M M Ryan

The Royal Children's Hospital, Melbourne, Victoria, Australia

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Publications (23)111.14 Total impact

  • 19th International Congress of the World-Muscle-Society; 10/2014
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    ABSTRACT: TTN encodes titin, the largest human protein. In striated muscle two titin molecules align “head to head” to span the full length of the sarcomere, providing a scaffold for sarcomere organisation, a sensing and signalling hub, and both passive and active modulation of muscle contraction. Dominant mutations in TTN are established causes of cardiomyopathy, tibial muscular dystrophy, and hereditary myopathy with early respiratory failure. More recently, several individuals with two truncating mutations have been described with increased internalised nuclei (CNM) with or without multi-minicores (MMC). Using next generation sequencing, we identified 14 individuals from 11 families with compound heterozygous or homozygous truncating TTN mutations. Presentation was in utero or during infancy in all cases. Weakness of truncal and respiratory muscles was often prominent, and early-onset scoliosis and respiratory failure were common complications. Three affected individuals had dilated cardiomyopathy (DCM) or left ventricular dysfunction, and one carrier parent developed DCM in later life. Two individuals had congenital aortic abnormalities (coarctation and stenosis). Many affected individuals had distinctive clinical features which are unusual for congenital myopathies, including congenital or early-onset hand and foot deformities, congenital scoliosis, spinal rigidity, cleft palate, distal hypermobility and short stature. The most common histological abnormality was a mixed CNM-MMC pattern. Novel histological patterns included typical congenital fibre-type disproportion (CFTD) and CNM-MMC with caps and nemaline rods. The presence of palatal clefts, facial dysmorphology, and cardiac malformations in several individuals with TTN mutations suggests that titin plays a role in foetal development. Mutations in TTN should be considered in any individual with predominant truncal and respiratory weakness, and CNM, MMC, CFTD, caps, rods, or any combination of these, on muscle biopsy.
    Neuromuscular Disorders 10/2014; 24(s 9–10):805. DOI:10.1016/j.nmd.2014.06.049 · 3.13 Impact Factor
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    ABSTRACT: Background/Objectives:Nutritional issues that are associated with Duchenne muscular dystrophy (DMD) remain poorly understood. The aim of this analysis was to describe and explore longitudinal observations of body mass index (BMI) in a cohort of children with DMD.Subjects/Methods:Anthropometric and clinical characteristics were collected retrospectively and longitudinally for boys with DMD seen in two large neuromuscular clinics. BMI Z-scores were determined using the Centers for Disease Control and Prevention reference values for children (2000).Results:Medical records (n=193) were examined from which 75% were included for analysis. The mean age of the cohort at the time of data collection was 11.9 years, with 72% of patients currently or previously using steroids. The highest prevalence of obesity based on the BMI Z-score was 50% at the age of 10 years. Longitudinally, BMI Z-scores from the age of 2 to 12 years plot approximately one s.d. above the mean, after which there is a marked and progressive decline. BMI gainers were identified for whom BMI Z-score increased by 1.65 units compared with the 0.09 units in non-gainers. BMI gainers were younger when they had their first BMI measurement (5.9 vs 7.2 years), and this measure was significantly lower compared with the non-gainers (BMI Z-score: 0.04 vs 1.17). In this cohort, BMI was associated with age, ambulatory status and lung function.Conclusions:This study demonstrates that boys with DMD using steroid therapy experience shifts in BMI. A declining BMI appears to be associated with increasing age. Interpretation of growth patterns is limited here by a lack of normative growth references in DMD.European Journal of Clinical Nutrition advance online publication, 14 May 2014; doi:10.1038/ejcn.2014.93.
    European journal of clinical nutrition 05/2014; 68(8). DOI:10.1038/ejcn.2014.93 · 2.95 Impact Factor
  • T. Jadhav · A.J. Kornberg · H. Peters · J. Lee · M.M. Ryan
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    ABSTRACT: Background Carpal tunnel syndrome is rare in children but is a recognised complication of the mucopolysaccharidoses. Clinicians should have a low threshold of suspicion for carpal tunnel syndrome in this group as symptoms may be atypical or minimal, especially in those with intellectual disabilities secondary to mucopolysaccharidoses. If untreated, carpal tunnel syndrome can cause significant, potentially permanent loss of hand function. We present findings in 11 children with mucopolysaccharidoses and suspected median neuropathies at the wrist, and propose guidelines for screening for carpal tunnel syndrome in children with these disorders. Methods Clinical and electrodiagnostic data of 11 children with confirmed mucopolysaccharidoses by enzymatic ± molecular testing, who were suspected on clinical grounds to have carpal tunnel syndrome, was reviewed. All subjects underwent motor and sensory conduction studies of bilateral median and ulnar nerves. The presence of carpal tunnel syndrome and its severity was determined. Subsequent details of intervention (s) and recurrence were noted. Results Three children had Hurler syndrome (MPS I), five had Hunter syndrome (MPS II), one had Sanfilippo syndrome (MPS III) and two had Morquio syndrome (MPS IV). Seven had motor and three sensory features referable to median nerve compression. Nine of the eleven children (2/3 with MPS I, 5/5 with MPS II, 0/1 with MPS III, 2/2 with MPS IV) had median neuropathies at the wrist (eight bilateral, one unilateral), which were mild in three, moderate in five, and severe in one. Three children presented with symptoms at 5 years age. Six underwent median nerve decompression. Four of these had recurrent symptoms several years after surgery. Recurrent carpal tunnel syndrome was confirmed on nerve conduction studies in two cases. To the best of our knowledge, this is the first report of carpal tunnel syndrome in MPS IV. Conclusion Some children with mucopolysaccharidoses experience early development of at least moderately severe carpal tunnel syndrome. We recommend screening for median neuropathies at the wrist from age 5 years for children with mucopolysaccharidoses, particularly types I, II and IV, regardless of whether they are symptomatic or asymptomatic of carpal tunnel syndrome and of the treatment received for their mucopolysaccharidosis.
    Clinical Neurophysiology 04/2014; 125(4):e4–e5. DOI:10.1016/j.clinph.2013.10.033 · 2.98 Impact Factor
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    ABSTRACT: The dystrophinopathies are allelic muscular dystrophies caused by X-linked recessive mutations in dystrophin, with only rare reports of asymptomatic adult males. The static cognitive impairment seen in dystrophinopathies is thought to be due to altered expression of dystrophin isoforms, but has only once been described in the absence of muscle weakness. We identified a cohort of patients with unexpected copy number variants (CNV) in the dystrophin gene, on microarrays performed for developmental delay or intellectual disability, in whom muscle weakness was minimal or absent. Subjects with a dystrophin CNV referred to the neurology or genetics departments at RCH Melbourne or GHSV were assessed. An additional family was identified from the CHW, and included. Twelve probands had a CNV in the dystrophin gene on microarray testing. Eight (seven male, one female; seven deletions, one duplication), age 0–9 years, had atypical phenotypes as described above. CNVs were found in 10 family members (five males and five females), including three asymptomatic adult males. In all but one family, MLPA confirmed loss of exons. Muscle weakness was absent or minimal. Serum CK was normal or mildly elevated. Muscle biopsy revealed morphologically normal muscle with normal dystrophin immunoreactivity. Microarray testing has revealed an extended spectrum of clinical phenotypes associated with mutations in dystrophin, that may include isolated developmental delay and asymptomatic individuals. Further study is required to understand the molecular basis of the apparent absence of muscle pathology in these patients, and the relationship of the dystrophin deletion to cognitive impairment.
    Neuromuscular Disorders 10/2012; 22(s 9–10):805–806. DOI:10.1016/j.nmd.2012.06.016 · 3.13 Impact Factor
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    ABSTRACT: Friedreich ataxia (FRDA), the most common hereditary ataxia, is due to a GAA triplet repeat expansion in intron 1 of the FXN gene in about 98% of affected individuals, resulting in deficiency of the mitochondrial protein frataxin. There is no treatment proven to alter its natural history. Resveratrol is a plant-derived compound. It was identified to increase frataxin expression in cellular and mouse models of FRDA, and is proposed to have anti-oxidant and neuroprotective properties. This is an open-label sequential clinical pilot study evaluating the effect of two different doses of resveratrol on lymphocyte frataxin levels over a 12-week period. Inclusion criteria include: (i) age >18 years; (ii) homozygosity for the GAA repeat expansion in FXN; (iii) at least minimum clinical evidence of ataxia; and (iv) adequate end organ function. A total of 28 participants will be enrolled (14 participants 1 g resveratrol daily; 14 participants 5 g resveratrol daily). The primary aim is to evaluate the effect of two doses of resveratrol on lymphocyte frataxin levels at 12 weeks compared to baseline. A number secondary aims will evaluate the effect of resveratrol on FXN mRNA expression, markers of oxidative stress, clinical measures of FRDA, and echocardiography findings at 12 weeks compared to baseline. The safety of resveratrol, and pharmacokinetic data will also be evaluated. This trial is expected to reach completion in August 2012. Preliminary data will be presented. Resveratrol shows promise as a treatment for FRDA. This clinical pilot trial will evaluate its effect on biomarker and clinical measures over a 12-week period. If evidence of biological effect is seen, a placebo-controlled study will be undertaken.
    Neuromuscular Disorders 10/2012; 22(9-10):851. DOI:10.1016/j.nmd.2012.06.161 · 3.13 Impact Factor
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    ABSTRACT: The four and a half LIM domain protein 1 (FHL1) gene encodes FHL1, a LIM domain containing protein that regulates skeletal and cardiac muscle function. FHL1 mutations are associated with variable phenotypes including reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy and Emery–Dreifuss muscular dystrophy. The FHL1 gene encodes three FHL1 isoforms (FHL1A, FHL1B, FHL1C). Patients with FHL1 mutations affecting all three isoforms exhibit a more severe phenotype, whereas mutations that affect only FHL1A are less severe. We describe a boy with a family history consistent with X-linked distal myopathy/cardiomyopathy. The boy first presented at age 8 with exercise intolerance and was found to have pes cavus, distal wasting, weakness of ankle dorsiflexion and areflexia. There was no clinical evidence of cardiac involvement. The patient’s brother had died suddenly from isolated hypertrophic cardiomyopathy some years prior. A maternal uncle had also died suddenly from complications of cardiomyopathy. In this subject, an echocardiogram at age 8 was normal, but by age 14 there was evidence of a hypertrophic cardiomyopathy. Muscle biopsy showed myopathic changes and prominent rimmed vacuoles. Sequencing of the FHL1 gene revealed a novel hemizygous c.764G>C missense mutation in exon 8, causing a C255S substitution affecting one of the zinc binding cysteine residues in the fourth LIM domain of FHL1A. The patient’s mother and maternal aunt were heterozygous for the mutation. No suitable samples could be identified for testing of the deceased sibling and maternal uncle. Over 26 FHL1 mutations have been reported to date, many of which cause phenotypes with shared clinicopathological features. This first report of a predominantly distal myopathy with hypertrophic cardiomyopathy occurring secondary to an FHL1 mutation further expands the clinical spectrum of FHL1-related myopathies.
    Neuromuscular Disorders 10/2012; 22(9-10):902-903. DOI:10.1016/j.nmd.2012.06.327 · 3.13 Impact Factor
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    ABSTRACT: There is considerable variation in the rate of disease progression and response to steroid therapy in males with Duchenne muscular dystrophy (DMD). Genetic influences may explain at least part of this heterogeneity. This retrospective case series explored the relationship between dystrophin gene mutations (DMD) and age at loss of ambulation (LOA). Medical histories (n = 144) were examined from two Australian neuromuscular clinics. Data were collected on clinical characteristics including DMD mutation type and location, age at LOA, anthropometry, lung function and steroid use. The relationship between age at LOA and genetic and clinical characteristics including age at chart review, duration of steroid treatment, and BMI z-score was explored via multiple regression analysis. Significant independent variables were also entered in a logistic regression to predict LOA <10 years of age. The mean (±SD) age of the cohort was 11.9 ± 4.0 years, and 51% of boys had lost the ability to walk independently. Mutation type and duration of steroid treatment were significant independent predictors of LOA <10 years in a logistic model explaining 31.2% of the variance in age of LOA. Boys with deletions in the dystrophin gene were six times more likely to stop walking before age 10 compared to boys with duplications, point or unknown mutations. This was reflected in the mean age at LOA in boys with deletions versus other mutations (9.30 ± 1.60 vs 10.97 ± 2.03 years, respectively, p < 0.0005). A longer duration of steroid therapy was associated with a reduction in risk of LOA <10 years. BMI had no relationship with age at LOA. Whilst the negative effects of steroid treatment such as weight gain and decreased bone health need to be considered, early introduction of steroids may provide some functional benefits, especially to boys with a documented deletion in DMD gene.
    Neuromuscular Disorders 10/2012; 22(9-10):835. DOI:10.1016/j.nmd.2012.06.111 · 3.13 Impact Factor
  • G Rance · M M Ryan · P Carew · L A Corben · E Yiu · J Tan · M B Delatycki
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    ABSTRACT: Auditory neuropathy disrupts the neural representation of sound and may therefore impair processes contingent upon inter-aural integration. The aims of this study were to investigate binaural auditory processing in individuals with axonal (Friedreich ataxia) and demyelinating (Charcot-Marie-Tooth disease type 1A) auditory neuropathy and to evaluate the relationship between the degree of auditory deficit and overall clinical severity in patients with neuropathic disorders. Twenty-three subjects with genetically confirmed Friedreich ataxia and 12 subjects with Charcot-Marie-Tooth disease type 1A underwent psychophysical evaluation of basic auditory processing (intensity discrimination/temporal resolution) and binaural speech perception assessment using the Listening in Spatialized Noise test. Age, gender and hearing-level-matched controls were also tested. Speech perception in noise for individuals with auditory neuropathy was abnormal for each listening condition, but was particularly affected in circumstances where binaural processing might have improved perception through spatial segregation. Ability to use spatial cues was correlated with temporal resolution suggesting that the binaural-processing deficit was the result of disordered representation of timing cues in the left and right auditory nerves. Spatial processing was also related to overall disease severity (as measured by the Friedreich Ataxia Rating Scale and Charcot-Marie-Tooth Neuropathy Score) suggesting that the degree of neural dysfunction in the auditory system accurately reflects generalized neuropathic changes. Measures of binaural speech processing show promise for application in the neurology clinic. In individuals with auditory neuropathy due to both axonal and demyelinating mechanisms the assessment provides a measure of functional hearing ability, a biomarker capable of tracking the natural history of progressive disease and a potential means of evaluating the effectiveness of interventions.
    Neuroscience 09/2012; 226C:227-235. DOI:10.1016/j.neuroscience.2012.08.054 · 3.33 Impact Factor
  • Neuromuscular Disorders 10/2011; 21(9):690-690. DOI:10.1016/j.nmd.2011.06.921 · 3.13 Impact Factor
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    ABSTRACT: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.
    Neurology 08/2011; 77(5):444-52. DOI:10.1212/WNL.0b013e318227b164 · 8.30 Impact Factor
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    ABSTRACT: The incidence, cause, and prognosis of sciatic neuropathy in children is not well understood. We report our 30-year experience of 53 patients with pediatric sciatic neuropathies (SN). Prospective review of the history, physical examination, electrophysiologic findings, and clinical course of children with SN. The etiology of SN injury was varied and included trauma (13), iatrogenic causes (13) (8 orthopedic surgeries and 5 miscellaneous surgeries), prolonged extrinsic compression and immobilization (6), tumors (7), vascular (5), idiopathic and progressive (4), infantile and nonprogressive (2), and unknown, presumed postviral (3). Electrophysiologic studies demonstrated abnormalities in motor conduction studies of the peroneal nerve in 44/53 (83%) or tibial nerve in 35/51 (67%). Sensory conduction studies were abnormal in sural nerve in 34 of 43 cases (79%), and superficial peroneal nerves in 15/25 (60%). Needle EMG was abnormal in peroneal innervated muscles in all subjects, in tibial nerve innervated muscles in 43/51 (84%), and in the hamstrings in 18/29 (62%). Prognosis for recovery was variable and depended on the etiology and the severity of the nerve injury. SN is an uncommon mononeuropathy in children. The causes of SN are varied in children compared to adults. Electrophysiologic studies in children may be limited by poor tolerance but play an important role in establishing the diagnosis.
    Neurology 03/2011; 76(11):976-80. DOI:10.1212/WNL.0b013e3182104394 · 8.30 Impact Factor
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    ABSTRACT: X-linked Charcot-Marie-Tooth disease (CMTX) is infrequently diagnosed in childhood, and its clinical and neurophysiologic features are not well-described. We reviewed clinical, neurophysiologic, and pathologic findings in 17 children with CMTX. This was a retrospective review of children with CMTX from 2 tertiary pediatric hospitals. The diagnosis of CMTX was based on an identifiable connexin 32 mutation (CMTX1) or a consistent pedigree and neurophysiologic features in children without a connexin 32 mutation (CMTX-other). Six boys and 2 girls from 8 kindreds had CMTX1, and 8 boys and 1 girl from 5 kindreds had other forms of CMTX (CMTX-other). Fifteen children, including males and carrier females, were symptomatic from infancy or early childhood (younger than 5 years). In addition to the typical Charcot-Marie-Tooth disease clinical phenotype, some patients had delayed motor development, sensorineural hearing loss, tremor, pathologic fractures, or transient CNS disturbances. Eleven children underwent nerve conduction studies. Median nerve motor nerve conduction velocities were in the intermediate to normal range (30-54 m/s) in all children older than 2 years. Axon loss, reflected by low-amplitude compound muscle action potentials, was present in all patients. A pattern of X-linked dominant inheritance, with carrier females showing an abnormal neurologic or neurophysiologic examination, correlated with the presence of a connexin 32 mutation in all but 2 pedigrees. The clinical phenotype of CMTX is broader than previously reported. Onset in males and carrier females is most often in early childhood. Families with an X-linked dominant inheritance pattern are likely to have CMTX1.
    Neurology 02/2011; 76(5):461-6. DOI:10.1212/WNL.0b013e31820a0ceb · 8.30 Impact Factor
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    J Burns · S Ramchandren · M M Ryan · M Shy · R A Ouvrier
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    ABSTRACT: We have shown that health-related quality of life (QOL) in children with inherited neuropathies (Charcot-Marie-Tooth disease [CMT]) is significantly reduced compared to population norms, thus establishing its utility as an outcome measure in therapeutic trials. However, the Australian ascorbic acid trial in children with CMT type 1A (CMT1A) identified no change in QOL scores despite a trend toward improvement in nerve conduction velocities in the treated group. The objective of this study was to identify clinical, electrophysiologic, and functional correlates of QOL in children with CMT1A, to guide future investigations of strategies to improve QOL and reduce disability in these patients. In this cross-sectional study, a series of multivariate regression models were developed to determine whether QOL scores could be explained by demographic and symptom data, standardized measures of gross motor function, foot/ankle and hand/finger involvement, electrophysiology, and gait characteristics in 70 children aged 5-16 years with CMT1A. Independent determinants of reduced QOL in children with CMT1A, from strongest to weakest, were leg cramps, hand tremor, short step length, reduced long jump distance, ankle inflexibility, poor agility and endurance, advancing age, and foot drop. Many of the standardized clinical and electrophysiologic measures used as endpoints in clinical trials of CMT correlated poorly with QOL. QOL is negatively affected by CMT1A in children. Multivariate modeling suggests that interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility might have a substantial effect on QOL in children with CMT1A.
    Neurology 08/2010; 75(8):726-31. DOI:10.1212/WNL.0b013e3181eee496 · 8.30 Impact Factor
  • CE D’Arcy · MM Ryan
    Journal of Clinical Neuroscience 11/2009; 16(11):1541-1541. DOI:10.1016/j.jocn.2009.07.071 · 1.32 Impact Factor
  • Neurology 10/2008; 71(10):776-7. DOI:10.1212/01.wnl.0000324929.33780.2f · 8.30 Impact Factor
  • J. Burns · R.A. Ouvrier · M. M. Ryan · K. N. North
    Neuromuscular Disorders 10/2008; 18(9):741-742. DOI:10.1016/j.nmd.2008.06.062 · 3.13 Impact Factor
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    ABSTRACT: We describe a kindred with an unusual congenital lower motor neuron disorder with significant but static muscle weakness predominantly affecting the lower limbs. The proband had talipes equinovarus and congenital hip contractures and did not walk until 19 months of age. Lower-extremity predominant, primarily proximal weakness was identified on assessment at three years. Over a 20 year follow-up there has been no clinical progression. The proband has a four-year-old daughter with very similar clinical findings. Electromyography and muscle biopsy suggest reduced numbers of giant normal duration motor units with little evidence of denervation or reinnervation. Dominant congenital spinal muscular atrophy predominantly affecting the lower limbs is rarely described. It is possible that the disorder is due to a congenital deficiency of motor neurons.
    Neuromuscular Disorders 08/2008; 18(7):530-5. DOI:10.1016/j.nmd.2008.04.016 · 3.13 Impact Factor
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    ABSTRACT: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations. The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined. All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations. Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.
    Neurology 06/2008; 70(19):1678-81. DOI:10.1212/01.wnl.0000311275.89032.22 · 8.30 Impact Factor

Publication Stats

280 Citations
111.14 Total Impact Points


  • 2008–2014
    • The Royal Children's Hospital
      • Children's Neuroscience Centre (CNC)
      Melbourne, Victoria, Australia
  • 2012
    • Murdoch Childrens Research Institute
      Melbourne, Victoria, Australia
  • 2009–2012
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 2011
    • University of Melbourne
      Melbourne, Victoria, Australia
  • 2008–2011
    • Children's Hospital at Westmead
      Sydney, New South Wales, Australia
  • 2010
    • Detroit Medical Center
      Detroit, Michigan, United States