Familial juvenile focal amyotrophy of the upper extremity (Hirayama disease). Superoxide dismutase 1 genotype and activity.

BACKGROUND: Juvenile focal amyotrophy of the arm is an unusual focal motor neuron disease that is rarely familial. Its pathogenesis is unknown. We recently described a family with amyotrophic lateral sclerosis associated with a mutation in the superoxide dismutase 1 (SOD1) gene substituting an aspartate for an alanine (D9OA). One of the carriers of this mutation had focal and nonprogressive amyotrophy of the arm, suggesting that focal amyotrophy might be associated with SOD1 mutations. OBJECTIVES: To describe the phenotype of 2 brothers with juvenile focal amyotrophy of the upper extremity and to characterize their SOD1 genotype and SOD activity. METHODS: Polymerase chain reaction and sequencing of the SOD1 gene and colorimetric measurement of the enzyme activity. RESULTS: We compared the phenotype of our patients to that of 375 patients described in the Western literature. The 5 exons of the SOD1 gene were normal, as was the SOD activity in red blood cells.

Transfer factor therapy in multiple sclerosis: a three-year prospective double-blind clinical trial.

One hundred five patients with MS were divided into three groups matched for age, sex, and disability, and treated with either placebo, transfer factor prepared from leukocytes of random donors, or transfer factor from leukocytes of family members living with the patients. There were no differences in the three treatment groups for changes in disability, activities of daily living, or evoked potentials. Eighteen months of transfer factor therapy had no effect on gamma-interferon production or natural killer cell activities.

Lujan-Fryns syndrome in the differential diagnosis of schizophrenia.

Schizophrenia is considered to be a heterogenous disorder. Different etiopathological mechanism can be attributed to a similar clinical picture as described in DSM-III-R criteria. We present a case of a young man diagnosed on different occasions as schizophrenic with mild mental retardation. Clinical examination revealed signs and symptoms most compatible with the diagnosis of Lujan-Fryns syndrome, an X-linked mental retardation syndrome with marfanoid features, frequently associated with psychotic or other psychiatric symptoms. In all patients with symptoms of schizophrenia and mental retardation Lujan-Fryns syndrome should be considered in the differential diagnosis.

Clinical parameters and intrathecal IgG synthesis as prognostic features in multiple sclerosis. Part I.

In a search for early prognostic features in multiple sclerosis, the progression rate was calculated in 200 consecutive multiple sclerosis patients who had had a lumbar puncture, and correlated with age at onset, type of disease course, the patient's sex, as well as with indices of blood-brain barrier breakdown and intrathecal IgG synthesis. The present study demonstrates that age at onset plays a role in determining whether the disease will be remitting-relapsing or chronic progressive. Age at onset is also a factor determining the rate of progression of the remitting-relapsing form, but is without influence on the progression of the chronic progressive form. A chronic progressive disease course per se (independent of age at onset) is also associated with a more rapid deterioration. The patient's sex does not appear to be a differentiating factor. Only inconsistent correlations were found between IgG index or number of oligoclonal bands in the CSF and disease progression.

Evolution of motor and sensory deficits in amyotrophic lateral sclerosis estimated by neurophysiological techniques.

Although amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motor neurons, there is evidence that the disease can affect other systems, including the sensory system. On the other hand, within the motor neuron pool there is possibly a predilection of the degenerative process for the motor neurons fibers with the fastest conduction velocity (MNFCV). We studied these two aspects of the disease in a group of 50 patients by prospectively assessing several sensory indices and by studying the selectivity of the spinal motor neuron loss. At baseline, nerve conduction studies and somatosensory evoked potentials showed abnormal slowing in the peripheral and central sensory pathways. Thermal thresholds for heating were elevated but were normal for cooling. In more than 60% of the patients at least one of the sensory tests studied was abnormal. However, except for a significant decrease in the amplitude of the sensory nerve action potentials of the sural nerves, these afferent dysfunctions were not progressive over the follow-up period of 6 months, in contrast to the marked deterioration in motor functions. Three different statistical models were applied to evaluate the presence of demyelination, selective loss of MNFCV, or the purely random degeneration of fast- and slow-conducting motor neurons. These data indicate a selective loss of the MNFCV and suggest that subclinical abnormalities of the sensory system in ALS are often present but almost nonprogressive. Furthermore, the amyotrophic lateral sclerosis disease process seems preferentially to affect MNFCV.

Short-term intensive cyclophosphamide treatment in multiple sclerosis. A retrospective controlled study.

The effect of short-term intensive cyclophosphamide therapy upon 21 patients with moderately advanced multiple sclerosis is compared with a non-treated control group of 21 patients retrospectively matched for global disability. The progression of the disease was evaluated by regular disability scoring, and the results were analyzed by non-parametric statistical tests. No significant differences in the progression of the disability could be detected during a follow-up period of 2 years.

Pathological findings in a patient with amyotrophic lateral sclerosis and multifocal motor neuropathy with conduction block.

We studied a 53-year-old woman with progressive weakness of the left arm, gradually spreading to the other limbs. Neurological examination revealed a motor neuron syndrome with paresis, fasciculations and atrophy. Electrophysiological studies showed multiple motor conduction blocks. The anti-GM1 IgM titer was elevated. The patient was thought to have a multifocal motor neuropathy. Despite intravenous cyclophosphamide treatment, however, she died with respiratory insufficiency. On postmortem examination, the brachial plexus showed patches of demyelination underlying different areas of motor conduction block. The spinal cord, however, revealed severe neuronal loss in the ventral horn and axonal loss in the corticospinal tract, indicative of amyotrophic lateral sclerosis. Demyelination of peripheral nerves could have been responsible for the other conduction blocks in this patient. The prominent degeneration of motor neurons, however, must also have played a role in the clinical picture. Some patients with the syndrome of a multifocal motor neuropathy may have MND rather than, or in addition to, a demyelinating peripheral motor neuropathy.

Pregnancy and multiple sclerosis: the influence on long term disability.

We studied 200 female patients with multiple sclerosis (MS) to investigate whether pregnancy after the onset of disease influences long term disability. As an index of progression, we used the time between disease onset and wheelchair dependence. Patients who had at least one pregnancy after onset were wheelchair dependent after 18.6 years, versus 12.5 years for the other women (P < 0.0001). This difference remains statistically significant after correction for age at onset of disease.

Demographic characteristics and prognosis in a Flemish amyotrophic lateral sclerosis population.

We describe the genetic and demographic characteristics of patients with amyotrophic lateral sclerosis (ALS) in Flanders, Belgium. Prognostic factors related to survival are examined. ALS was familial in 8.6% of all MND patients. In 6 of 8 apparently unrelated families, an SOD1 mutation was found. In sporadic ALS, mean age at onset was 57.1 years. There was a male preponderance (1.2:1) and the disease had a bulbar onset in 19%. Median survival was 32 months (95% CI 26-46). The presence of an APOE-epsilon 4 allele was not associated with a bulbar onset of ALS, an earlier age at onset or a shorter median survival. Variables examined in a multivariate analysis included age, sex, site of onset, delay from onset to diagnosis, and % forced vital capacity. Shorter survival was independently associated with higher age, bulbar onset, a short diagnostic delay, and a lower percent-predicted vital capacity at study entry. Simple clinical baseline characteristics can assist the clinician in estimating prognosis in ALS. The demographic characteristics of the Flemish ALS population do not seem to differ from those described in other parts of the world.

Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency.

BACKGROUND: Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. OBJECTIVE: To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. METHODS: GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed. RESULTS: Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20 years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late-presenting mild dopa-responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20 years of age, major depressive disorder, often recurrent, and obsessive-compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to l-dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients. CONCLUSION: Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.

Diagnosis of ulnar neuropathy: a new approach.

Conventional electrodiagnosis used to detect an ulnar neuropathy at the elbow depends on accurate determination of ulnar nerve length across this segment. We present a new approach, using the difference in latency of the compound nerve action potentials (CNAPs) of the ulnar and median nerves elicited by stimulation at the wrist and recorded 10 cm above the elbow. Sixty normal controls were examined in order to determine the normal upper limit (1.4 ms) of the difference in CNAP latency of the ulnar and the median nerves (Dlat index). Values obtained in 10 patients with ulnar nerve lesions are discussed. This test was shown to be both sensitive and specific, was independent of ulnar nerve length, and was easy to perform.

Deletion in the CMT1A locus on chromosome 17p11.2 in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (NHPP) is an autosomal dominant disease of peripheral nerves, characterized by recurrent focal neuropathies often with an underlying asymptomatic polyneuropathy. We report the clinical, electrophysiological, and histopathological findings in three families with HNPP and confirm the presence of a deletion on chromosome 17p11.2, including all the markers known to be duplicated in Charcot-Marie-Tooth disease type 1A. This deletion appears to be the underlying molecular deficit in this disease and provides additional evidence for the importance of this locus for peripheral nerve function.

Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that is inherited as an autosomal dominant trait in approximately 10% of cases. Recently we and others identified several single-base mutations in the Cu/Zn superoxide dismutase (SOD1) gene in patients with familial ALS (FALS). Using single-strand conformational polymorphism, we studied the C to G mutation in exon 2 of the SOD1 gene (resulting in a leucine to valine substitution in position 38) in affected and unaffected members of a large Belgian family with FALS. We measured the SOD1 activity in red blood cell lysates in 14 members of this family, including the only surviving clinically affected patient. SOD1 activity of the family members carrying the mutation was less than half that of members without the mutation. In addition, in 11 patients with sporadic ALS and 11 age- and sex-matched controls, red blood cell SOD1 activity was normal. These studies indicate that SOD1 activity is reduced in these FALS patients but not in sporadic ALS patients. Moreover, this SOD1 enzyme abnormality is detectable years before onset of clinical ALS in carriers of this FALS mutation.