Hugh J. McMillan

Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency

BackgroundD-bifunctional protein (DBP) deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (16½ and 14 years old) with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa.Methods and resultsBiochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS) platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val) and hydratase domain (c.1547T>C; p.Ile516Thr) of the 17β-hydroxysteroid dehydrogenase type 4 gene (HSD17B4). These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP hydratase and dehydrogenase activity were markedly decreased but detectable.ConclusionsWe propose that the DBP phenotype seen in this family represents a distinct and novel subtype of DBP deficiency, which we have termed type IV based on the presence of a missense mutation in each of the domains of DBP resulting in markedly reduced but detectable hydratase and dehydrogenase activity of DBP. Given that the biochemical testing in plasma was normal in these patients, this is likely an underdiagnosed form of DBP deficiency.

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.

Myostatin inhibitor ACE‐031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo‐controlled clinical trial

Introduction: ACE‐031 is a fusion protein of activin receptor type IIB and IgG1‐Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD). Methods: ACE‐031 was administered subcutaneously every 2–4 weeks to DMD boys in a randomized, double‐blind, placebo‐controlled, ascending‐dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics. Results: ACE‐031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6‐minute walk test (6MWT) distance in the ACE‐031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass. Conclusion: ACE‐031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non–muscle‐related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458–464, 2017

Serum Transaminase Levels in Boys With Duchenne and Becker Muscular Dystrophy

OBJECTIVE: Serum alanine transaminase (ALT) and aspartate transaminase (AST) levels are commonly used as biochemical indicators of hepatocellular injury but can also detect occult muscle disease. High concomitant serum creatine phosphokinase (CPK) levels can point to muscle as the source of high transaminase levels. Nevertheless, clinicians may be reluctant to attribute high transaminase levels to muscle. METHODS: Study patients were boys with a genetic or biopsy-confirmed dystrophinopathy whose concomitant serum CPK, ALT, and AST levels were measured. RESULTS: We report 82 enzyme data sets from 46 patients with Duchenne muscular dystrophy (DMD) and 9 with Becker muscular dystrophy. Our results show a linear relationship between serum CPK and serum ALT and AST and a logarithmic relationship between serum enzyme levels and age for boys with DMD. We developed a mathematical model to predict serum ALT and AST levels when the serum CPK level and age are known. For 6 boys, initial failure to consider muscle as a cause of high transaminase levels led to delay of diagnosis and extensive testing for hepatic dysfunction. A second group of 4 boys with known DMD were investigated for liver disease after high transaminase levels were detected. Serum transaminase levels were highest in ambulant boys with DMD, whose levels reached 1220 U/L (ALT) (22.6 times higher than upper-limit normal levels) and 801 U/L (AST) (12.3 times higher than upper-limit normal levels). CONCLUSIONS: By recognizing muscle as a potential source of serum transaminase levels, clinicians can avoid unnecessary and invasive procedures, expedite clinical diagnosis, and avoid unnecessary cessation of concomitant drug therapy.

Compound heterozygous mutations in glycyl-tRNA synthetase are a proposed cause of systemic mitochondrial disease

BackgroundGlycyl-tRNA synthetase (GARS) is an aminoacyl-tRNA synthetase (ARS) that links the amino acid glycine to its corresponding tRNA prior to protein translation and is one of three bifunctional ARS that are active within both the cytoplasm and mitochondria. Dominant mutations in GARS cause rare forms of Charcot-Marie-Tooth disease and distal spinal muscular atrophy.Case presentationWe report a 12-year old girl who presented with clinical and biochemical features of a systemic mitochondrial disease including exercise-induced myalgia, non-compaction cardiomyopathy, persistent elevation of blood lactate and alanine and MRI evidence of mild periventricular leukomalacia. Using exome sequencing she was found to harbor compound heterozygous mutations within the glycyl-tRNA synthetase (GARS) gene; c.1904C > T; p.Ser635Leu and c.1787G > A; p.Arg596Gln. Each mutation occurred at a highly conserved site within the anticodon binding domain.ConclusionOur findings suggest that recessive mutations in GARS may cause systemic mitochondrial disease. This phenotype is distinct from patients with previously reported dominant mutations in this gene, thereby expanding the spectrum of disease associated with GARS dysregulation.

Duchenne muscular dystrophy: Canadian paediatric neuromuscular physicians survey.

BACKGROUND Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. METHOD To assess the current care of paediatric DMD patients in Canada, a questionnaire was mailed to 17 physicians who were members of the Canadian paediatric neuromuscular group. Areas of enquiry included; 1) multidisciplinary team composition; 2) means of DMD diagnosis; 3) corticosteroid use; surveillance and management for: 4) orthopaedic, 5) respiratory and 6) cardiac complications and 7) health maintenance (nutrition & immunizations). RESULTS Completed surveys were returned by 14/17 (82%) of physicians. Twelve respondents followed DMD patients. All centres had multidisciplinary teams, including respirology (11/12), child neurology or physiatry (11), physiotherapy (9), occupational therapy (9) and orthopaedic surgery (7). Deflazacort 0.9 mg/kg/d was used at all centres, which was continued after loss of independent ambulation (11), along with routine calcium and vitamin D supplementation (10). Night splints were prescribed at all centres. Routine surveillance studies included pulmonary function testing (11), sleep studies (10), EKG/echocardiogram (10), bone density (DEXA) scans (10), spine radiography (9), and dietician referral (4). CONCLUSION Paediatric DMD patients are receiving relatively consistent care in multidisciplinary clinics across Canada, in accordance with recommended guidelines for DMD.

Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl–Transfer Ribonucleic Acid (RNA) Synthetase (KARS) Mutations: The Expanding Phenotype of Aminoacyl–Transfer RNA Synthetase Mutations in Human Disease

Aminoacyl–transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of enzymes required for the first step of protein translation. Each aminoacyl–transfer RNA synthetase links a specific amino acid to its corresponding transfer RNA component within the cytoplasm, mitochondria, or both. Mutations in ARSs have been linked to a growing number of diseases. Lysyl–transfer RNA synthetase (KARS) links the amino acid lysine to its cognate transfer RNA. We report 2 siblings with severe infantile visual loss, progressive microcephaly, developmental delay, seizures, and abnormal subcortical white matter. Exome sequencing identified mutations within the KARS gene (NM_005548.2):c.1312C>T; p.Arg438Trp and c.1573G>A; p.Glu525Lys occurring within a highly conserved region of the catalytic domain. Our patients’ phenotype is remarkably similar to a phenotype recently reported in glutaminyl–transfer RNA synthetase (QARS), another bifunctional ARS gene. This finding expands the phenotypic spectrum associated with mutations in KARS and draws attention to aminoacyl–transfer RNA synthetase as a group of enzymes that are increasingly being implicated in human disease.

Autoimmune Neuromuscular Disorders in Childhood

Opinion statementAutoimmune neuromuscular disorders in childhood include Guillain-Barré syndrome and its variants, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), juvenile myasthenia gravis (JMG), and juvenile dermatomyositis (JDM), along with other disorders rarely seen in childhood. In general, these diseases have not been studied as extensively as they have been in adults. Thus, treatment protocols for these diseases in pediatrics are often based on adult practice, but despite the similarities in disease processes, the most widely used treatments have different effects in children. For example, some of the side effects of chronic steroid use, including linear growth deceleration, bone demineralization, and chronic weight issues, are more consequential in children than in adults. Although steroids remain a cornerstone of therapy in JDM and are useful in many cases of CIDP and JMG, other immunomodulatory therapies with similar efficacy may be used more frequently in some children to avoid these long-term sequelae. Steroids are less expensive than most other therapies, but chronic steroid therapy in childhood may lead to significant and costly medical complications. Another example is plasma exchange. This treatment modality presents challenges in pediatrics, as younger children require central venous access for this therapy. However, in older children and adolescents, plasma exchange is often feasible via peripheral venous access, making this treatment more accessible than might be expected in this age group. Intravenous immunoglobulin also is beneficial in several of these disorders, but its high cost may present barriers to its use in the future. Newer steroid-sparing immunomodulatory agents, such as azathioprine, tacrolimus, mycophenolate mofetil, and rituximab, have not been studied extensively in children. They show promising results from case reports and retrospective cohort studies, but there is a need for comparative studies looking at their relative efficacy, tolerability, and long-term adverse effects (including secondary malignancy) in children.

Histomorphometry and Bone Matrix Mineralization Before and After Bisphosphonate Treatment in Boys With Duchenne Muscular Dystrophy: A Paired Transiliac Biopsy Study

Duchenne muscular dystrophy (DMD) is a genetic disorder causing progressive muscle weakness. To prolong independent ambulation, DMD patients are treated with glucocorticoids, which, in turn, can increase bone fragility. In a cohort with vertebral fractures, intravenous bisphosphonate (iv BP) therapy stabilized vertebrae and reduced back pain. To characterize the effects of glucocorticoid therapy and bisphosphonate treatment on bone tissue and material properties, paired transiliac biopsy samples (before and after on average 2.4 years of iv BP) from 9 boys with DMD were studied for histomorphometry and bone mineralization density distribution (BMDD) and compared to reference values. Before iv BP, the boys had low cancellous bone volume (BV/TV) and cortical thickness (Ct.Wi) (both on average 56% of the healthy average, p < 0.001 versus reference), and mineralizing surface (MS/BS) in the lower normal range (on average 74% of the healthy average). The average degree of mineralization of cancellous (Cn.CaMean) and cortical compartments (Ct.CaMean) was 21.48 (20.70, 21.90) wt% and 20.42 (19.32, 21.64) wt%, respectively (median [25th, 75th percentiles]), which was not different from reference. After iv BP, BV/TV and Ct.Wi were, on average, unchanged. However, at the individual patient level, BV/TV Z‐scores increased in 2, remained unchanged in 4, and declined in 3 patients. Additionally, on average, MS/BS decreased (–85%, p < 0.001), Cn.CaMean (+2.7%) increased, whereas the heterogeneity of cancellous (Cn.CaWidth –19%) and cortical bone mineralization (Ct.CaWidth –8%, all p < 0.05) decreased versus baseline. The changes in bone mineralization are consistent with the antiresorptive action of iv BP. At the same time, our observations point to the need for novel therapies with less or absent bone turnover suppression, including the fact that bone turnover was low even before bisphosphonate therapy, that bone turnover declined further (as expected) with treatment, and that declines in trabecular bone volume were observed in some boys despite bisphosphonate therapy.

Hereditary neuropathy with liability to pressure palsies in childhood: Case series and literature update.

Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) is a rare condition in childhood with a diverse range of clinical presentations. We analyzed the clinical presentation and electrophysiological data of 12 children with a confirmed PMP22 gene deletion and reviewed the published reports of HNPP in children and compared our data with the reports from the literature review. Peroneal palsy was the most common presentation (42%) followed by brachial plexus palsy in 25% of our cases. Nerve conduction studies were always suggestive of the diagnosis demonstrating 3 major patterns: multifocal demyelination at the area of entrapment, generalized sensory-motor polyneuropathy and a combination of the two first patterns in a vast majority (60%). Surprisingly, there was bilateral or unilateral electrophysiological entrapment of the median nerve at the carpal tunnel in all our patients. The clinical presentation of HNPP in childhood is heterogeneous and electrophysiological findings are helpful in establishing the diagnosis. Any unexplained mononeuropathy or multifocal neuropathy should lead to PMP22 gene testing to look for the deletion. Early diagnosis is important in order to facilitate appropriate genetic counseling and also for the appropriate care for these patients.