A short form of gross motor function measure for Fukuyama congenital muscular dystrophy

ObjectivesThe objective of this study was to confirm the validity of a short form of gross motor function measure for Fukuyama congenital muscular dystrophy (GMFM for FCMD).MethodsThis study is a case series and was conducted at the Tokyo Women’s Medical University. Fifteen patients with FCMD were assessed using both the GMFM for FCMD with 68 items, which was created as a motor function measure for patients with FCMD on the basis of Rasch analysis, and the original GMFM with 88 items. The correlation between the GMFM for FCMD and the Ueda classification was assessed. Time required for each assessment was also evaluated.ResultsWe found significant correlation between the GMFM for FCMD and the Ueda classification (r = 0.935); furthermore, the mean assessment time tended to decrease when using the GMFM for FCMD.ConclusionsGMFM for FCMD may be an appropriate motor function scale for patients with FCMD and might help decrease the assessment time.     

Urinary titin as a biomarker in Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is the second most prevalent childhood-onset muscular dystrophy in Japan. It is an autosomal recessive disorder caused by the fukutin mutation (FKTN), characterized by muscle wasting and brain abnormalities. So far, serum creatine kinase (CK) is recognized as the only biomarker for FCMD. Recently, an ELISA assay to quantify the N-terminal fragment of titin in urine was developed. Urinary titin concentration is elevated in patients with Duchenne muscular dystrophy (DMD) compared to normal controls. Levels vary according to age with excellent sensitivity and specificity for detecting DMD, and they can be used as a diagnostic and disease progression marker. In this study, we measured the urinary titin concentration of 18 patients with FCMD. It was remarkably higher than normal controls and correlated with CK. Especially in homozygotes, the score for gross motor function measure, which is a quantitative motor scale for FCMD, was correlated with urinary titin concentration. Elevated urinary titin concentrations were thought to be reflective of a common pathophysiology with DMD. Urinary titin concentrations can assist with making the diagnosis of FCMD and to estimate the patient's motor function at that point.     

Assessment of the upper limb muscles in patients with Fukuyama muscular dystrophy: Noninvasive assessment using visual ultrasound muscle analysis and shear wave elastography

Fukuyama-type congenital muscular dystrophy (FCMD) is severe, childhood-onset muscular dystrophy. Recently, our group has discovered a potential treatment using antisense oligonucleotides. Therefore, an effective, reliable, and objective method of assessing muscle is needed. Ultrasound is a minimally invasive tool that can be applied without radiation exposure or pain. Evaluating tissue stiffness by shear wave elastography (SWE) has especially recently attracted attention. Here, we aimed to evaluate SWE value of the upper limb muscles: biceps brachii, triceps brachii, brachioradialis, abductor pollicis brevis, and abductor finger muscle in patients with FCMD. Upper extremity function was evaluated by visual muscle ultrasound analysis (VMUA) and SWE in 13 patients with FCMD and 20 healthy controls. The motor function evaluation tool was used to evaluate motor function, and the correlation with the dynamics of the SWE was determined. VMUA scaled using the Heckmatt scale was higher in patients with FCMD. SWE was also significantly higher and stiffer in the biceps brachii and brachioradialis in patients with FCMD. Furthermore, the severity of FCMD symptoms was correlated with muscle stiffness. We conclude that VMUA and SWE can be useful tools for monitoring muscle atrophy and upper limb function in patients with FCMD.     

National registry of patients with Fukuyama congenital muscular dystrophy in Japan

Fukuyama congenital muscular dystrophy (FCMD) is the second most common form of muscular dystrophy in the Japanese population and is caused by mutations in the fukutin (FKTN) gene. In 2011, the Japan Muscular Dystrophy Association (JMDA) developed a nationwide registry of genetically confirmed patients with FCMD. We retrospectively reviewed the registry dataset of patients with FCMD to obtain data, including age, sex, developmental milestones, intellectual level, complications, and primary treatments. In total, 207 patients with FCMD (104 boys and 103 girls) were registered by the end of September 2013. Mean patient age at first registration was 8.1 ± 7.8 years (median, 6 years; range, 0–42 years). A homozygous 3-kb founder insertion mutation in the FKTN gene was present in 80% of registrants, whereas 20% had a compound heterozygous mutation. Sixty-nine patients (33%) had febrile seizures and/or epilepsy. Myopia was the most frequently detected abnormality (8.7%), followed by strabismus (5.9%). Overall, 16% of patients required respiratory support and this percentage increased with age. Cardiac dysfunction was detected in 16%, and dysphagia was observed in 22% of patients with FCMD. The FCMD patient registry is useful for clarifying the natural history of FCMD and recruiting patients for clinical trials.     

Muscular involvement assessed by MRI correlates to motor function measurement values in oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a progressive skeletal muscle dystrophy characterized by ptosis, dysphagia, and upper and lower extremity weakness. We examined eight genetically confirmed OPMD patients to detect a MRI pattern and correlate muscle involvement, with validated clinical evaluation methods. Physical assessment was performed using the Motor Function Measurement (MFM) scale. We imaged the lower extremities on a 1.5 T scanner. Fatty replacement was graded on a 4-point visual scale. We found prominent affection of the adductor and hamstring muscles in the thigh, and soleus and gastrocnemius muscles in the lower leg. The MFM assessment showed relative mild clinical impairment, mostly affecting standing and transfers, while distal motor capacity was hardly affected. We observed a high (negative) correlation between the validated clinical scores and our visual imaging scores suggesting that quantitative and more objective muscle MRI might serve as outcome measure for clinical trials in muscular dystrophies.     

Congenital muscular dystrophy with characteristic radiological findings similar to those with Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is the most common congenital muscular dystrophy in Japan and there are isolated reports of non-Japanese patients with FCMD. We report an Indian patient with congenital muscular dystrophy and characteristic radiological findings similar to those with FCMD.     

A motor function measurement scale for neuromuscular diseases - description and validation study

A new scale for motor function measurement has been developed for neuromuscular diseases. After the study of a preliminary and a first version, the validation study included 303 patients, aged 6 to 62 years. Seventy-two patients had Duchenne muscular dystrophy, 32 Becker muscular dystrophy, 30 limb-girdle muscular dystrophy, 39 facio-scapulo-humeral dystrophy, 29 myotonic dystrophy, 21 congenital myopathy, 10 congenital muscular dystrophy, 35 spinal muscular atrophy and 35 hereditary neuropathy. The sensitivity for change was evaluated with 152 patients one year after. The scale comprised 32 items, in three dimensions: standing position and transfers, axial and proximal motor function, distal motor function. High correlations (>0.80) were found between the total score and other scores: Vignos and Brooke grades, Functional Independence Measure, the global severity of disability evaluated with visual analog scales by physicians and physiotherapists. This scale is reliable, does not require any special equipment and is well accepted by patients. It takes an average of 36 min (range 8-75) to complete the scale. Preliminary results of the second evaluation showed good sensitivity to change since last visit, considering rating by patient, investigator or physiotherapist. Also, significant differences in scores are obtained with the greatest deterioration observed in Duchenne patients.     

Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype

Six genes including POMT1, POMT2, POMGNT1, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of α-dystroglycan (α-DG). Abnormal glycosylation of α-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and 1D and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described.     

Coagulation and fibrinolysis disorder in muscular dystrophy

To investigate whether there are any basic abnormalities of coagulation and fibrinolysis in muscular dystrophy, we measured serum levels of the MM isozyme of creatine kinase (CK-MM), fibrin and fibrinogen degradation products (FDP), plasma levels of fibrinogen, antithrombin (AT), and D-dimer in 36 patients with Duchenne muscular dystrophy (DMD), 11 with Becker muscular dystrophy (BMD), 5 with Fukuyama congenital muscular dystrophy (FCMD), 5 with myotonic dystrophy (MyD), and 5 with spinal muscular atrophy (SMA) type 2. FDP levels were elevated in the patients with DMD, BMD, and FCMD (1.0 to 84.9 microg/ml), but not in the patients with MyD and SMA type 2. In DMD, BMD, and FCMD, FDP levels significantly correlated with CK-MM, but not with age, fibrinogen, AT, D-dimer, and type of dystrophy (multiple regression analysis; r(2) = 0.814, P < 0.0001). These findings suggested that enhanced coagulation and fibrinolysis are associated with muscle degeneration in patients with DMD, BMD, and FCMD.     

A motor function measure for neuromuscular diseases. Construction and validation study

A new scale for motor function measurement has been developed for neuromuscular diseases. The validation study included 303 patients, aged 6-62 years. Seventy-two patients had Duchenne muscular dystrophy, 32 Becker muscular dystrophy, 30 limb-girdle muscular dystrophy, 39 facio-scapulo-humeral dystrophy, 29 myotonic dystrophy, 21 congenital myopathy, 10 congenital muscular dystrophy, 35 spinal muscular atrophy and 35 hereditary neuropathy. The scale comprised 32 items, in three dimensions: standing position and transfers, axial and proximal motor function, distal motor function. Agreement coefficients for inter-rater reliability were excellent (kappa=0.81-0.94) for nine items, good (kappa=0.61-0.80) for 20 items and moderate (kappa=0.51-0.60) for three items. High correlations were found between the total score and other scores: Vignos (r=0.91) and Brooke (r=0.85) grades, Functional Independence Measure (r=0.91), the global severity of disability evaluated with visual analog scales by physicians (r=0.88) and physiotherapists (r=0.91). This scale is reliable, does not require any special equipment and is well-accepted by patients. Its sensitivity to change is being assessed to permit its use in clinical trials of neuromuscular diseases.     

Timed function tests,motor function measure,and quantitative thigh muscle MRI in ambulant children with Duchenne muscular dystrophy: A cross-sectional analysis

The development of new therapeutic agents for the treatment of Duchenne muscular dystrophy has put a focus on defining outcome measures most sensitive to capture treatment effects. This cross-sectional analysis investigates the relation between validated clinical assessments such as the 6-minute walk test, motor function measure and quantitative muscle MRI of thigh muscles in ambulant Duchenne muscular dystrophy patients, aged 6.5 to 10.8 years (mean 8.2, SD 1.1). Quantitative muscle MRI included the mean fat fraction using a 2-point Dixon technique, and transverse relaxation time (T2) measurements. All clinical assessments were highly significantly inter-correlated with p < 0.001. The strongest correlation with the motor function measure and its D1-subscore was shown by the 6-minute walk test. Clinical assessments showed no correlation with age. Importantly, quantitative muscle MRI values significantly correlated with all clinical assessments with the extensors showing the strongest correlation. In contrast to the clinical assessments, quantitative muscle MRI values were highly significantly correlated with age. In conclusion, the motor function measure and timed function tests measure disease severity in a highly comparable fashion and all tests correlated with quantitative muscle MRI values quantifying fatty muscle degeneration.     

Three-dimensional MR imaging of brain surface anomalies in fukuyama-type congenital muscular dystrophy

Fukuyama-type congental muscular dystrophy (FCMD), the second most common childhood muscular dystrophy in Japan, is characterized by the association with severe brain anomalies such as pachygyria and focal interhemispheric fusion. Conventional imaging techniques such as X-ray CT scan and MRI are ineffective for visualization of these brain surface anomalies. Here we investigated the efficacy of three-dimensional (3-D) reconstruction of brain surface MR images for the detection of brain anomalies in FCMD patients. 3-D brain surface MR images clearly visualized anomalies of cerebral gyrus such as pachygyria, as well as focal interhemispheric fusion. In addition, reconstructed horizontal images visualized structural derangement such as abnormal protrusion of white matter into gray matter. MR image abnormalities were confirmed by autopsy in 1 patient. These abnormalities were never observed in Duchenne muscular dystrophy (DMD) patients. Our results indicate the efficacy of the present method for the differential diagnosis between FCMD and DMD with severe mental retardation, which is essential for the genetic study to identify the causative gene of FCMD. © 1995 John Wiley & Sons, Inc.     

Vascular alterations in Fukuyama type congenital muscular dystrophy

Blood vessels in muscle biopsy specimens from 6 Fukuyama type congenital muscular dystrophy (FCMD) patients were examined by electron microscopy and compared with ones in non-diagnostic biopsy specimens from age-matched controls and patients with childhood neuromuscular disorders. The most striking feature was the blister-like swelling of vascular endothelial cells in the biopsied muscle specimens from 5 of the 6 patients with FCMD. Morphometric analysis of capillaries in biopsied muscles showed the extremely greater capillary, endothelial and pericyte areas in the FCMD patients than in controls. These phenomena are quite similar to those found in Duchenne muscular dystrophy (DMD) at the preclinical stage and suggest an as yet undetermined process in blood vessels in FCMD as well as DMD. An immunohistochemical study involving dystrophin antibodies showed positive staining in FCMD.     

Evaluating motor function in children with Down syndrome: validity of the GMFM

The Gross Motor Function Measure (GMFM) was developed and validated originally by Russell and colleagues as an evaluative assessment of gross motor function in children with cerebral palsy (CP). The present study reports the results of reliability and validity testing of the GMFM for use with children with Down syndrome (DS). One hundred and twenty-three children with DS were assessed twice over a 6-month period, using the GMFM and the motor scale of the Bayley Scales of Infant Development - second edition (BSDD-II). In addition to the usual method of scoring the GMFM using only observed motor behaviours (standard score), parent reports of children's activities not seen by the assessor on the day of testing were also obtained and a second score (reported score) was calculated for each GMFM assessment. Test-retest and interrater reliabilities were excellent (all > 0.90). Observed correlations between change on GMFM and judgements of change made independently by parents, intervenors, and masked video raters were lower than hypothesized. However, the pattern of change scores in predefined age and severity subgroups supported the contention that the GMFM was able to detect differential amounts of change as predicted. The GMFM was shown to be relatively more responsive to change in gross motor function than the motor scale of the BSID-II. The 'reported' scores on the GMFM demonstrated better evidence of reliability, validity, and responsiveness than the standard scoring method and this approach is recommended for use when assessing children with DS.     

A Portuguese case of Fukuyama congenital muscular dystrophy caused by a multi-exonic duplication in the fukutin gene

Fukuyama congenital muscular dystrophy (FCMD) is one of the most common autosomal recessive diseases among the Japanese population, due to a founder mutation of the fukutin gene (FKTN). Mutations in FKTN are now being described in an increasing number of non-Japanese patients. We report a Portuguese child with FCMD. The diagnosis was supported by clinical, histological, magnetic resonance imaging (MRI) and genetic studies. Genetic analysis of FKTN by Multiplex Ligation Probe Amplification (MLPA) revealed a homozygous duplication from exon 4 to exon 7. This in-frame duplication was confirmed by cDNA analysis. To our knowledge this is the first report of a FCMD case caused by an intragenic gross exonic duplication in the FKTN gene. This report widens the clinical and mutational spectrum in FCMD and corroborates the importance of screening for large deletions and duplications in CMD patients.     

Immunocytochemical analysis of dystrophin in congenital muscular dystrophy.

Using immunocytochemical methods, we examined the intensity and distribution of dystrophin and spectrin immunostaining of skeletal muscles from 51 congenital muscular dystrophy (CMD) patients including 36 Fukuyama congenital muscular dystrophy (FCMD) and 15 non-FCMD (other CMD). 17 age-matched spinal muscular atrophy (SMA) and 5 Duchenne muscular dystrophy (DMD) patient biopsies were studied as controls. All 15 non-FCMD and SMA patients showed normal localization of dystrophin at the surface membrane of each muscle fiber which was undetectable in DMD. In contrast, 34 of 36 FCMD patients exhibited an unusual immunostaining pattern with occasional (17-43%; mean = 28) negative or abnormally immunoreacted (partially deficient, fluffy or intense) fibers for dystrophin. Dystrophin was absent in 2 of 36 patients having a clinical diagnosis of FCMD, and intragenic deletion of the DMD gene was detected in one. Spectrin, a membrane cytoskeletal protein related to dystrophin, also showed an increased number of abnormally immunostained fibers in FCMD (25%), but not so high in age-matched DMD (9%) or SMA patient muscle (0%). Thus, our results suggested the presence of intrinsic factor(s) that produce abnormality of the plasma membrane of FCMD muscle.     

Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype

Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker–Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.     

Changes in the clinical picture of Fukuyama type. Congenital muscular dystrophy in its advanced stage: effectiveness of mechanical ventilation systems

We studied the clinical courses of Fukuyama type congenital muscular dystrophy (FCMD) based on a long-term follow-up of 7 patients. Their peak motor function varied from controlling the head incompletely to standing with support. Six patients had epilepsy, which in some cases was diagnosed with difficulty because of changing seizure types and multiple joint contracture. Six patients underwent endotracheal intubation, and in 5 of them long-term mechanical ventilation began at the age of 15 to 20 years. Three of them underwent trachestomy intermittent positive pressure ventilation (TIPPV), whereas recently 2 patients were treated successfully with nasal intermittent positive pressure ventilation (NIPPV). Mechanical in-exsufflation (MI-E) was effective in clearing airway secretion of 4 patients. With disease progression, the motor, mental, nutritional, cardiorespiratory and swallowing functions of FCMD patients should be assessed to ensure adequate management by NIPPV and MI-E.     

Clinical significance of serum cardiac myosin light chain I in patients with muscular dystrophy

We examined serum cardiac myosin light chain I (LCI), serum creatine kinase (CK) levels and left ventricular function in patients with muscular dystrophy and secondary cardiac involvement. LCI levels were determined by a two-site immunoradiometric assay method in 25 patients with muscular dystrophy and 10 normal subjects. This study included 15 patients with Duchenne muscular dystrophy (DMD), 8 patients with Fukuyama type congenital muscular dystrophy (FCMD) and 2 sisters with non-Fukuyama type congenital muscular dystrophy (nFCMD). We measured the value of left ventricular fractional shortening (FS) using echocardiography. All patients with DMD and FCMD showed moderate or severe skeletal muscle weakness. The mean values of LCI were significantly higher in patients with DMD (11.0 +/- 8.3 ng/ml, p less than 0.01) and in patients with FCMD (1.6 +/- 1.4 ng/ml, p less than 0.05) than in normal subjects (0.3 +/- 0.2 ng/ml). In patients with DMD, LCI level correlated closely with CK level (r = 0.81, p less than 0.01) but not with FS (r = 0.35, n.s.). In patients with FCMD, LCI level correlated significantly with CK level (r = 0.75, p less than 0.05) but not with FS (r = 0.44, n.s.). Close correlation between LCI and CK levels was thought to result from the cross reaction between cardiac LCI and myosin light chains of skeletal muscle in the assay method we used. Two siblings with nFCMD showed mild skeletal muscle weakness. A 22-year-old sister with mild left ventricular dysfunction (FS = 0.41) showed high level of CK (4794/U/L) and mild elevation of LCI (7.3 ngml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hint and luck for identification of a gene for Fukuyama muscular dystrophy, fukutin]

Fukuyama type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy, associated with brain anomalies due to neuronal overmigration. By taking advantages of the presence of a consanguineous patient with both FCMD and xeroderma pigmentosum group A, we performed homozygosity mapping using consanguineous FCMD families mainly, and localized the FCMD locus to chromosome 9q31-33. Subsequently, we have identified the gene responsible for FCMD on 9q31, which encodes a novel 461-amino-acid protein termed fukutin. Most FCMD-bearing chromosomes are derived from a single ancestral founder (87%), and a 3kb-retrotransposal insertion was found to be a founder mutation. Two independent point mutations in this gene have also been detected on chromosomes carrying the non-founder haplotype. FCMD is the first human disease to be caused by an ancient retrotransposal integration. We further identified the gene for muscle-eye-brain (MEB) disease, which encodes POMGnT1. Recent studies have revealed that posttranslational modification of alpha-dystroglycan is associated with congenital muscular dystrophy with brain malformations. Since hypoglycosylation of alpha-dystroglycan is common amongst several other disorders, a new clinical entity called alpha-dystroglycanopathy is proposed. However, only POMGnT1 (MEB) and POMT1 (WWS) are shown to have a definite enzymatic activity, and no enzymatic activity has been detected in fukutin. We show positive interactions between fukutin and POMGnT1. Fukutin may form a protein complex with POMGnT1 and modulate POMGnT1's enzymatic activity. Through cDNA microarray, we also show aberrant neuromuscular junction formation and delayed muscle fiber maturation in alpha-dystroglycanopathies, suggesting a new pathomechanism.