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Objective To explore the diversity of clinical manifestations and gene mutations of riboflavin⁃responsive multiple acyl⁃coenzyme A dehydrogenase deficiency (MADD). Methods and Results The clinical, blood biochemical, EMG, muscle biopsy and genetic analysis results of 5 patients with riboflavin⁃responsive MADD were collected, to analyze and summarize the clinical characteristics of riboflavin⁃responsive MADD. The onset age of 5 patients was 13-32 years old, with an average age of 20.40 years old. The main manifestation was fluctuating or progressive muscle weakness, involving facial, neck, proximal limb and respiratory muscles and often aggravated after exercise, fatigue, and infection. Serum creatine kinase (CK) increased slightly to moderately in 5 patients, and blood lactic acid increased significantlyafterexercisein2patients. The EMG of 4 patients showed myogenic damage, and the EMG of one patient showed neurogenic damage in the early stage of the disease and mainly myopathic damage in laterstage. Muscle biopsy of 2 patients showed a large amount of lipid droplet deposition in muscle fibers positive for oil red O staining. Genetic analysis revealed that 4 patients showed homozygous or compound heterozygous mutations in the ETFDH gene(one patient carried homozygous mutations of G250A; 2patients carried compound heterozygous mutations of G250A and G524A; one patient carried compound heterozygous mutations of T1211C and C1454G), the remaining one case carried the G1399C heterozygous mutationin ETFDH geneandthe C725T heterozygousmutationin ETFB gene. Conclusions In mainland of China, riboflavin⁃responsive MADD mainly presents as a lipid deposition disease involving skeletal muscle, with a progressive or fluctuating course. It is easily misdiagnosed as several types of muscular dystrophy, mitochondrial myopathy, glycogen storage disease, myasthenia gravis and peripheral neuropathy. Themutation ETFDH gene is its main cause. Since riboflavin⁃responsive MADD has a good prognosis, the vitamin B2 diagnostic treatment should be given when the patients are suspected of riboflavin⁃responsive MADD, combined with urine organic acid, blood acylcarnitine, muscle biopsy and genetic analysis to confirm the diagnosis. DOI：10.3969/j.issn.1672⁃6731.2020.06.011

Objective To carry out preimplantation genetic diagnosis (PGD) for Duchenne muscular dystrophy (DMD) carrier, so as to prevent the birth of affected infants with DMD. Methods One DMD gene carrier with a deletion of exon 10-30 received fertilization with intracytoplasmic sperm injection (ICSI). DMD gene and haplotype were tested after amplification of genome DNA in multiple displacement amplification (MDA), then healthy embryos were transferred to uterus according to the genetic results. Genetic testing was made in second trimester and after delivery, and also periodic follow-up was made for over 3 years. Results The second cycle of PGD was successful, and a total of 14 single blastomeres obtained from 7 embryos were used for genetic analysis. The success rate of MDA was 13/14, and the allele dropout rate was 18.75% (18/96). Three unaffected embryos were transferred, resulting in twin pregnancy. One healthy boy and one healthy girl were born in cesarean section at the pregnant week of 35. Genetic results on DNA from both amniotic fluid at 16 weeks of gestation and peripheral blood after birth were normal. During the 3-year follow-up, both 2 infants were normal in growth and development, motor function and dynamic monitor of serum creatine kinase (CK). Conclusions Preimplantation genetic diagnosis can help DMD gene carrier give birth to healthy infants, and these infants have normal development. DOI: 10.3969/j.issn.1672-6731.2015.06.008

Background DMD gene point mutation, mainly nonsense mutation, always cause the most severe Duchenne muscular dystrophy (DMD). However, we also observed some cases of Becker muscular dystrophy (BMD) carrying DMD point mutation. This paper aims to explore the mechanism of DMD point mutation causing BMD, in order to enhance the understanding of mutation types of BMD. Methods Sequence analysis was performed in 11 cases of BMD confirmed by typical clinical manifestations and muscle biopsy. The exon of DMD gene was detected non-deletion or duplication by multiplex ligation-dependent probe amplification (MLPA). Results Eleven patients carried 10 mutation types without mutational hotspot. Six patients carried nonsense mutations [c.5002G>T, p.(Glu1668X); c.1615C > T, p.(Arg539X); c.7105G > T, p.(Glu2369X); c.5287C > T, p.(Arg1763X); c.9284T > G, p.(Leu3095X)]. One patient carried missense mutation [c.5234G > A, p.(Arg1745His)]. Two patients carried frameshift mutations (c.10231dupT, c.10491delC). Two patients carried splicing site mutations (c.4518 + 3A > T, c.649 + 2T > C). Conclusions DMD gene point mutation may result in BMD with mild clinical symptoms. When clinical manifestations suggest the possibility of BMD and MLPA reveals non?deletion or duplication mutation of DMD gene, BMD should be considered. Study on the mechanism of DMD point mutation causing BMD is very important for gene therapy of DMD. DOI: 10.3969/j.issn.1672-6731.2015.06.005

Objective Use T2 mapping to evaluate the fatty infiltration of thigh muscles in Duchenne muscular dystrophy (DMD) patients, so as to analyze the value of T2 mapping and T2 relaxation time in the diagnosis of DMD. Methods Sixteen DMD patients who were admitted from January 2004 to January 2013 in our hospital and were diagnosed by clinical confirmation and gene detection have participated into this study. These 16 male patients formed the DMD group. Six age- and sex-matched healthy boys were selected as control group. Clinical functional scale, thigh axial T1WI-turbo spin echo (TSE), T2WI-TSE, spectral attenuated inversion recovery (SPAIR)-T2WI and T2 mapping were performed in both 2 groups. T1WI fatty infiltration scale and T2 relaxation time were assessed in adductor magnus, gracilis, adductor longus, sartorius, rectus femoris, vastus intermedius, vastus medialis, vastus lateralis, biceps femoris, semitendinosus and semimembranosus. Spearman rank correlation was conducted to assess the correlation between T2 relaxation time and T1WI fatty infiltration scale or clinical functional scale. Results Compared with control group, the T2 relaxation time of 8 muscles (adductor magnus, adductor longus, rectus femoris, vastus intermedius, vastus medialis, vastus lateralis, biceps femoris and semimembranosus) in DMD group were prolonged (P < 0.05, for all). The longest average T2 relaxation time was found in adductor magnus. The T2 relaxation time of adductor magnus, vastus intermedius, vastus lateralis, biceps femoris, rectus femoris, adductor longus and vastus medialis was positively correlated with T1WI fatty infiltration scale (P < 0.05, for all), and the T2 relaxation time of adductor magnus and semimembranosus was positively correlated with clinical funetional scale (P < 0.05, for all). A positive correlation was found in adductor magnus between T2 relaxation time and both T1WI fatty infiltration scale (rs = 0.867, P = 0.000) and clinical functional scale (rs = 0.651, P = 0.005). Conclusions T2 relaxation time could be used in the quantitative and objective analysis of DMD clinical severity, and adductor magnus was considered to be the most valuable muscle to reflect the clinical severity of DMD. DOI: 10.3969/j.issn.1672-6731.2015.06.004

Objective The clinical manifestation and electron transfer flavoprotein dehydrogenase (ETFDH) gene mutation of riboflavin-responsive lipid storage myopathy were analyzed for early diagnosis and treatment.mutation of riboflavin-responsive lipid storage myopathy were analyzed for early diagnosis and treatment. Methods Clinical material, ETFDH gene mutation and the motor function before and after vitamin B2 treatment in 3 patients from 2 predigrees were collected from August 2012 to March 2013 in our hospital. Results Case 1 was 16-year-old female. The chief complaint was difficulty of breathing and expectorating for over 3 years. Clinical symptoms included progressive respiratory muscle and proximal limb muscle weakness and worsen by fever, cardiac involvement, myopathic electromyography (EMG) changes and deposition of lipid droplets in muscle fiber by oil red O staining. Case 2 and Case 3 were brothers, the chief complaint of whom was fatigue after exercise for more than 1 year and 1 month, respectively. Clinical symptoms included significantly weakness of lower limbs and neck muscles after exercise and myopathic EMG changes. All 3 patients from two predigrees presented ETFDH gene mutation [c.250G > A (Ala84Thr) homozygous mutations and c.250G > A (Ala84Thr) and c.524G > A (Arg175His) compound heterozygous mutations, respectively]. They all had a dramatic response to vitamin B2 treatment with muscle strength and motor function recovering to normal. The symptoms of Case 1 were completely disappeared with vitamin B2 treatment for over 10 months, including respiratory muscle and proximal limb muscle weakness, and the motor function of her limbs returned to normal, characterized by completing over 10 squat-stand in 1 min. Case 2 could walk and run as ordinary people, raise his head without difficulty and play basketball about 2 h without fatigue after vitamin B2 treatment for over 2 months. Case 3 could participate in any kind of strenuous exercise without fatigue after vitamin B2 treatment for over 2 months. Conclusions Riboflavin-responsive lipid storage myopathy is mainly characterized by proximal limb and trunk muscle weakness and intolerance of movement, however, rare cases with first symptom of respiratory muscle weakness should also be concerned. In addition, it is a treatable genetic disease. The patients could be cured or significantly improved with vitamin B2 monotherapy. So vitamin B2 exploratory treatment should be given when the patients are suspected of riboflavin-responsive lipid storage myopathy. doi: 10.3969/j.issn.1672-6731.2014.06.004

Background To investigate the gene mutation and clinical features of hypokalemic periodic paralysis (HypoPP) in a Han family. Methods Mutation analyses of CACNA1S, SCN4A and KCNE3 gene were screened by DNA direct sequencing in the proband (Ⅲ3). Then, other patients and one asymptomatic relative were tested for the mutation detected in the proband before. Besides, clinical information was collected and analyzed carefully so as to detect whether the mutations were responsible for HypoPP. Results KCNE3 gene was not detected in the propositus (Ⅲ 3). Mutations of IVS25-194C/T in CACNA1S gene were detected in the propositus (Ⅲ 3) and other patients (Ⅱ 1, Ⅲ 4, Ⅳ 3), while it was not detected in the asymptomatic relative (Ⅲ1). Given that it was an intron mutation, we presumed that it was not responsible for HypoPP in this family. In addition, mutations of IVS18-130G/A in SCN4A gene were detected in all patients (except for Ⅰ1) and asymptomatic relative (Ⅲ 1). Since it was an intron mutation and it was detected in symptomatic or asymptomatic members simultaneously, we also presumed that it was not responsible for HypoPP in this family. Interestingly, a missense mutation (V662I) of c.1984G > A in exon 12 of SCN4A gene was detected in the proband (Ⅲ 3) and asymptomatic relative (Ⅲ 1). However, it was not detected in other symptomatic members ( Ⅱ 1, Ⅲ 4, Ⅳ 3). Based on clinical information and bioinformatics, we presumed that it was not causative mutation for the disease in this pedigree. Conclusions This pedigree research enriched the data of gene mutation and clinical features of HypoPP in China. Besides for gene KCNE3, CACNA1S and SCN4A, other gene mutations accounted for HypoPP in the Han family should be further studied. doi: 10.3969/j.issn.1672-6731.2014.06.006

Objective In order to make a well understanding on glycogen storage disease typeⅡ (GSDⅡ), this paper explored clinical features and genetic analysis of 7 patients with late-onset glycogen storage disease typeⅡ. Methods Clinical data of 7 patients with late-onset glycogen storage disease type Ⅱ were collected and acid α-glucosidase (GAA) gene sequencing was performed. Results Seven patients who belong to 4 families were at the age of 13-31 years old. The first symptom occurred at 6-17 years old, and the age at first and definitive diagnosis was 12-29 and 12-30 years old, respectively. The initial symptoms were mostly related to limb girdle muscular atrophy and weakness. The GAA activity ranged from 0 to 5.27 nmol/(mg·h). Sequencing analysis revealed 14 sequence variants, including 2 novel mutations (Q81X and c.1355_1356delC), 2 pseudodeficiency alleles (G576S and E689K), 8 polymorphic loci, and 2 sequence variants previously related with glycogen storage disease type Ⅱ pathogenesis (W746C and D645E). Conclusions Due to the apparently diagnostic delay, prognosis of patients with glycogen storage disease type Ⅱ could be improved by increasing the clinician's awareness of the disease. It is essential to combine clinical history with GAA activity and GAA gene analysis when we make a definitive diagnosis of glycogen storage disease type Ⅱ. Though siblings share the same set of GAA mutations, the phenotype regarding the course and severity of disease could vary substantially. doi: 10.3969/j.issn.1672-6731.2014.05.008

Objective To evaluate the effect of Myozyme on one ventilator dependent patient with late-onset glycogen storage disease typeⅡ (GSDⅡ). Methods Myozyme infusion was administered based on manufacturer's recommendations at 20 mg/kg every 2 to 4 weeks, beginning at actual body weight, and was continuously treated for 6 times. No premedication was performed except 5 mg dexamethasone was administered at the first use of Myozyme. Clinical assessment was completed every day and was lasted for 16 months including motor function, the time free of ventilation, and the change of respiration parameters. Results Myozyme was well tolerated without adverse reactions. Pain on shoulder began to alleviate the next day after taking Myozyme. With the prolonged time and increased number of taking drugs, the time free of ventilation and doing in-situ stepping prolonged, and the speed of stepping in-situ also increased. Besides, the strength of lifting the upper limbs increased, and both the time and speed of walking free of ventilation prolonged. The maximus curative effect occured at the 7th month (3 months after drug withdrawal) after treatment and returned to pre-treatment levels at the 8th month (4 months after drug withdrawal). The pain on shoulder was the first symptom that got improved, and the fastest symptom that returned to baseline. Conclusions Myozyme has positive effect on ventilated patients with late-onset glycogen storage disease type Ⅱ. doi: 10.3969/j.issn.1672-6731.2014.05.009

Objective To explore the clinical features, genetic characters and the importance of prenatal diagnosis in spinocerebellar ataxia 3 (SCA3) patients. Methods SCA3/ATXN3 gene was determined by using PCR and segmental analysis techniques in 2 patients among a SCA3 Chinese Han family which included 9 patients in four generations. One patient was the proband's fetus. The clinical characters were also documented and analyzed in this family. Results There were 9 patients in this family with autosomal dominant inheritance feature. The initial symptoms in all affected members except the fetus were the gait disorders accompanied by dysphasia. Inability of upward gaze and bilateral Barbinski's signs were noted in proband. The onset age became earlier from generation to generation in this family which was around 50 year⁃old, 40 to 45 year⁃old, 28 year⁃old in generation Ⅰ, Ⅱ and Ⅲ, respectively. CAG repeats in SCA3/ATXN3 allele were 77 in proband, as well as in the fetus, while the normal SCA3/ATXN3 allele CAG repeats were less than 44. Conclusion SCA3 is the most frequent subtype of SCA in Asian. Unsteadiness of gait are first noted in most patients accompanied by other different symptoms and signs. Genetic anticipation was found in SCA3. But gene analysis revealed less dynamic mutation frequence in this family. Since there was no effective treatment in SCA3, hereditary consultation and prenatal diagnosis play an important role in disease prevention and hereditary. DOI：10.3969/j.issn.1672⁃6731.2012.03.010

Objective In order to understand tuberous sclerosis complex better, the clinical manifestation, imaging characteristics, and genetic characteristics of tuberous sclerosis complex from 3 pedigrees were investigated. Methods The clinical data of patients from 3 tuberous sclerosis families were collected. The gene mutation type of TSC2 of proband in pedigree one was determined by PCR and direct gene sequencing. Results All of the 3 probands went to our clinic for the reason of epilepsy. Brain imaging examination noted intracranial nodular calcification. EEG showed comprehensive spines and slow waves, sharp waves. The pedigree 1 has family history, two male patients and 3 female patients, all had facial angiofibromas and epilepsy. Gene mutation analysis of TSC2 demonstrated the c.1444 ⁃ 2A > C mutation in index patient. All the 3 index patients had mental retardation, autism and hypopigmented macule. Conclusion For infants and young children with epilepsy as the first symptom, accompanied by mental retardation, autism, facial angiofibromas or hypopigmented macule and other skin abnormalities, brain imaging examination noted intracranial nodular calcification are highly suggestive of tuberous sclerosis complex. TSC1 and TSC2 gene analysis contribute to the diagnosis of this disease, genentic counseling and prenatal diagnosis. DOI：10.3969/j.issn.1672⁃6731.2012.03.013