Xing-Hua Luan

Myotonia congenita: novel mutations in CLCN1 gene

Myotonia congenita belongs to the group of non-dystrophic myotonia caused by mutations of CLCN1gene, which encodes human skeletal muscle chloride channel 1. It can be inherited either in autosomal dominant (Thomsen disease) or recessive (Becker disease) forms. Here we have sequenced all 23 exons and exon-intron boundaries of the CLCN1 gene, in a panel of 5 unrelated Chinese patients with myotonia congenita (2 with dominant and 3 with recessive form). In addition, detailed clinical analysis was performed in these patients to summarize their clinical characteristics in relation to their genotypes. Mutational analyses revealed 7 different point mutations. Of these, we have found 3 novel mutations including 2 missense (R47W, V229M), one splicing (IVS19+2T>C), and 4 known mutations (Y261C,G523D, M560T, G859D). Our data expand the spectrum of CLCN1 mutations and provide insights for genotype–phenotype correlations of myotonia congenita in the Chinese population.

Infantile spinal muscular atrophy with respiratory distress type I presenting without respiratory involvement: Novel mutations and review of the literature.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1), also known as distal spinal muscular atrophy 1 (DSMA1) or distal hereditary motor neuropathies type 6 (dHMN6), is a rare autosomal recessive motor neuron disorder that affects infants and is characterized by diaphragmatic palsy, distal muscular weakness and muscle atrophy. The disease is caused by mutations in the gene encoding immunoglobulinm-binding protein 2 (IGHMBP2). We present a female child with novel compound heterozygous mutations in IGHMBP2 gene c.344C>T (p.115T>M) and c.1737C>A (p.579F>L), displaying distal limbs weakness and atrophy without signs of diaphragmatic palsy or respiratory insufficiency. We review 20 reported SMARD1 cases that have no respiratory involvement or have late onsets. We propose that IGHMBP2 gene mutations are characterized by significant phenotypic heterogeneity. Diaphragmatic palsy and respiratory distress may be absent and SMARD1 should be considered in infantile with the onset of peripheral neuropathies.

Novel ATM mutations with ataxia-telangiectasia.

Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia.

Limb-girdle congenital myasthenic syndrome in a Chinese family with novel mutations in MUSK gene and literature review

OBJECTIVES To describe the clinical and genetic features of a Chinese congenital myasthenic syndromes (CMS) patient with two novel missense mutations in muscle specific receptor tyrosine kinase (MUSK) gene and review 15 MUSK-related CMS patients from 8 countries. METHODS The patient was a 30-year-old man with chronic progressively proximal limb weakness for 22 years and diagnosed as muscular dystrophy before. Serum creatine kinase (CK) was normal. Repetitive nerve stimulation (RNS) test showed decrements at low rate stimulation. Weakness became worse after conventional doses of pyridostigmine. Mild multiple atrophy of thigh and leg muscle was observed in MRI. Open muscle biopsy and genetic analysis were performed. One hundred healthy individuals were set for control. RESULTS Muscle biopsy showed mild variation in fiber size. Two missense mutations in MUSK gene (p.P650T and p.I795S) were identified in the patient. The mutation of p.I795S was identified in his father and p.P650T in his mother. Both of them were not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. CONCLUSION In this study, we identified a limb-girdle CMS (LG-CMS) patient carrying two novel heterozygous missense mutations in MUSK gene. CMS related genes should be analyzed in patients with limb-girdle weakness, normal CK, decrement of CMAP at RNS and mild change in muscle biopsy or MRI.

Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18

2759 Hereditary spastic paraplegia type 18 (HSP18) is a complicated form of autosomal recessive HSP characterized by progressive weakness and spasticity of the lower extremities, dysarthria, and cognitive decline.[1‐3] In the year 2011, HSP18, also known as Spastic Paraplegia 18 (SPG18), was firstly identified due to a candidate gene endoplasmic reticulum lipid raft‐associated protein 2 (ERLIN2) on chromosome 8p11.2 in one Saudis family.[1] During the past 5 years, another two families with SPG18 due to ERLIN2 mutations have been reported presenting with complicated phenotype.[2,3] Here, we reported a patient born in a nonconsanguineous family who possessed an autosomal recessive pure form of HSP owing to novel mutations in ERLIN2. Patient was characterized by late‐onset spasticity of lower extremities without significant speech involvement or cognitive disability.

Case report: A Chinese child with Andersen–Tawil syndrome due to a de novo KCNJ2 mutation

• We identified one de novo novel mutation in KCNJ2 gene in a Chinese patient with Andersen–Tawil syndrome.

Mutations of SCN4A gene cause different diseases: 2 case reports and literature review

SCN4A encodes the Nav1.4 channel and mutations in SCN4A lead to different ionic channelopathies. In this study, one sporadic individual of periodic paralysis, one paramyotonia family and 200 normal healthy controls are enrolled. Genomic DNA was extracted from peripheral blood leukocytes, followed by polymerase chain reaction and DNA sequencing of candidate genes, including SCN4A and CACNA1S. As a result, heterozygous mutations c.2024G>A (R675Q) and c.1333G>A (V445M) of gene SCN4A were identified in the hypokalemic periodic paralysis patient and the paramyotonia congenita family respectively. Both mutations were not detected in healthy controls. Compared with reported cases, patients with mutation R675Q usually do not present hypokalemic periodic paralysis but hyperkalemic or normokalemic periodic paralysis. The mutation V445M was first reported in Chinese patients with nondystrophic myotonias. In addition, we carried out literature review by summarizing clinical features of the 2 mutations and establish the genotype–phenotype correlations to provide guidance for diagnosis.

Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review

PURPOSE To describe the clinical and genetic features of a Chinese progressive myoclonus epilepsy (PME) patient related with SCARB2 mutation without renal impairment and review 27 SCARB2-related PME patients from 11 countries. METHODS The patient was a 27-year-old man with progressive action myoclonus, ataxia, epilepsy, dysarthria and absence of cognitive deterioration. Renal functional test was normal. Electroencephalography (EEG) showed progressively slowed background activity and sporadic generalized spike-and-wave discharges. Electromyography (EMG) showed slowed motor and sensory nerve conduction velocities and distal motor latency delay accompanied by normal compound motor action potential (CMAP) and amplitudes of sensory nerve action potential (SNAP). The amplitude of cortical components of brainstem auditory-evoked potential (BAEP) was normal with slightly prolonged latencies. Generalized atrophy, ventricle enlargement and white matter degeneration was observed in brain magnetic resonance imaging (MRI). Open muscle biopsy and genetic analysis were performed. Two hundred healthy individuals were set for control. Quantitative real time PCR (qPCR), western blotting and immunofluorescence were carried out to evaluate the fate of the SCARB2 mRNA and lysosomal-membrane type 2 (LIMP2) protein level. RESULTS One homozygous mutation in SCARB2 gene (c.1187 + 5G > T) was identified in the patient. Each of his parents carried a heterozygous variant. This mutation was not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. qPCR revealed a significantly lower level of SCARB2 mRNA in peripheral blood cell of the proband compared with his parents and healthy control individuals. Muscle biopsy showed mild variation in fiber size. Western blotting and immunofluorescence detected an extremely weak signal of LIMP2 protein from skeletal muscle of the proband. CONCLUSION In this study, we identified a SCARB2-related PME patient with normal renal function and a novel homozygous splicing mutation. SCARB2 gene should be analyzed in patients with progressive action myoclonus, epilepsy, peripheral neuropathy, without cognitive deterioration or renal failure.

The study of exercise tests in paroxysmal kinesigenic dyskinesia

OBJECTIVE To unravel if there was muscular ion channel dysfunction in paroxysmal kinesigenic dyskinesia (PKD) patients using the exercises tests (ET). METHODS Sixty PKD patients including 28 PRRT2 mutations carriers were enrolled in this study, as well as 19 hypokalaemic periodic paralysis (HypoPP) patients as the positive controls and 45 healthy subjects as the negative controls. ET including long exercise test (LET) and short exercise test (SET) was performed in the corresponding subjects. RESULTS In the LET, both the overall PKD patients and HypoPP patients had greater CMAP amplitude and area increments during exercise than healthy controls. At most 25% of PKD patients were identified from the normality with greater amplitude increment than the area. On the contrary, 50% of HypoPP patients were differentiated with greater area increment than the amplitude. More percentage of PRRT2- patients than PRRT2+ patients had abnormal average amplitude increment. Unexpectedly, five PKD patients had abnormal maximum CMAP amplitude decrements after exercise in the LET, and one had abnormal maximum immediate amplitude decrement in the SET. CONCLUSIONS Distinct ET manifestations were found in PKD patients compared to normal controls and HypoPP patients. SIGNIFICANCE Abnormal muscle membrane excitability might be involved in the mechanisms responsible for PKD.

A case report of anti-N-methyl-d-aspartate receptor autoimmune encephalitis with sensory attack. Is limbic encephalitis only “limbic”?

1Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. 2Department of Neurology, Shanghai Sixth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. 3Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. 4Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China. *The first two authors contributed equally to this work.