Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance.

X-linked Emery-Dreifuss muscular dystrophy is caused by loss of function of emerin, an integral protein of the inner nuclear membrane. Yet emerin null mice are essentially normal, suggesting the existence of a critical compensating factor. We show that the lamina-associated polypeptide1 (LAP1) interacts with emerin. Conditional deletion of LAP1 from striated muscle causes muscular dystrophy; this pathology is worsened in the absence of emerin. LAP1 levels are significantly higher in mouse than human skeletal muscle, and reducing LAP1 by approximately half in mice also induces muscle abnormalities in emerin null mice. Conditional deletion of LAP1 from hepatocytes yields mice that exhibit normal liver function and are indistinguishable from littermate controls. These results establish that LAP1 interacts physically and functionally with emerin and plays an essential and selective role in skeletal muscle maintenance. They also highlight how dissecting differences between mouse and human phenotypes can provide fundamental insights into disease mechanisms.

A novel mutation in PNPLA2 leading to neutral lipid storage disease with myopathy.

BACKGROUND: Mutations in PNPLA2, a gene encoding adipose triglyceride lipase, lead to neutral lipid storage disease with myopathy. OBJECTIVE: To report the clinical and molecular features of a case of neutral lipid storage disease with myopathy resulting from a novel mutation in PNPLA2. DESIGN: Case report. SETTING: University hospital. PATIENT: A 65-year-old man with progressive muscle weakness and high serum creatine kinase levels. INTERVENTION: Direct sequencing of the PNPLA2 gene. RESULTS: Identification of a novel homozygous mutation in the patient's PNPLA2 gene confirmed the suspected diagnosis of neutral lipid storage disease with myopathy. CONCLUSION: Screening of the PNPLA2 gene should be considered for patients presenting with high levels of creatine kinase, progressive muscle weakness, and systemic lipid accumulation. The presence of Jordans anomaly can be a strong diagnostic clue.

Senataxin mutations and amyotrophic lateral sclerosis.

We studied three patients with mutations in the senataxin gene (SETX). One had juvenile onset of ALS. The second case resembled hereditary motor neuropathy. The third patient had an overlap syndrome of ataxia-tremor and motor neuron disease, phenotypes previously associated with SETX mutations. Our patients were all apparently sporadic, with no other affected relative. Two relatives of patient no. 2 carried the SETX c.4660T > G transversion but did not manifest motor neuron disease, abnormal eye movements, ataxia, or tremor suggesting that genetic or environmental modifiers may influence expression of this SETX polymorphism. Relatives of patients 1 and 3 were not available for examination or SETX mutation screening. Mutations causing ALS4 may be more frequent and heterogeneous than expected. Screening for SETX mutations should be considered in patients with apparently sporadic juvenile-onset ALS, hereditary motor neuropathy, and overlap syndromes with ataxia and motor neuron disease.

Utility of skin biopsy to evaluate peripheral neuropathy.

Skin biopsy for epidermal nerve fiber analysis provides an important objective test for the diagnosis of peripheral neuropathy, particularly small fiber sensory neuropathy (SFSN). The determination of epidermal nerve fiber density (ENFD) is reliable, with high diagnostic specificity and good sensitivity. Because of false negatives, biopsy results must be interpreted in conjunction with neurologic findings and laboratory results, including objective tests of sensory and autonomic function. SFSN most commonly is length dependent and is idiopathic in about half the patients. Biopsy of a proximal site (thigh) and a distal site (calf) typically shows greater abnormality of ENFD distally than proximally. More severe abnormality of ENFD in the thigh than in the calf raises the possibility of a non-length-dependent SFSN. The causes of this type of neuropathy, such as Sjögren's syndrome, sarcoidosis, and celiac disease, may be treatable.

A prospective cohort study of neuropsychological test performance in ALS.

Our objective was to determine the prevalence and predictors of cognitive impairment in ALS, measure differences in survival among impaired and unimpaired patients, and assess changes in neuropsychological test performance over time. Fifty patients were enrolled in a prospective cohort study of neuropsychological performance. ANOVA and chi(2) tests assessed differences in clinical characteristics and neuropsychologic test results; general estimating equations assessed change in test performance; multiple regression determined which variables contributed to cognitive status; and Cox models compared survival. Thirty-six patients were categorized as cognitively normal, and 14 were impaired. Impaired patients were older at testing (p = 0.024), but no more likely to have bulbar signs. Predicators of impairment were symptom duration (p < 0.001), motor function (p < 0.001), and rate of ALS progression (p < 0.001). The Benton recognition (p < 0.001), Boston naming (p = 0.001), Wisconsin Card Sort (p = 0.001) and word generation (p = 0.001) tests contributed most strongly to cognitive status. Survival was worse in impaired patients (p = 0.027). Over time, only animal word generation declined (p = 0.016). In conclusion, 28% percent of patients were cognitively impaired. Older age and more severe ALS were associated with impairment. The strongest neuropsychological predictors of cognitive status were measures of executive, episodic memory and language function. Cognitively impaired patients had shorter survival time.

Collagen nerve protector in rat sciatic nerve repair: A morphometric and histological analysis.

Peripheral nerve repair is often complicated by fibroblastic scar formation, nerve dysfunction, and traumatic neuroma formation. Use of bio-absorbable protective wraps may improve outcomes of these repairs. This study histologically compared the incidence of neuroma formation, connective tissue proliferation, and axonal regrowth in transected rat sciatic nerves repaired with and without tubular collagen nerve sleeves. Twenty Sprague-Dawley rats underwent unilateral sharp sciatic nerve transection and microscopic nerve repair with four epineural sutures and were randomly treated with or without an encircling collagen nerve sleeve. Normal nerves from the contralateral sciatic nerve were also examined. At sacrifice three months later, the nerves were evaluated for traumatic neuroma formation, perineural scar formation, and morphometric analysis. Histological examination of normal and repaired nerves by a neuropathologist demonstrated healing, minimal Wallerian degeneration and no traumatic neuroma formation. Distal section analysis (nine nonwrapped, 10 wrapped), revealed no significant differences in total fascicular area, myelinated fibers per nerve, fiber density, myelin area per nerve, myelinated fiber diameter, axon diameter, myelin thickness, or G-ratio. Significantly greater (P = 0.005) inner epineural connective tissue formation was observed in nonwrapped nerves (0.62 mm(2) +/- 0.2) versus wrapped nerves (0.35 mm(2) +/- 0.16). The ratio of connective tissue to fascicular area was larger in nonwrapped (1.08 +/- 0.26) versus wrapped nerves (0.63 +/- 0.22) (P < 0.001). This study demonstrated decreased inner epineural connective tissue formation with use of a collagen nerve wrap during primary repair of peripheral nerve transection in a rat sciatic nerve model.

Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease.

Neuropathy following vaccination has been reported; however, biopsy-confirmed small fiber neuropathy has not been described. We report five patients who developed paresthesias within one day to two months following vaccination for rabies, varicella zoster, or Lyme disease. On examination, there was mild sensory loss in distal extremities, preserved strength, normal or minimally abnormal electrodiagnostic findings, and decreased epidermal nerve fiber densities per skin biopsy. Empiric immunomodulatory therapy was tried in two patients and was ineffective. All patients' symptoms have improved, but persist. We conclude that an acute or subacute, post-vaccination small fiber neuropathy may occur and follow a chronic course.

Reduction of a 4q35-encoded nuclear envelope protein in muscle differentiation.

Muscular dystrophy and peripheral neuropathy have been linked to mutations in genes encoding nuclear envelope proteins; however, the molecular mechanisms underlying these disorders remain unresolved. Nuclear envelope protein p19A is a protein of unknown function encoded by a gene at chromosome 4q35. p19A levels are significantly reduced in human muscle as cells differentiate from myoblasts to myotubes; however, its levels are not similarly reduced in all differentiation systems tested. Because 4q35 has been linked to facioscapulohumeral muscular dystrophy (FSHD) and some adjacent genes are reportedly misregulated in the disorder, levels of p19A were analyzed in muscle samples from patients with FSHD. Although p19A was increased in most cases, an absolute correlation was not observed. Nonetheless, p19A downregulation in normal muscle differentiation suggests that in the cases where its gene is inappropriately re-activated it could affect muscle differentiation and contribute to disease pathology.

Amyotrophic lateral sclerosis and neurosarcoidosis: a case report.

Amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis without definable biomarkers. The pathomechanism of motor neuron degeneration in ALS has yet to be elucidated. Here we present a case of limb-onset ALS, with autopsy findings of Bunina bodies and skein-like inclusions, as well as sarcoid granulomas predominating among motor neurons. The targeting of the motor neurons by the sarcoid inflammation raises questions regarding the role of cellular immunity in the pathomechanisms for ALS.

Amyotrophic lateral sclerosis with ragged-red fibers.

BACKGROUND: Motor neuron diseases (amyotrophic lateral sclerosis [ALS] and spinal muscular atrophy [SMA]) have been rarely associated with mitochondrial respiratory chain defects. OBJECTIVES: To describe a patient with typical ALS and the finding of ragged-red fibers in muscle biopsy specimens and to review the literature on respiratory chain defects in ALS and SMA. DESIGN: Case report and review of the literature. SETTING: Collaboration between tertiary care academic hospitals. PATIENT: A 65-year-old man with typical ALS. MAIN OUTCOME MEASURES: The patient had 10% ragged-red fibers and 3% cytochrome-c oxidase-negative fibers in muscle biopsy specimens but no biochemical defects of respiratory chain enzymes or alterations of mitochondrial DNA (mtDNA). RESULTS: Amyotrophic lateral sclerosis with ragged-red fibers has been reported in 5 families and is associated with mtDNA mutations in some subjects. Spinal muscular atrophy without mutations in the survival motor neuron gene (SMN; OMIM 600354) has been associated with mtDNA depletion or with mutations in the cytochrome-c oxidase assembly gene (SCO2; OMIM 604377). CONCLUSION: Respiratory chain defects can mimic ALS or SMA and should be considered in the differential diagnosis.

X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1.

Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G-->C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.

Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice.

The prion protein (PrP) level in muscle has been reported to be elevated in patients with inclusion-body myositis, polymyositis, dermatomyositis, and neurogenic muscle atrophy, but it is not clear whether the elevated PrP accumulation in the muscles is sufficient to cause muscle diseases. We have generated transgenic mice with muscle-specific expression of PrP under extremely tight regulation by doxycycline, and we have demonstrated that doxycycline-induced overexpression of PrP strictly limited to muscles leads to a myopathy characterized by increased variation of myofiber size, centrally located nuclei, and endomysial fibrosis, in the absence of intracytoplasmic inclusions, rimmed vacuoles, or any evidence of a neurogenic disorder. The PrP-induced myopathy correlates with accumulation of an N-terminal truncated PrP fragment in the muscle, and the muscular PrP displayed consistent mild resistance to protease digestion. Our findings indicate that overexpression of wild-type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation.

Adult-onset nemaline myopathy and monoclonal gammopathy.

A 45-year-old man with severe proximal muscle weakness had findings diagnostic of adult-onset nemaline myopathy. He also had a monoclonal gammopathy. This is the fifth report of adult-onset nemaline myopathy in a patient with monoclonal gammopathy, suggesting that the occurrence of these entities may be more than a chance association. Myocyte-bound immunoglobulin or light chains were not detected and immunotherapy was not effective in this patient. Other causes of adult-onset nemaline myopathy were ruled out, including the most common mutations of sarcomeric thin filament genes.

Sporadic amyotrophic lateral sclerosis and breast cancer: Hyaline conglomerate inclusions lead to identification of SOD1 mutation.

Autopsy of patients with sporadic amyotrophic lateral sclerosis (ALS) rarely provides clues to a genetic etiology. We studied a 66-year-old woman who developed progressive weakness, fasciculations and upper motor neuron signs 1 year after mastectomy and chemotherapy for a breast carcinoma. She died 14 months after the onset of neurological symptoms. Autopsy showed characteristic features of ALS but also with posterior column degeneration and conglomerate hyaline inclusions. These features suggested a mutation of SOD1 mutation although no other family members were affected. DNA analysis of autopsy tissue indicated an I113T SOD1 mutation.

Fatal CNS vasculopathy in a patient with refractory celiac disease and lymph node cavitation.

Celiac disease is an enteropathy occurring in genetically predisposed individuals due to a dietary intolerance to gluten. Patients with celiac disease may develop a neurological disorder of unknown cause, although autoimmune mechanisms are suspected. We report on a 56-year-old man with celiac disease, who became refractory to a gluten-free diet and died of a rapidly progressive encephalopathy. Magnetic resonance imaging indicated focal lesions of the cerebellum and brainstem, and electrodiagnostic studies suggested an axonal neuropathy. Autopsy revealed a flattened small-bowel mucosa with intraepithelial lymphocytosis, a spectrum of degenerative changes of the intra-abdominal and mediastinal lymph nodes, including cavitary degeneration, and splenomegaly. Histologically, the lymph nodes showed pseudocyst formation and lymphocytic vasculitis with fibrinoid necrosis, and sections of the brain exhibited fibrinoid degeneration of small blood vessels, sparse perivascular lymphocytic infiltrates, and perivascular ischemic lesions. Identical T-cell clones were identified in the duodenum, stomach, lymph nodes, and spleen. This patient had an unusual neurological disorder related to a vasculopathy, probably mediated by a circulating neoplastic clone of activated T cells.

Benign course of glycogen storage disease type IIb in two brothers: nature or nurture?

Two brothers with the childhood variant of type II glycogenosis (GSD-IIb) treated with nutrition and exercise therapy (NET) from a young age showed an unusually benign course. Muscle biopsy from the older brother, which showed characteristic vacuolar glycogen accumulation at age 2, had reverted to normal by age 16. A muscle biopsy from the younger brother was normal at 5 years. It is uncertain whether this anomalous evolution was spontaneous (nature) or due to the symptomatic therapy (nurture), but NET should be considered in patients with GSD-IIb until enzyme replacement or gene therapy become generally available.

Early-onset toe walking in rippling muscle disease due to a new caveolin-3 gene mutation.

The authors describe a family with autosomal dominant rippling muscle disease (RMD) and prominent early-onset toe walking. Molecular analysis revealed a novel heterozygous G > A transition at nucleotide position 136 in exon 2 of the caveolin-3 gene (CAV3). The role of Achilles tendon lengthening in more severe forms of RMD is discussed.

Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings.

BACKGROUND: Celiac disease (CD) is increasingly recognized in North America and is associated with a peripheral neuropathy. OBJECTIVE: To report the clinical characteristics and skin biopsy results in patients with CD and small-fiber neuropathy symptoms. DESIGN: Case series. SETTING: Academic peripheral neuropathy clinic. PATIENTS: Eight patients with CD and neuropathy symptoms. Intervention Three-millimeter punch biopsy using the panaxonal marker protein gene product 9.5 to assess epidermal nerve fiber (ENF) density and a gluten-free diet. MAIN OUTCOME MEASURE: Clinical data and ENF density. RESULTS: All patients had asymmetric numbness and paresthesias. Three had more prominent involvement of hands than feet, and 3 had facial numbness. Celiac disease was diagnosed in 5 after their neuropathy began. The following serum antibody levels were elevated: tissue transglutaminase (n = 6), IgA gliadin (n = 4), and IgG gliadin (n = 7). Results of nerve conduction studies were normal in 7 patients. One patient had mildly reduced sural amplitudes. The ENF density was reduced in 5 patients. The ENF density was at the low limit of the normal range in 3 additional patients, 2 of whom had morphologic changes in axons. Three patients had decreased ENF density at the thigh or forearm, which was more severe than at the distal leg, compatible with a non-length-dependent process. Four reported improvement with a gluten-free diet. One had no improvement after 4 months. Symptoms developed in 2 while receiving a gluten-free diet. CONCLUSIONS: Patients with CD may have a neuropathy involving small fibers, demonstrated by results of skin biopsy. The pattern of symptoms, with frequent facial involvement and a non-length-dependent pattern on skin biopsy findings, suggests a sensory ganglionopathy or an immune-mediated neuropathy. Improvement of symptoms in some patients after initiating a gluten-free diet warrants further study.