Fukuyama Congenital Muscular Dystrophy Research Articles

Assessment of skeletal muscle in patients with Fukuyama congenital muscular dystrophy (FCMD) using bioelectrical impedance analysis (BIA)

Background: It was reported that gene therapy can provide a possible basis for the treatment of patients with FCMD. There is now a greater need for safe, non-invasive techniques for evaluate of skeletal muscle volume in FCMD.

P.45 - Complications of advanced Fukuyama congenital muscular dystrophy from a nationwide registry

P.45 - Complications of advanced Fukuyama congenital muscular dystrophy from a nationwide registry

Rapidly progressive heart failure requiring transplantation in muscular dystrophy: a need for frequent screening

Fukuyama congenital muscular dystrophy weakens both skeletal and cardiac muscles, but the rate of cardiomyopathic progression can accelerate faster than that of skeletal muscles. A 14-year-old boy with Fukuyama congenital muscular dystrophy presented with mild skeletal myopathy but severe cardiomyopathy requiring heart transplantation within 1 year of declining heart function. These patients need frequent screening regardless of musculoskeletal symptoms.

Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan.

Fukuyama congenital muscular dystrophy (FCMD), which is caused by mutations in the fukutin gene, is the second most common form of childhood muscular dystrophy in Japan. The founder haplotype is the most prevalent in the chromosomes of Japanese FCMD patients, and corresponds to an SVA retrotransposal insertion in the 3'-untranslated region of fukutin. Although other mutations have been reported, the mutation corresponding to the second most prevalent haplotype in Japanese FCMD patients remained unknown. Recently a deep-intronic point mutation c.647+2084G>T was identified in Korean patients with congenital muscular dystrophy. Here, we performed mutational analysis of 10 patients with the second most prevalent haplotype and found that all of them were compound-heterozygous for the SVA insertion and this c.647+2084G>T mutation. The fukutin mRNA of these patients contained a pseudoexon between exon 5 and exon 6, which was consistent with the previous Korean study. As expected, the mutated fukutin protein was smaller than the normal protein, reflecting the truncation of fukutin due to a premature stop codon. Immunostaining analysis showed a decrease in the signal for the glycosylated form of α-dystroglycan. These findings indicated that this mutation is the second most prevalent loss-of-function mutation in Japanese FCMD patients.

Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy

BackgroundOne of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited. AimTo compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD). MethodsWe compared cardiac involvement between 30 patients with FCMD and 181 patients with DMD using echocardiography and serum biomarkers. All patients were receiving regular checkups at Kobe University Hospital. We used single regression analysis to compare echocardiographic parameters, age, and serum biomarkers. ResultsAlmost all clinical and echocardiographic parameters were lower in patients with FCMD than DMD. The brain natriuretic peptide concentration in patients with FCMD showed no correlation with age or left ventricular ejection fraction (r=0.231, p=0.22 and r=0.058, p=0.76, respectively). A log-rank test revealed that the risk of left ventricular systolic dysfunction was lower in patients with FCMD than DMD (p=0.046, hazard ratio=0.348). ConclusionThe clinical progression of cardiac dysfunction is significantly milder in patients with FCMD than DMD, while skeletal muscle involvement is significantly worse in patients with FCMD. These data suggest that the pathophysiological findings of FCMD can be explained by less severe cardiac dysfunction in FCMD than DMD.

Spinal correction in patients with Fukuyama congenital muscular dystrophy.

Fukuyama congenital muscular dystrophy (FCMD) is one of the most common congenital progressive muscular dystrophies in Japan. Some patients develop a severe spinal deformity that leads to an unstable sitting position or pain. Since 2008, we have treated FCMD using posterior spinal fusion. This study reports the short-term clinical and radiographic results of posterior spinal correction and fusion in FCMD. We retrospectively reviewed 11 consecutive FCMD patients, average age 13 years old, treated with posterior spinal instrumentation and fusion between 2008 and 2015. All patients were non-ambulatory and complained about difficulty sitting and/or buttock pain. Posterior spinal correction was performed to halt progression of spinal deformity and improve their sitting balance. Assessment was performed clinically and with radiological measurements at a mean follow up period of 34.5 months. To evaluate functional status of patients after surgery objectively, a Muscular Dystrophy Spine Questionnaire (MDSQ) was obtained at the final follow up. The mean height, weight and body mass index of the patients were 144.1±11.8cm, 26.5±8.7kg and 12.5±2.6kg/m2. The average intensive care unit stay was 1.3 days. Five patients had complications related to surgery. The mean preoperative major Cobb angle and pelvic obliquity (PO) were 65.5±41.7° and 31.4±28.9°, respectively, were corrected to 34.4±29.7° and 20.0±18.7° just after the surgery, and were maintained at 35.1±29.9° and 20.5±21.1° at the final follow up. The average MDSQ score was 35.8±13.2 at the final follow up. Posterior spinal correction and fusion in FCMD achieved good radiographic results and clinical improvement with acceptable perioperative complications. FCMD patients are mentally impaired and physically small, so post-operative observation and close attention to perioperative complications are critical.

Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.

The gross motor function measure is valid for Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is the second most common muscular dystrophy in Japan. FCMD is an autosomal recessive disorder caused by mutations in the fukutin gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities, and mental retardation associated with cortical migration defects, and most patients are never able to walk. To date, the development of a quantitative motor scale for FMCD has been difficult due to the moderate-to-severe intellectual impairment that accompanies FCMD. Gross motor function measure (GMFM), originally developed as a quantitative motor scale for cerebral palsy, can precisely and quantitatively assess motor function without complicated instructions, and was recently reported to be useful in the assessment of Down syndrome and spinal muscular atrophy. To confirm the validity of GMFM for the assessment of FCMD, 41 FCMD patients (age range: 0.6–24.4 years) were recruited for this study. The GMFM scores correlated significantly with those of two previously used motor scales, and the time-dependent change in GMFM scores was consistent with the natural course of FCMD. The inter-rater reliability, based on determinations made by four physiotherapists blinded to each other's assessment results, was excellent. We concluded GMFM to be a useful and valid measure of motor function in FCMD patients.

P.32 - Detection of early change in Fukuyama congenital muscular dystrophy by STIR skeletal muscle MRI

P.32 - Detection of early change in Fukuyama congenital muscular dystrophy by STIR skeletal muscle MRI

P.254 - Japanese nationwide registry for Fukuyama congenital muscular dystrophy patients

P.254 - Japanese nationwide registry for Fukuyama congenital muscular dystrophy patients

Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients with undiagnosed early-onset neuromuscular disorders.

Neuromuscular disorders are clinically and genetically heterogeneous diseases with broadly overlapping clinical features. Progress in molecular genetics has led to the identification of numerous causative genes for neuromuscular disorders, but Sanger sequencing-based diagnosis remains labor-intensive and expensive because the genes are large, the genotypes and phenotypes of neuromuscular disorders overlap and multiple genes related to a single phenotype exist. Recently, the advent of next-generation sequencing (NGS) has enabled efficient, concurrent examination of several related genes. Thus, we used NGS for target resequencing of neuromuscular disease-related genes from 42 patients in whom undiagnosed early-onset neuromuscular disorders. Causative genes were identified in 19/42 (45.2%) patients (six, congenital muscular dystrophy; two, Becker muscular dystrophy (BMD); three, limb-girdle muscular dystrophy; one, concurrent BMD and Fukuyama congenital muscular dystrophy; three, nemaline myopathy; one, centronuclear myopathy; one, congenital fiber-type disproportion; one, myosin storage myopathy; and one, congenital myasthenic syndrome). We detected variants of uncertain significance in two patients. In 6/19 patients who received a definitive diagnosis, the diagnosis did not require muscle biopsy. Thus, for patients with suspected neuromuscular disorders not identified using conventional genetic testing alone, NGS-based target resequencing has the potential to serve as a powerful tool that allows definitive diagnosis.

Homozygote Deletion of Fukutin Gene (FKTN) Exon 3 Causes Dilated Cardiomyopathy and Mild Limb-Girdle Muscular Dystrophy without Brain Involvement

Background: FKTN mutations (MIM607440) cause three different forms of muscular dystrophy-dystroglycanopathy: a severe congenital form with brain and eye anomalies (MIM253800; Fukuyama congenital muscular dystrophy = FCMD); a less severe congenital form without intellectual disability (MIM613152); and a milder limb-girdle form (MIM611588). In addition, FKTN mutations can also cause dilated cardiomyopathy (CMD1X; MIM611615) with or without limb-girdle muscle involvement.

Central Nervous Involvement in Patients with Fukuyama Congenital Muscular Dystrophy

Fukuyama congenital muscular dystrophy (FCMD), the second most common muscular dystrophy in the Japanese population, is an autosomal recessive disorder caused by mutations in the fukutin (FKTN) gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities and central nervous system involvement with mental retardation and seizures associated with cortical migration defects. The FKTN gene product is thought to be necessary for maintaining migrating neurons in an immature state during migration, and for supporting migration via α-dystroglycan in the central nervous system. Typical magnetic resonance imaging findings in FCMD patients are cobblestone lissencephaly and cerebellar cystic lesions. White matter abnormalities with hyperintensity on T(2)-weighted images are seen especially in younger patients and those with severe phenotypes. Most FCMD patients are mentally retarded and the level is moderate to severe, with IQs ranging from 30 to 50. In our recent study, 62% of patients developed seizures. Among them, 71% had only febrile seizures, 6% had afebrile seizures from the onset, and 22% developed afebrile seizures following febrile seizures. Most patients had seizures that were controllable with just 1 type of antiepileptic drug, but 18% had intractable seizures that must be treated with 3 medications.

G.P.270 - Assessment of growth and development in patients with Fukuyama congenital muscular dystrophy using bioelectrical impedance analysis

G.P.270 - Assessment of growth and development in patients with Fukuyama congenital muscular dystrophy using bioelectrical impedance analysis

G.P.269 - Correlation between crural muscle fatty change and maximum motor function in Fukuyama congenital muscular dystrophy patients

G.P.269 - Correlation between crural muscle fatty change and maximum motor function in Fukuyama congenital muscular dystrophy patients

Respiratory management of patients with Fukuyama congenital muscular dystrophy

BackgroundFukuyama congenital muscular dystrophy (FCMD), characterized by intellectual impairment associated with cortical migration defects, is an autosomal recessive disorder caused by mutation in the fukutin gene. It is the second most common type of muscular dystrophy in Japan. Respiratory dysfunction, along with cardiomyopathy, can be life-threatening in patients with advanced-stage FCMD. However, few reports have focused on this issue. MethodsWe retrospectively studied respiratory dysfunction and therapeutic management in 48 genetically diagnosed FCMD patients (mean age 11.0years; range 3.6–31.9years). ResultsMechanical ventilation was initiated at a median age of 12.1years in 16 patients, 14 of whom received non-invasive positive pressure ventilation (NPPV) while the other 2 underwent tracheostomy with invasive ventilation (TIV). The two TIV cases had unexpectedly required the initiation of ventilatory support at the ages of 15.7 and 18.0years, respectively, because of unsuccessful extubation followed by serious respiratory infections, despite rather good respiratory function before these episodes. Patients carrying a compound heterozygous founder mutation or with a severe phenotype tended to need ventilatory support 2–3years earlier than homozygous patients and those with the typical or mild phenotype. Mechanical insufflation–exsufflation (MI–E) interventions were also employed in six patients with serious dysphagia and were well-tolerated in all cases. ConclusionFor respiratory management, it is important to regularly evaluate respiratory function in FCMD patients over 10years of age, since intellectual impairment and insomnia often mask the signs of respiratory dysfunction. Most patients, despite poor cooperation due to intellectual impairment, can tolerate NPPV and MI–E provided that a carefully worked-out plan is adopted.

Abstract 3333: The expression of FKTN gene in gastric cancer related to radiation exposure: research on atomic bomb survivors

Abstract While radiation use increases, the Life Span Study (LSS) atomic bomb survivor cohort of Radiation Effects Reserach Foundation (RERF) from 1951-2003 shows a significant cancer risk for most major organs in the body, including stomach. To identify genes associated with gastric cancer, we utilize Escherichia coli ampicillin secretion trap (CAST) method, which is a powerful tool for novel cancer biomarkers. By this method, we found that FKTN (fukutin) was overexpressed in gastric cancer. Fukutin localizes to the Golgi apparatus and normally has low expression, but overexpresses in some cell lines. It is thought to forms a complex with protein POMGnT1, a glycosyltransferase involved in the synthesis of O-mannosyl glycan attached to mucin-like domain of alpha-dystroglycan. The POMGnT1 activity was also downregulated by fukutin mutation and resulted in Fukuyama congenital muscular dystrophy: brain malformation, one of the most common autosomal-recessive disorders in Japan. To elucidate the molecular mechanisms of radiation carcinogenesis, we analyzed FKTN expression from sporadic gastric cancer cohort and LSS cohort by immunohistochemistry. In the sporadic cohort of 695 gastric cancer samples, there was a significant correlation of FKTN expression in differentiated type gastric cancer. For mucin markers, a significant relationship was detected between FKTN and CD10 (p<0.0001). The LSS cohort of 86 gastric cancer samples showed FTKN expression downregulated in high-dose than in low-dose exposed patients (p<0.0001), but with no correlation between FKTN and mucin phenotype expression. This is the first analysis on the expression of fukutin protein in gastric cancers among atomic-bomb survivors and the radiation dose response, using immunohistochemistry. These results suggest that FTKN has a possible relationship with radiation exposure and gastric cancer among atomic bomb survivors. Citation Format: Trang T.B. Pham. The expression of FKTN gene in gastric cancer related to radiation exposure: research on atomic bomb survivors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3333. doi:10.1158/1538-7445.AM2015-3333

MRI findings in Fukuyama-type congenital muscular dystrophy of Chinese

Objective To investigate the MRI features of Fukuyama-type congenital muscular dystrophy(FCMD) in Chinese. Methods The MRI and clinical data of 3 patients with FCMD which had been diagnosed by gene analysis were retrospectively analyzed.Two females and one male were included in this study, and they underwent MR examination at 0.5,2.3,5.0 years old respectively. The main clinical manifestations were muscular hypotonia and severe developmental delay. Abnormalities on MR images were analyzed and recorded by two experienced radiologists. Results Unlayerdpoly microgyria involved in frontal lobes, numerous intraparenchymal cysts at the peripheral hemispheres and prolonged T1 and T2 signal in the white matter were found in all the 3 cases. Disorganized cerebellar folia, lissencephaly of cerebral cortices, flattened pons were detected in 2 cases. Cystic region of white matter incerebral cortices and enlarged fourth ventricle could be seen in one case. Conclusion There are typical MR imaging featuresof FCMD, and preliminary diagnosis can be made by the combination with clinical symptoms and biochemical analysis. Key words: Muscular dystrophies; Brain; Magnetic resonance imaging

Founder mutation causes classical Fukuyama congenital muscular dystrophy (FCMD) in Chinese patients.

Fukuyama congenital muscular dystrophy (FCMD) is a congenital muscular dystrophy rarely reported outside Japan. Here, we report three patients with Fukuyama congenital muscular dystrophy (FCMD) in China who shared a similar clinical phenotype and 3-kb insertion in the FKTN 3' untranslated region. Immunofluorescence staining was undertaken on muscle biopsies from three patients using alpha dystroglycan antibody (IIH6). Genomic DNA from patients and parents was extracted from peripheral blood leukocytes. Polymerase chain reaction and DNA sequencing were employed to analyze the exons and surrounding intron sequences of the fukutin (FKTN) gene to detect mutations. Haplotype analysis was also performed on each patient and their parents. All patients had delayed mental and motor development, febrile convulsions, muscle weakness, and moderate to significant raised levels of serum creatine kinase (7000-11,160 U/L, 25-60×normal). Brain MRI scans showed micropolygyria and extensive dysplasia in the white matter and brainstem. Electromyography revealed myopathic changes. Muscle immunofluorescence studies demonstrated reduced IIH6 staining. Genetic testing showed compound heterozygous mutations of FKTN. Cases 1 and 2 had a c.139C>T (p.Arg47(∗)) heterozygous mutation. Case 3 had a c.346C>T (p.Gln116(∗)) heterozygous mutation. All patients had a heterozygous 3-kb insertion in the FKTN 3' untranslated region. Haplotype analyses suggested that these patients had the same haplotype as Japanese patients.

Fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression.

α-Dystroglycanopathy (α-DGP) is a group of muscular dystrophy characterized by abnormal glycosylation of α-dystroglycan (α-DG), including Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease, Walker-Warburg syndrome, and congenital muscular dystrophy type 1D (MDC1D), etc. LARGE, the causative gene for MDC1D, encodes a glycosyltransferase to form [-3Xyl-α1,3GlcAβ1-] polymer in the terminal end of the post-phosphoryl moiety, which is essential for α-DG function. It has been proposed that LARGE possesses the great potential to rescue glycosylation defects in α-DGPs regardless of causative genes. However, the in vivo therapeutic benefit of using LARGE activity is controversial. To explore the conditions needed for successful LARGE gene therapy, here we used Large-deficient and fukutin-deficient mouse models for MDC1D and FCMD, respectively. Myofibre-selective LARGE expression via systemic adeno-associated viral gene transfer ameliorated dystrophic pathology of Large-deficient mice even when intervention occurred after disease manifestation. However, the same strategy failed to ameliorate the dystrophic phenotype of fukutin-conditional knockout mice. Furthermore, forced expression of Large in fukutin-deficient embryonic stem cells also failed to recover α-DG glycosylation, however coexpression with fukutin strongly enhanced α-DG glycosylation. Together, our data demonstrated that fukutin is required for LARGE-dependent rescue of α-DG glycosylation, and thus suggesting new directions for LARGE-utilizing therapy targeted to myofibres.