Burden of Spinal Muscular Atrophy (SMA) on Patients and Caregivers in Canada.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neurodegenerative disease characterized by progressive muscular weakness, which occurs in one in 6,000 to 10,000 live births. The burden of SMA on Canadian patients and caregivers is not known. OBJECTIVE: To characterize the burden of SMA in Canada as reported by patients and caregivers, including disease and treatment impacts, indirect costs, and caregiver burden. METHODS: Surveys were distributed by Cure SMA Canada and Muscular Dystrophy Canada to individuals with SMA and their caregivers. The online surveys were anonymous and completed between January 28 and February 21, 2020. RESULTS: 965 patient and 962 caregiver responses met the eligibility criteria. Patients reported SMA subtypes as: type I (25.0%), type II (41.3%), type III (29.3%). Using the EQ-5D, patients were shown to have impaired quality of life with an average health utility index of 0.49 (SD: 0.26). The median expenditure was $4,500 CAD (IQR: $1,587 - $11,000) for assistive devices; $6,800 CAD (IQR: $3,900-$13,000) on health professional services; and $1,200 CAD (IQR: $600 -$3,100) on SMA-related travel and accommodation in the past 12 months. Caregivers reported needing respite care (45.7%), physiotherapy for an injury from a lift/transfer (45.7%), or other health impacts (63.3%). Caregivers reported changes to personal plans, sleep disturbances, and work adjustments, with a mean Caregiver Strain Index score of 7.5 [SD: 3.3]. CONCLUSION: SMA in Canada is associated with a significant burden for patients and their caregivers.

Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.

BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

The time to and determinants of first fractures in boys with Duchenne muscular dystrophy.

Boys with vertebral fractures (VF) identified through routine spine radiographs had milder, less symptomatic, and fewer VF compared to those diagnosed with VF following consultation for back pain. Spontaneous (i.e., medication-unassisted) reshaping of fractured vertebral bodies was absent. Long bone fractures were present even before Duchenne muscular dystrophy (DMD) diagnosis in some boys. INTRODUCTION: The objective of the study was to determine the time to and characteristics of first fractures in Duchenne muscular dystrophy. METHODS: This study was a retrospective longitudinal study of 30 boys with DMD <18 years. Boys were classified into four groups according to their first fracture: those with VF identified on routine lateral spine radiographs, those with VF diagnosed following consultation for back pain, those with long bone fractures, and those without fractures. RESULTS: Compared to boys diagnosed with VF as their initial fracture following consultation for back pain, those with VF surveillance radiographs had shorter durations of glucocorticoid (GC) therapy at the time of VF diagnosis (median 1.6 versus 5.3 years, p < 0.01), higher areal (mean ± standard deviation -1.4 ± 0.7 versus -3.1 ± 0.8, p = 0.01), and volumetric (-0.3 ± 0.5 versus -2.6 ± 0.8, p < 0.01) lumbar spine bone mineral density Z-scores, as well as fewer VF (median 1.4 versus 5.2 per person, p < 0.01) and a lower median spinal deformity index (median 1.5 versus 9.5, p < 0.01). Vertebral body reshaping following VF was not observed. Ten boys sustained a long bone fracture as their first fracture at a mean age of 8.9 ± 4.0 years; four of these boys later sustained a total of 27 incident VF. CONCLUSIONS: Routine lateral spine radiographs led to detection of VF in their earlier stages, vertebral body reshaping following VF was absent, and VF were frequent after the first long bone fracture. These results support the inclusion of a lateral spine radiograph starting at the time of GC initiation as part of routine bone health monitoring in DMD.

Chemotherapy-induced Peripheral Neuropathy Among Paediatric Oncology Patients.

BACKGROUND: Vinca alkaloids and platinum-containing chemotherapeutic drugs have the potential to cause chemotherapy-induced peripheral neuropathy (CIPN). This study determined the frequency of CIPN among children who were treated for acute lymphoblastic leukemia (ALL), lymphoma, brain tumour or Wilms tumour. PROCEDURE: This retrospective cohort study reviewed 252 patients treated at the Children's hospital of Eastern Ontario from 2001-2011. Patients were considered to have CIPN if they developed clinical symptoms of CIPN such as limb paraesthesia, weakness and/or ataxia during chemotherapy and their treating neurologist or oncologist deemed that their symptoms were due to a peripheral cause. Patients were excluded if their treatment regime did not include chemotherapy. RESULTS: The overall frequency of CIPN was 18.3% (46/252). Tumour-specific CIPN rates were: 18.9% (29/154) for ALL; 9.4% (3/32) for lymphoma; 17.9% (5/28) for Wilms tumour; and 23.7% (9/38) for brain tumour patients. Nerve conduction studies were completed for 17% of patients (all tumour types) and were abnormal in all but one patient. Among surviving CIPN patients (41/46), 93% showed no clinical deficits at their last examination, which was on average 56 months from time of diagnosis to last follow-up visit. CONCLUSIONS: The frequency of CIPN was less than that previously reported in adults receiving chemotherapy. Children with CIPN have a favourable outcome with most showing clinical improvement during the maintenance phase of treatment or after chemotherapy completion.

Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy.

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N-acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic-absence seizures. An extensive genetic and metabolic work-up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA-PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.

The use of intravenous bisphosphonate therapy to treat vertebral fractures due to osteoporosis among boys with Duchenne muscular dystrophy.

UNLABELLED: The impact of intravenous bisphosphonate treatment to treat painful vertebral fractures in boys with DMD has not been documented. In this retrospective observational study of seven boys, 2 years of intravenous bisphosphonate therapy was associated with back pain improvement and stabilization or increases in the height ratios of fractured vertebrae. INTRODUCTION: Boys with Duchenne muscular dystrophy (DMD) are at risk for vertebral fractures. We studied the impact of intravenous bisphosphonate therapy for the treatment of painful vertebral fractures in DMD. METHODS: This was a retrospective observational study in seven boys with DMD (median 11.6 years, range 8.5 to 14.3) treated with intravenous pamidronate (9 mg/kg/year) or zoledronic acid (0.1 mg/kg/year) for painful vertebral fractures. RESULTS: At baseline, 27 vertebral fractures were evident in the seven boys. After 2 years of bisphosphonate therapy, 17 of the fractures had an increase in the most severely affected vertebral height ratio, 10 vertebrae stabilized, and none showed a decrease in height ratio. Back pain resolved completely (N = 3) or improved (N = 4). The median change in lumbar spine volumetric bone mineral density Z-score was 0.5 standard deviations (interquartile range, -0.3 to 1.7). Two boys had three incident vertebral fractures in previously normal vertebral bodies that developed over the observation period. There was a decline in the trabecular bone formation rate on trans-iliac bone biopsy but no evidence of osteomalacia. First-dose side effects included fever and malaise (N = 4), hypocalcemia (N = 2), and vomiting (N = 1); there were no side effects with subsequent infusions. CONCLUSIONS: Intravenous bisphosphonate therapy was associated with improvements in back pain and stabilization to improvement in vertebral height ratios of previously fractured vertebral bodies. At the same time, such therapy does not appear to completely prevent the development of new vertebral fractures in this context.

Brainstem compression: a predictor of postoperative cerebellar mutism.

PURPOSE: Cerebellar mutism is a common complication of posterior fossa tumor resection. We observed marked, preoperative brainstem compression on MR imaging, among patients who developed postoperative mutism. This study was designed to investigate if an association was indeed present. MATERIALS AND METHODS: Patients (18 months-18 years) undergoing resection of a midline, posterior fossa tumor were retrospectively reviewed. Demographic data, tumor pathology, mutism onset and duration, and postoperative complications were obtained from hospital records. Pre- and postoperative MR images were studied to assess tumor size and the severity of pons compression (an estimate of the mechanical and distortional forces imparted by the tumor). RESULTS: Patients with mutism showed greater preoperative pons compression and a greater increase in postoperative pons diameter. CONCLUSION: We predict that brainstem compression may represent white-matter injury from (1) surgical manipulation and traction, and (2) axonal damage caused by the release of the tumor's compressive force and ensuing axon distortion and dysfunction. The results provide support that mutism may be largely caused by white-matter damage disrupted axon integrity and function.

Ophthalmoplegic migraine: inflammatory neuropathy with secondary migraine?

BACKGROUND: This critical review provides a summary of the clinical presentation, neuroimaging, treatment and prognosis in pediatric ophthalmoplegic migraine (OM). The features of OM are not in keeping with its classification as a migraine-variant. METHOD: We review 3 new and 37 reported pediatric OM cases. RESULTS: Headache was an inconsistent feature, with 25% patients showing no evidence of pain at the initial OM episode. Patients demonstrated: 1) prolonged time for symptom resolution to occur (median time 3 weeks); 2) tendency for recurrent episodes to have more severe and persistent nerve involvement; 3) evidence of permanent neurological sequelae with recurrent episodes (30% of patients); 4) rapid improvement and shortened duration with corticosteroid therapy and; 5) transient, reversible MRI contrast enhancement of the affected cranial nerve (86% of patients). These features would not be expected in primary migraine headache. CONCLUSION: A detailed understanding of the natural history of OM is essential for the clinical. This review provides support that OM may result from cranial nerve inflammation with headache a secondary and later feature of this condition.

Divergent reproductive endocrinology of the estrous cycle and pregnancy in dwarf hamsters (phodopus).

Progesterone (P4) and prolactin (PRL) in peripheral circulation of Siberian hamsters (Phodopus sungorus) throughout an estrous cycle and pregnancy were determined by repeated, small volume sampling from individuals housed in modified home cages. As predicted, the endocrinology of P. sungorus reproduction is similar to the rat, mouse and golden hamster and shows none of the eight distinctive features known for Djungarian hamsters (Phodopus campbelli). Specifically, in P. sungorus there is no evidence for resumption of pituitary PRL surges in late pregnancy, P4 concentrations during the differentiation of the corpus luteum on day 2 of pregnancy are higher (as opposed to lower) than concentrations on the comparable day of an unmated estrous cycle (diestrus 1), P4 concentrations increase throughout pregnancy, PRL surges are common during the estrous cycle, including a reliable surge on proestrus, and P4 plays an important role in facilitating the expression of behavioral receptivity. We conclude that 'novel' P. campbelli reproductive endocrinology has evolved since a common ancestor was shared with P. sungorus. With a time frame (the available time since the divergence of the two species) and an ecological context (known niches and behavior in the wild) these species offer the opportunity to study endocrinological evolution in progress.

Evolutionary change in the endocrinology of behavioral receptivity: divergent roles for progesterone and prolactin within the genus Phodopus.

Siberian (Phodopus sungorus) and Djungarian (P. campbelli) hamsters are phenotypically similar and were long considered subspecies. Progesterone (P4) and prolactin (PRL) changes (determined by repeated sampling of individuals) during the behavioral receptivity of both an ovulatory cycle and a postpartum mating, as well as the hormonal requirements for behavioral receptivity, were determined. Changes in P. sungorus were similar to well-described hormonal changes in rats, mice, and golden hamsters, suggesting that previously described differences between P. campbelli and those species had evolved recently. Specifically, 1) P4 facilitated behavioral receptivity at low priming doses of estradiol in P. sungorus but was not needed in P. campbelli; 2) in P. sungorus, P4 increases were synchronous across females and of similar amplitude during each estrus, whereas in P. campbelli, P4 increases were less synchronous across females and were reduced in amplitude postpartum; and 3) PRL profiles were similar (high average PRL levels, few high surges detected) in each species on Day 18, but on proestrus, cyclic P. sungorus had elevated PRL levels and frequent surges while cyclic P. campbelli had lower PRL levels and rare surges. As the endocrinology of P. campbelli also differs from known laboratory rodents in other ways, additional within-genus divergence is predicted.

Length of delay to birth of a second litter in dwarf hamsters (Phodopus): evidence for post-implantation embryonic diapause.

In Phodopus, all first litters are born after an 18 (or 19) day gestation. Birth of subsequent litters conceived during a postpartum estrus is routinely, but not always, delayed beyond 18 days. With an interval from first mating to birth of a second litter of as little as 36 days, Phodopus have the most compressed reproductive cycle of any eutherian mammal. Although pups of the Siberian hamster P. sungorus gain thermal independence from maternal care faster than pups of the Djungarian hamster P. campbelli, no species difference in the extent of delay to second litters was found. However, poor growth of first litter pups as a result of unintentional limitation of water bottle access increased delays before birth of a second litter in P. sungorus. Weight of pups in the first litter was a good predictor of the length of delay. In P. campbelli, females with large pups early in lactation were the only ones to deliver a second litter without delay, and short delays enhanced weaning weights for pups in the first litter. Patterns in P. sungorus were similar. The timing of the delay in second litters was investigated in P. campbelli. Delayed implantation during second pregnancies was common. Postimplantation embryonic diapause occurred in 43% of females following unilateral ovariohysterectomy on day 8 of a first pregnancy. As pup growth curves also implicated a postimplantation embryonic diapause, Phodopus may be the only known mammalian genus outside the order Chiroptera in which postimplantation diapause can occur.