Alternating hemiplegia of childhood is a predominantly sporadic neurodevelopmental syndrome of uncertain etiology. In more than 3 decades since its description, little progress has been made in ...understanding its etiology or in identifying effective treatments. In 1998, in collaboration with the Alternating Hemiplegia of Childhood Foundation, an international registry was established to help document clinical outcomes and promote research efforts.
We present phenotypic data on 103 patients who met existing diagnostic criteria for alternating hemiplegia of childhood. Although some of these subjects may have been included in previously published reviews, our focus was directed toward the earliest manifestations of symptoms and evolution of features over time. Data sources included written questionnaires, face-to-face and telephone interviews, clinical examination, and medical charts. Characteristics of disease onset, medical comorbidities, episode triggers, diagnostic workup, and treatment are presented.
Paroxysmal eye movements were the most frequent early symptom, manifesting in the first 3 months of life in 83% of patients. Hemiplegic episodes appeared by 6 months of age in 56% of infants. Background slowing shown by electroencephalography during typical paroxysmal events, including hemiplegic, tonic, or dystonic episodes was frequent (21 of 42 cases). Distinct convulsive episodes with altered consciousness believed to be epileptic in nature were reported in 41% of patients. Ataxia (96%) and cognitive impairment (100%) were frequent nonepisodic symptoms. Empiric pharmacologic treatment approaches offered little benefit in most subjects and resulted in adverse effects in 20% of patients. Prolonged episodes were completely or temporarily aborted during sleep in all subjects.
This descriptive analysis of a large cohort of children indicates that paroxysmal ocular movements are an early, highly suggestive symptom, followed by paroxysmal episodes of focal dystonia or flaccid, alternating hemiplegia in early infancy in the majority of subjects. Current challenges in diagnosis and management contribute to poor outcomes. Early diagnosis and multicenter collaboration are needed to facilitate trials to identify more effective therapies.
Introduction: The test–retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which ...typically developing children (TD) achieve maximum MHFMS scores was also studied. Methods: Twenty‐two children with SMA type II mean age (SD) = 20 (5) months, range 9–30 months) were tested twice using the MHFMS. Twenty‐five TD children mean age (SD) = 18 (7) months, range 9–30 months) were tested once. Results: The average difference between MHFMS scores for SMA children was 0.18 first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8). Reliability was excellent (ICC1,3 = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 mean (SD) = 39.2 (1.2) and achieved maximum test scores at 12 months of age. Discussion: MHFMS scores in young children with SMA type II showed excellent test–retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow‐up. Muscle Nerve, 2011
Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Maximum ulnar compound muscle action ...potential (CMAP) data were collected at two visits over a 4–6‐week period in children with SMA types II and III, 2–17 years of age, at four academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS‐Extend. CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non‐ambulatory SMA cohorts (ROC = 0.88). CMAP had excellent test–retest reliability (ICC = 0.96–0.97, n = 64) and moderate to strong correlation with the MHFMS and MHFMS‐Extend (r = 0.61–0.73, n = 68, P < 0.001). Maximum ulnar CMAP amplitude and area is a feasible, valid, and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status. Muscle Nerve, 2010
ABSTRACT
Introduction: Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength ...and motor function. Methods: We evaluated feasibility, safety, and effects on strength and motor function of a home‐based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks. Results: Nine children with SMA, aged 10.4 ± 3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain‐free (99.8%), and no study‐related adverse events occurred. Trends in improved strength and motor function were observed. Conclusions: A 12‐week supervised, home‐based, 3‐day/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA. Muscle Nerve 52: 559–567, 2015
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.
Bench to bedside progress has been widely anticipated for a growing number of neurodegenerative disorders. Of these, spinal muscular atrophy (SMA) is perhaps the best poised to capitalize on advances ...in targeted therapeutics development over the next few years. Several laboratories have achieved compelling success in SMA animal models using sophisticated methods for targeted delivery, repair, or increased expression of the survival motor neuron protein, SMN. The clinical community is actively collaborating to identify, develop, and validate outcome measures and biomarkers in parallel with laboratory efforts. Innovative trial design and synergistic approaches to maximize proactive care in conjunction with treatment with one or more of the promising pharmacologic and biologic therapies currently in the pipeline will maximize our chances to achieve meaningful outcomes for patients. This review highlights recent promising scientific and clinical advances bringing us ever closer to effective treatment(s) for our patients with SMA.
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