Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.

BACKGROUND: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. METHODS: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. RESULTS: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. CONCLUSIONS: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.

A controlled study of reverse transcriptase in serum and CSF of HIV-negative patients with ALS.

Reverse transcriptase has been detected in the serum of HIV-negative patients with amyotrophic lateral sclerosis (ALS). An ALS-like disorder in HIV-positive patients can remit with antiretroviral therapy. Using the product enhanced assay technique, we measured reverse transcriptase activity in the serum and CSF of 23 HIV-negative patients with ALS and 21 neurologic disease controls. Results for CSF were not significant, whereas reverse transcriptase was detected in 56% of ALS sera vs 19% of controls.

A pilot, double-blind, placebo-controlled trial of indinavir in patients with ALS.

There is some evidence of retroviral infection in ALS. A randomized, double-blind, placebo-controlled trial of indinavir in ALS was performed to assess safety and efficacy trends. Nephrolithiasis and gastrointestinal side effects were frequent with indinavir treatment. Group differences in the rate of decline were not significant between the groups for the ALS Functional Rating Scale (p = 0.36) or for the secondary variables. The toxicity and negative efficacy trends discourage further indinavir trials in ALS.

An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy.

A 32-year-old woman presenting with a rapidly progressive ALS-like syndrome was found to be HIV positive with a CD4 count of 44/mm(3). The patient recovered completely during 1 year after treatment with nelfinavir, zidovudine, and lamivudine, and recovery is sustained nearly 4 years later. Recovery was accompanied by HIV RNA becoming undetectable in plasma and CSF.

Electrophysiologic correlates of weakness in L5/S1 radiculopathy.

INTRODUCTION: Management of patients with radiculopathy involves estimating the degree of physiologic and anatomic injury, and weighing that to predict the likely clinical course. OBJECTIVE: To determine whether low distal peroneal and tibial CMAP amplitudes correlate with weakness and fibrillations of functionally relevant muscles in L5/S1 radiculopathy (LSR). METHODS: We reviewed clinical and electrophysiologic data in 66 consecutive patients with LSR. RESULTS: A significantly greater number of patients with low peroneal CMAP amplitudes had weakness of L5 (p = 0.025) and S1 innervated leg muscles (p < 0.001). Low tibial CMAP amplitudes were also associated with weakness of S1 innervated muscles (p < 0.038). The association of low peroneal CMAP amplitudes with weakness persisted when weakness of at least 3 muscles was considered in the analysis for L5 (p < 0.0001) and S1 (p = 0.014) innervated muscles. CONCLUSIONS: Low peroneal and tibial CMAP amplitudes may serve as surrogate measures for segmental weakness of functionally relevant muscles in LSR.

Syringomyelia presenting as ulnar neuropathy at the elbow.

OBJECTIVES: Syringomyelia may present with confusing, unilateral patterns of segmental muscle involvement and dissociated sensory loss. The objective of this study was to report a patient with Chiari malformation type 1 (CM1) and syringomyelia who had an unusual presentation suggesting ulnar neuropathy at the elbow. RESULTS: A 24-year-old woman presented with clinical evidence of ulnar neuropathy at the elbow except that there was disproportionate abductor digiti mini (ADM) atrophy and weakness, equivocal ipsilateral abductor pollicis brevis weakness and hyporeflexia in both arms. Nerve conduction studies revealed marked amplitude reduction of the left ulnar ADM-compound muscle action potential (ADM-CMAP) with a normal first dorsal interosseous-CMAP amplitude, no focal slowing or conduction block, and a normal ulnar sensory response amplitude. Electromyography (EMG) showed multi-segmental, left C7-T1 fibrillations and chronic reinnervation changes. Magnetic resonance imaging (MRI) of the cervical spine demonstrated CM1 and syringomyelia. CONCLUSIONS: Syringomyelia may clinically mimic ulnar neuropathy at the elbow.

Ulnar-median and median-ulnar anastomoses in the forearm: a patient report.

Reports of an ulnar-median anastomosis in the forearm (UMAF) are rare and its existence has been questioned. A patient with clinical and electrophysiologic evidence of ulnar neuropathy at the elbow (UNE) had unexpected fibrillations in the abductor pollicis brevis muscle (APB). Additional nerve conduction studies suggested both ulnar-median and median-ulnar anastomoses in the forearm. The unexpected finding of APB fibrillations in a patient with UNE should raise the possibility of the rare UMAF.

Blood pressure elevations in riluzole-treated patients with amyotrophic lateral sclerosis.

OBJECTIVE: To determine whether riluzole is associated with blood pressure elevations in patients with amyotrophic lateral sclerosis (ALS). BACKGROUND: Though previously reported, hypertension is not considered a frequent adverse effect of riluzole. METHODS: We reviewed data from 35 consecutive ALS patients on riluzole, and 88 randomly selected controls without and 20 patients with ALS who were not on riluzole. RESULTS: A significantly greater number of ALS patients on riluzole had blood pressure elevations (28 of 35 patients) compared to controls (26 of 88, p<0.001; 8 of 20, p = 0. 007). Median systolic and diastolic blood pressures were both significantly higher in riluzole-treated (140/86 mm Hg) than in control patients without ALS (120/70 mm Hg, p<0.001). Systolic, but not diastolic, blood pressures were significantly higher in riluzole-treated patients than in controls with ALS (126 mm Hg, p = 0.002). CONCLUSIONS: Riluzole treatment may be associated with mild blood pressure elevations. Future prospective trials of riluzole should closely assess hypertension.

The short exercise test is normal in proximal myotonic myopathy.

OBJECTIVES: Proximal myotonic myopathy (PROMM) is a multisystem disorder that may mimic myotonic dystrophy (MD). Previously we demonstrated that the 60 s exercise test was normal in two siblings with PROMM. The test enabled distinction of PROMM from MD, as there is a well documented immediate post-exercise compound muscle action potential (CMAP) amplitude decline in MD. METHODS: We now performed exercise testing using several exercise durations in 8 PROMM patients from 6 kinships, and one MD patient, extending our previous observations. Repetitive stimulation and needle electromyography findings were also recorded. RESULTS: The 10 (n = 8), 30 (n = 5), and 60 (n = 5) s, and the 5 min (n = 1) exercise tests were normal in all PROMM patients. Specifically, the maximum post-exercise CMAP amplitude decline was 8%. In contrast, the MD patient had CMAP amplitude declines of 48% (10 s exercise test) and 26% (30 s exercise test). The distribution of repetitive stimulation and motor unit duration abnormalities were variable and less diagnostically useful. CONCLUSIONS: The 10, 30, and 60 s exercise tests help distinguish PROMM from MD. As the 10 s exercise test is rapid and easily tolerated, we recommend this test for clinical testing.

Miller Fisher syndrome: axonal, demyelinating or both?

Controversy exists concerning whether Miller Fisher syndrome (MFS) is the result of a predominantly axonal or demyelinating polyneuropathy and whether the Guillain-Barré syndrome variant of acute ataxia and areflexia without ophthalmoplegia, ataxic Guillain-Barré syndrome (atxGBS), has a distinct pathophysiology. We explored these issues by reviewing the electrophysiologic features of 6 patients with MFS and 2 patients with atxGBS. EMG laboratory records were reviewed and electrophysiologic findings were categorized as axonal or demyelinating neuropathy using previously defined criteria. Of the 6 patients with MFS, 5 had electrophysiologic evidence suggestive of an axonal, predominantly sensory polyneuropathy; only 1 patient met criteria for demyelinating polyneuropathy. Both patients with atxGBS had demyelinating sensorimotor polyneuropathy. Electrophysiologic abnormalities in MFS typically suggest a predominantly axonal, sensory polyneuropathy, though demyelinating forms occur and may be under-diagnosed using current criteria. AtxGBS, in our experience, is a predominantly demyelinating polyneuropathy.

Hereditary neuropathy and vocal cord paralysis in a man with childhood diphtheria.

We present the case of a 37-year-old Afghani man with a history of childhood diphtheria, who was diagnosed with bilateral vocal cord paralysis at age 15 years. At about this time he developed progressive muscular wasting and distally predominant weakness, and subsequently developed respiratory insufficiency, necessitating nocturnal ventilatory support. His examination suggested a distal symmetric sensorimotor neuropathy, and his brother was similarly affected, although to a lesser degree. Electromyography (EMG) and nerve conduction studies revealed this process to be purely axonal. A diagnosis of possible hereditary motor and sensory neuropathy (HMSN) type IIc, hereditary axonal polyneuropathy with vocal cord paralysis, is proposed, although the question of early diphtheritic involvement of the vocal cords and peripheral nerves is also considered.

Treatment of mononeuropathy multiplex in hepatitis C virus and cryoglobulinemia.

Recent reports advocate alpha-interferon (alpha-Ifn) treatment for mononeuropathy multiplex in hepatitis C virus-associated cryoglobulinemia. We report 2 patients with this disorder to describe two underrecognized treatment outcomes--worsening of polyneuropathy with initiation of alpha-Ifn, in the absence of immunosuppression, and deterioration of liver function with prednisone, despite improvement of polyneuropathy.

Median mixed and sensory nerve conduction studies in carpal tunnel syndrome.

OBJECTIVE: To assess the sensitivities and specificities of velocity differences between median mixed nerve conduction across the wrist (Medmxpw) and (I) median mixed nerve conduction in the forearm (Medmxf) and (II) palm to D2 sensory conduction (MedpD2). DESIGN AND METHODS: We prospectively studied 67 limbs of patients with clinically definite carpal tunnel syndrome (CTS). Medmxf and Medmxpw were performed by stimulating the median nerve at the elbow and palm respectively and recording at the proximal wrist crease. We also compared conventional median sensory (D2-wrist) and mixed (palm-wrist) tests in all patients. Thirty limbs of asymptomatic subjects served as normal controls and 21 limbs of subjects with other neuropathies served as diseased controls; control data was collected prospectively. RESULTS: The sensitivity of the MedpD2-Medmxpw difference (0.87) was significantly greater than that of the Medmxf-Medmxpw difference (0.61, P < 0.001). Both tests were similar and highly specific (0.98 and 0.96, respectively). CONCLUSIONS: The MedpD2-Medmxpw study is among the most sensitive and specific electrophysiologic tests for CTS.

Clozapine-induced myotoxicity in patients with chronic psychotic disorders.

Muscle dysfunction related to clozapine treatment is largely unrecognized. We evaluated weekly creatine kinase (CK) levels in 37 consecutive clozapine-treated outpatients with chronic psychotic disorders. Those with CK elevations underwent clinical neurologic evaluation, electromyography (EMG), and nerve conduction studies. Patients with probable myopathy had a quadriceps muscle biopsy. Twenty control patients had a single CK level determination. Twenty-nine of 37 clozapine-treated patients had CK elevations. Three patients had extreme CK elevations (> 20,000 IU/L), without myoglobinuria. Mean CK levels were significantly greater in clozapine patients (194 IU/L) than in control patients (142.3, p = 0.033). Of 18 clozapine-treated patients evaluated clinically, 6 had mild proximal weakness. EMG in 13 patients was myopathic in 5, normal in 5, and neurogenic in 3. Muscle biopsy in 5 patients showed rare regenerating myofibers and mild acute denervation (1), mild type II fiber atrophy (1), minimal acute denervation (1), and normal muscle (2). In conclusion, clozapine therapy may be associated with CK elevations and, rarely, mild myopathy.

Extraocular muscle involvement in Becker muscular dystrophy.

We report limitation of gaze and slow saccadic eye movements by clinical examination and video-oculography in a patient with Becker muscular dystrophy. This rare association suggests that a dystrophinopathy should be considered in a patient with features characteristic of Becker muscular dystrophy even when mild impairment of eye movements is present.