Pipis et al . describe the characteristics and longitudinal follow-up of 225 patients with Charcot-Marie-Tooth disease type 2A, caused by mutations in MFN2 . They describe how different mutations affect disease onset and rate of progression and identify sensitive clinical assessments that can be used for disease monitoring.

Background: Nephropathic cystinosis is a lysosomal storage disorder. Patient survival years after renal transplantation has revealed systemic complications including distal myopathy and dysphagia. Methods: We evaluated 20 adult patients with nephropathic cystinosis using patient-reported and clinical outcome measures. Standard motor measures, video fluoroscopy swallow studies, and tests of respiratory function were performed. We also used Rasch analysis of an initial survey to design a 16-item survey focused on upper and lower extremity function, which was completed by 31 additional patients. Results: Distal myopathy and dysphagia were common in patients with nephropathic cystinosis. Muscle weakness ranges from mild involvement of intrinsic hand muscles to prominent distal greater than proximal weakness and contractures. Conclusions: In addition to further characterization of underlying dysphagia and muscle weakness, we propose a new psychometrically devised, disease specific, functional outcome measures for distal myopathy in patients with nephropathic cystinosis. K E Y W O R D S distal myopathy, dysphagia, nephropathic cystinosis, outcome measures, psychometrics

Background: Nephropathic cystinosis is a lysosomal storage disorder with late-onset systemic complications, such as myopathy and dysphagia. Currently employed outcome measures lack sensitivity and responsiveness for dysphagia and myopathy, a limitation to clinical trial readiness. Methods: We evaluated 20 patients with nephropathic cystinosis in two visits over the course of a year to identify outcomes sensitive to detect changes over time. Patients also underwent an expiratory muscle strength training program to assess any effects on aspiration and dysphagia. Results: There were significant differences in the Timed Up and Go Test (TUG) and Timed 25-Foot Walk (25-FW) between baseline and 1-y follow-up (P < .05). Maximum expiratory pressure (MEP) and peak cough flow (PCF) significantly improved following respiratory training (P < .05). Conclusions: Improved respiratory outcomes may enhance patients ability to expel aspirated material from the airway, stave off pulmonary sequelae associated with chronic aspiration, and yield an overall improvement in physical health and wellbeing.

Objective To characterize the prevalence, onset, and burden of urinary and bowel dysfunction in adult patients with adrenoleukodystrophy (ALD) and to evaluate any sex differences in symptom presentation. Methods In this retrospective and prospective study, we performed medical record review (n = 103), analyzed the results of clinically indicated urodynamic testing (n = 11), and developed and distributed a symptom and quality of life (QOL) survey (n = 59). Results Urinary and bowel symptoms are highly prevalent in both males (75.0%) and females (78.8%) in this population, most commonly urinary urgency, often leading to incontinence. Time to onset of first urinary or bowel symptom occurs approximately a decade earlier in males. Seventy-two percent of symptomatic patients report a limitation to QOL. Urodynamic evaluation provides evidence of three distinct mechanisms underlying lower urinary tract dysfunction: involuntary detrusor contractions (indicating uncontrolled neuronal stimulation with or without leakage), motor underactivity of the bladder, and asynergy between detrusor contraction and sphincter relaxation. Conclusions Beyond gait and balance difficulties, urinary and bowel symptoms are common in adults with ALD and impair QOL. Males are affected at a younger age but both sexes experience a higher symptom burden with age. As this population also experiences gait and balance impairment, patients with ALD are more vulnerable to urinary urgency leading to incontinence. Urodynamic evaluation may help better elucidate the pathophysiologic mechanisms underlying neurogenic lower urinary tract dysfunction, which can allow more targeted treatment.

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Introduction/Aims: Nephropathic cystinosis is a lysosomal storage disorder with known myopathic features, including dysphagia. Evaluation of oropharyngeal swallowing physiology can be standardized using the Modified Barium Swallow Impairment Profile (MBSImP), a validated assessment tool used to analyze and rate swallowing across 17 distinct physiologic domains. Our objective was to better characterize swallowing impairments in nephropathic cystinosis using MBSImP analysis. Methods: We retrospectively evaluated 40 video fluoroscopic swallowing studies performed at two time points over 1 y in patients with nephropathic cystinosis with various levels of oral and pharyngeal stage dysphagia. Patients completed two selfadministered dysphagia outcome measures (the M. D. Anderson Dysphagia Inventory [MDADI] and the 10-item Eating Assessment Tool [EAT-10]).Results: We demonstrated oral stage and pharyngeal stage dysphagia across domains that impacted bolus control, transit, and clearance through both the oral cavity and pharyngeal lumen. Also captured were deficits related to onset and completeness of laryngeal closure that impact airway protection during swallow. There were significant correlations between pharyngeal total score and EAT-10 (r = 0.5, p < 0.001) and between oral total score and EAT-10 (r = 0.7, p < 0.001), MDADI-e (r = À0.6, p < 0.001), MDADI-p (r = À0.5, p < 0.001) and MDADI-c (r = À0.6, p < 0.001).There were no differences in oral or pharyngeal total scores across the 1-y time span.Discussion: This study identifies oral and pharyngeal stage dysphagia as crucial to patients with nephropathic cystinosis and paves the path for future studies of treatment targets.

Context Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. Objective To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. Design We conducted a retrospective medical chart review of pediatric patients with ALD. Setting All patients were seen in a leukodystrophy clinic in an academic medical center. Patients We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). Main Outcome Measures We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. Results Thirty-one (27%) patients were diagnosed with ALD by NBS and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9,12.12] months vs 6.05 [3.74,8.35] years) (p&lt;0.001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. Conclusions Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.