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Neuromuscular
Research paper
Rapidly progressive scoliosis and respiratory deterioration in Ullrich congenital muscular dystrophy
  1. Takahiro Yonekawa1,2,3,
  2. Hirofumi Komaki2,
  3. Mari Okada1,
  4. Yukiko K Hayashi1,
  5. Ikuya Nonaka1,2,
  6. Kenji Sugai2,
  7. Masayuki Sasaki2,
  8. Ichizo Nishino1
  1. 1Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan
  2. 2Department of Child Neurology, National Center Hospital, NCNP, Kodaira, Tokyo, Japan
  3. 3Department of Education, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan 
  1. Correspondence to Dr Ichizo Nishino, Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, 4-1-1, Ogawa-Higashicho, Kodaira, Tokyo 187 8502, Japan; nishino{at}ncnp.go.jp

Abstract

Objective To characterise the natural history of Ullrich congenital muscular dystrophy (UCMD).

Patients and methods Questionnaire-based nationwide survey to all 5442 certified paediatric and adult neurologists in Japan was conducted from October 2010 to February 2011. We enrolled the 33 patients (age at assessment, 11±6.6 years) who were reported to have collagen VI deficiency on immunohistochemistry in muscle biopsies. We analysed the development, clinical manifestations, Cobb angle and %vital capacity (%VC) in spirogram.

Results Cobb angle over 30° was noted at age 9.9±5.3 years (n=17). The maximum progression rate was 16.2±10°/year (n=13). %VC was decreased exponentially with age, resulting in severe respiratory dysfunction before pubescence. Scoliosis surgery was performed in 3 patients at ages 5 years, 9 years and 10 years. Postoperative %VC was relatively well maintained in the youngest patient. Non-invasive ventilation was initiated at age 11.2±3.6 years (n=13). Twenty-five (81%) of 31 patients walked independently by age 1.7±0.5 years but lost this ability by age 8.8±2.9 years (n=11). Six patients never walked independently.

Conclusions The natural history of scoliosis, respiratory function and walking ability in UCMD patients were characterised. Although the age of onset varied, scoliosis, as well as restrictive respiratory dysfunction, progressed rapidly within years, once they appeared.

  • MUSCULAR DYSTROPHY
  • NEUROMUSCULAR
  • CLINICAL NEUROLOGY

https://doi.org/10.1136/jnnp-2012-304710

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    Introduction

    Ullrich congenital muscular dystrophy (UCMD) is, after Fukuyama CMD, the second most common CMD in Japan.1 UCMD is characterised by proximal joint contractures, distal joint hyperlaxity, proximal muscle weakness, scoliosis and respiratory failure.1–4 The prevalence of UCMD is reported to be 1.3 per million in northern England.5 Mutations in either COL6A1, COL6A2 or COL6A3 gene, each encoding a subunit of collagen VI (COL6), are known to cause UCMD. We have previously shown that there are two modes of COL6 deficiency: complete COL6 deficiency (CD) and sarcolemma specific COL6 deficiency (SSCD),6 ,7 which are associated with recessive and de novo dominant mutations in COL6 genes, respectively.1

    To date, there is no cure for UCMD, and patients rely on supportive treatment of symptoms such as spinal deformity and respiratory failure. However, pathological hypotheses leading to myofibre degeneration in COL6-deficient skeletal muscle have been proposed and therapeutic targets have been suggested.8 There is currently a clinical trial for UCMD patients based upon the theory of impaired autophagy.9 ,10 Furthermore, a gene-based therapy to inhibit mutant transcripts by antisense has also been proposed because an abnormal mutated subunit can be assembled into growing supramolecular structures and sequester normal subunits into non-functional complexes, thus exerting dominant-negative effect.11 ,12 Advances in such therapeutic research make knowledge of the natural course of the disease and appropriate outcome measures necessary. However, only limited information is available, especially regarding the rate of disease progression.13 We have therefore attempted to determine the natural history of UCMD.

    Patients and methods

    This clinical study was performed in conformity with the Declaration of Helsinki for investigation involving human subjects and was approved by the ethics committee of the National Center of Neurology and Psychiatry.

    A questionnaire-based nationwide survey was conducted from October 2010 to February 2011. The questionnaire was mailed to all 5442 certified paediatric and adult neurologists by the Japanese Society of Child Neurology and the Japanese Society of Neurology, and we received 1881 (34.6%) responses. This survey consisted of questions about perinatal and developmental aspects, age and clinical manifestations at diagnosis, age at assessment, age at loss of ambulation, age at scoliosis surgery, age at initiation of non-invasive ventilation (NIV), data of Cobb angle on x-ray and %vital capacity (VC) in spirogram, in addition to pathological findings and COL6 immunohistochemistry in biopsied muscle (table 1).

    View this table:
    Table 1

    Summary of questionnaire items in this study

    Among 40 patients reported to have UCMD, we enrolled 33 patients (15 men and 18 women) with COL6 deficiency: 5 with CD and 28 with SSCD, on immunohistochemistry in skeletal muscle. Sequence analysis of COL6 genes was performed using genomic DNA from 32 patients, 19 (59.4%) of whom carried identifiable mutations (table 2). All the 14 patients, who were not genetically confirmed, manifested clinical features compatible with UCMD in addition to COL6 deficiency (tables 2 and 3).14 Age at muscle biopsy was 3.2±2 years (mean±SD). Age at assessment was 11±6.6 years. We analysed the information on perinatal abnormalities, development, clinical features, deterioration of ability to walk, progression of scoliosis and respiratory dysfunction.

    View this table:
    Table 2

    Clinical, pathological and genetical findings in the 33 patients

    View this table:
    Table 3

    Perinatal, developmental history and disease progression in our series

    Results

    Perinatal abnormalities and clinical manifestations are shown in tables 2 and 3. Congenital hip dislocation, torticollis and arthrogryposis multiplex were noted in 36.4%, 27.3% and 20% of patients, respectively. More than 50% of patients had distal joint hyperlaxity, protruding calcaneus, high arched palate, proximal joint contractures and scoliosis. Creatine kinase level at muscle biopsy was 315±110 IU/L (n=31). Among patients with CD, homozygous or compound heterozygous mutations were identified in three but a heterozygous mutation was identified in one patient. All the 15 patients with SSCD carried a heterozygous mutation (table 2).

    Twenty-five (81%) of 31 patients were able to sit and walk independently. Six patients (19%) never walked, three of whom had CD by muscle immunohistochemistry (tables 2 and 3). Head control, sitting and independent ambulation were completed at median ages of 4 months, 9 months and 18 months, respectively (figure 1A). In contrast, achievement of speaking phrases was not delayed, ranging from ages 12 months to 25 months (figure 1A). Most patients became able to walk independently by age 2 years but this ability deteriorated with age (figure 1B). Loss of ambulation occurred at age 8.8±2.9 years (n=11). Patient 18 was reported to walk with knee-ankle-foot orthoses at age 11 years. Patients 20 and 30, respectively, required a wheelchair at ages 13 years and 6 years. Half of the patients became wheelchair-bound by age 11 years (figure 1B). Six patients became wheelchair-bound by age 7 years, two of whom had CD and loss of ambulation at ages 5.5 years and 6 years, respectively. Two of four patients with SSCD who carried a heterozygous c.850G>A (p.Gly284Arg) mutation in COL6A1 did not acquire independent ambulation (tables 2 and 3).

    Figure 1
    Figure 1

    (A) Age ranges at completion of neck control, sit, independent ambulation and phrases. The boxes represent the range from the 25–75th percentile, while the bars span the 10–90th percentile. (B) Kaplan-Meier curve showing deterioration of walking ability in Ullrich congenital muscular dystrophy (n=24). Patients 20 and 30, respectively, become wheelchair-bound at ages 13 years and 6 years. (C) Severity and progression of scoliosis (n=23). Open circles, solid squares and triangles indicate preoperative Cobb angles from Patients 8, 9 and 21 who underwent scoliosis surgery at ages 10 years, 9 years and 5 years, respectively. (D) %Vital capacity (%VC) (n=20). Solid line represents the regression curve (%VC=144.8*exp (−0.146*Age)+7.386, R2=0.6684). Solid squares and triangles respectively represent values from Patients 9 and 21 who underwent scoliosis surgery at ages 9 years and 5 years. (E) Kaplan-Meier curve showing the percentage of patients with non-invasive ventilation (NIV) (n=31).

    The severity and progression of scoliosis were assessed by Cobb angle (n=23). Maximum Cobb angles are shown in table 3. Patient 28 was reported to suffer from marked scoliosis albeit no data of Cobb angle was available. Cobb angle over 30° was noted at age 9.9±5.3 years in 17 patients (table 4). Among them 13 patients had Cobb angle data available for 3 or more years and show a maximum progression rate of 16.2±10°/year. Overall, although the onset of scoliosis varied, it progressed rapidly within years once scoliosis was noted (figure 1C). Surgical intervention for scoliosis was performed in Patients 8, 9 and 21 at ages 10 years, 9 years and 5 years, respectively. Presurgical and postsurgical Cobb angle data were available in the last two patients, both of whom showed improvement from 107° to 80° and 90° to 40°, respectively.

    View this table:
    Table 4

    Data of Cobb angle in 23 patients

    Percent VCs at survey are shown in table 3. Patients 8 and 27 had 32% and 70.4% of predicted VC at ages 8 years and 6 years, respectively. Respiratory function, measured by %VC (n=20), decreased exponentially with age accompanied by a sharp decline below age 10 years (figure 1D). Importantly, postoperative VC was relatively well maintained in the patient who underwent surgery at age 5 years (figure 1D). The percentage of patients requiring NIV increased with age (figure 1E). Half of the patients required NIV by age 12 years. Age at initiation of NIV was 11.2±3.6 years (n=13) (table 3). On the other hand, %VC at mean age of NIV initiation was estimated at around 36%.

    Discussion

    This is the first nationwide survey of the natural history of UCMD in Japan. This study confirmed the previously reported clinical features of UCMD: delayed motor milestone, absence of mental retardation, distal joint hyperlaxity, proximal joint contractures, scoliosis and respiratory involvement.1–4 Furthermore, we characterised the natural history of scoliosis, respiratory function and ambulation in this relatively large UCMD series.

    UCMD is on a disease spectrum of COL6 related myopathy. Intermediate phenotypes, named mild UCMD or severe Bethlem myopathy, have been known, and currently there is no clear-cut definition of two major phenotypes.8 ,15 According to the clinical classification of early onset COL6-related myopathies, all the patients in our series can be classified into the most severe (early-severe) or moderate-progressive groups.16 ,17 The age at loss of ambulation was slightly younger compared with the previous observations (10.7±4.8 years and 10.1±4.4 years).13 ,17 Interestingly, patients with CD never walked independently or became unable to walk by age 6 years, indicating that CD is most likely to be associated with the more severe phenotype than SSCD. On the other hand, 3 (10.7%) of 28 patients with SSCD did not acquire independent ambulation. Unlike patients with CD, a great heterogeneity in the maximal motor capacity was observed in those with SSCD, ranging from no acquisition of walking ability to retaining ambulation throughout childhood. Four patients with a heterozygous c.850G>A (p.Gly284Arg) mutation in COL6A1 showed a wide variety in their ability to walk (table 3). In this study we were not able to confirm recessive mutations and a heterozygous mutation in 2 with CD and 13 with SSCD, respectively. The mutation detection rate (59.4%) was comparable with those reported to be up to 60% in other groups,15 and those patients without a putative mutation identified may carry deletions or duplications of one or more exons as well as intronic, regulatory mutations.

    The onset of scoliosis preceded loss of ambulation in UCMD. This pattern of scoliosis progression was also pointed out by Nadeau et al.13 Development of scoliosis in Duchenne muscular dystrophy, on the other hand, is strongly related to the loss of walking ability.18 In Duchenne muscular dystrophy, typically, scoliosis is not evident in ambulatory patients and starts after patients become wheelchair dependent. In UCMD, in contrast, scoliosis developed even when patients were still ambulant and is characterised by marked progression from early stage. For the first time, we characterised scoliosis progression in this study. It is noteworthy that scoliosis progresses rapidly, within years, once it starts. The early-onset and rapidly-progressive scoliosis in UCMD may well accelerate physical disability, such as difficulty in sitting, standing and walking, and cause pain. More importantly, scoliosis may well compromise respiratory function by reducing chest wall compliance.

    VC declined exponentially with age, with a sharp decrease by age 10 years. Nadeau et al showed that forced VC (%predicted) in UCMD declined by 6.6±1.9%/year from age 6 years to 10 years compared with by 0.4±3%/year from age 11 years to 15 years.13 Although the parameters were different, both studies indicate that UCMD patients develop restrictive respiratory dysfunction rapidly in the first decade of life. This decay in VC might be associated with proximal joint and vertebral contractures together with weakness of the diaphragm. Considering the slower decline of %VC in the youngest patient after surgical correction of scoliosis, earlier surgical intervention to correct spinal deformity may be beneficial for maintaining chest wall compliance, thus preventing progressive respiratory dysfunction. Takaso et al successfully performed scoliosis surgery in three patients with UCMD at ages 11 years, 13 years and 17 years, respectively (not enrolled in the present study).19 However, in these patients, surgery did not prevent deterioration of respiratory function suggesting that at such older ages pulmonary and chest wall compliance might be too severely compromised for patients to benefit from scoliosis surgery, and earlier surgical intervention may be more beneficial. However, further studies are necessary to conclude the efficacy of early scoliosis surgery.

    Acknowledgments

    The authors thank Kanako Goto and Rieko Koyama for their technical assistance.

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    Footnotes

    • Contributors TY: designed the study, performed literature search, analysed the data and wrote the manuscript. HK, MO and YKH: supervised all aspects of this study, including the study design, interpretation and manuscript preparation. IN, KS and MS gave valuable comments for the manuscript. IN was involved in analysing and interpreting all the data and also supervised the study design, execution and manuscript preparation.

    • Funding This study was supported by Intramural Research Grant (23-5) for Neurological and Psychiatric Disorders of NCNP, Research on rare and intractable diseases and Research on Applying Health Technology from the Ministry of Health, Labour and Welfare of Japan.

    • Competing interests None.

    • Ethics approval The ethics committee of National Center of Neurology and Psychiatry.

    • Provenance and peer review Not commissioned; externally peer reviewed.