Postural control and the relation with cervical sensorimotor control in patients with idiopathic adult-onset cervical dystonia.

Cervical dystonia (CD) is a movement disorder characterized by involuntary muscle contractions leading to an abnormal head posture or movements of the neck. Dysfunctions in somatosensory integration are present and previous data showed enlarged postural sway in stance. Postural control during quiet sitting and the correlation with cervical sensorimotor control were investigated. Postural control during quiet sitting was measured via body sway parameters in 23 patients with CD, regularly receiving botulinum toxin treatment and compared with 36 healthy controls. Amplitude and velocity of displacements of the center of pressure (CoP) were measured by two embedded force plates at 1000 Hz. Three samples of 30 s were recorded with the eyes open and closed. Disease-specific characteristics were obtained in all patients by the Tsui scale, Cervical Dystonia Impact Profile (CDIP-58) and Toronto Western Spasmodic Rating Scale (TWSTRS). Cervical sensorimotor control was assessed with an infrared Vicon system during a head repositioning task. Body sway amplitude and velocity were increased in patients with CD compared to healthy controls. CoP displacements were doubled in patients without head tremor and tripled in patients with a dystonic head tremor. Impairments in cervical sensorimotor control were correlated with larger CoP displacements (rs ranged from 0.608 to 0.748). Postural control is impaired and correlates with dysfunction in cervical sensorimotor control in patients with CD. Treatment is currently focused on the cervical area. Further research towards the potential value of postural control exercises is recommended.

Patient homozygous for a recessive POLG mutation presents with features of MERRF.

Both dominant and recessive missense mutations were recently reported in the gene encoding the mitochondrial DNA polymerase gamma (POLG) in patients with progressive external ophthalmoplegia (PEO). The authors report on a patient homozygous for a recessive missense mutation in POLG who presented with a multisystem disorder without PEO. The most prominent features were myoclonus, seizure, and sensory ataxic neuropathy, so the clinical picture overlapped with the syndrome of myoclonus, epilepsy, and ragged red fibers (MERRF).

Highly heterogeneous nature of delta-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria.

The properties of 9 delta-aminolevulinate dehydratase (ALAD) mutants from patients with ALAD porphyria (ADP) were examined by bacterial expression of their complementary DNAs and by enzymologic and immunologic assays. ALADs were expressed as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and purified by glutathione-affinity column chromatography. The GST-ALAD fusion proteins were recognized by anti-ALAD antibodies and were enzymatically active as ALAD. The enzymatic activities of 3 ALAD mutants, K59N, A274T, and V153M, were 69.9%, 19.3%, and 41.0% of that of the wild-type ALAD, respectively, whereas 6 mutants, G133R, K59N/G133R, F12L, R240W, V275M, and delTC, showed little activity (< 8%). These variations generally reflect the phenotype of ALAD in vivo in patients with ADP and indicate that GST-ALAD fusion protein is indeed useful for predicting of the phenotype of ALAD mutants. The location of F12L mutation in the enzyme's molecular structure indicates that its disturbance of the quaternary contact of the ALAD dimer appears to have a significant influence on the enzymatic activity. Mouse monoclonal antibodies to human ALAD were developed that specifically recognized a carboxy terminal portion of ALAD, or other regions in the enzyme. This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder.

Molecular analysis of delta-aminolevulinate dehydratase deficiency in a patient with an unusual late-onset porphyria.

Cloning, expression, and genotype studies of the defective gene for delta-aminolevulinate dehydratase (ALAD) in a patient with an unusual late onset of ALAD deficiency porphyria (ADP) were carried out. This patient was unique in that he developed the inherited disease, together with polycythemia, at the age of 63. ALAD activity in erythrocytes of the patient was less than 1% of the normal control level. ALAD complementary DNA (cDNA) isolated from the patient's Epstein-Barr virus (EBV)-transformed lymphoblastoid cells had 2 base transitions in the same allele, G(177) to C and G(397) to A, resulting in amino acid substitutions K59N and G133R, respectively. It has been verified that the patient had no other ALAD mutations in this and in the other allele. By restriction fragment length polymorphism (RFLP) analysis, all family members of the proband who had one-half ALAD activity compared with the ALAD activity of the healthy control were shown to have the same set of base transitions. Expression of ALAD cDNA in CHO cells revealed that K59N cDNA produced a protein with normal ALAD activity, while G133R and K59N/G133R cDNA produced proteins with 8% and 16% ALAD activity, respectively, compared with that expressed by the wild type cDNA. These findings indicate that while the proband was heterozygous for ALAD deficiency, the G(397) to A transition resulting in the G133R substitution is responsible for ADP, and the clinical porphyria developed presumably due to an expansion of the polycythemic clone in erythrocytes that carried the mutant alad allele.

Dysphagia in a patient with giant osteophytes: case presentation and review of the literature.

A patient with increasing dysphagia due to external bone compression of the oesophagus is presented. Radiographic evaluation revealed the underlying condition to be a diffuse idiopathic skeletal hyperostosis with exuberant and bumpy change within the anterior longitudinal ligament.

Value of somatosensory and motor evoked potentials in predicting arm recovery after a stroke.

OBJECTIVES: Prediction of motor recovery in the arm in patients with stroke is generally based on clinical examination. However, neurophysiological measures may also have a predictive value. The aims of this study were to assess the role of somatosensory (SSEPs) and motor (MEPs) evoked potentials in the prediction of arm motor recovery and to determine whether these measures added further predictive information to that gained from clinical examination. METHODS: Sixty four patients who had had a stroke and presented with obvious motor deficit of the arm were examined in terms of three clinical variables (motor performance, muscle tone, and overall disability) and for SSEPs and MEPs. Clinical and neurophysiological examinations were done at entry to the study (2 to 5 weeks poststroke), and at about 2 months after stroke. Further clinical follow up was conducted at 6 and 12 months after stroke. RESULTS: Neurophysiological measures made in the acute phase were of little use alone in predicting motor recovery of the arm at 2, 6, and 12 months after stroke. At 2 months, the absence of SSEPs and MEPs indicated a very poor outcome. Conversely, if the responses were preserved, a great variation in motor outcome was found. Multiple regression analysis showed that the addition of SSEPs and MEPs to the clinical examination increased the possibility of predicting arm recovery in the long term. In the acute phase, the combination of the motor score and SSEPs were best able to predict outcome. The long term outcome based on variables taken at 2 months, was best predicted through incorporating the three clinical measures and MEPs. CONCLUSIONS: Neurophysiological measures alone are of limited value in predicting long term outcome. However, predictive accuracy is substantially improved through the combined use of both of these measures and clinical variables.

Hereditary hepatic porphyria due to homozygous delta-aminolevulinic acid dehydratase deficiency: studies in lymphocytes and erythrocytes.

Activities of delta-aminolevulinic acid (ALA) dehydratase and porphobilinogen (PBG) deaminase, and haem content were determined in EB-virus transformed lymphocytes from two patients with homozygous ALA dehydratase deficiency, and their family members to determine the expression of the specific gene defect in this cell type. ALA dehydratase activity, but not PBG deaminase activity or haem content, was markedly decreased in lymphocyte preparations from both patients with homozygous enzyme deficiency, and moderately decreased in subjects heterozygous for enzyme deficiency. Immunochemical quantitation of erythrocyte ALA dehydratase suggested the presence of a cross-reactive material in a patient with a late-onset of acute hepatic porphyria due to the homozygous enzyme deficiency.

Porphyric neuropathy and hereditary delta-aminolevulinic acid dehydratase deficiency in an adult.

A man without a history of porphyric attacks developed a subacute motor neuropathy at the age of 63. At the same time the first signs of a myeloproliferative disorder were found. He had a homozygous deficiency of erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) with autosomal recessive inheritance. Treatment with parenteral glucose and with hematin had a beneficial influence on the plasma ALA levels. The finding of a motor neuropathy with increased plasma levels of ALA but not of porphobilinogen (PBG) supports the potential role of ALA in the pathogenesis of porphyric neuropathy.

Biochemical diagnosis of an hereditary aminolaevulinate dehydratase deficiency in a 63-year-old man.

Porphyrin metabolism was investigated in a 63-year-old male patient who developed a subacute onset polyneuropathy with predominance of motor signs in the upper limb. The screening for lead, cadmium, mercury, aluminum and thallium was negative. The study of porphyrin metabolism showed remarkable abnormalities, particularly a very high level of plasmatic 5-aminolaevulinic acid contrasting with a normal level of porphobilinogen and a nearly complete loss of activity of aminolaevulinic acid dehydratase with no regenerative response to dithiothreitol or zinc ions. The other causes of aminolaevulinic acid dehydratase deficiency (tyrosinaemia, alcoholism, smoking, cirrhosis, renal insufficiency, diabetes mellitus) were ruled out. The diagnosis of primary aminolaevulinic acid dehydratase deficiency was proposed and confirmed by the familial study, which revealed the existence of several heterozygous members in this family.

Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies.

A histochemical assay was routinely performed of myoadenylate deaminase (MAD) in muscle biopsy specimens. MAD was absent in 13 cases, i.e. 2.9% of the specimens. In 10 cases the deficiency was confirmed biochemically. The diagnoses in the 13 patients were: polyneuropathy (n = 5), infantile spinal muscular atrophy (n = 3), congenital myopathy with type 2 fibre atrophy, facioscapulohumeral myopathy, polymyositis, myotonic dystrophy and hyperornithinaemia with gyrate atrophy of the retina. In contrast, 35 unrelated patients presenting with exercise-related muscle cramps or pains showed normal histochemical MAD activity. The biopsy specimens in all of these patients were essentially normal and in none of them was the diagnosis of a neuromuscular disease made. The results failed to confirm the association of MAD deficiency with aches, cramps and pains or exertional myalgia.

Familial periodic paralysis with hypokalaemia. Study of a muscle biopsy in the myopathic stage of the disorder.

A 51 year-old male patient was affected by a dominantly inherited periodic paralysis. With large potassium supplements and ageing, the number and severity of attacks became considerably reduced. Increasing weakness and atrophy of the lower extremities were documented by clinical examination and by computer-assisted tomography of the muscles. A biopsy was taken in the vastus lateralis muscle without any attempt to induce a hypokalaemic paralytic attack. Light microscopy showed multiple intra- and extracellular vacuoles, rimmed vacuoles, myonecrosis, fatty degeneration and endomysial fibrosis. The endomysial nerve bundles were normal. Both fiber types were vacuolated. Quantitative studies revealed abnormal variability coefficients and increased atrophy factors for all types. Electron microscopy showed dilatations of the tubular system and of the sarcoplasmic reticulum communicating with large vacuoles limited by a single membrane. Other vacuoles were covered by a basement membrane and could contain collagen fibers or capillaries. Accumulation of myeloid bodies and of 10-13 nm filaments were also noted in the sarcoplasm. Cytoplasmic bodies were present. No tubular aggregates could be found. The nerve bundles were normal. These findings were in part similar to the ones reported by Gérard et al. (1978) in the son's biopsy during an induced paralytic attack. Significant findings in our case are the sequence of events leading to muscle fibre destruction, still detectable at an advanced stage of the disease. Myopathic changes represent a delayed but severe complication of the disorder.

Cardiac manifestations of Becker-type muscular dystrophy.

The electro-, phonomechano- and echocardiographic manifestations observed in a family with documented X-linked Becker-type muscular dystrophy (BMD) are described. Important myocardial dystrophic lesions may occur in young patients with BMD. They are associated with typical electrocardiological findings which were described as a distinctive pattern in Duchenne-type muscular dystrophy. Myocardial involvement is seldom observed in heterozygotes for BMD.

Neurophysiological studies in adrenomyeloneuropathy. A report on five cases.

Neurophysiological studies were performed in 5 patients in two families suffering from adrenomyeloneuropathy (AMN). The diagnosis was supported by electron microscopy of nerve twigs in all cases and by the demonstration in 2 cases of increased levels of saturated very long chain fatty acids in cultured fibroblasts (Moser, personal communication). Measurements of the sensory-motor conduction velocities demonstrated the variability of the peripheral nerve damage in AMN, further confirmed by quantitative studies of sensory nerve biopsies. Somatosensory evoked potentials (SEP) were abnormally delayed and their configuration was abnormal, mainly following stimuli applied to the lower limbs. Our data suggest a more severe involvement of the fasciculus gracilis and an extension of the lesions to the medial lemnisci in agreement with the few postmortem reports showing multifocal demyelination. Brain stem auditory evoked potentials (BAEP) were delayed, pointing towards lesions between cochlear nerve and superior olivary nucleus and also at lateral lemniscal level. Morphological confirmation is lacking but the close topographical relationship between the secondary auditory pathways and the medial lemnisci indicates that even small lesions could damage simultaneously both pathways. Neurophysiological studies contribute to the diagnosis of AMN, they confirm the inter- and intrafamilial variability of the clinical features and help to explain the signs and symptoms of this condition.

Bulbo-spinal lower motor neuron disease. Accumulation of neurofilaments in perikarya and axons.

Two sporadic adult cases of bulbo-spinal lower motor neuron disease are reported. In the first patient, the disease lasted 8 months and was characterized by a bulbar onset followed by a progressive cephalocaudal involvement of the lower motor neurons in the spinal cord. In the second case of 14 months duration, the cervical spinal cord was affected at first while medulla oblongata and lower limbs were involved later on. There was a slight increase of the protein contents in the CSF. Postmortem examination confirmed the selective involvement of the lower motor neurons in medulla oblongata and spinal cord with severe loss at cervico-medullary level in case 1 and more diffuse loss in case 2, in keeping with the clinical signs. Bodian silver staining and electron microscopy showed the accumulation of neurofilaments in anterior born cells' perikarya and in proximal axonal dilatations. The nosology of the disorder and the comparison with lesions found in various types of motor neuron disease in humans and animals are discussed.

Pathology of peripheral nerves in metachromatic leucodystrophy. A comparative study of ten cases.

Results of qualitative and quantitative studies on 1 to 13 peripheral nerves from 10 cases (6 late infantile, 2 juvenile and 2 adult cases) of metachromatic leucodystrophy (MLD) are reported. Peripheral nerve biopsies are still useful despite the arylsulphatase A assays on leucocytes and cultured fibroblasts, since they provide extremely rapid and reliable diagnostic information. The following points are investigated: (1) are there differences in the severity and characteristics of demyelination according to MLD subtypes; (2) are there major differences in various nerves of one patient; (3) are some inclusions characteristic of a given MLD subtype; (4) is there a direct relationship between demyelination and storage of characteristic inclusions? While question 1 can be answered positively, the three following ones must receive a negative or at best an equivocal answer.

Myoadenylate deaminase deficiency in a patient with facial and limb girdle myopathy.

Absence of AMP-deaminase was demonstrated by histochemical and biochemical methods in a muscle biopsy of a 25-year-old woman with facial and limb girdle myopathy. Venous ammonia failed to rise after ischaemic exercise. This patient further contributes to the variety of clinical pictures associated with AMP-deaminase deficiency. Whereas AMP-deaminase has been shown to play an essential role in the regulation of adenine nucleotide metabolism in the liver, its physiological function in muscle remains uncertain.

Neurogenic scapuloperoneal syndrome in childhood.

Two brothers presented with a slowly progressive scapuloperoneal syndrome starting in early childhood. Initially there were myopathic EMG changes, but these changed to those of denervation. Neuromuscular biopsies at an interval of five years confirmed the neurogenic character of the muscle atrophy.