Novel antibody associations in immune-mediated necrotising myopathy without inflammation.

INTRODUCTION: The patient presenting with proximal muscle weakness, elevated serum creatinine kinase and myopathic electromyography and biopsy findings has a wide differential diagnosis that includes toxic, autoimmune, paraneoplastic and congenital myopathies. Autoimmune myopathies are important to identify because they may respond to immunosuppressive therapies. METHODS: We describe two cases of immune-mediated necrotizing myopathy each associated with a novel antibody. RESULTS: Case 1 describes a progressive myopathy in a statin user. Antibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase were identified and the patient responded to steroid therapy. Case 2 describes an aggressive myopathy associated with antibodies to signal recognition particle. There was no response to steroids. Clinical improvement followed treatment with rituximab and cyclophosphamide. CONCLUSION: The identification of myositis-specific antibodies is important because they are associated with distinct clinical phenotypes and may guide the physician in terms of treatment strategies.

Sensory-motor polyneuropathy occurring in variant maple syrup urine disease.

Maple syrup urine disease (MSUD; OMIM 248600) results from an inherited deficiency of the branched-chain ketoacid dehydrogenase (BCKD) complex. Approximately 20% of patients with BCKD deficiency are non-classic variants of MSUD with differing clinical severity. Outcomes for this cohort are generally favourable; episodes of metabolic decompensation do not appear to correlate with adverse events if acute management is promptly provided. A case of predominantly axonal sensory-motor neuropathy following metabolic decompensation which persisted for a number of months is presented in an adolescent girl with variant (intermediate type) MSUD. EMG and nerve conduction studies suggested a pre-existent asymptomatic chronic neuropathy, exacerbated by the acute decompensation. Peak leucine concentration at decompensation was 1083 µmol/L. The patient had laboratory signs of secondary mitochondrial respiratory chain dysfunction at presentation. She had been on a moderate dose of thiamine prior to decompensation; thiamine and pyridoxine blood concentrations were normal. This, to our knowledge, is the first report of a neuropathy presenting in a patient with a decompensation of variant MSUD. We propose that this presentation resembles the intermittent neuropathy observed in pyruvate dehydrogenase deficiency and may reflect secondary inhibition of pyruvate dehydrogenase activity by MSUD metabolites.

Short-chain acyl-CoA dehydrogenase deficiency associated with early onset severe axonal neuropathy.

Two unusual cases of axonal neuropathy associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency are described. These two unrelated infants presented with profound generalised weakness, particularly affecting the upper limbs. Clinical examination revealed generalised peripheral hypotonia and weakness, with absent deep tendon reflexes. An axonal polyneuropathy was confirmed on electromyogram (EMG) and nerve conduction studies (NCS) and, following an extensive metabolic screen, an acylcarnitine and organic acid profile consistent with a short-chain fatty acid beta-oxidation defect was found. In both cases, SCAD deficiency was confirmed by enzyme analysis. Genetic analysis showed the presence of common gene variations in the SCAD gene. SCAD deficiency is a rare disorder with a wide clinical phenotype. SCAD deficiency associated with axonal neuropathy has not previously been reported. As highlighted in these cases, it may be necessary to include axonal neuropathy as a presenting feature of SCAD.

Merosin-deficient congenital muscular dystrophy and cortical dysplasia.

Congenital muscular dystrophy (CMD) encompasses a heterogenous group of muscle disorders with autosomal recessive inheritance, characterized by muscular weakness and hypotonia at birth or within the first few months of life and developmental delay. Merosin-deficient CMD is a clinically distinct form which may be associated with significant abnormalities of the brain detectable by neuroimaging. We report two siblings of consanguineous parents with merosin-deficient CMD in an Irish family who in addition to the characteristic white matter abnormalities on neuroimaging, had occipital dysplasia. Clinical, electrophysiological muscle biopsy findings and neuroimaging were very similar in both cases. Although merosin-deficient CMD with white matter abnormalities on neuroimaging is well documented in the literature, the association with occipital dysplasia has only rarely been reported. The appearance of an identical cortical defect in these siblings suggests an underlying genetic mechanism.

Paramyotonia congenita and hyperkalemic periodic paralysis associated with a Met 1592 Val substitution in the skeletal muscle sodium channel alpha subunit--a large kindred with a novel phenotype.

Paramyotonia congenita (PC) and Hyperkalemic periodic paralysis (HyperPP) are caused by amino acid substitutions in the alpha subunit of the human skeletal muscle sodium channel. One such substitution, methionine for valine at position 1592, has been associated with HyperPP with myotonia and cold sensitivity. We report clinical, electromyographic (EMG), genetic and pathological features of a large kindred with the Met1592Val substitution. Affected members were phenotypically heterogenous and had episodic potassium-sensitive paralysis, and stiffness and weakness induced by exercise and cold, which was confirmed by EMG studies. These features indicate a combined PC-HyperPP phenotype not previously described with this mutation.

Intracranial adenoid cystic carcinoma: case report and review of the literature.

BACKGROUND: Adenoid cystic carcinoma (cylindroma) is a relatively common head and neck tumor that is slow growing, but locally aggressive and thus prone to recurrence. It is of particular interest to neurosurgeons and neurologists because of its tendency to locally infiltrate neural structures and to spread perineurally. Intracranial involvement has been regarded as rare. METHODS: A case report of a patient with adenoid cystic carcinoma involving the Gasserian ganglion region is presented. The world literature on intracranial involvement of adenoid cystic carcinoma is reviewed. A discussion of the characteristics of this lesion is provided. RESULTS: Our literature review revealed 119 previously reported cases of adenoid cystic carcinoma with intracranial involvement. Our case represents only the tenth reported intracranial case with an unknown primary site. CONCLUSIONS: Although intracranial adenoid cystic carcinoma is regarded as rare, we have accumulated over 100 such reports. A wide variety of primary sites and intracranial sites have been described.

Successful treatment of neuropathies in patients with diabetes mellitus.

OBJECTIVES: To report and characterize two forms of disabling progressive peripheral neuropathy in patients with diabetes mellitus, which respond to anti-inflammatory and/or anti-immune treatment. DESIGN: Review of clinical, electrophysiologic, and pathologic findings and results of treatment. SETTING: University medical center. PATIENTS: Twenty-one patients with diabetes mellitus to whom we gave anti-inflammatory and/or anti-immune treatment for progressive peripheral neuropathy during the past 6 years. MAIN OUTCOME MEASURES: Patients were interviewed and examined at intervals before and after beginning treatment with intravenous immunoglobulin (n = 15), prednisone (n = 13), cyclophosphamide (n = 5), plasma exchange (n = 3), and azathioprine (n = 1) (alone or in combination). RESULTS: Fifteen patients had evidence of axonal neuropathy by electrophysiologic studies (group A). All 15 patients had non-insulin-dependent diabetes mellitus, 10 patients had weight loss, and 13 patients had prominent involvement of thighs and/or thoracic bands consistent with diabetic amyotrophy or mononeuropathy multiplex. Small vessel disease was seen in all 10 patients who underwent biopsy, with perivascular or vascular inflammation seen in seven patients. Six patients had demyelinating neuropathy by electrophysiologic criteria (group B). All these patients had insulin-dependent diabetes mellitus, and no one had weight loss. The process was asymmetric in three patients and involved thoracic or abdominal regions in two patients. Onion bulbs were seen in all four patients who underwent biopsy, but no vascular inflammation or occlusion was seen. In all patients in both groups, worsening of their conditions stopped and improvement started after beginning treatment. CONCLUSION: Neuropathies responsive to anti-inflammatory and/or anti-immune therapy in patients with diabetes mellitus include (1) multifocal axonal neuropathy caused by inflammatory vasculopathy, predominantly in patients with non-insulin-dependent diabetes mellitus, indistinguishable from diabetic proximal neuropathy or mononeuropathy multiplex, and (2) demyelinating neuropathy indistinguishable from chronic inflammatory demyelinating polyneuropathy, predominantly in patients with insulin-dependent diabetes mellitus.

Determination of the histological distribution of insulin like growth factor 1 receptors in the rat gut.

The histological distribution of insulin like growth factor 1 (IGF 1) receptors in the rat gut was studied. Immunostaining of IGF 1 receptors identified localisation on the villus epithelium, in the crypts, and in Brunner's glands of the small intestine. These tissues represent areas of high cell growth/differentiation, division, and macromolecular synthesis respectively, which constitute biological activities long associated with IGF 1. Cellular localisation of IGF 1 receptors was seen in the lamina propria by IGF 1 receptor immunostaining and ligand binding of biotinylated IGF 1. IGF 1 receptor immunostaining in the spleen showed receptor localisation to the splenic pulp thus pointing to macrophages as the possible IGF 1 receptor positive cells in the lamina propria. The results further implicate IGF 1 as an important growth factor in gut maintenance.

Genetic mapping of human heart-skeletal muscle adenine nucleotide translocator and its relationship to the facioscapulohumeral muscular dystrophy locus.

The mitochondrial heart-skeletal muscle adenine nucleotide translocator (ANT1) was regionally mapped to 4q35-qter using somatic cell hybrids containing deleted chromosome 4. The regional location was further refined through family studies using ANT1 intron and promoter nucleotide polymorphisms recognized by the restriction endonucleases MboII, NdeI, and HaeIII. Two alleles were found, each at a frequency of 0.5. The ANT1 locus was found to be closely linked to D4S139, D4S171, and the dominant skeletal muscle disease locus facioscapulohumeral muscular dystrophy (FSHD). A crossover that separated D4S171 and ANT1 from D4S139 was found. Since previous studies have established the chromosome 4 map order as centromere-D4S171-D4S139-FSHD, it was concluded that ANT1 is located on the side of D4S139, that is opposite from FSHD. This conclusion was confirmed by sequencing the exons and analyzing the transcripts of ANT1 from several FSHD patients and finding no evidence of aberration.

Salivary insulin-like growth factor-I originates from local synthesis.

Insulin-like growth factor-I (IGF-I) is a GH-dependent growth factor found in its highest concentrations in plasma. It is also measurable in saliva. The origins of salivary IGF-I concentrations were studied. Intracardial administration of Sprague-Dawley rats with 125I-labelled IGF-I and subsequent analysis of plasma and saliva samples by exclusion gel chromatography and SDS-PAGE, followed by autoradiography, demonstrated the apparent inability of IGF-I to cross from the plasma pool through to saliva. 125I-Labelled IGF-I was not chromatographed immediately before injection, resulting in administration of free iodide along with the iodinated peptide. This free iodide was demonstrable in saliva, indicating that movement of substances from plasma to saliva was measurable using the levels of 125I activity administered. Free iodide in saliva was not contributed to by 125I-labelled IGF-I degradation since 125I-labelled IGF-I was shown to be stable in saliva over 24 h. These data indicated that IGF-I in saliva is produced locally. Identification of a 4.7 kb IGF-I mRNA transcript in rat parotid salivary gland was consistent with IGF-I synthesis within that tissue.

A normal population study of human salivary insulin-like growth factor 1 (IGF 1) concentrations from birth through puberty.

Insulin-like growth factor 1 (IGF 1) concentrations in mixed saliva samples, collected from a normal population (n = 327, ranging in age from birth to adolescence), were determined by RIA. Salivary IGF 1 concentrations remained steady over a 24-h period when collected at basal rates, but were diminished in saliva samples collected at a maximally stimulated flow rate. A similar pattern was observed for males and females, when IGF 1 levels in saliva were plotted as a function of age. The pattern was that of low levels in early childhood, rising with age, peaking in puberty and falling again in late adolescence. Salivary IGF 1 measurement differed from plasma measurement in three ways: 1) salivary IGF 1 concentrations (70 +/- 50 pM) were 100- to 200-fold less than plasma IGF 1 levels; 2) salivary IGF 1 levels in age-matched male and female samples were not different outside of pubertal influences; 3) salivary IGF 1 levels in neonates were highly variable with concentrations ranging up to pubertal concentrations. The study provides salivary IGF 1 reference data for a pediatric population.

Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy.

The muscle mitochondria of a patient with Kearns-Sayre/chronic external ophthalmoplegia plus syndrome were found to be completely deficient in respiratory complex I activity and partially deficient in complex IV and V activities. Treatment of the patient with coenzyme Q10 and succinate resulted in clinical improvement of respiratory function, consistent with the respiratory deficiencies. Restriction enzyme analysis of the muscle mtDNA revealed a 4.9-kilobase deletion in 50% of the mtDNA molecules. Polymerase chain reaction analysis demonstrated that the deletion was present in the patient's muscle but not in her lymphocytes or platelets. Furthermore, the deletion was not present in the muscle or platelets of two sisters. Hence, the mutation probably occurred in the patient's somatic cells. Direct sequencing of polymerase chain reaction-amplified DNA revealed a 4977-base-pair deletion removing four genes for subunits of complex I, one gene for complex IV, two genes for complex V, and five genes for tRNAs, which paralleled the respiratory enzymes affected in the disease. A 13-base-pair direct repeat was observed upstream from both breakpoints. Relative to the direction of heavy-strand replication, the first repeat was retained and the second repeat was deleted, suggesting a slip-replication mechanism. Sequence analysis of the human mtDNA revealed many direct repeats of 10 base pairs or greater, indicating that this mechanism could account for other reported deletions. We postulate that the prevalence of direct repeats in the mtDNA is a consequence of the guanine-cytosine bias of the heavy and light strands.

Free insulin-like growth factor I (IGF-I) and IGF-II in human saliva.

We found that human saliva contains both insulin-like growth factor I (IGF-I) and IGF-II but no significant binding proteins, and that salivary IGF-I levels correlated with plasma GH levels. Mixed saliva had globular proteins precipitated by freezing/thawing. After centrifugation the clear supernatant was used directly in the IGF-I RIA (Van Wyk and Underwood antibody) and in a human placental membrane RRA for IGF-II. The lower limits of detection for IGF-I and IGF-II were 0.7 ng/mL (micrograms/L) and 1.2 ng/mL (micrograms/L), respectively. Iodinated IGF added to saliva was not degraded, as assessed by trichloroacetic acid precipitability and placental membrane binding. In saliva from 14 normal subjects, IGF-I was measurable in all. IGF-II was detectable only in 8 of 14 subjects; the mean value in these 8 subjects was 2.6 +/- 0.6 (+/- SE) ng/mL (micrograms/L). The mol wt of salivary IGF was similar to that of free plasma IGF after acid or neutral pH gel chromatography. Human saliva contained no significant IGF-binding protein. Eluates from neutral gel chromatography of concentrated (20-fold) normal saliva did not inhibit IGF-II binding to placental membrane receptors. Eluted proteins from saliva samples subjected to prior acid gel chromatography failed to bind radiolabeled IGF after neutralization. Saliva samples assayed for binding protein using an amniotic fluid binding protein RIA had values at or below the lower limit of detection [less than 0.06 micrograms eq/mL (mgeq/L)]. Salivary IGF-I concentrations did not change with increasing salivary flow rates above normal, with time of day, or with storage at room temperature for up to 24 h before freezing. The mean IGF-I concentration in mixed saliva from 14 normal young adults (8 men) was 2.3 +/- 0.3 (+/- SE) ng/mL (micrograms/L), and their mean plasma IGF-I level was 315 +/- 27 ng/mL (micrograms/L). Mean salivary IGF-I was significantly lower in 15 patients with GH deficiency [1.3 +/- 0.2 ng/mL (micrograms/L); P less than 0.01] and 8-fold higher in 5 acromegalic patients [17.2 +/- 6.3 ng/mL (micrograms/L); P less 0.01]. Removal of their GH adenomas led to a fall in salivary IGF-I to 5.6 +/- 1.3 ng/mL (micrograms/L); P less than 0.05). In summary, saliva contains free IGFs but no significant quantities of specific binding proteins. Salivary IGF-I levels reflect the GH status of the donor.