. The purpose of this study was to determine if differences exist in gait patterns, clinical examination and functional measures between CMT type I (CMT1) and type II (CMT2) in childhood to young adults. It was hypothesized that individuals with CMT2 would present with greater ankle weakness, increased and/or prolonged ankle dorsiflexion in stance during gait and demonstrate greater disease severity on the CMT Pediatric Scale (CMTPedS) compared to CMT1. METHODS: Twenty-seven individuals diagnosed with CMT1 or CMT2 underwent three-dimensional gait analysis, clinical examination and evaluation of disease severity using the CMTPedS. Subjects groups were divided based on CMT type: CMT1 (n = 20) and CMT2 (n = 7). RESULTS: CMT2 group presented with a trend towards increased plantar flexion weakness compared to CMT1 of 61.1 ±â€¯58.1 N to 137.9 ±â€¯51.4 N (p < 0.012), respectively. CMT2 presented with significantly decreased dorsiflexion strength, 31.9 ±â€¯30.9 N, compared to CMT1, 80.4 ±â€¯37.4 N, (p < 0.0052) which negatively influenced gait patterns in CMT2. Associated gait findings demonstrated CMT2 group with significantly decreased peak ankle power generation in stance compared to CMT1 (1.46 ±â€¯0.39 W/kg to 3.13 ±â€¯0.98 W/kg respectively) (p < 0.0001). CMT1 was more likely to demonstrate a dorsiflexion moment in loading response than CMT2. There was a consistent trend of a higher score and therefore greater disease severity for CMT2 based on CMTPedS. CONCLUSION: Study results suggest that at a given age, individuals with CMT2 have greater limitations in terms of gait function and disease severity than individuals with CMT1. Overall the CMT2 was shown to have greater gait limitations at the ankle during stance and swing with associated compensatory mechanisms at the knee and hip in swing.

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

Development and validation of the Charcot-Marie-Tooth Disease Infant Scale.

Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Fever-Induced Paroxysmal Weakness and Encephalopathy, a New Phenotype of ATP1A3 Mutation.

BACKGROUND: We identified a group of patients with ATP1A3 mutations at residue 756 who display a new phenotype, distinct from alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndromes. METHODS: Four patients with c.2267G>A (R756H) mutations from two families and two patients with c.2267G>T (R756L) mutations from one family are described and compared with the previously reported patients with mutations resulting in R756H and R756C protein variants. RESULTS: Patients with ATP1A3 R756H have onset in childhood of infrequent, fever-triggered paroxysms of encephalopathy and weakness with slowly improving but persistent deficits. Motor findings of weakness are mostly generalized, and patients may also have bulbar or oculomotor problems. Longer-term outcomes range from mild motor apraxia with near-normal function to persistent dysphagia, dysarthria, cognitive deficit, motor apraxia, and inability to walk because of ataxia. Patients with ATP1A3 R756L have a similar phenotype that includes paroxysmal, stepwise progression of ataxia associated with infections. CONCLUSIONS: ATP1A3 mutations affecting residue 756 result in a clinical syndrome, separate from those associated with previously described ATP1A3 mutations, which consists chiefly of fever-induced paroxysmal weakness and encephalopathy (FIPWE). Patients with R756L and R756C protein variants display more prominent ataxia, overlapping with the relapsing encephalopathy with cerebellar ataxia syndrome previously described in a patient with the c.2266C>T (R756C) mutation. All patients reported with mutations at residue 756 to date have had a similar episodic course and clinical features. Patients with mutations of ATP1A3 residue 756 appear to have a distinct clinical phenotype compared with patients with other ATP1A3 mutations, with fever-induced encephalopathy as key differentiating feature.

Mitochondrial Membrane Protein-Associated Neurodegeneration Mimicking Juvenile Amyotrophic Lateral Sclerosis.

BACKGROUND: Mitochondrial membrane protein associated neurodegeneration (MPAN) is the third most common subtype of neurodegeneration with brain iron accumulation (NBIA) and caused by mutations of the orphan gene C19ORF12 encoding a transmembrane mitochondrial protein. Like other NBIA disorders, the hallmark of neuropathology is iron deposition in the basal ganglia, but the clinical presentation is highly variable. METHODS: We present the relevant clinical history, neurological examination, electrophysiological and neuroimaging tests of a currently ten-year-old girl. The genetic analysis was carried out by exome sequencing focused on known NBIA and juvenile amyotrophic lateral sclerosis (ALS) genes. RESULTS: The patient presented at four years of age with progressive lower extremity weakness and generalized hypotonia. She was initially diagnosed with juvenile ALS based on clinical signs, negative brain magnetic resonance imaging (MRI) and electromyography findings. As the disease progressed, a repeat brain MRI showed iron deposition in the basal ganglia at nine years of age. Exome sequencing of genes known to be associated with NBIA revealed a compound heterozygous mutation of C19ORF12 gene. CONCLUSIONS: A C19orf12 gene mutation should be considered in young children with clinical signs of progressive upper and lower motor neuron disease. Finding iron accumulation in the basal ganglia helps to focus the genetic testing, but it may not be apparent for several years.

Pediatric Charcot-Marie-Tooth disease.

Heritable diseases of the peripheral nerves (Charcot-Marie-Tooth disease [CMT]) affect the motor units and sensory nerves, and they are among the most prevalent genetic conditions in the pediatric patient population. The typical clinical presentation includes distal muscle weakness and atrophy, but the severity and progression are largely variable. Improvements in supportive treatment have led to better preservation of patients' motor functions. More than 80 genes have been associated with CMT. These genetic discoveries, along with the developments of cellular and transgenic disease models, have allowed clinicians to better understand the disease mechanisms, which should lead to more specific treatments.

Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.