A diagnostic confidence scheme for CLN3 disease.

Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long-term natural history studies. Using genotype and phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3-PLUS. Phenotypes included the classical juvenile-onset syndromic phenotype, a "vision loss only" phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test-retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.

Low Psychosine in Krabbe Disease with Onset in Late Infancy: A Case Report.

Krabbe disease (KD) is a rare inherited neurodegenerative disorder caused by a deficiency in galactocerebrosidase enzyme activity, which can present in early infancy, requiring an urgent referral for hematopoietic stem cell transplantation, or later in life. Newborn screening (NBS) for KD requires identification and risk-stratification of patients based on laboratory values to predict disease onset in early infancy or later in life. The biomarker psychosine plays a key role in NBS algorithms to ascertain probability of early-onset disease. This report describes a patient who was screened positive for KD in New York State, had a likely pathogenic genotype, and showed markedly reduced enzyme activity but surprisingly low psychosine levels. The patient ultimately developed KD in late infancy, an outcome not clearly predicted by existing NBS algorithms. It remains critical that psychosine levels be evaluated alongside genotype, enzyme activity levels, and the patient's evolving clinical presentation, ideally in consultation with experts in KD, in order to guide diagnosis and plans for monitoring.

Beyond gait and balance: urinary and bowel dysfunction in X-linked adrenoleukodystrophy.

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.

Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies.

Leukodystrophies are a group of neurodegenerative genetic disorders that affect approximately 1 in 7500 individuals. Despite therapeutic progress in individual leukodystrophies, guidelines in neurologic care are sparse and consensus among physicians and caregivers remains a challenge. At patient advocacy meetings hosted by Hunter's Hope from 2016-2018, multidisciplinary experts and caregivers met to conduct a literature review, identify knowledge gaps and summarize best practices regarding neurologic care. Stages of severity in leukodystrophies guided recommendations to address different levels of need based on a newly defined system of disease severity. Four core neurologic domains prioritized by families were identified and became the focus of this guideline: sleep, pain, seizures/epilepsy, and language/cognition. Based on clinical severity, the following categories were used: presymptomatic, early symptomatic, intermediate symptomatic, and advanced symptomatic. Across the leukodystrophies, neurologic care should be tailored to stages of severity while accounting for unique aspects of every disease and multiple knowledge gaps present. Standardized tools and surveys can help guide treatment but should not overburden families.

Clinical trial readiness study of distal myopathy and dysphagia in nephropathic cystinosis.

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 well-being.

Clinical myopathy in patients with nephropathic cystinosis.

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.