Kevin J. Felice

A longitudinal study comparing thenar motor unit number estimates to other quantitative tests in patients with amyotrophic lateral sclerosis

The following data were obtained on 21 amyotrophic lateral sclerosis (ALS) patients, aged 36–76 years (mean: 58 years), at baseline and months 4, 8, and 12: thenar motor unit number estimate (MUNE) using multiple point stimulation, mean thenar surface‐recorded motor unit action potential negative‐peak area, thenar compound muscle action potential amplitude, isometric hand grip strength, total Medical Research Council (MRC) manual muscle testing score, Appel ALS rating scale, and forced vital capacity (FVC). The absolute mean rate of change per month was significantly greater (P < 0.01) for MUNE values than for MRC and FVC values in the 21 ALS patients. In a subset of patients (n = 6) with slowly progressive disease, the absolute mean rate of change per month was significantly greater (P < 0.01) for MUNE values than for all other test values. In addition, MUNE values were the most sensitive index for documenting changes in disease progression over time.

Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A-->G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing?

Congenital end-plate acetylcholinesterase (AChE) deficiency (CEAD), the cause of a disabling myasthenic syndrome, arises from defects in the COLQ gene, which encodes the AChE triple-helical collagenlike-tail subunit that anchors catalytic subunits of AChE to the synaptic basal lamina. Here we describe a patient with CEAD with a nonsense mutation (R315X) and a splice-donor-site mutation at position +3 of intron 16 (IVS16+3A-->G) of COLQ. Because both A and G are consensus nucleotides at the +3 position of splice-donor sites, we constructed a minigene that spans exons 15-17 and harbors IVS16+3A-->G for expression in COS cells. We found that the mutation causes skipping of exon 16. The mutant splice-donor site of intron 16 harbors five discordant nucleotides (at -3, -2, +3, +4, and +6) that do not base-pair with U1 small-nuclear RNA (snRNA), the molecule responsible for splice-donor-site recognition. Versions of the minigene harboring, at either +4 or +6, nucleotides complementary to U1 snRNA restore normal splicing. Analysis of 1,801 native splice-donor sites reveals that presence of a G nucleotide at +3 is associated with preferential usage, at positions +4 to +6, of nucleotides concordant to U1 snRNA. Analysis of 11 disease-associated IVS+3A-->G mutations indicates that, on average, two of three nucleotides at positions +4 to +6 fail to base-pair, and that the nucleotide at +4 never base-pairs, with U1 snRNA. We conclude that, with G at +3, normal splicing generally depends on the concordance that residues at +4 to +6 have with U1 snRNA, but other cis-acting elements may also be important in assuring the fidelity of splicing.

Further observations on forearm flexor weakness in inclusion body myositis

In order to further characterize and provide a possible mechanism for the asymmetrical involvement of forearm muscles in inclusion body myositis (IBM), we measured isometric hand and pinch grip strength, and forearm muscle girth on 15 IBM patients. Forearm muscle strength and girth were significantly greater on the dominant versus nondominant side: mean grip strength, 173.9 vs. 98.8 N; mean pinch strength, 47.6 vs. 29.7 N; and mean forearm girth, 22.5 vs. 19.9 cm. This observation may suggest a role for exercise in delaying the disease progression in IBM.

Apparent conduction block in patients with ulnar neuropathy at the elbow and proximal Martin–Gruber anastomosis

A Martin–Gruber anastomosis (MGA) commonly results in an abnormal decline in amplitude across the forearm segment when ulnar motor nerve conduction studies are performed. A recent report described a proximal MGA resembling partial conduction block in a patient with ulnar neuropathy at the elbow (UNE). As a result, we screened patients with similar findings. We detected a proximal MGA in three patients over a period of 2 years, which suggests that this may be an under‐recognized anomaly. We conclude that a proximal MGA must be excluded in all cases of UNE showing apparent partial conduction block across the elbow segment. Muscle Nerve, 2004

Cervical root stimulation in a case of classic neurogenic thoracic outlet syndrome.

We performed C8 nerve root stimulation in addition to other electromyographic (EMG) studies in a surgically proven case of classic thoracic outlet syndrome (TOS). The patient was a 19‐year‐old woman with a 2‐year history of right hand cramps and progressive weakness and atrophy of hand muscles, especially the thenar eminence. Routine EMG studies showed evidence for an axon‐loss lower trunk brachial plexopathy. Stimulation studies of the C8 nerve roots demonstrated proximal conduction block on the affected side only. The diagnosis was further supported by cervical spine radiographs, which demonstrated a cervical rib, and surgical exploration of the brachial plexus, which demonstrated upward compression and stretching of the lower trunk by a fascial band extending from the anomalous cervical rib to the first thoracic rib. The patient noted a modest improvement in hand function postoperatively. Root stimulation studies can help in the diagnosis of classic TOS by providing more precise localization and information regarding the degree, if any, of proximal motor conduction block.

Multiple recurrences of diabetic muscle infarction: case report and literature review.

This is the report a case of diabetic muscle infarction (DMI) associated with multiple recurrences and a review of the literature on DMI from the first description in 1965 to the present. Specifically the review of the clinical, laboratory, and muscle histopathologic features of 86 reported cases of DMI. Patients with DMI usually present with acute or subacute focal lower extremity muscle pain or swelling. Elevations in the white blood cell count and erythrocyte sedimentation rate are common laboratory findings. Magnetic resonance imaging, a highly sensitive diagnostic test in DMI, shows increased T2-weighted signal and edema in affected muscles. Typical muscle histopathology includes muscle fiber necrosis and endomysial inflammation. Slow symptomatic improvement usually occurs over a period of 1 to 6 months. Conservative therapy and analgesics seem appropriate for most patients. Although self-limiting, DMI is often associated with recurrent muscle infarctions and multisystem diabetes-related complications. Diabetes-induced arteriosclerosis and microangiopathy are the suggested causes of DMI. It is concluded that DMI is an uncommon but probably underrecognized disorder causing focal muscle pain and swelling, usually of thigh or calf muscles, in patients with diabetes mellitus complicated by poorly controlled hyperglycemia and multiorgan complications.

The Clinical Features of Facioscapulohumeral Muscular Dystrophy Associated With Borderline (>/=35 kb) 4q35 EcoRI Fragments.

Objectives: The objectives of this study were to characterize the clinical features of facioscapulohumeral muscular dystrophy (FSHD) in patients with borderline (≥35 kb) EcoRI fragments and to compare patients with borderline EcoRI fragments with FSHD patients harboring fragments of <35 kb. Background: Most patients with FSHD harbor 4q35 EcoRI fragments of less than 35 kb. The clinical findings in patients with borderline fragments are not well known. Methods: The authors conducted a retrospective review of patients with FSHD followed at a regional neuromuscular center over a 12-year period. Results: Eleven patients with DNA-positive FSHD, found to harbor borderline (≥35 kb) EcoRI fragments (group 1), were compared with 30 patients with fragments of <35 kb (group 2). Group 1 patients were less likely (18%) to present with the classic FSHD phenotype as compared with group 2 patients (63%). Statistically significant differences in clinical disease severity and manual muscle testing scores were noted between the 2 groups, with group 1 patients showing less severe weakness and disability at presentation. Conclusions: Patients with borderline fragments are more likely to have a partial or less severe form of FSHD, probably resulting from a less disruptive DNA alteration at the 4q35 locus.

Fulminant lipid storage myopathy due to multiple acyl-coenzyme a dehydrogenase deficiency

Introduction: The lipid storage myopathies, primary carnitine deficiency, neutral lipid storage disease, and multiple acyl coenzyme A dehydrogenase deficiency (MADD), are progressive disorders that cause permanent weakness. These disorders of fatty acid metabolism and intracellular triglyceride degradation cause marked fat deposition and damage to muscle cells. Methods: We describe a rapidly progressive myopathy in a previously healthy 33‐year‐old woman. Over 4 months, she developed a proximal and axial myopathy associated with diffuse myalgia and dysphagia, ultimately leading to respiratory failure and death. Results: Muscle biopsy showed massive accumulation of lipid. Plasma acylcarnitine and urine organic acid analysis was consistent with MADD. This was confirmed by molecular genetic testing, which revealed 2 pathogenic mutations in the ETFDH gene. Conclusions: This report illustrates a late‐onset case of MADD and reviews the differential diagnosis and evaluation of patients with proximal myopathy and excessive accumulation of lipid on muscle biopsy. Muscle Nerve 52: 289–293, 2015

Biopsy‐proven alpha‐glucosidase deficiency with normal lymphocyte enzyme activity

Alpha‐glucosidase deficiency is a rare cause of muscle disease in adults. The diagnosis relies on recognition of the salient clinical features and determination of significantly reduced alpha‐glucosidase (GAA) activity. Lymphocytes are the usual tissue for diagnostic enzymology; discrepant results from analyses of different tissues are unusual. We report a patient with clinical, electromyographic, and biopsy findings indicative of alpha‐glucosidase deficiency whose muscle and lymphocyte enzyme results were markedly discrepant on multiple analyses. As a result, we conclude that all patients with suspected alpha‐glucosidase deficiency and a normal lymphocyte GAA assay should also have a determination of GAA activity in muscle or skin fibroblasts. Muscle Nerve 29: 440–442, 2004

Late-Onset Friedreich's Ataxia Presenting as a Spastic Paraparesis.

A 55-year-old woman presented with a 10-yeai history of a progressive gait disorder. Her examination showed a spastic paraparesis with brisk deep tendon reflexes, but only minimal limb ataxia and no evidence for a sensory neuropathy The patient was found to be homozygous for the GAA trinucleotide repeal diagnostic of Friedreichs ataxia The presentation of Friedreichs ataxia as a spastic paraparesis reinforces the appreciation of the variable phenotype of this disease.