Improving the efficacy of exome sequencing at a quaternary care referral centre: novel mutations, clinical presentations and diagnostic challenges in rare neurogenetic diseases.

BACKGROUND: We used a multimodal approach including detailed phenotyping, whole exome sequencing (WES) and candidate gene filters to diagnose rare neurological diseases in individuals referred by tertiary neurology centres. METHODS: WES was performed on 66 individuals with neurogenetic diseases using candidate gene filters and stringent algorithms for assessing sequence variants. Pathogenic or likely pathogenic missense variants were interpreted using in silico prediction tools, family segregation analysis, previous publications of disease association and relevant biological assays. RESULTS: Molecular diagnosis was achieved in 39% (n=26) including 59% of childhood-onset cases and 27% of late-onset cases. Overall, 37% (10/27) of myopathy, 41% (9/22) of neuropathy, 22% (2/9) of MND and 63% (5/8) of complex phenotypes were given genetic diagnosis. Twenty-seven disease-associated variants were identified including ten novel variants in FBXO38, LAMA2, MFN2, MYH7, PNPLA6, SH3TC2 and SPTLC1. Single-nucleotide variants (n=10) affected conserved residues within functional domains and previously identified mutation hot-spots. Established pathogenic variants (n=16) presented with atypical features, such as optic neuropathy in adult polyglucosan body disease, facial dysmorphism and skeletal anomalies in cerebrotendinous xanthomatosis, steroid-responsive weakness in congenital myasthenia syndrome 10. Potentially treatable rare diseases were diagnosed, improving the quality of life in some patients. CONCLUSIONS: Integrating deep phenotyping, gene filter algorithms and biological assays increased diagnostic yield of exome sequencing, identified novel pathogenic variants and extended phenotypes of difficult to diagnose rare neurogenetic disorders in an outpatient clinic setting.

COVID-19: Neurology residents' perspective.

Throughout this pandemic, neurology resident education and service has, and will continue to be, affected during this unprecedented time. Balancing the safety of our residents as well as the anticipated inpatient service demands, we have, and continue to, make changes to meet the needs of our community. Education certainly has been affected but we have made great effort to maintain normalcy. We are leveraging web-based technologies to continue formal didactics. The American Academy of Neurology has provided program directors with various tools to share to provide high-yield academic education. AAN Synapse, distance learning modules, and podcasts are a few examples. Each residency training program will likely face different challenges depending on location and community structure. We have an obligation to help all of our colleagues in the hospital in providing quality and compassionate care during this time of need. Our training and education will only benefit from this experience teaching us lessons on adaptability, the importance of teamwork, and self-sacrifice.

Lumbar arachnoiditis: Does imaging associate with clinical features?

OBJECTIVES: Lumbar arachnoiditis is a rare and debilitating neurologic disorder with multiple etiologies and a spectrum of imaging and clinical characteristics. Prior reports have anecdotally claimed that no association exists between findings of arachnoiditis observed on magnetic resonance imaging (MRI) and those assessed clinically. The purpose of this study was to determine if MRI features of lumbar arachnoiditis associate with the clinical findings of the disorder. PATIENTS AND METHODS: Twenty eight patients with lumbar arachnoiditis reported on MRI between 2012 and 2018 were retrospectively identified. A variety of MRI and clinical features of lumbar arachnoiditis were cataloged for these patients based on common findings discovered through literature review. Imaging findings included cauda equina nerve root contour and thickening, adhesion location, level of involvement, enhancement, and Delamarter group. Clinical findings included demographics, etiology, symptom dynamics, and signs/symptoms. Fisher's exact tests were used to determine associations between the imaging and clinical features of lumbar arachnoiditis. RESULTS: In general, MRI findings did not associate with the clinical features of lumbar arachnoiditis with a few exceptions. Most notably, confounding lumbar pathology was associated with symptom dynamics (p = 0.004) and nerve root contour was associated with motor and sensory symptoms (p = 0.01). The suspected arachnoiditis etiology of the majority of patients was either post-operative or post-infectious in nature. CONCLUSION: MRI findings in lumbar arachnoiditis offer limited insight into the clinical presentation of the disorder.

Dropped head syndrome due to neuromuscular disorders: Clinical manifestation and evaluation.

In this article, we discuss the clinical approach to patients with dropped head syndrome and identify the various neuromuscular causes of dropped head syndrome including muscle, neuromuscular junction, peripheral nerve and motor neuron etiologies. We aim to increase awareness of recognition the entity of dropped head syndrome and factors that may predict response to immunomodulating therapy in dropped head syndrome.

The sensitivity comparison of bar electrode and disposable ring electrode for recording of lateral femoral cutaneous nerve.

OBJECTIVES: To compare the sensitivity of bar electrode and disposable ring electrode for recording of lateral femoral cutaneous (LFCN). MATERIALS AND METHODS: A total of 23 subjects (13 females, 10 males, mean age: 49.6 ± 9.6 (range: 29-63) were recruited in the study. A total of 36 recordings were obtained with each electrode (with bar and disposable ring electrodes) from the subjects. The comparison of data was performed with percentages and student T-table test. RESULTS: The response rate was 98% (35 out of 36 recordings) with bar electrode and 88% (32 out of 36 recordings) with disposable ring electrode. Although the sensitivity rate of bar electrode is slightly higher than of disposable ring electrode, there were no statistically significant differences in detecting the onset latency, peak latency, and amplitude of LFCN. CONCLUSION: The recording sensitivity of LFCN is higher with bar electrode than disposable ring electrode. However, disposable ring electrode can be used alternatively.

Underrecognized anomaly: proximal martin-gruber anastomosis at the elbow.

PURPOSE: A proximal Martin-Gruber anastomosis (MGA) is an underrecognized anomaly and can mimic ulnar neuropathy at the elbow on electrodiagnostic testing. Martin-Gruber anastomosis is mainly recognized as a crossover from median nerve or its branches to ulnar nerve at the forearm, but may occur at the elbow (proximal MGA). The authors report their experience with MGA at the elbow. METHODS: Using standard nerve conduction techniques, the authors prospectively detected electrodiagnostic evidence of a proximal MGA at the elbow over the course of 4 years. An accompanying ulnar neuropathy was diagnosed based on clinical findings, focal conduction slowing, and needle electromyography. RESULTS: A proximal MGA involving branch of ulnar nerve was detected in 16 cases. The detection of proximal MGA to the first dorsal interosseous muscles was more sensitive than to the adductor digiti minimi muscles in their series. CONCLUSIONS: A proximal MGA is an underrecognized anomaly. This study is the largest series for proximal MGA in the literature. The authors recommend considering proximal MGA in any cases of ulnar neuropathy at the elbow, especially if the apparent conduction block is not associated with slowing of conduction velocity, and a discrepancy between clinical and electrodiagnostic findings is present.

Ulnar neuropathy with prominent proximal Martin-Gruber anastomosis.

Martin-Gruber anastomosis (MGA) is the most common nerve anastomosis in the upper extremities and it crosses from the median nerve to the ulnar nerve. Proximal MGA is an under recognized anastomosis between the ulnar and median nerves at or above the elbow and should not be missed during nerve conduction studies. We presented two patients with ulnar neuropathy mimicking findings including numbness and tingling of the 4th and 5th digits and mild weakness of intrinsic hand muscles. However, both cases had an apparently remarkable conduction block between the below- and above-elbow sites that was disproportionate to their clinical findings. To explain this discrepancy, a large MGA was detected with stimulation of the median nerve at the elbow. Thus, proximal MGA should be considered in ulnar neuropathy at the elbow when apparent conduction block or/and discrepancy between clinical and electrodiagnostic findings is found.

The electrodiagnostic sensitivity of proximal lower extremity muscles in the diagnosis of L5 radiculopathy.

The aim of this study was to assess the electrodiagnostic (EDx) sensitivity of proximal lower extremity muscles, including tensor fascia lata (TFL) and gluteus medius (GMED), in the diagnosis of L5 radiculopathy.Eleven EDx recordings with L5 radiculopathy were collected. The motor unit action potentials were assessed for morphology, stability, and firing characteristics. A descriptive analysis was performed. In proximal L5-supplied muscles, 4 of 11 recordings were abnormal in TFL only, with normal GMED; 4 of 11 recordings had similar findings in both muscles; 2 of 11 had abnormal findings in both muscles, but TFL had more noticeable findings; and 1 had abnormal findings in both muscles, but GMED findings were more noticeable. No patient had abnormalities limited to GMED. TFL was more sensitive than GMED in detecting L5 radiculopathy. Knowing which muscles are more likely to show abnormalities can improve the efficiency of EMG and reduce patient discomfort. Muscle Nerve 45: 891-893, 2012.

A study of Gulf War veterans with a possible deployment-related syndrome.

A previous symptom-based survey of veterans of the 1990-1991 Persian Gulf War suggested a neurological syndrome (blurred vision, loss of balance/dizziness, tremors/shaking, and speech difficulty). The authors conducted the present study to determine whether specific findings could indicate an organic basis for this possible syndrome. They completed an extensive clinical and laboratory evaluation on Gulf War veterans with all 4 symptoms, using 3 comparison groups. A single clinically based neurological syndrome could not be identified. No deployment-related exposure appeared to explain the pattern of symptoms, but this evaluation suggested comorbidities and possibly multiple vaccines as important contributors. Many of the neurological symptoms reported by the studied veterans appear to have an organic basis, but comorbidities must be excluded before researchers can conclude that a definitive syndrome exists.