Nitrous Oxide-induced Myeloneuropathy Due to Recreational Abuse.

BACKGROUND: The recreational use of nitrous oxide (N2O) has increased in recent years with a noticeable surge in the incidence of nitrous oxide-related myeloneuropathy. OBJECTIVES: To raise awareness of increasing myeloneuropathy due to recreational nitrous oxide misuse in Israel. METHODS: We conducted a case series documenting the clinical and investigative features of eight patients presenting with nitrous oxide-induced myeloneuropathy who were admitted to our departments. RESULTS: Paresthesia was the chief complaint in all patients, with sensory gait ataxia being a common feature, which was often accompanied by Romberg's sign and mild lower limb weakness. Vitamin B12 levels were below the normal range in seven patients, accompanied by elevated homocysteine and methylmalonic acid levels. Magnetic resonance imaging scans revealed hyperintense signals in the dorsal columns of the cervical spine. All patients improved following vitamin B12 injections. CONCLUSIONS: Enhancing awareness, prompting the use of appropriate investigations, and advocating for timely treatment are needed to overcome the risks associated with nitrous oxide misuse.

Riboflavin-responsive lipid-storage myopathy in elderly patients.

There are scarce reports of riboflavin-responsive lipid storage myopathy in elderly patients with onset in their sixties. We describe three elderly patients with riboflavin-responsive lipid-storage myopathy. All three patients (aged 67-71 years on first examination) had subacute onset of neck extensors and proximal limb weakness progressing to inability to rise from a sitting position or to walk. Muscle biopsies showed vacuoles with lipid content, mainly in type 1 fibers. Genetic analysis failed to identify any pathogenic variant in one patient, identified a heterozygous variant of uncertain significance c.812 A > G; p.Tyr271Cys in the ETFDH gene in the second patient, and revealed a heterozygote likely pathogenic variant c.1286-2 A > C in the ETFDH gene predicted to cause abnormal splicing in the third patient. All patients responded to treatment with riboflavin and carnitine, and regained normal strength. This report emphasizes the importance of muscle biopsy in revealing treatable lipid storage myopathy in elderly patients with progressive myopathy of unidentifiable cause.

Ser77Tyr transthyretin amyloidosis in Israel: Initial manifestations and diagnostic features.

OBJECTIVE: Amyloidosis due to the transthyretin Ser77Tyr mutation (ATTRS77Y) is a rare autosomal-dominant disorder, characterized by carpal-tunnel syndrome, poly- and autonomic-neuropathy, and cardiomyopathy. However, related symptoms and signs are often nonspecific and confirmatory tests are required. We describe the age and frequency of early symptoms and diagnostic features among individuals of Jewish Yemenite descent in Israel. METHODS: Records of mutation carriers were retrospectively reviewed. ATTRS77Y diagnosis was defined by the presence of amyloid in tissue and/or amyloid-related cardiomyopathy. RESULTS: We identified the Ser77Tyr mutation at the heterozygous state in 19 amyloidosis patients (mean age at diagnosis: 62 ± 5.7 years, range 49-70) and 30 amyloid-negative carriers. The probability for disease diagnosis increased from 4.4% at age 49 to 100% at 70 and occurred earlier in males. Initial symptoms preceded diagnosis by 5 ± 3.8 years (range 0-12) and were commonly sensory changes in the extremities. Erectile dysfunction predated these in 8/13 (62%) males. In two patients cardiac preceded neurological symptoms. Two patients declined symptoms. Electrophysiological studies near the time of diagnosis indicated a median neuropathy at the wrist in 18/19 (95%) and polyneuropathy in 13/19 (68%). Skin biopsy revealed epidermal denervation in 15/16 (94%) patients. Cardiomyopathy was identified in 16/19 (84%). Sensory complaints or epidermal denervations were present in 17/30 (57%) of amyloid-negative carriers and co-occurred in 10/30 (33%). INTERPRETATION: ATTRS77Y symptoms commonly occur after age 50, but may begin earlier. Median neuropathy, skin denervation and cardiomyopathy are frequently identified. Symptoms may be absent in patients and common in amyloid-negative carriers.

X-linked myopathy with excessive autophagy: First report of an Israeli family presenting with late onset lower limb girdle weakness.

X-linked myopathy with excessive autophagy (XMEA) is a rare disorder characterized by slow progressive muscle weakness and distinctive pathology of excessive autophagic vacuoles on muscle biopsy. Here we report on five patients, in a single family, with proximal lower limb weakness. The proband, a 25-year-old man, presented with 5 years of progressive lower limbs proximal muscle weakness. His maternal grandfather and three of his maternal male cousins had similar clinical findings and were initially suspected to have Becker muscular dystrophy. Muscle biopsy in two affected family members demonstrated autophagic myopathy, and guided the genetic investigations to the identification of a pathogenic mutation, c.272G > C in the VMA21 gene, known to cause XMEA [1]. To the best of our knowledge this is the first identified Israeli Jewish family afflicted by XMEA.

Glycogen Debrancher Enzyme Deficiency Myopathy.

ABSTRACT: Glycogen storage disease type III is a rare inherited disease caused by decreased activity of glycogen debranching enzyme. It affects primarily the liver, cardiac muscle, and skeletal muscle. Pure involvement of the skeletal muscle with adult onset is extremely rare. We report on a patient with myopathy due to glycogen storage disease III, and describe the clinical features, and pathologic and genetic findings.

Multi-system neurological disorder associated with a CRYAB variant.

We report a multiplex family with extended multisystem neurological phenotype associated with a CRYAB variant. Two affected siblings were evaluated with whole exome sequencing, muscle biopsy, laser microdissection, and mass spectrometry-based proteomic analysis. Both patients and their mother manifested a combination of early-onset cataracts, cardiomyopathy, cerebellar ataxia, optic atrophy, cognitive impairment, and myopathy. Whole exome sequencing identified a heterozygous c.458C>T variant mapped to the C-terminal extension domain of the Alpha-crystallin B chain, disrupting its function as a molecular chaperone and its ability to suppress protein aggregation. In accordance with the molecular findings, muscle biopsies revealed subsarcolemmal deposits that appeared dark with H&E and trichrome staining were negative for the other routine histochemical staining and for amyloid with the Congo-red stain. Electron microscopy demonstrated that the deposits were composed of numerous parallel fibrils. Laser microdissection and mass spectrometry-based proteomic analysis revealed that the inclusions are almost exclusively composed of crystallized chaperones/heat shock proteins. Moreover,  a structural model suggests that Ser153 could be involved in monomer stabilization, dimer association, and possible binding of partner proteins. We propose that our report potentially expands the complex phenotypic spectrum of alpha B-crystallinopathies with possible effect of a CRYAB variant on the central nervous system.

Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations.

Diagnosis in the early stages of hereditary transthyretin (ATTR) amyloidosis is imperative to support timely treatment to prevent or delay disease progression. Genetic testing in the setting of genetic counselling enables identification of carriers of a TTR gene mutation who are therefore at risk of developing TTR-associated disease. Knowledge of different genotypes and how they manifest in symptomatic disease should facilitate development of a structured and targeted approach to enable diagnosis of symptomatic disease in ATTR amyloidosis mutation carriers on the first manifestation of the earliest detectable sign or symptom. A group of experts from across Europe, Israel and Japan met to reach a consensus on such an approach. The proposed approach involves establishing a baseline for key clinical parameters, determination of the timing and frequency of follow-up in TTR mutation carriers based on a predicted age of disease onset, and recognition of the likely initial clinical signs and symptoms aligned with the phenotype of the specific TTR gene mutation and family history. Minimum criteria for diagnosis of symptomatic disease have been agreed, which it is hoped will ensure diagnosis of ATTR amyloidosis at the earliest possible stage in people with a known TTR mutation.

[ON NERVE CONDUCTION STUDIES AND ELECTROMYOGRAM IN THE COMMUNITY].

INTRODUCTION: Nerve conduction studies (NCS) and electromyograms (EMG) constitute an expansion of the neurological examination and help to reach the diagnosis or localize the pathological process. Planning the electrophysiological study and drawing conclusions depend on the skills of the examiner, his experience and the time available for the study. The studies carried out within the framework of the community are carried out in part by skilled physicians, but the time and conditions at their disposal do not enable the proper performance of the studies. The main faults in performing NCS are fewer than needed nerve tests, lack of paying attention to conduction blocks, lack of reporting of proximal amplitudes, lack of reporting of the duration and dispersion of the potentials, and lack of display of potential curves in the summary report. The main drawbacks in the EMG studies are missed spontaneous activity due to too short a stay of the needle electrode in the muscle, a subjective assessment of the size of the motor units and the recruitment pattern because of not using the EMG software for this evaluation objectively. Electrophysiological studies have been performed improperly for many years, causing damage to patients and misleading referring physicians. This actuality should be changed.

Apparent C8-T1 radiculopathy with hand weakness due to mid-cervical spondylosis.

Hand weakness and wasting in the setting of mid-cervical spondylosis and disc herniation without radiological evidence for compression of the C8 or T1 roots has been rarely reported. We retrospectively studied the data of patients with hand weakness and mid-cervical spondylosis. The clinical and radiological findings were compared to a control group of patients with weakness of the arm or forearm muscles and similar mid-cervical spondylosis. We found 19 patients with weakness and atrophy of the intrinsic hand muscles, and 13 patients with weakness proximal to the hand muscles to serve as a control group. Eleven patients (58%) had lower limb hyperreflexia or Babinski sign. Nine patients (47%) had compression of the C7 root, 12 patients (63%) had compression of C6, 8 patients (42%) had compression of C5, and 2 patients (11%) had compression of the root C4. In all but three patients (84%), magnetic resonance imaging (MRI) showed cord compression. In the control group, five patients (38%) showed hyperreflexia of the lower limbs and Babinski sign. Five patients (38%) had compression of the C7 root, eight patients (62%) had compression of C6, and twelve patients (92%) had compression of C5. Cord compression was found in eight patients (62%). Hand muscle weakness and wasting due to mid-cervical spondylosis seems to be more common than usually believed. The lack of clinical-radiological correlation should not mislead the clinician from the correct diagnosis, and should not delay the surgical decompression of the cord and the roots.

Electrical stimulation of the posterior tibial nerve reduces neuropathic pain in patients with polyneuropathy.

Peripheral neuropathic pain (PNP) is caused by neuronal damage to the peripheral nervous system and usually affects the distal extremities. This open-label study examined the effect of short-term peripheral nerve stimulation (PNS) on individuals with PNP due to polyneuropathy. A total of 12 patients (mean age, 63.0 ± 10.0 years, 41.7% male) with daily bilateral PNP for at least 6 months (mean duration, 7.4 ± 7.8 years) received a total of six direct electrical stimulation therapies to the posterior tibial nerve at 3-4-day intervals. Eight patients completed the study and were included in the efficacy analysis. The average pain at baseline was 36.6 ± 3.80 estimated by the Short-Form McGill Pain Questionnaire. After the last stimulation, pain was significantly reduced by 85.5% to 4.88 ± 3.1 (p = 0.008). Six patients (75%) had over 50% decrease in pain after the first stimulation therapy and 99.2% after the final stimulation therapy. The patients also reported statistically significant decreases in pain level (measured by visual analog scale), ranging from 54.85% to 87.50% after each of the stimulations as compared to the pain experienced prior to the stimulations. The procedure was safe without any serious adverse events. PNS has demonstrated excellent efficacy and improvement of PNP symptoms. Further studies in larger patient populations are warranted.

Congenital myasthenic syndrome in Israel: Genetic and clinical characterization.

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.

Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture.

BACKGROUND: Human skeletal muscles express three major myosin heavy chain (MyHC) isoforms: MyHCIIx (MYH1) in fast type 2B muscle fibers, MyHCIIa (MYH2) in fast type 2A fibers and MyHCI/ß-cardiac MyHC (MYH7) in slow type I skeletal fibers and cardiac ventricles. In line with its expression pattern, MYH7 mutations have been reported in association with hypertrophic or dilated cardiomyopathy, skeletal myopathies or a combination of both. We analyzed the clinical and molecular phenotype of two unrelated families of Jewish Moroccan ancestry that presented with apparently autosomal dominant inheritance of progressive Laing-like distal myopathy with non-specific myopathic changes, but uncommon marked contractures and wasting of the neck extensors. METHODS: Clinical phenotyping, whole exome sequencing and restriction analysis, generation of mutants followed by cell culture transfection and imaging. RESULTS: Using whole exome sequencing we identified in both families two novel heterozygous proline substitutions located in exon 31 of MYH7 within its rod domain: c.4309G>C (p.Ala1437Pro) and c.4301G>C (p.Arg1434Pro). Here we show that the phenotype caused by these mutations includes marked cervical muscle contracture, and report that the severity of the phenotype varies significantly, to the extent of non-penetrance in one of the families. Finally, we provide evidence that both proline substitutions impair myosin self-assembly in non-muscle cells transfected with ß-myosin constructs carrying the mutations, but do not prevent incorporation of the mutant molecules into the sarcomere. CONCLUSIONS: This study expands our clinical and molecular knowledge of MYH7 rod mutations causing skeletal myopathies, and underscores the importance of discussing disease penetrance during genetic counseling.

Painful small fiber neuropathy with gastroparesis: A new phenotype with a novel mutation in the SCN10A gene.

Gain-of-function mutations in the SCN10A gene (encoding the Nav1.8 voltage gated sodium channel) have been reported in a small number of patients. All presented with predominantly painful sensory neuropathy, congruent with the expression of Nav1.8 in nociceptive sensory neurons of the dorsal root ganglion. Only a few had mild autonomic symptoms, including dry eyes and mouth, orthostatic dizziness, palpitations, diarrhea and constipation. The underlying mechanism of the autonomic symptoms in these patients is unclear. We describe a 37-year-old woman with severe progressive gastroparesis and diffuse painful small fiber sensory neuropathy that started at age 32. Due to the severe dysphagia she could not ingest solid food, and lost eight kilograms. The gastroparesis was documented by esophageal manometry and gastric scintigraphy. The neuropathic pain started distally and then intensified and spread to most body areas. The patient harbored a novel heterozygous mutation: c.G4915A:p.D1639N in the SCN10A gene. To the best of our knowledge, this is the first description of such a phenotype due to a Nav1.8 mutation. Thus, our study expands the clinical spectrum of Nav1.8 associated disorders, and suggests that mutations in this sodium channel should be considered in patients with gastrointestinal motility dysfunction and painful neuropathy.

Frequent misdiagnosis of adult polyglucosan body disease.

Adult polyglucosan body disease (APBD) is a rare glycogenosis manifesting progressive spastic paraparesis, sensorimotor polyneuropathy and neurogenic bladder. Misdiagnosis of APBD may lead to unnecessary investigations and to potentially harmful therapeutic interventions. To examine the frequency of misdiagnosis of APBD, we retrospectively reviewed the clinical data of 30 patients diagnosed between 1991 and 2013. Diagnosis was based on the combination of typical clinical and imaging findings, reduced glycogen branching enzyme activity, and the presence of p.Y326S GBE1 mutation. Initial symptoms started in the 5th-6th decade with bladder dysfunction (47 %), gait problems (33 %) or both. Diagnosis of APBD was delayed by 6.8 (±4.8) years. Consistent signs at diagnosis were spasticity in the legs (93 %), decreased or absent ankle reflexes (100 %), bilateral extensor plantar response (100 %) and distal sensory deficit (80 %). Nerve conduction study showed invariable sensorimotor polyneuropathy, and MRI demonstrated cervical spinal cord atrophy (100 %) and leukoencephalopathy (97 %). All 30 patients were initially misdiagnosed. Common misdiagnoses included cerebral small vessel disease (27 %), multiple sclerosis (17 %), amyotrophic lateral sclerosis (17 %) and peripheral neuropathies (20 %). Consequently, 27 % received inappropriate therapy. In addition, lower urinary tract symptoms in 60 % of men were attributed solely to prostatic disorders but did not respond to medical treatment or prostatectomy. These findings suggest that despite limited clinical variability, APBD is invariably misdiagnosed and patients are often mistreated. Physicians' unfamiliarity with the typical clinical and imaging features of APBD appears as the main reason for misdiagnosis.

Adult onset limb-girdle muscular dystrophy - a recessive titinopathy masquerading as myositis.

Rarely, inflammation can be present in genetic myopathies, such as dysferlinopathies, facioscapulohumeral muscular dystrophy and GNE-myopathy (hereditary inclusion body myopathy). This may lead to erroneous initial diagnosis and unnecessary therapy which bear serious side effects. We report on an unusual case of mutations in the TTN gene presenting with inflammatory infiltrates in the muscle biopsy. Only after intensive immune-modulating therapies failed, a genetic myopathy was considered. Exome sequencing and search for mutated muscle protein-encoding genes disclosed compound heterozygous mutations in TTN: K26320T and A6135G. The parents carry one each of the mutations. Titinopathy could be considered also in patients presenting with inflammatory infiltrates resistant to therapy.

Survival-apoptosis associated signaling in GNE myopathy-cultured myoblasts.

GNE Myopathy (GNEM) is a neuromuscular disorder caused by mutations in the GNE gene. It is a slowly progressive distal and proximal muscle weakness sparing the quadriceps. In this study, we applied our model of mutated M743T GNE enzyme skeletal muscle-cultured myoblasts and paired healthy controls to depict the pattern of signaling proteins controlling survival and/or apoptosis of the PI3K/AKT, BCL2, ARTS/XIAP pathways, examined the effects of metabolic changes/stimuli on their expression and activation, and their potential role in GNEM. Immunoblot analysis of the GNEM myoblasts indicated a notable increased level of activated PTEN and PDK1 and a trend of relative differences in the expression and activation of the examined signaling molecules with variability among the cultures. ANOVA analysis showed a highly significant interaction between the level of PTEN and the patients groups. In parallel, the interaction between the level of BCL2, BAX and PTEN with the specific PI3K/AKT inhibitor-LY294002 was highly significant for BCL2 and nearly significant for PTEN and BAX. The pattern of the ARTS/XIAP signaling proteins of GNEM and the paired controls was variable, with no significant differences between the two cell types. The response of the GNEM cells to the metabolic changes/stimuli: serum depletion and insulin challenge, as indicated by expression of selected signaling proteins, was variable and similar to the control cells. Taken together, our observations provide a clearer insight into specific signaling molecules influencing growth and survival of GNEM muscle cells.

Myotonia in DNM2-related centronuclear myopathy.

Centronuclear myopathy (CNM) is a rare hereditary myopathy characterized by centrally located muscle fiber nuclei. Mutations in the dynamin 2 (DNM2) gene are estimated to account for about 50 % of CNM cases. Electromyographic recordings in CNM may show myopathic motor unit potentials without spontaneous activity at rest. Myotonic discharges, a distinctive electrical activity caused by membrane hyperexcitability, are characteristic of certain neuromuscular disorders. Such activity has been reported in only one CNM case without a known genetic cause. We sequenced the DNM2 gene and the genes associated with myotonia (CLCN1, SCN4A, DMPK and ZNF9) in a sporadic adult patient with CNM and myotonic discharges. Sequencing the entire coding region and exon-intron boundaries revealed a heterozygous c.1106g-a substitution in exon 8, resulting in a R369Q change in the DNM2. Sequencing the CLCN1, SCN4A, DMPK and ZNF9 genes ruled out mutations in these genes. This is the first report of DNM2-related CNM presenting with myotonia. The diagnosis of CNM should be considered in patients with myotonic discharges of an unknown cause.

Association of the M3151 variant in the transient receptor potential vanilloid receptor-1 (TRPV1) gene with type 1 diabetes in an Ashkenazi Jewish population.

BACKGROUND: Type 1 diabetes in humans is an autoimmune disease in which Tcells target pancreatic islets of Langerhans, leading to the progressive destruction of the insulin-producing beta cells. Both genetic and environmental factors contribute to the development of autoimmune diabetes. The non-obese diabetic (NOD) mouse model of human type 1 diabetes demonstrates two missense mutations in the transient receptor potentialvanilloid receptor-1 (TRPVi) gene. OBJECTIVES: To investigate whether polymorphism in the TRPV1 gene may play a role in the predisposition to human type 1 diabetes. METHODS: We genotyped 146 Ashkenazi Jewish type 1 diabetic patients and 205 Ashkenazi Jewish healthy controls for the rs222747 (M3151), rs224534 (T4691) and rs8065080 (1585V) variants of the TRPV1 gene. RESULTS: There was a significant increase in the rs222747 (M3151) variant of the TRPV1 gene in the type 1 diabetes cohort compared to the control: rs222747 (M3151) homozygous: (61% vs. 48.3%, P = 0.02). Logistic regression analysis revealed that type 1 diabetes was significantly associated with rs222747 (M3151), such that having diabetes increased the odds of rs222747 homozygosity (M3151) by 67.2%, odds ratio 1.6, 95% confidence interval 1.08-2.57, P < 0.02. No difference was found in the rs224534 (T4691) and rs8065080 (1585V) allelic variants. There was no difference in any of the TRPV1 variants by gender, age when type 1 diabetes was diagnosed, body mass index, glycemic control, blood pressure, positive autoantibodies (ICA, GAD, IAA), and other autoimmune diseases. CONCLUSIONS: Our study demonstrates that TRPV1 may be a susceptible gene for type 1 diabetes in an Ashkenazi Jewish population. These results should be replicated in the same ethnic group and in other ethnic groups.