Survival analysis and life expectancy of pediatric patients with spinal muscular atrophy in Thailand.

Background: Survival data for Thai patients with 5q spinal muscular atrophy (SMA), the leading cause of infant mortality worldwide, are lacking. Objective: This study aimed to determine the survival rates and life expectancies of pediatric patients with SMA types 1, 2, and 3. Methods: We conducted a retrospective cohort analysis of genetically confirmed 5q SMA patients aged 0-18 years who were treated between 1999 and 2021 at the pediatric neuromuscular clinic of Siriraj Hospital, Bangkok, Thailand. Mortality data were sourced from the Civil Registration Office. Results: The study included 113 patients: 37 with SMA type 1, 53 with type 2, and 23 with type 3. Life expectancy varied significantly by SMA type: 2.2 years for type 1, 11 years for type 2, and 16.5 years for type 3. The median survival times for SMA type 1 and 2 were 1.9 and 19 years, respectively. In SMA type 2, early onset (<1 year) correlated with a shorter median survival than later onset (≥1 year) (log-rank test P = 0.009). Early onset SMA type 2 had a median survival time of 15.9 years, while 75 % of those with later onset SMA type 2 survived until the age of 19 years. Cox proportional hazards analysis revealed that each month's delay in disease onset reduced the annual mortality risk by 17 % for type 1 patients and by 20 % for type 2 patients. Compared with female patients, male patients with type 2 disease had a 12-fold increased mortality risk. Conclusions: Age at onset is a significant predictor of survival and life expectancy in patients with SMA types 1 and 2. These insights are crucial for genetic counseling and prognostic discussions in clinical settings.

Gene Distribution in Pediatric-Onset Inherited Peripheral Neuropathy: A Single Tertiary Center in Thailand.

BACKGROUND: Inherited peripheral neuropathy presents a diagnostic and therapeutic challenge due to its association with mutations in over 100 genes. This condition leads to long-term disability and poses a substantial healthcare burden on society. OBJECTIVE: This study aimed to investigate the distribution of genes and establish the genotype-phenotype correlations, focusing on pediatric-onset cases. METHODS: Exome sequencing and other analytical techniques were employed to identify pathogenic variants, including duplication analysis of the PMP22 gene. Each patient underwent physical examination and electrophysiological studies. Genotypes were correlated with phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. RESULTS: We identified 35 patients with pediatric-onset inherited peripheral neuropathy. Pathogenic or likely pathogenic variants were confirmed in 24 out of 35 (68.6%) patients, with 4 of these variants being novel. A confirmed molecular diagnosis was achieved in 90.9% (10/11) of patients with demyelinating Charcot-Marie-Tooth disease (CMT) and 56.3% (9/16) of patients with axonal CMT. Among patients with infantile-onset CMT (≤2 years), the most common causative genes were MFN2 and NEFL, while GDAP1 and MFN2 were frequent causes among patients with childhood- or adolescent-onset CMT (3-9 years). CONCLUSIONS: The MFN2 gene was the most commonly implicated gene, and the axonal type was predominant in this cohort of Thai patients with pediatric-onset inherited peripheral neuropathy.

Long-read Nanopore sequencing identified D4Z4 contractions in patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder caused by abnormal expression of the DUX4 protein, commonly resulting from a contraction of D4Z4 repeat units with the presence of a polyadenylation (polyA) signal. More than 10 units of the D4Z4 repeat, with a length of 3.3 kb per unit, are typically required to silence DUX4 expression. Consequently, molecular diagnosis of FSHD is challenging. We used Oxford Nanopore technology to perform whole-genome sequencing of seven unrelated patients with FSHD, their six unaffected parents, and 10 unaffected controls. All seven patients were successfully identified to harbor one to five D4Z4 repeat units and the polyA signal, whereas none of the 16 unaffected individuals met the molecular diagnostic criteria. Our newly developed method provides a straightforward and powerful molecular diagnostic tool for FSHD.

Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum.

Muscular dystrophies and congenital myopathies are heterogeneous groups of inherited muscular disorders. An accurate diagnosis is challenging due to their complex clinical presentations and genetic heterogeneity. This study aimed to determine the utilisation of exome sequencing (ES) for Thai paediatric patients with muscular disorders. Of 176 paediatric patients suspected of genetic/inherited myopathies, 133 patients received a molecular diagnosis after performing conventional investigations, single gene testing, and gene panels. The remaining 43 patients from 42 families could be classified into three groups: Group 1, MLPA-negative Duchenne muscular dystrophy (DMD) with 9 patients (9/43; 21%), Group 2, other muscular dystrophies (MD) with 18 patients (18/43; 42%) and Group 3, congenital myopathies (CM) with 16 patients (16/43; 37%). All underwent exome sequencing which could identify pathogenic variants in 8/9 (89%), 14/18 (78%), and 8/16 (50%), for each Group, respectively. Overall, the diagnostic yield of ES was 70% (30/43) and 36 pathogenic/likely pathogenic variants in 14 genes were identified. 18 variants have never been previously reported. Molecular diagnoses provided by ES changed management in 22/30 (73%) of the patients. Our study demonstrates the clinical utility and implications of ES in inherited myopathies.

Health-related quality of life in Thai children with spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a chronic genetic disease that causes varying degrees of disability. There is currently no data specific to the health-related quality of life (HRQoL) of Thai children and adolescents with SMA. Accordingly, this study aimed to evaluate the HRQoL of Thai pediatric SMA, and to identify factors significantly associated with HRQoL and other aspects of quality of life. The findings of this study will help to improve overall care in this vulnerable pediatric population. METHODS: This prospective cross-sectional descriptive study was conducted at the Division of Neurology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand during 2015-2018. HRQoL was measured using the Thai language version of the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scale (PedsQL™). The PedsQL™ was administered to SMA children aged 2-18 years and their parents. Disease severity was evaluated by pediatric neurologists, and patients were classified according to their SMA subtype. RESULTS: Forty-two Thai pediatric SMA (mean age: 9.8 ± 5.0 years, 25 males) and their families were recruited. The mean PedsQL™ total score was 57.3 ± 13.6 by child self-report, and 54.3 ± 14.8 by parent proxy-report. The PedsQL™ scores of Thai SMA children were found to be significantly lower than those reported in healthy Thai children. The mean PedsQL™ total score among healthy Thai children was 78.7 ± 9.3 by child self-report, and 79.0 ± 12.8 by parent proxy-report. Factors independently associated with lower HRQoL were non-ambulation, household income less than 18,500 Thai baht/month, mechanical ventilation, and inability to attend school. CONCLUSION: HRQoL score was found to be an accurate reflection of patient and parent perception of SMA, which suggests the value of this tool for prioritizing interventions to improve the quality of life of Thai SMA. The results of this study also provide a baseline measurement of quality of life among Thai SMA.

Prognostic model for time to achieve independent walking in children with Guillain-Barré syndrome.

BACKGROUND: Guillain-Barré Syndrome (GBS) is an immune-mediated peripheral neuropathy. Clinical features and outcomes in children differ from adults. Currently, there is no prognostic model to predict outcomes in children and existing models for adults are not suitable. OBJECTIVES: To identify factors that are associated with outcomes and develop clinical model to predict time to independent walking in children with GBS. METHODS: Between 2005 and 2018, 41 patients with GBS were identified by retrospective chart review. Factors associated with independent walking were analyzed with the Kaplan-Meier method. A prediction model was developed based on regression coefficients from Cox's proportional hazard model. RESULTS: The disability score at maximum weakness and nerve conduction study results were associated with independent walking and included in the model. Scores range from 0 to 5. A score of 5 predicts 34 days to independent walking while a score of 0 predicts 5 months (mean 158 days, p = 0.008). CONCLUSION: This scoring system for pediatric patients provides predicts the time needed to achieve independent walking, an important milestone of recovery for communication with parents, and to assist clinicians to optimize treatment. Further studies of predictive factors and external validation are needed to improve precision of the model. IMPACT: This is the first study to create a prognostic scoring system for individual outcomes in children with GBS. A clinical prognostic model can predict time to achieve independent walking in individual pediatric patients with GBS. This model can assist clinicians to optimize treatment and guide decisions on rehabilitation to prevent long-term disability.

Polyneuritis Cranialis Associated with BNT162b2 mRNA COVID-19 Vaccine in a Healthy Adolescent.

A 16-year-old Thai girl developed right facial palsy, a lower motor neuron lesion, and numbness 3 h after receiving the first dose of the BNT162b2 mRNA vaccine. Neurological examination showed the involvement of the right cranial nerves (CN) V, VII, IX, and X. Electrophysiological tests revealed the absence of an F wave response, suggesting a proximal demyelinating process. Magnetic resonance imaging of the brain demonstrated abnormal enhancement of the right CN VII. The cerebrospinal fluid profile on day 7 after the onset of symptoms was normal. The patient was diagnosed with polyneuritis cranialis, a rare variant of Guillain-Barre syndrome. She was successfully treated with intravenous immunoglobulin therapy.

Congenital myasthenic syndromes in the Thai population: Clinical findings and novel mutations.

Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of genetic disorders of the neuromuscular junction. Next generation sequencing has been increasingly used for molecular diagnosis in CMS patients. This study aimed to identify the disease-causing variants in Thai patients. We recruited patients with a diagnosis of CMS based on clinical and electrophysiologic findings, and whole exome sequencing was performed. Thirteen patients aged from 2 to 54 years (median: 8 years) from 12 families were enrolled. Variants were identified in 9 of 13 patients (69%). Five novel variants and two previously reported variant were found in the COLQ, RAPSN and CHRND gene. The previously reported c.393+1G>A splice site variant in the COLQ gene was found in a majority of patients. Five patients harbor the homozygous splice site c.393+1G>A variant, and two patients carry compound heterozygous c.393+1G>A, c.718-1G>T, and c.393+1G>A, c.865G>T (p.Gly289Ter) variants. The novel variants were also found in RAPSN (p.Cys251del, p.Arg282Cys) and CHRND (p.Met481del). Molecular diagnosis in CMS patients can guide treatment decisions and may be life changing, especially in patients with COLQ mutations.

Genotype and age at diagnosis in Thai boys with Duchenne muscular dystrophy (DMD).

Gene-based therapy is a treatment for Duchenne muscular dystrophy (DMD) has become lately available; limited use for specific of mutation and percentages of the patients. Diagnosis in Thailand is made by muscle biopsy or multiplex ligation-dependent probe amplification (MLPA). Appropriate treatment in developing countries is difficult because gene sequencing is expensive and has limited availability. We aimed to identify the clinical and genetic characteristics of Thai DMD. Patients aged 0-22 years were recruited from the pediatric neuromuscular clinic of Siriraj Hospital during 2017-2019. Ninety-four charts were reviewed for clinical and laboratory data. Patients with negative MLPA who underwent next generation sequencing were consented. The mean age at onset and diagnosis was 4 and 7 years, respectively. Approximately 70% of patients had loss of ambulation by the mean age of 9.6 ±â€¯1.8 years. Eighty percent were treated with glucocorticoids. Genetic testing was performed in 70 patients. Molecular analysis revealed mutations in 90% of cases, including exon deletions in 48.57%, nonsense mutations in 20%, frameshift mutations in 12.86%, splice site in 7.14%, exon duplications in 5.71%, and in-frame deletion in 2.86%. Gene sequencing should be performed because baseline genetic mutation data is essential for gene-based therapies that will become available in the future.

Reliability and validity of the Thai pediatric quality of life inventory™ 3.0 neuromuscular module.

BACKGROUND: Neuromuscular disorders (NMDs) are chronic illnesses that adversely impact the lives of patients and their families. The Pediatric Quality of Life™ 3.0 Neuromuscular Module (PedsQL™ 3.0 NMM) was designed to assess health-related quality of life (HRQoL) among children with NMDs. The objective of this cross-sectional study is to evaluate the reliability and validity of the PedsQL™ 3.0 NMM Thai version. METHODS: Formal permission to translate the PedsQL™ 3.0 NMM into Thai language was granted by the inventor, and the translation process followed linguistic translation guidelines. The PedsQL™ 3.0 NMM Thai version was administered to children with NMD and their parents/caregivers at the Division of Neurology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Re-test was performed within 2-4 weeks after the initial test. RESULTS: One hundred and three children with NMD and their parents or caregivers were enrolled. Internal reliability as measured by Cronbach's alpha was > 0.7 (total score: child α = 0.88, parent α = 0.91). Test-retest reliability showed good agreement with an intraclass correlation coefficient (ICC) of 0.69 and 0.82 for the total score of the child report and the parent report, respectively. The mean (SD) quality of life total score for the child self-report was 74.9 (13.9) among ambulatory patients, and 60.7 (15.2) among non-ambulatory patients (maximum quality of life score is 100). The mean total quality of life score for the parent proxy-report was 70 (14.5) among ambulatory patients, and 55.2 (18.3) among non-ambulatory patients. The child total score was in good agreement with the parent/caregiver total score. CONCLUSIONS: PedsQL™ 3.0 NMM Thai version is a reliable and valid measure of HRQoL in Thai children with NMDs.

Case series: Childhood Charcot-Marie-Tooth: Predominance of axonal subtype.

Case series reports on clinical features of pediatric hereditary neuropathy in Thailand is scarce. Subtype and clinical presentation in childhood-onset CMT differ from adult-onset. The aim of this study is to investigate the CMT phenotype in Thai children. We retrospectively reviewed children diagnosed with CMT who followed up with Pediatric Neurology, Siriraj Hospital from January 1999 to June 2016. CMT subtypes determined by clinical presentation and neurophysiologic studies. Mutation analysis of PMP22 genes was performed in all demyelinating cases. The disease burden was assessed by CMT Neuropathy Score version 2 (CMTNSv2), CMT Examination Score (CMTES) and CMT Pediatric Scale (CMTPedS). 30 patients from 29 families with Hereditary Neuropathies, 25 diagnosed with CMT and 5 with HSAN. 8-year-old was the average age at first medical visit with disease-related problems. Twenty (67%) were male. Twenty-three were sporadic (77%). 16.7% was autosomal dominant and 6.7% was autosomal recessive. Clinical presentations in CMT children were walking difficulty and foot deformities. Nine (36%) CMT patients had demyelinating and sixteen (64%) had axonal. Forty percent had a history of delayed walking after 15-month-old. Foot deformities presented in all CMT patients, and twelve had foot surgery. 2 axonal CMT patients were wheelchair-dependence. Mean (SD) CMTNSv2, CMTES and CMTPedS were 15.44(9), 11.05(7) and 34(4) respectively. Our findings suggest Thai CMT children are predominantly axonal type. Patients with low socioeconomic status and mild symptoms may not seek healthcare. International collaboration in genetic testing is crucial in diagnosis and initiation of clinical trials in future.

Concurrent positive anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase antibody with reducing body myopathy: Possible double trouble.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy is less common in children but has been associated with more favorable prognosis than adult patients after immunotherapies. We report anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody positivity in a 6-year-old boy with progressive muscle weakness, scoliosis, spinal rigidity, multiple joint contractures, mild left ventricular hypertrophy, and elevated serum creatine kinase. In contrast to most of previously reported pediatric anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, he showed little response to immunotherapies. Muscle biopsy contained changes suggestive of myofiber necrosis and regeneration and reducing bodies. The diagnosis of reducing body myopathy was later confirmed by reported c.368A>G (p.His123Arg) mutation in the FHL1 gene. Although the level of association between these two conditions is still inconclusive, this is the first report of concurrent positive anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody with reducing body myopathy emphasizing the possibility of co-occurrence of immune mediated necrotizing myopathy and muscular dystrophy and importance of comprehensive diagnostic investigations in unusual cases.

Reliability and validity of the Thai version of the Pediatric Quality of Life inventory™ 3.0 Duchenne Muscular Dystrophy module in Thai children with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is the most common genetic neuromuscular disorder in children. This chronic illness may impact the physical, family, social and school life of affected children and their families. These impacts can be assessed using a disease-specific measure of health-related quality of life (HRQOL). The Pediatric Quality of Life Inventory™ (PedsQL™) 3.0 DMD Module is designed to assess quality of life in children with DMD. This study aimed to evaluate the reliability and validity of the Thai version of the PedsQL™ 3.0 DMD Module in Thai children aged 5-18 years. METHOD AND MATERIALS: The Thai translation of the PedsQL™ 3.0 Duchenne Muscular Dystrophy Module was performed in accordance with established guidelines using forward-back translation and was approved by the creator of the instrument. The Thai version of the scale was administered to children with DMD and their parents at the neuromuscular clinic at Siriraj Hospital and during the annual DMD Day meeting. Psychometric properties were established, and a re-test was performed within 2-4 weeks. RESULTS: Fifty-six children were enrolled. An acceptable level of internal reliability was achieved, as measured by α > 0.7 (total score: child report α = 0.88, parent report α = 0.92). Test-retest reliability showed good agreement, with the following intraclass correlation coefficients (ICCs) for the total score (calculated using all subscales from the child reports and parent reports): child report ICCs = 0.74 and parent report ICCs = 0.88. The mean total scale score was 66.03 for ambulatory children and 55.87 (P = 0.08) for non-ambulatory children according to child self-reports and 70.01 (ambulatory) and 54.29 (non-ambulatory) (P ≤ 0.01) according to parent proxy reports. The child self-reports were in acceptable agreement with the parent proxy reports for most subscales (ICC range 0.49-0.81). CONCLUSIONS: The PedsQL™ 3.0 DMD Module Thai version is a reliable and valid measure of disease-specific health-related quality of life in Thai children with Duchenne muscular dystrophy.

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.

Functional outcome measures for infantile Charcot-Marie-Tooth disease: a systematic review.

A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth (CMT) disease is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT-specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited "good" face, discriminant, convergent and concurrent validity, and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine-motor skills. Scoring of items ranged from 2- to 7-point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions.

Impact of muscle biopsy on diagnosis and management of children with neuromuscular diseases: A 10-year retrospective critical review.

BACKGROUND: Muscle biopsy facilitates morphologic, biochemical, and ultrastructural analysis of muscle for the purpose of making definitive neuromuscular diagnosis. However, muscle biopsy is an expensive, invasive, time-consuming, and resource-dependent procedure. The need for general anesthesia in children also increases the risks associated with this procedure. The aim of this study was to investigate the benefits of muscle biopsies performed over a 10-year period, with a focus on indications, suspected and histopathologic diagnosis, and impact on diagnosis and management decisions. METHODS: We retrospectively reviewed results of muscle biopsies performed in children at our center during the 2004 to 2014 study period. Clinical presentations, biopsy complications, pathologic results, and changes in management decision were reviewed and analyzed. RESULTS: Biopsies from 92 patients were included. Mean age of patients was 7.1years, and 66.3% were male. There were no perioperative complications, and definitive diagnosis was made in 74 patients. Regardless of whether pathologic changes were found or not, information gained from muscle biopsy significantly impacted prognosis and subsequent genetic counseling. CONCLUSIONS: Muscle biopsy is a safe and useful diagnostic tool in children suspected of having neuromuscular diseases, especially in those with muscle diseases. Definitive pathologic diagnosis helps to optimize treatment, counseling, and surveillance. THE TYPE OF STUDY AND LEVEL OF EVIDENCE: Study of diagnostic test: level 1.

Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene.

We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations.

Predictors of Abnormal Neuroimaging of the Brain in Children With Epilepsy Aged 1 Month to 2 Years: Useful Clues in a Resource-Limited Setting.

Neuroimaging should be performed on infants with seizure. However, there are economic limitations in performing neuroimaging in a resource-limited setting. The younger the age, the higher the risk of having abnormal neuroimaging. The aim was to determine frequency and predictors of abnormal neuroimaging in children with epilepsy aged 1 month to 2 years. History, physical examination, electroencephalogram (EEG), and neuroimaging were reviewed. Thirty-seven of 49 (76%) had neuroimaging studies; 19 computed tomography (CT), 14 magnetic resonance imaging (MRI), and 4 had both. Abnormal neuroimaging was found in 19 (51%). Predictors of abnormal neuroimages are developmental delay, abnormal head circumference, and abnormal neurologic examination. Eight children (21%) had lesions on neuroimaging studies that altered or influenced management. Of 8 patients with normal examination and EEG, 1 had a brain tumor and another had arteriovenous malformation. Neuroimaging should be considered as an essential aid in the evaluation of infants with epilepsy, even in a resource-limited setting.

Inclusion body myositis and sarcoid myopathy: coincidental occurrence or associated diseases.

Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy characterized by selective weakness of finger flexors and quadriceps muscles commonly refractory to treatment. Another chronic inflammatory disorder, sarcoidosis, commonly involves muscle. The comorbidity of inclusion body myositis and sarcoid myopathy is rare. We describe clinical and muscle biopsy findings of a patient with sarcoidosis and inclusion body myositis. A 66-year-old man presented with a 6-year history of progressive, asymmetrical and selective weakness of the quadriceps, biceps and finger flexor muscles; he had a remote history of pulmonary sarcoidosis. A quadriceps muscle biopsy revealed a chronic inflammatory myopathy with ubiquitinated inclusion bodies, rimmed vacuoles, expression of major histocompatibility complex class I, numerous COX-negative fibers and TDP-43 cytoplasmic aggregates (features of IBM) and multiple non-necrotizing granulomata (feature of sarcoidosis). Clinical and histopathologic features of the current illness suggested the patient had sarcoidosis with inclusion body myositis overlap. This patient may represent the coincidental occurrence of both idiopathic inflammatory disorders. Alternatively, sarcoidoisis may promote the development of inclusion body myositis by a similar immune-mediated pathophysiologic process.