Physical fatigability and muscle pain in patients with Hashimoto thyroiditis.

INTRODUCTION: Hashimoto thyroiditis (HT) may lead to muscle weakness due to hypothyroid dysfunction. However, clinical experience treating patients with HT suggests that neuromuscular symptoms may develop in these patients despite long-standing euthyroidism. METHODS: In 24 euthyroid patients with HT and 25 healthy controls, physical fatigability was assessed using the arm movement test (AMT) and 6-min walk test (6MWT). Fatigability was based on calculation of linear trend (LT) reflecting dynamic performance within subsequent constant time intervals. Perception of physical fatigue and muscle pain was analyzed using fatigue (FSMC) and pain questionnaires. Obtained results were correlated with clinical, neurophysiological and lab findings. RESULTS: HT patients showed a negative LT in 6MWT significantly differing from stable performance in controls. LT in AMT did not differ between HT and controls. FSMC scores and pain perception revealed significantly higher levels in HT patients than in controls. Physical FSMC score was primarily influenced by pain perception (standardized regression coefficient, beta = 0.633, p = 0.002). Neither pain score nor physical fatigue score showed a correlation with LT in 6MWT nor did mood, or anti-TPO antibody titer. CONCLUSION: A significant physical fatigability could be shown in euthyroid HT patients despite missing obvious neuromuscular deficits in routine testing. Further, elevated pain and fatigue perception in HT patients seem to contribute to nonspecific muscle complaints in these patients. A possible pathogenic role of thyroid autoimmunity in hidden neuromuscular involvement may be suggested.

Treatment of adult idiopathic inflammatory myopathies with conventional immunosuppressive drugs : Results of a retrospective study.

OBJECTIVES: To gain information about the efficacy of immunosuppressive drugs as first-, second-, and third-line treatment of idiopathic inflammatory myopathies (IIM). METHODS: 112 treatment cycles of 63 patients with dermatomyositis (n = 23), polymyositis (n = 33), overlap syndromes (n = 4), and undifferentiated connective tissue diseases (n = 3) were analyzed by retrospective chart analysis. Data regarding muscle strength, muscle enzymes, treatment duration, and treatment discontinuation were collected. RESULTS: Azathioprine (38 cycles) and methotrexate (MTX; 24 cycles) were applied significantly longer than glucocorticoid monotherapy (9 cycles; 25 ± 21, 26 ± 29 and 7 ± 4 months, respectively; p < 0.05). MTX and azathioprine achieved a significant reduction of serum creatine kinase (CK), with MTX showing more marked effects. Treatment cycles with immunosuppressants other than MTX or azathioprine (n = 22) or with combinations of immunosuppressive drugs (n = 19) were mostly applied as third-line therapy, indicating their application in more refractory cases. Significant improvement of muscle strength was confined to MTX and azathioprine and to the first-line treatment. 8% of MTX patients withdrew due to the lack of efficacy, compared with 29% of patients taking azathioprine and 6 of 9 patients taking glucocorticoid monotherapy. In the 12 patients with Jo-1 syndrome, MTX treatment was effective for a longer time than azathioprine (44 ± 21 months vs. 27 ± 24 months, p < 0.05). CONCLUSION: Our data confirm the effectiveness of MTX and azathioprine in the treatment of inflammatory myopathies and stress the importance of a potent first-line therapy.

Polyglucosan myopathy and functional characterization of a novel GYG1 mutation.

OBJECTIVES: Disorders of glycogen metabolism include rare hereditary muscle glycogen storage diseases with polyglucosan, which are characterized by storage of abnormally structured glycogen in muscle in addition to exercise intolerance or muscle weakness. In this study, we investigated the etiology and pathogenesis of a late-onset myopathy associated with glycogenin-1 deficiency. MATERIALS AND METHODS: A family with two affected siblings, 64- and 66-year-olds, was studied. Clinical examination and whole-body MRI revealed weakness and wasting in the hip girdle and proximal leg muscles affecting ambulation in the brother. The sister had weakness and atrophy of hands and slight foot dorsiflexion difficulties. Muscle biopsy and whole-exome sequencing were performed in both cases to identify and characterize the pathogenesis including the functional effects of identified mutations. RESULTS: Both siblings demonstrated storage of glycogen that was partly resistant to alpha-amylase digestion. Both were heterozygous for two mutations in GYG1, one truncating 1-base deletion (c.484delG; p.Asp163Thrfs*5) and one novel missense mutation (c.403G>A; p.Gly135Arg). The mutations caused reduced expression of glycogenin-1 protein, and the missense mutation abolished the enzymatic function as analyzed by an in vitro autoglucosylation assay. CONCLUSION: We present functional evidence for the pathogenicity of a novel GYG1 missense mutation located in the substrate binding domain. Our results also demonstrate that glycogenin-1 deficiency may present with highly variable distribution of weakness and wasting also in the same family.

[Postvaccinal complication and medical malpractice law]. / Impfkomplikation und Arzthaftungsrecht.

The case report involves a 38-year-old female patient with muscular atrophy, paresis and sensory deficits in the right upper limb following several vaccinations. A legal dispute ensued over whether medical malpractice could have caused the neurological deficits. Medical malpractice could not be confirmed. Even vaccinations administered correctly can lead to neurological impairment.

The significance of pathological spontaneous activity in various myopathies.

OBJECTIVE: Pathological spontaneous activity (PSA) in electromyography (EMG) has not yet been systematically analysed in various types of myopathies. METHODS: 136 Patients with well-defined myopathies were retrospectively analysed for the presence of PSA in distal, proximal, and paravertebral muscles. PSA comprised fibrillations (fib)/positive sharp waves (PSW) and high frequency discharges (HFD; i.e., myotonic and complex repetitive discharges). RESULTS: fib/PSW occurred more frequently than HFD. HFD were rarely myotonic in nature. 50% and more patients presented with HFD in PROMM (80%), Pompe's disease (70%), matrin-3 myopathy (60%), sIBM (50%), CNM (50%), while far less than 50% of the patients showed RD in LGMD2I (21%), LGMD2A (17%), LGMD2B (17%), LGMD2L (14%), FSHD (4%), BMD (0%). Four different HFD patterns were proposed. CONCLUSION: The segregation of myopathies relative to the occurrence of PSA and especially HFD in a high prevalence group and in a low prevalence group may be diagnostically valuable. SIGNIFICANCE: The screening for HFD by means of EMG is also valuable in the diagnosis of non-myotonic myopathies.

[Treatability of sporadic late onset nemaline myopathy]. / Behandelbarkeit der "sporadic late onset nemaline myopathy".

Sporadic late onset nemaline myopathy (SLONM) is an extremely rare disorder which can be associated with monoclonal gammopathy of unclear significance (MGUS). Clinically SLONM appears mostly after the fourth decade of life as rapidly progressing tetraparesis, respiratory insufficiency and features, such as dropped head syndrome, facial and bulbar involvement. Diagnosis is confirmed by muscle biopsy with detection of nemaline bodies and also frequently lobulated fibres. Immunosuppressant and immunomodulating therapies have been shown to be ineffective but clinical improvement accompanied by disappearance of monoclonal gammopathy and even nemaline bodies was reported following autologous stem cell transplantation and chemotherapy with melphalan. This article presents the case of a 53-year-old man with a 4-year history of SLOMN with MGUS in which administration of intravenous immunoglobulin therapy (IVIG) was not successful in reversing gammopathy, histopathological changes or clinical symptoms.

[Ocular myasthenia gravis]. / Okuläre Myasthenie.

Ocular myasthenia gravis, although clinically often characterized by typical classical features, can cause considerable diagnostic problems. This article aims to provide a pragmatic approach to the pathogenesis, clinical features, diagnostics and therapeutic strategies in the clinical routine.

[Myofibrillary myopathy due to the ZASP mutation Ala147Thr : two cases with exclusively distal leg involvement]. / Myofibrilläre Myopathie bei ZASP-Mutation Ala147Thr : Zwei Fälle mit rein distalem Phänotyp der Beine.

This article describes two patients with late onset myofibrillary myopathy due the ZASP mutation Ala147Thr. The Z-band alternatively spliced PDZ motif containing protein (ZASP) is a sarcomeric protein and interacts with α-actinin at the Z-disk. So far, myopathy due the ZASP mutation Ala147Thr was usually associated with distal and proximal involvement. The two patients with the ZASP mutation Ala147Thr described here showed only distal involvement of the legs without proximal weakness and involvement of the upper limb 6 and 19 years after onset of muscle weakness, respectively.

C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis.

Mutations in C19orf12 have been recently identified as the molecular genetic cause of a subtype of neurodegeneration with brain iron accumulation (NBIA). Given the mitochondrial localization of the gene product the new NBIA subtype was designated mitochondrial membrane protein-associated neurodegeneration. Frequent features in the patients described so far included extrapyramidal signs and pyramidal tract involvement. Here, we report three C19orf12-mutant patients from two families presenting with predominant upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis with juvenile onset. While extrapyramidal signs were absent, all patients showed neuropsychological abnormalities with disinhibited or impulsive behavior. Optic atrophy was present in the simplex case. T2-weighted cranial MRI showed hypointensities suggestive of iron accumulation in the globi pallidi and the midbrain in all patients. Sequence analysis of C19orf12 revealed a novel mutation, p.Gly66del, compound heterozygous with known mutations in all patients. These patients highlight that C19orf12 defects should be considered as a differential diagnosis in patients with juvenile onset motor neuron diseases. Patients have to be examined carefully for neuropsychological abnormalities, optic neuropathy, and signs of brain iron accumulation in MRI.

Unusual manifestations in two cases of necrotizing myopathy associated with SRP-antibodies.

Anti-SRP (signal recognition particle) positive necrotizing myopathy is commonly not associated with neoplasms. We demonstrate two histologically confirmed cases with unusual manifestations of anti-SRP positive necrotizing myopathy. A 65-year-old man presented with rapidly progressing weakness and mild difficulties in swallowing and speaking. Screening for underlying disorders revealed a moderately differentiated renal adenocarcinoma. The muscular symptoms partially improved after tumor nephrectomy and prednisone treatment. However, the patient developed pulmonary metastases and died of the sequelae of pneumonia 11 months after the diagnosis of renal cancer. The second patient developed rapidly complete external ophthalmoplegia, severe bulbar dysarthrophonia and dysphagia, bilateral facial palsy, loss of patellar and ankle jerk reflexes, and severe symmetrical tetraparesis of both proximal and distal muscles. CSF showed mildly increased protein levels, neurography axonal impairment of motor nerves. Screening revealed no evidence for infections, ganglioside antibodies, and carcinoma. MRI was normal. The disease course suggested an overlap syndrome of Miller-Fisher-syndrome, axonal Guillain-Barré-syndrome and Bickerstaff brainstem encephalitis. In conclusion SRP antibodies might be found in necrotizing myopathies associated with autoimmune mediated overlap syndromes and neoplasms. The pathomechanism is not clear. Any otherwise unexplained evidence of necrotizing myopathy should prompt the screening for SRP antibodies.

[Muscular dystrophy due to mutations in anoctamin 5: clinical and molecular genetic findings]. / Muskeldystrophie infolge Anoctamin-5-Mutationen : Klinische und molekulargenetische Befunde.

Recessive mutations in the anoctamin 5 (ANO5) gene have been recently identified in families with limb girdle muscular dystrophy (LGMD2L) and distal non-dysferlin Miyoshi myopathy. Anoctamin 5 is supposed to be a putative calcium-activated chloride channel. We report five German patients (four index patients) with muscle dystrophy due to mutations in the ANO5 gene. Sequencing of the ANO5 exons 5, 13 and 20 was performed to screen for a common c.191dupA mutation and two other reported mutations (c.1295C>G and p.R758C). The whole coding region of the ANO5 gene was sequenced to identify new mutations. Phenotypically, three patients showed LGMD and one patient Miyoshi type distal myopathy. One sibling had asymptomatic hyperCKemia. The age at onset was 64, 38 and 40 years in patients with LGMD and 23 years in the patient with distal myopathy. The four symptomatic patients showed remarkable asymmetric muscle involvement. There was marked CK elevation (11 to 30 times). Electron microscopy showed multifocal gaps in the sarcolemmal membrane. All patients harboured the common c.191dupA mutation in at least one allele. Two patients with LGMD were homozygous and the third patient and his asymptomatic sister were compound heterozygous for the c.191dupA mutation and a novel p.T548I mutation. The patient with distal myopathy harboured the p.R758C mutation in the second allele. Mutations in the ANO5 gene seem to be a relatively common cause of muscular dystrophy in Germany. Cases with late onset or asymptomatic hyperCKemia can occur. Clinically, asymmetric manifestation is typical.

[Facioscapulohumeral muscular dystrophy. Clinical picture, atypical forms, diagnostics, genetics]. / Fazioskapulohumerale Muskeldystrophie. Klinik, Atypien, Diagnostik, Genetik.

The classic phenotype of the facioscapulohumeral muscular dystrophy (FSHD) includes an initially restricted pattern of asymmetric weakness of facial and shoulder girdle muscles. Disease progression is usually slow and typically accompanied by foot extensor muscle weakness and pelvic girdle weakness. Atypical patterns of FSHD that include isolated camptocormia and facial muscle sparing exceed current diagnostic criteria. No causal genetic lesion in FSHD has been identified yet. In the vast majority of cases, FSHD results from a heterozygous partial deletion of a critical number of repetitive elements (D4Z4) on chromosome 4q35 (4qA allele). Molecular diagnostic testing is appropriate to confirm the diagnosis of FSHD without need for muscle biopsy. Penetrance of this dominantly inherited disorder is high, exhibiting a great phenotypic variability in clinical pattern and disease progression even among affected members of the same family.

Phenotype variability and histopathological findings in centronuclear myopathy due to DNM2 mutations.

Autosomal-dominant centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene (DNM2) is a rare congenital myopathy histopathologically characterized by centrally located nuclei and a radial arrangement of sarcoplasmic strands around the central nuclei. A total of 1,582 consecutive muscle biopsies of adult patients (age ≥ 18 years) were screened for morphologically characteristic signs of CNM. Patients with CNM were screened for mutations in DNM2. Clinical data and complementary neurophysiologic, respiratory, cardiac, and muscle MRI data in these patients were analyzed. Six index patients had histopathological signs of CNM (0.38%). Three had the heterozygous p.R465W and 2 siblings the heterozygous p.E368K DNM2 mutation. In 2 patients mutational screening for DNM2, BIN1, MTM1, and RYR1 was negative. Apart from the siblings, there was no positive history, parental mutation screening in 2 cases was negative. Both the percentage of muscle fibers with centralized nuclei and the ratio of muscle fibers with centralized to internalized nuclei were higher in DNM2-CNM compared to non-DNM2-CNM (50% vs. 18% and 94% vs. 63%). The onset was already neonatal or in infancy in 3/5 patients with DNM2 mutation. Symptoms in DNM2-CNM included bilateral ptosis (n = 3), paresis of the external ocular muscles (n = 2), axonal neuropathy (n = 4), restrictive ventilatory involvement (n = 5), and contractures (n = 5), including muscular torticollis (n = 1) and masticatory muscles (n = 2). DNM2-CNM patients and non-DNM2-CNM patients could not be distinguished by clinical features. DNM2-CNM often shows de novo mutations. In addition to the feature of radial sarcoplasmic strands, the ratio of centrally to internalized nuclei might help to differentiate DNM2-CNM from other forms of CNM. Other genes than currently known seem to cause the clinical and histopathological phenotype of CNM.

[Chronic progressive external ophthalmoplegia--symptom or syndrome?]. / Chronisch progressive externe Ophthalmoplegie--Symptom oder Syndrom?

The term chronic progressive external ophthalmoplegia (CPEO) is not only a symptom but is also used as a syndrome within the group of mitochondrial diseases. However, the symptom CPEO might also occur in other well defined mitochondrial syndromes such as MELAS, MNGIE, SANDO. The molecular bases of the syndrome CPEO are mostly single or multiple deletions of the mtDNA, less frequently point mutations. Multiple deletions are caused by defects of nuclear encoded proteins. In this case, the mode of inheritance might be autosomal dominant or recessive. However, all these types of mtDNA mutations are not only associated with the symptom or syndrome of CPEO but might also cause other well defined mitochondrial syndromes. Thus, the diagnosis of CPEO either as a symptom or as a syndrome requires the subtle characterisation of the complete clinical phenotype as well as the precise genotype. Only on this basis a valid prognosis and information about the mode of inheritance are possible.

Puusepp's sign--clinical significance of a forgotten pyramidal sign.

The pyramidal signs in the lower extremity can be divided into three groups: (1) Babinski's group characterised by dorsoflexion of the great toe, (2) pyramidal signs marked by plantar flexion of the toes (e.g. Rossolimo's sign), and (3) synkinetic movements such as Strümpell's phenomenon. Puusepp's sign described by the Estonian neurologist and neurosurgeon Ludvig Puusepp belongs to none of these three groups. Its eliciting does not differ from that of Babinski's sign. The response, however, is different and consists of a tonic slow abduction of the little toe. We showed its relevance on the basis of clinical examination of six patients: four females aged 29, 50, 43 and 57 years and two males aged 42 and 49 years. The diagnoses were as follows: a new relapse of multiple sclerosis, a secondary progressive multiple sclerosis, a left middle cerebral artery stroke, a lumbago resulting in L3-L4 fusion surgery, an amyotrophic lateral sclerosis and a left intracerebral haemorrhage respectively. Puusepp's sign was the only elicitable pyramidal sign in all the patients but two. The 50-year-old female patient revealed on neurological examination Babinski's sign on the left side and Puusepp's sign on the right side. The testing of pyramidal signs in the 57-year-old woman displayed a bilateral Strümpell's sign and a left Puusepp's sign. These six cases showed that although rarely recognized in the clinical practice Puusepp's sign contributed to establishing the diagnosis of a central motor neuron involvement in the case of an absent Babinski's sign. Thus, its testing does not differ from that of Babinski's sign which requires only a little attention from the examiner, but provides an important piece of clinical information.

Gasperini syndrome as clinical manifestation of pontine demyelination.

The Gasperini syndrome is a very rare brainstem disease characterized by the typical combination of ipsilateral lesions of the cranial nerves V-VII and dissociated contralateral hemihypesthesia, whereas both contralateral and ipsilateral hypacusis was described. Since the first description in 1912, only a few cases of this crossed brainstem syndrome were published so far. Pontine infarction and bleedings were the reported causes of the syndrome. Here we report a 44-year-old man with the classical Gasperini syndrome due to pontine demyelination in multiple sclerosis. The clinical findings were correlated with changes on MRI. The present case shows that classical crossed brainstem syndromes are topological terms not invariably associated with brainstem ischemia in particular vascular areas and may contribute to the differential diagnosis of peripheral facial nerve palsy.