Angelo Sghirlanzoni

Phenotypic heterogeneity in hereditary neuropathy with liability to pressure palsies associated with chromosome 17p11.2-12 deletion

Hereditary neuropathy with liability to pressure palsies (HNPP) is commonly associated with a 1.5-megabase deletion on chromosome 17p11.2-12. We analyzed the phenotypic expression of the deletion in 39 HNPP patients from 16 families carrying the deletion. Two-thirds of the individuals had episodes of acute mononeuropathy, often involving nerve territories of the upper limbs or brachial plexus; however, 41% of affected subjects were unaware of their disease, and 25% were almost or totally free of symptoms; one-third complained of chronic symptoms and four older patients had a picture of polyneuropathy. Electrophysiologic abnormalities differed among affected subjects, ranging from conduction abnormalities localized at common entrapment sites to diffuse conduction slowing, usually more evident at entrapment sites; patients from one family had preeminent proximal involvement. The spectrum of phenotypic expression of deletion-associated HNPP appears to be broader than previously thought. The prevalence of the disease is probably underestimated, and the availability of molecular diagnosis should increase disease detection. NEUROLOGY 1996;46: 1133-1137

Myasthenia gravis: Prolonged treatment with steroids

We have evaluated chronic corticosteroid treatment in 60 myasthenic patients; 92% were followed for more than 3 years and 82% longer than 4 years. Improvement was noted in 72% of the patients. The best results were seen in those whose symptoms started after the age of 40 years. There was a correlation between the starting dose of prednisone and the rate of improvement. Complete withdrawal of steroids was possible only for 3 patients.

Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis

SummaryAzathioprine (Aza) has been used alone or in combination with steroids for two groups of myasthenic patients. Positive responses were noted in 75% of patients on Aza alone and in 70% receiving the combined regimen. The clinical course of the two groups differed in terms of respiratory crisis and need for plasma exchange. With an appropriate Aza administration schedule side-effects were not a limiting factor to its use. Aza treatment induced a reduction in anti-AchR-antibody level that was correlated with clinical improvement and greatly decreased the need for steroids.

Gene dosage effects in hereditary peripheral neuropathy Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies

A duplication of a 1.5-Megabase genomic region encompassing the gene for the peripheral myelin protein 22 (PMP22) is found on chromosome 17p11.2-12 in Charcot-Marie-Tooth disease type 1A (CMT1A), whereas the reciprocal deletion is associated with hereditary neuropathy with liability to pressure palsies(HNPP). Since most CMT1A patients harbor three copies of the PMP22 gene, and most HNPP patients carry only a single copy, a gene dosage effect has been proposed as a mechanism for both diseases. We have analyzed the steady-state expression of PMP22 protein in sural nerve biopsies from three CMT1A and four HNPP patients. Quantitative immunohistochemical determination showed that PMP22 protein expression relative to that of myelin protein zero and myelin basic protein was increased in all CMT1A patients and reduced in all HNPP patients, as compared with biopsy samples of patients with normal PMP22 gene expression. These data demonstrate that both neuropathies result from an imbalance of PMP22 protein expression.

Cellular immune response against acetylcholine receptor in myasthenia gravis I. Relevance to clinical course and pathogenesis

The cellular immune response to acetylcholine receptor from Torpedo electric organ was studied in 100 myasthenic patients and 41 healthy subjects. The mean stimulation index (SI) was 2 ± 0.15 for the patients, and 1.06 ± 0.08 for the controls. Stimulation was significantly greater when the test medium contained autologous serum rather than a standard universal serum (AB serum). Young patients were generally good responders (SI, 2.39 ± 0.26), but older patients usually did not respond (mean SI, 1.18 ± 0.13). Among the younger patients, men had higher responses than women (mean SI, 3.13 ± 0.63 and 2.05 ± 0.23, respectively). There was no correlation between degree of lymphocytic reactivity and duration or severity of symptoms.

HMSN III phenotype due to homozygous expression of a dominant HMSN II gene

We describe two siblings with hereditary motor and sensory neuropathy (HMSN) type III. Their parents were both affected with autosomal dominant axonal HMSN. The neuropathy in the siblings probably resulted from homozygous expression of the HMSN II gene. Together with other reports of homozygous HMSN I, this family suggests that HMSN III is heterogenous and encompasses the most severe homozygous expression of neuropathic genes.

Cellular immune response to acetylcholine receptor in myasthenia gravis II. Thymectomy and corticosteroids

We studied 11 patients with myasthenia gravis who demonstrated a cellular immune response to acetylcholine receptor (AChR) of the electric organ of Torpedo marmorata. After thymectomy, there was a marked decrease in the patients lymphocyte reactivity to AChR. The mean reduction of the stimulation index (SI) was 50 percent, but the response to the nonspecific mitogen phytohemagglutinin (PHA) was not affected. In six cases, the lymphocyte response was measured at intervals up to 22 months after thymectomy; in all six, the immune response to AChR remained decreased. In some cases, the response continued to decrease, even to normal values. The effect of corticosteroid treatment was tested in other patients. The cellular immune response to AChR was significantly lower in treated patients (mean SI, 1.64 ± 0.25) than in untreated controls (mean SI, 2.41 ± 0.38), with no significant difference in the response to PHA. These data suggest that a decrease in the cellular immune response to AChR may be one mechanism by which thymectomy and corticosteroids are therapeutic in myasthenia.

Detection of hereditary neuropathy with liability to pressure palsies among patients with acute painless mononeuropathy or plexopathy

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies or brachial plexopathies, commonly associated with a chromosome 17p11.2‐12 deletion encompassing the peripheral myelin protein‐22 (PMP22) gene. We tried to identify criteria distinguishing HNPP among patients with acute painless mononeuropathy/plexopathy. We investigated by pulsed‐field gel electrophoresis the presence of the deletion in 27 patients with isolated or recurrent acute painless mononeuropathy or brachial plexopathy, and no obvious cause of neuropathy. Eight patients carried the deletion, whereas 19 had neither the deletion nor mutations in the PMP22 gene. Age at onset, presenting modality, precipitating events, and rate of recovery did not significantly differ in the two groups. Family history was informative for HNPP diagnosis in 3 cases only. HNPP patients more often showed recurrent episodes, brachial plexopathy, and clinical or electrophysiologic involvement of other nerves. Non‐HNPP patients more frequently had peroneal palsy, recent weight loss, and normal electrophysiologic examination in other nerves. Signs of generalized neuropathy and evidence of disease in other family member are often subtle in HNPP and must be thoroughly investigated in patients with acute painless mononeuropathy/plexopathy.

Partial laminin α2 chain deficiency in a patient with myopathy resembling inclusion body myositis

It is becoming evident that clinical phenotypes associated with partial laminin α2 chain deficiency are variable. We recently observed a 29‐year‐old man with leukoencephalopathy and vacuolar myopathy resembling inclusion body myositis. Laminin α2 immunohistochemical analysis showed reduction of the protein on muscle fiber surfaces. Molecular analysis revealed two novel compound heterozygous mutations in the LAMA2 gene. This is the first report linking a mutation in the LAMA2 gene with leukoencephalopathy and inclusion body‐like myositis. Ann Neurol 2000;47:811–816

Peripheral nerve involvement in Churg-Strauss syndrome.

SummaryPeripheral neuropathy associated with bronchial asthma, multisystem organ dysfunction and idiopathic hypereosinophilia may be found in Churg-Strauss syndrome, hypereosinophilic syndrome and polyarteritis nodosa. Some authors have diagnosed their patients according to the presence in tissue biopsies of the three histological criteria of Churg and Strauss (necrotizing vasculitis, tissue eosinophilic infiltration, extravascular granulomas). We have observed three patients with a common history of a prodromal phase of allergic diseases (bronchial asthma and rhinitis) followed by a vasculitic phase with mononeuritis multiplex, purpura and arthritis, associated with hypereosinophilia of more than 1500 cells/mm3. All responded well to steroid treatment. Sural nerve biopsy revealed true vasculitis in two of these cases and a mild perivascular inflammatory infiltration in the other. On the basis of their characteristic clinical pattern, we think that our cases best fit the diagnosis of Churg-Strauss syndrome even though the typical histological features were not found in the sural nerves examined.