Rat animal models are widely used owing to their relatively superior cognitive abilities and higher similarity compared with mouse models to human physiological characteristics. However, their use is limited because of difficulties in establishing embryonic stem cells and performing genetic modifications, and insufficient embryological research. In this study, we established optimal superovulation and fertilized-egg transfer conditions, including optimal hormone injection concentration (≥150 IU/kg of PMSG and hCG) and culture medium (mR1ECM), to obtain high-quality zygotes and establish in vitro fertilization conditions for rats. Next, sgRNA with optimal targeting activity was selected by performing PCR analysis and the T7E1 assay, and the CRISPR/Cas9 system was used to construct a rat model for muscular dystrophy by inducing a deficiency in the fukutin gene without any off-target effect detected. The production of fukutin knockout rats was phenotypically confirmed by observing a drop-in body weight to one-third of that of the control group. In summary, we succeeded in constructing the first muscular dystrophy disease rat model using the CRISPR/CAS9 system for increasing future prospects of producing various animal disease models and encouraging disease research using rats.

Recently, motorized mobility devices (or power mobility devices (PMDs)) have been introduced for infants and toddlers who lack the means for self-mobility. Previous reports have primarily focused on PMDs for individuals with cerebral palsy. Few have explored PMDs for individuals with neuromuscular diseases who have intellectual disabilities. This report presents a case study of the early introduction of a PMD for an infant with Fukuyama congenital muscular dystrophy and presents the results of an interview with the father regarding psychological aspects and the child\'s manipulative abilities. The PMD was introduced at the age of 1 year and 10 months, and the changes during the 19 months after the introduction were evaluated six times, using the Assessment of Learning Powered mobility use tool (ALP). A semi-structured interview with the father was conducted 19 months after the introduction. The ALP evaluation and the interview were conducted by one physical therapist and two physical therapy students, and the results were shared with the hospital\'s physical therapist and nurses at the nursing facility. This report provides a basis for expanding the scope of PMD use and for considering the family\'s involvement, especially for the child.

The causative gene of Fukuyama congenital muscular dystrophy (fukutin) is involved in formation of the basement membrane through glycosylation of alpha-dystroglycan. However, there are other proposed functions that have not been fully understood. Using cultured astrocytes (1321N1), we found nuclear localization of fukutin and a positive relationship between fukutin expression and cell proliferation. Among potential proteins regulating cell proliferation, we focused on cyclin D1, by reverse-transcription polymerase chain reaction, Western blotting, immunocytochemistry, enzyme-linked immunosorbent assay (ELISA), and sandwich ELISA. Expression of cyclin D1 was significantly downregulated by fukutin knockdown and significantly upregulated by fukutin overexpression. Moreover, fukutin was proven to bind to the activator protein-1 (AP-1) binding site of cyclin D1 promoter, as well as the AP-1 component c-Jun. The c-Jun phosphorylation status was not significantly influenced by knockdown or overexpression of fukutin. The present results provide in vitro evidence for a novel function of fukutin, which participates in cell proliferation by enhancing cyclin D1 expression through forming a complex with AP-1. It is likely that fukutin is a potential cofactor of AP-1.

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.

BACKGROUND: Marked decreases in serum creatine kinase levels have been noted in Duchenne and Becker muscular dystrophies as rare complications of autoimmune or autoinflammatory diseases.
METHODS: The influence of systemic inflammation on serum creatine kinase levels was reviewed from the charts of three subjects with Fukuyama congenital muscular dystrophy.
RESULTS: A total of 30 infectious events were identified. Elevated serum C-reactive protein levels coincided with decreased creatine kinase levels on 19 occasions. In one subject, administration of 2 mg/kg/d prednisolone for bronchial asthma resulted in a decrease in creatine kinase level on six other occasions.
CONCLUSIONS: Apart from an increase in endogenous cortisol secretion, certain inflammation-related molecules could play a role in mitigating muscle cell damage in Fukuyama congenital muscular dystrophy during febrile infectious episodes. Corticosteroids may be a promising agent for the treatment of muscular symptoms in this disorder.

BACKGROUND: Recent advances in respiratory management have improved survival for patients with Fukuyama congenital muscular dystrophy (FCMD), characterized by congenital muscular dystrophy and brain malformation. Previous studies reported that more than half of patients exhibit seizures in childhood. However, little is known about epilepsy after childhood.
METHODS: To elucidate the long-term clinical course of epilepsy, we retrospectively reviewed all medical records in nine patients (6 males, mean age 20.7 years) with FCMD diagnosed between 1981 and 2019.
RESULTS: The follow-up periods ranged from 6 to 30 years (mean 18.4 years). A total of 75 EEG recordings were available from nine patients. In some patients, EEGs were normal during early childhood but tended to show paroxysmal discharges with age. Overall, epileptic seizures were observed in six patients. Except for one presenting with afebrile seizure at one year of age, the remaining five patients developed epilepsy between 13 and 22 years of age. The most common seizure type was focal impaired awareness seizure. After adolescence, four patients exhibited status epilepticus. Their convulsive movements of the seizures became less prominent with progression of the disease. At the last evaluation, most patients (5/6) had uncontrolled seizures.
CONCLUSIONS: Despite presence of distinct brain malformation, epileptic seizures may develop after childhood in FCMD patients. Our experience suggests that clinicians should be careful not to overlook epileptic seizures, especially in advanced-stage patients who had profound muscle weakness.

OBJECTIVE: The 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).
METHODS: This 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.
RESULTS: We 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.
CONCLUSIONS: GMFM for FCMD may be an appropriate motor function scale for patients with FCMD and might help decrease the assessment time.

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.

BACKGROUND: Fukuyama congenital muscular dystrophy (FCMD), caused by fukutin mutations, is the most common form of Japanese CMD. We followed a Japanese CMD sibship without fukutin mutation, and herein identified new FKRP mutations causing MDC1C rarely reported in Oriental countries.
METHODS: Two affected siblings, individuals 1 (I-1, male) and 2 (I-2, female), were born uneventfully to unaffected, non-consanguineous parents. Severe hypotonia was soon apparent and serum CK levels were elevated: I-1: 1025 IU/L (normal range <130 IU/L) and I-2: 5350 IU/L. I-1 had neither shown head control, nor said any words until he died of pneumonia at the age of 23months. I-2 learned to sit at 4years and 10months and spoke sentences at 6years and 5months. She had received respiratory support since 9years of age and died at 22years. Both showed a low-density area in the cerebral white matter on CT. MRI of I-2 revealed diffuse hyperintensity in the cerebral white matter on T2-WI, polymicrogyria over the frontal and parietal lobes, and disorganized folia and cysts in the cerebellum.
RESULTS: Next generation and Sanger sequencing were performed for I-2. Heterozygous FKRP mutations were identified in exon 4: c.1167_1168delGC, p.Gly391Leufs∗72 and c.501_502GT>CC, p.Arg167Ser, p.Cys168Arg.
CONCLUSIONS: Recently, fukutin and FKRP were identified as sequentially acting ribitol 5-phosphate transferases involved in the post-translational modification of α-dystroglycan. This may explain the clinical similarities between the two disorders.

BACKGROUND: One 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.
OBJECTIVE: To compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD).
METHODS: We 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.
RESULTS: Almost 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).
CONCLUSIONS: The 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.