Analysis of HINT1 gene variant in a case with neuromyotonia and axonal neuropathy / 中华医学遗传学杂志

OBJECTIVE@#To explore clinical and genetic features of a pedigree affected with autosomal recessive neuromyotonia and axonal neuropathy (NMAN).@*METHODS@#For the proband and her parents, clinical data was collected, genomic DNA was extracted from peripheral blood samples. Triplet primed-PCR was carried out to detect dynamic mutation of DMPK and ZNF9 genes, which are responsible for myotonic dystrophy, by capillary electrophoresis. High-throughput sequencing was used to screen variants of candidate genes for Mendelian disorders involving the nervous system. Candidate variants were confirmed by Sanger sequencing. The genotype of the variant was determined in the parents and 100 healthy controls. Pathogenicity of the variant was assessed by ACMG criterion.@*RESULTS@#Mutation of DMPK and ZNF9 genes was excluded. DNA sequencing has identified a homozygous missense variant (c.335C>T, p.R119W) in the HINT1 gene. Both parents were found to carry the variant. The same variant was not found among the healthy controls. According to the ACMG criterion, the missense variant was classified as a pathogenic variant.@*CONCLUSION@#The c.335C>T (p.R119W) of the HINT1 gene probably underlie the disease in this pedigree. Above finding provided further evidence for the connection between HINT1 and NMAN and enriched the mutation spectrum of HINT1 gene.

The Diagnosis and Treatment of Autoimmune Encephalitis

Autoimmune encephalitis causes subacute deficits of memory and cognition, often followed by suppressed level of consciousness or coma. A careful history and examination may show early clues to particular autoimmune causes, such as neuromyotonia, hyperekplexia, psychosis, dystonia, or the presence of particular tumors. Ancillary testing with MRI and EEG may be helpful for excluding other causes, managing seizures, and, rarely, for identifying characteristic findings. Appropriate autoantibody testing can confirm specific diagnoses, although this is often done in parallel with exclusion of infectious and other causes. Autoimmune encephalitis may be divided into several groups of diseases: those with pathogenic antibodies to cell surface proteins, those with antibodies to intracellular synaptic proteins, T-cell diseases associated with antibodies to intracellular antigens, and those associated with other autoimmune disorders. Many forms of autoimmune encephalitis are paraneoplastic, and each of these conveys a distinct risk profile for various tumors. Tumor screening and, if necessary, treatment is essential to proper management. Most forms of autoimmune encephalitis respond to immune therapies, although powerful immune suppression for weeks or months may be needed in difficult cases. Autoimmune encephalitis may relapse, so follow-up care is important.

Channelopathies / 소아과

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.

Myasthenia in Acquired Neuromyotonia

BACKGROUND: Acquired neuromyotonia (NMT) forms part of the spectrum of acquired peripheral nerve hyperexcitability syndrome, and is thought to be caused by antibodies to voltage-gated potassium channels (VGKC). Exertional weakness is unusual unless autoimmune myasthenia gravis (MG) is superimposed. CASE REPORT: A case of acquired NMT accompanied by exertional weakness without coexistence of seropositive MG is reported herein. CONCLUSIONS: Clinical and electrophysiological observations suggest that the cholinergic overactivity in NMT can compromise the safety factor sufficiently to cause a defect in neuromuscular junction transmission.

Anesthetic experience using total intravenous anesthesia in a patient with Isaacs' syndrome: A case report / 대한마취과학회지

We report on an anesthetic experience with a 74-year-old female with Isaacs' syndrome, who underwent elective surgery for open rotator cuff repair. Isaacs' syndrome is a rare peripheral motor neuron disorder with clinical manifestations such as involuntary muscle twitching, cramps, mild weakness and increased sweating. To avoid prolonged neuromuscular blockade, the patient was observed with neuromuscular monitoring during total intravenous anesthesia with propofol, remifentanil, and atracurium. No adverse events were observed during the anesthetic management, and the patient recovered smoothly from the neuromuscular blockade. We describe the clinical characteristics of Isaacs' syndrome and its specific considerations in anesthesia.

Ocular Neuromyotonia in a Patient with Orbital Metastasis

No abstract available.

Isaac's syndrome associated with myasthenia gravis and thymoma.

A 65-year-old male developed fatigable weakness of ocular and bulbar muscle and positive anti-acetyl cholinesterase antibodies suggesting the diagnosis of myasthenia gravis. His condition responded to anticholinesterase and immunotherapy. However, 18 months later, he developed painful paresthesiae, muscle cramps with hyperhiderosis, and was diagnosed as having Isaac's syndrome (neuromyotonia, continuous muscle fibre activity). Computed tomography of the chest revealed a thymic mass, which was confirmed after surgery and histopathology as thymic cell carcinoma. The co-occurrence of myasthenia gravis and continuous muscle fiber activity should prompt the consideration of the occurrence of these disorders as one of the paraneoplastic manifestations, most often due to a thymic neoplasm. Both these conditions respond to treatment of underlying thymoma. This case is a very rare presentation worth reporting.

Isaacs' Syndrome Associated With Acetylcholine Receptor Antibodies Developed After Removal of Malignant Thymoma

Isaacs' syndrome is a rare and heterogeneous syndrome of continuous muscle fiber activity that originates from peripheral nerves. We report a 56-year-old male patient who showed symptoms of Isaacs' syndrome after the removal of a malignant thymoma. Needle electromyography revealed spontaneously occurring repetitive myokymic discharge in the affected muscles. Acetylcholine receptor (AChR) antibodies were significantly elevated, but clinical and electrophysiologic findings did not indicate the presence of myasthenia gravis. We deduce that in Isaacs' syndrome, raised AChR antibodies may facilitate rather than inhibit cholinergic action.

Neuromyotonia: clinical profile of twenty cases from northwest India.

OBJECTIVES: We are presenting 20 cases of the intriguing clinico-electromyographic entity, now considered a potassium channel disorder, Neuromyotonia. Our experience with the clinical manifestations, underlying abnormalities and response to various therapies is documented. MATERIALS AND METHODS: Patients with diffuse pain or undulating muscle movements, with or without stiffness were sent for electromyographic and further studies. Patients with "neuromyotonic discharges" were included after exclusion of hypocalcaemia. RESULTS: Our cases included 19 males and one female of age group 15 to 52 years, the majority being between 30 to 45 years. Undulating movements were seen in 19, of which two had focal twitching. Muscle stiffness was a complaint in five; pain was the chief presenting complaint of 19, which started in the calf in all. Irritability, insomnia and a peculiar worried pinched face were present in 12 patients. CSF was abnormal with mildly raised protein in eight. Curiously, 11 of these patients had taken ayurvedic treatment for various complaints in the preceding one month. Bell's palsy was associated in four, peripheral neuropathy in two and residual poliomyelitis in two. Electromyographic evidence of spontaneous activity in the form of "neuromyotonic discharges" was seen in all. Antibodies to voltage gated potassium channels was tested in one patient and was positive (titer was 1028 pM). Membrane stabilizers (e.g, phenytoin sodium) in our experience did not provide adequate rapid relief; we tried high-dose intravenous Methylprednisolone in 19 with significant amelioration of complaints. One patient was offered intravenous immunoglobulin, to which he responded. CONCLUSIONS: Neuromyotonia is a heterogeneous condition and can present in varied ways including diffuse nonspecific pain. This uncommon condition is potentially treatable and can be picked up with high index of suspicion.

Acquired neuromyotonia (Isaacs' syndrome): a case report with autonomic physiologic studies.

Acquired neuromyotonia (Isaacs' syndrome) is a rare disorder characterized by hyperexcitability of peripheral motor nerves. The cardinal features consist of myokymia, pseudomyotonia and contracture of hands and feet. The diagnosis of Isaacs' syndrome is based on the clinical features and classic electromyographic findings. Serum antibodies against Voltage-Gated Potassium Channels (VGKCs) are detected in some cases. The authors report a 17 year-old man presented with difficulty in walking, writing and respiratory discomfort for 7 months. His body weight had decreased from 120 to 70 kilograms during that period. Physical examination was remarkable for profound sweating. Muscles were in a state of contraction, action myotonia without percussion myotonia, myokymia and carpopedal spasm. Electromyography showed classical neuromyotonic and myokymic discharges. The investigations for conditions associated with Isaacs' syndrome were unrevealing. VGKCs antibody were not performed. Treatment with carbamazepine resulted in substantial improvement of the symptoms within 7 days.

Oculomotor Neuromyotonia with Lid Lag

A 52-year-old woman developed episodic diplopia during a period of six months. Between the episodes, depression of the right eye was mildly impaired and lid lag was evident in the right eye on downward gaze. On resuming the primary position after prolonged leftward gaze, she developed a right esotropia and limitation of abduction, elevation, and depression in the right eye. Lid lag may be a sign suggesting oculomotor neuromyotonia in patients with episodic diplopia. The isolated lid lag without lid retraction suggests primary aberrant oculomotor regeneration as a mechanism of this phenomenon.

A Case of Morvan Syndrome

Neuromyotonia, or Isaacs' syndrome, consists of continuous muscle fiber activity caused by hyperexcitability of the peripheral nerves. Rarely, these patients also develop CNS symptoms characterized by confusion, insomnia, hallucinations, and agitation. A rare disease consisting of neuromyotonia, autonomic symptoms, and CNS dysfunction is called Morvan's syndrome. We report a 24-year-old man who presented with insomnia, malaise, anorexia, hyperhidrosis, palpitation and myokymia in both the lower extremities. The pathomechanism of Morvan's syndrome is related to the voltage-gated K+ channel (VGKC) antibodies.

A Case of Idiopathic Ocular Neuromyotonia

Ocular neuromyotonia (ONM) is an episodic involuntary contraction of one or more extraocular muscles, resulting from spontaneous neural discharges of ocular motor nerves. Previous radiation therapy to pituitary or other juxtasellar tumor and vascular compressions are the most common reported causes of ONM. We report one unique case of ONM involving the abducens nerve without any other organic brain lesion and prior radiation therapy.

A Case of Isaacs' Syndrome Associated with Small Cell Lung Cancer

Isaacs' syndrome consists of spontaneously occurring muscle activity of peripheral nerve origins. This syndrome arises in association with/without polyneuropathy and rarely with malignancy. A 63-year-old man was admitted to our hospital due to generalized painful muscle stiffness. He complained of difficulty with standing and with finger exten-sion after grasping. Chvostek's and Trousseau's signs were noticed. Electrolytes, calcium, CK, and LDH were in the normal range. Small cell lung cancer was diagnosed by a needle biopsy. Electrophysiological testing revealed normal nerve conduction studies with the exception of a grossly abnormal EMG. Continuous neuromyotonic discharges with firing rates of 120-200 Hz were seen at rest. The amplitude of the response typically waned with 0.5-1.5 seconds of duration. The discharges persisted throughout sleep, after diazepam injection, and with brachial plexus blockage.Muscle stiffness improved with the administration of oral phenytoin. Under chemotherapy and radiotherapy, tumor remission was partially achieved and neurological symptoms markedly improved.

A Case of Isaacs' Syndrome

A case of Isaacs syndrome with Trousseau s phenomenon wac studied electrophysiologically and histologically. The needle electromyography showed typical neuromyotonic discharges of spontaneous recurrent high-frequency(150-300Hz) bursts of motor unit activity with 0.5-3 second of duration and typical waning pattern This discharge was not suppressed by brachial plexus block Motor and sensory nerve conduction velocities were either s!ightly below or in the lower range of normal. In repetitive nerve stimulation test a decremental response to low rate stimulation was noted in abductor digiti quinti muscle. On sural nerve biopsy, there was a decrease in the number of myelinated nerve fibers showing both axonal and myelin degeneration The clinical and electrophysiologic abnormalities improved considerably after treatment with phenytoin.