Adolescent/adult-onset homocysteine remethylation disorders characterized by gait disturbance with/without psychiatric symptoms and cognitive decline: a series of seven cases.

Homocysteine remethylation disorders are rare inherited disorders caused by a deficient activity of the enzymes involved in the remethylation of homocysteine to methionine. The adolescent/adult-onset remethylation disorders are rarely reported. We analyzed the clinical and genetic characteristics of seven cases with adolescent/adult remethylation disorders, including 5 cases of the cobalamin C disease (cblC) and 2 cases of the methylenetetrahydrofolate reductase deficiency. The average onset age was 21.1 (range 14 to 40) years. All patients complained of gait disturbances. Other common symptoms included psychiatric symptoms (5/7) and cognitive decline (4/7). Acute encephalopathy, dysarthria, anorexia, vomiting, ketoacidosis, anemia, cataract, and hand tremor were also observed. The mean total homocysteine in serum when the patients were diagnosed was 94.6 (range 53.1-154.5) mol/L. Electrophysiological studies revealed neuropathy in the lower limbs (6/7). The brain MRI showed reversible altered signal from the dorsal portions of the cerebellar hemispheres (1/7), periventricular hyperintensity (2/7), and delayed/impaired myelination (2/7). The sural nerve biopsy performed in one case showed a modest loss of myelinated fibers. Five patients showed heterozygous mutations of the MMACHC gene, including c.482G>A (5/5), c.609G>A (2/5), and c.658-660delAAG (3/5). Two patients showed heterozygous mutations of the MTHFR gene, including c.698C>A (2/2), c.698C>G (1/2), and c.236+1G>A (1/2). The patients responded well to the treatments with significant improvements. Adolescent/adult-onset remethylation disorders are easily misdiagnosed. We recommend testing the serum homocysteine concentrations in young/adult patients with unexplained neuro-psychotic symptoms. Furthermore, individuals with significantly elevated serum homocysteine concentrations should be further tested by organic acid screening and genetic analysis.

Identification of novel mutations of the CLCN1 gene for myotonia congenital in China.

OBJECTIVES: The identification of disease-specific genetic and electrophysiological patterns for myotonia congenital (MC) could help clinicians apply in the findings of genetic studies to improve diagnosis. We examined the molecular, clinical, and histopathological characteristics of eight patients with MC. METHODS: Optimization PCR was used to exclude myotonic dystrophies and the CLCN1 gene was sequenced in patients having clinical and electrophysiological features indicative of MC. RESULTS: Genetic screening identified nine CLCN1 mutations among the eight patients, including two missense, three nonsense, two insertion, and two deletion mutations. The patients showed typical myotonia and muscle hypertrophy. In contrast to the previous studies, secondary dystonia, joint contracture, and abnormal cardiac activity were also observed. Patients with novel mutations did not show any new muscle pathology compared with established mutations. Disscussion: Molecular genetics analysis offers an accurate method for diagnosing MC. The results of this analysis should be considered alongside clinical and electrophysiological characteristics. In this study, novel mutations in CLCN1 were detected, and the spectrum of CLCN1 mutations known to be associated with MC was expanded.

Early myocardial damage assessment in dystrophinopathies using (99)Tc(m)-MIBI gated myocardial perfusion imaging.

BACKGROUND: Early detection of muscular dystrophy (MD)-associated cardiomyopathy is important because early medical treatment may slow cardiac remodeling and attenuate symptoms of cardiac dysfunction; however, no sensitive and standard diagnostic method for MD at an earlier stage has been well-recognized. Thus, the aim of this study was to test the early diagnostic value of technetium 99m-methoxyisobutylisonitrile ((99)Tc(m)-MIBI) gated myocardial perfusion imaging (G-MPI) for MD. METHODS AND RESULTS: Ninety-one patients underwent (99)Tc(m)-MIBI G-MPI examinations when they were diagnosed with Duchenne muscular dystrophy (DMD) (n=77) or Becker muscular dystrophy (BMD; n=14). (99)Tc(m)-MIBI G-MPI examinations were repeated in 43 DMD patients who received steroid treatments for 2 years as a follow-up examination. Myocardial defects were observed in nearly every segment of the left ventricular wall in both DMD and BMD patients compared with controls, especially in the inferior walls and the apices by using (99)Tc(m)-MIBI G-MPI. Cardiac wall movement impairment significantly correlated with age in the DMD and BMD groups (r s=0.534 [P<0.05] and r s=0.784 [P<0.05], respectively). Intermittent intravenous doses of glucocorticoids and continuation with oral steroid treatments significantly improved myocardial function in DMD patients (P<0.05), but not in BMD patients. CONCLUSION: (99)Tc(m)-MIBI G-MPI is a sensitive and safe approach for early evaluation of cardiomyopathy in patients with DMD or BMD, and can serve as a candidate method for the evaluation of progression, prognosis, and assessment of the effect of glucocorticoid treatment in these patients.

Optimization PCR for Detection CTG/CCTG-Repeat Expansions in the Diagnosis of Myotonic Dystrophies.

CONTEXT: Myotonic dystrophies (DMs) are a group of autosomal dominant neuromuscular disorders which are caused by large CTG/CCTG-repeat expansions in untranslated regions of DMPK/ZNF9 gene. The "phenotypic overlap" in DMs creates complication in distinguishing patients with DM1 from patients with DM2 and underscores the need for these patients to undergo genetic test; therefore, detection and accurate sizing of the CTG/CCTG-repeat expansions are necessary. Templates with long CTG/CCTG tandem repeats are difficult to amplify by convention PCR. AIMS: The aim of our study was to develop an efficient, economic amplification method which based on combination of primer design, modified annealing, and extension conditions in PCR amplification. SETTINGS AND DESIGN: We detected and analyzed the CTG-repeat expansions in patients having clinical, electrophysiological, and muscle pathology features indicative of DMs by optimization PCR. If no CTG-repeat expansions were detected, we subsequently analyzed the CCTG-repeat expansions in the remaining patients. RESULTS: 42 participants included 25 DMs patients and 17 family members. 22 patients showed CTG-repeat expansions, the CTG-repeat ranged from 53 to 683 and the average was 535; 3 patients showed CCTG-repeat expansions, the CCTG-repeat ranged from 400 to 450 and the average was 416. CONCLUSIONS: Molecular genetic tests are essential for DMs diagnosis; Optimization PCR under the optimal conditions of primer design, modified annealing, and extension conditions can be used for efficient PCR in DMs diagnosis; Optimization PCR can greatly improve the positive detection of DMs, provide an economic, accurate, and rapid method for routine diagnostic use.

Clinical and skeletal muscle biopsy characteristics of 25 patients with floppy infant syndrome.

AIMS: Floppy infant syndrome (FIS) comprises of a group of disorders with a common symptom of generalized hypotonia at birth or in early life, which causes diagnostic challenge. In the current work, we aimed to describe the clinical and histopathological characteristics of FIS to help improve the diagnosis of this condition. METHODS: We collected information on the clinical characteristics, laboratory data, electrophysiological test results and detailed skeletal muscle biopsy histopathological features of 25 infants with FIS. We then discussed the final diagnoses and analyzed the neuromuscular features. RESULTS: Among the 25 infants with FIS, there were 7 cases of spinal muscular atrophy (SMA), 4 cases of congenital muscular dystrophy (CMD) (3 cases of merosin-deficient CMD and 1 case of Ullrich CMD), 8 cases of congenital myopathy (2 cases of central core disease, 1 case each of nemaline myopathy and centronuclear myopathy, and 4 cases of congenital fiber-type disproportion), and 6 cases of metabolic myopathy (3 cases of lipid storage myopathy, 2 cases of Pompe's disease, and 1 case of Leigh's syndrome). The histopathological characteristics of muscle biopsy were found to be distinct for these subgroups. CONCLUSIONS: FIS is caused by a variety of neuromuscular disorders that have common clinical manifestations, including SMA, CMD, congenital myopathies and metabolic myopathies. Skeletal muscle biopsy is an essential tool for the definite and differential diagnoses of FIS, especially of neuromuscular origin.

[Mutation analysis of a Chinese family with autosomal dominant Emery-Dreifuss muscular dystrophy].

OBJECTIVE: To investigate the clinical, pathological and genetic characteristics in a family with autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD). METHODS: Clinical data and skeletal muscle specimens were collected from two patients (the proband and her daughter) for pathological analysis. DNA samples of the proband and her family members (7 persons from 3 generations) were obtained for PCR amplification and direct DNA sequencing of the lamin A/C (LMNA) gene. Haplotype analysis was performed after the identification of mutation. RESULTS: The proband had typical clinical manifestation of EDMD: joint contracture, progressive muscle weakness and atrophy and cardiac conduction dysfunction. Muscular pathology revealed myopathic changes combined with slight neuropathic changes. A heterozygous missense mutation 1583 (C to G)(T528R) was identified in exon 9 of the LMNA gene in the two patients, but not in other family members. Haplotype analysis indicated that the proband and her daughter shared the same causative haplotype. CONCLUSION: This is the first report of the phenotype and genotype of AD-EDMD in Chinese.

[A clinical and pathological analysis of inclusion body myositis].

OBJECTIVE: To study the clinical and pathological characteristics of inclusion body myositis (IBM). METHODS: Comprehensive analysis of the characteristics of the clinical, laboratory and pathological of 20 patients with IBM was carried out. RESULTS: Pathological features of biopsied skeletal muscle, inflammatory cells infiltrated in the perimysium, endomysium or around the blood vessels. Muscle fibers in different size, degenerating, necrotic and regenerating fibers scattered, with connective tissue elements increased. Rimmed vacuoles located in the muscles, with amyloid substance deposited around it. Ragged red fibers (RRF), abnormal distribution and types of muscle fibers. Electronmicroscopically, structure of myofibrils disordered, and Z line derangement or dismissed. In the inclusion bodies of sarcoplasma, many myelin bodies and phagocytic vacuoles aggregated, around with lipid drops and glycogen particle. CONCLUSIONS: It is difficult to diagnose IBM with clinical features, while skeletal muscle biopsy and pathological analysis is a trustworthy measure for the definite diagnosis of IBM.