Claudia Ciano

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

Infantile neuroaxonal dystrophy Clinical spectrum and diagnostic criteria

Objective: To present clinical, neurophysiologic, and neuroradiologic findings in 13 patients with infantile neuroaxonal dystrophy (INAD), focusing on aspects that assist early diagnosis. Background: Clinicopathologic diagnostic criteria for INAD were delineated by Aicardi and Castelein in 1979, but atypical cases are reported frequently and little is known of the diagnostic utility of MRI. Methods: The authors reviewed the clinical, neurophysiologic, and MRI findings of 13 patients who met the diagnostic criteria for INAD. Results: Symptoms onset was between 6 months and 2 years of age. In nine patients the clinical course was typical, with rapid motor and mental deterioration; in four patients progression was slower and the clinical picture was different. Electromyographic (EMG) signs of chronic denervation, fast rhythms on EEG and abnormal visual evoked potentials were observed in all patients during the disease course. Cerebellar atrophy with signal hyperintensity in the cerebellar cortex on T2-weighted images were the most characteristic MRI findings; hypointensity in the pallida and substantia nigra was also observed in two patients. α-N-acetyl-galactosaminidase activity on leukocytes was normal in the 10 patients tested. Conclusions: EMG and MRI abnormalities are the earliest and most suggestive signs of INAD, which has a clinical and radiologic spectrum that is broader than reported previously.

Myoclonus–dystonia syndrome: Clinical presentation, disease course, and genetic features in 11 families

Myoclonus–dystonia syndrome (MDS) is an inherited movement disorder with clinical and genetic heterogeneity. The epsilon sarcoglycan (SGCE) gene is an important cause of MDS. We report the results of a clinical and genetic study of 20 patients from 11 families. We disclosed six novel and two previously described mutations in nine families. The majority of patients had a phenotype of myoclonus and dystonia in combination, but clinical findings considered atypical, such a very early onset, distal myoclonus, and legs involvement, were detected in a significant proportion of cases. The disease course was variable, from progression to spontaneous remission of the motor symptoms. There were no obvious differences between mutation‐positive and ‐negative cases.

Overlapping phenotypes in complex spastic paraplegias SPG11, SPG15, SPG35 and SPG48.

Hereditary spastic paraplegias are a heterogeneous group of neurodegenerative disorders, clinically classified in pure and complex forms. Genetically, more than 70 different forms of spastic paraplegias have been characterized. A subgroup of complicate recessive forms has been distinguished for the presence of thin corpus callosum and white matter lesions at brain imaging. This group includes several genetic entities, but most of the cases are caused by mutations in the KIAA1840 (SPG11) and ZFYVE26 genes (SPG15). We studied a cohort of 61 consecutive patients with complicated spastic paraplegias, presenting at least one of the following features: mental retardation, thin corpus callosum and/or white matter lesions. DNA samples were screened for mutations in the SPG11/KIAA1840, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG48/AP5Z1 and SPG54/DDHD2 genes by direct sequencing. Sequence variants were found in 30 of 61 cases: 16 patients carried SPG11/KIAA1840 gene variants (26.2%), nine patients carried SPG15/ZFYVE26 variants (14.8%), three patients SPG35/FA2H (5%), and two patients carried SPG48/AP5Z1 gene variants (3%). Mean age at onset was similar in patients with SPG11 and with SPG15 (range 11-36), and the phenotype was mostly indistinguishable. Extrapyramidal signs were observed only in patients with SPG15, and epilepsy in three subjects with SPG11. Motor axonal neuropathy was found in 60% of cases with SPG11 and 70% of cases with SPG15. Subjects with SPG35 had intellectual impairment, spastic paraplegia, thin corpus callosum, white matter hyperintensities, and cerebellar atrophy. Two families had a late-onset presentation, and none had signs of brain iron accumulation. The patients with SPG48 were a 5-year-old child, homozygous for a missense SPG48/AP5Z1 variant, and a 51-year-old female, carrying two different nonsense variants. Both patients had intellectual deficits, thin corpus callosum and white matter lesions. None of the cases in our cohort carried mutations in the SPG21/ACP33 and SPG54/DDH2H genes. Our study confirms that the phenotype of patients with SPG11 and with SPG15 is homogeneous, whereas cases with SPG35 and with SPG48 cases present overlapping features, and a broader clinical spectrum. The large group of non-diagnosed subjects (51%) suggests further genetic heterogeneity. The observation of common clinical features in association with defects in different causative genes, suggest a general vulnerability of the corticospinal tract axons to a wide spectrum of cellular alterations.

Chronic inflammatory demyelinating polyradiculoneuropathy: long-term course and treatment of 60 patients

Abstract The objective of this study was to assess the long-term course and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We evaluated, according to a predefined protocol, a series of 60 CIDP patients who received a long-term course of steroids and immunosuppressants. Eighteen of them also had monoclonal gammopathy of undetermined significance (MGUS). Mean follow-up was 4.4 years and was similar for CIDP and CIDP-MGUS patients. At the end of the follow-up, improvement was ascertained in 60% of patients (69% CIDP, 39% CIDP-MGUS). Complete remission was achieved in 13%. Out of 26 patients receiving steroids as a monotherapy, 19 improved (73%). The following variables were predictive of a better outcome: female gender, younger age at onset, relapsing-remitting course, and absence of axonal damage at neurophysiologic study. In the multivariate analysis, younger age at onset and demyelination without axonal damage still retained an independent positive value.

Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease.

Objective: To investigate whether Unverricht–Lundborg disease (ULD) and Lafora body disease (LBD) can be differentiated on the basis of their neurophysiologic profiles. Methods: Somatosensory evoked potentials (SSEPs), long-loop reflexes (LLRs), and the influence of conditioning nerve stimulation on the motor potentials evoked by transcranial stimulation in 8 patients with LBD and 10 patients with ULD were investigated. Results: Both groups showed sensorimotor cortex hyperexcitability, but their electrophysiologic profiles were different. Enlarged P25 to N33 SSEP components and enhanced LLRs were common in the ULD patients, whereas medium-latency “giant” SSEP components and less consistently enhanced LLRs were more frequently found in the patients with LBD. Cortical relay time was extremely brief in ULD but varied in LBD. Conditioning somatosensory stimuli differently affected motor cortex excitability, leading to early facilitation in ULD and delayed and prolonged facilitation in LBD. Conclusions: Patients with Unverricht–Lundborg disease (ULD) and Lafora body disease (LBD) have different electrophysiologic profiles. The ULD findings point to an aberrant subcortical or cortical loop (possibly short-cutting the somatosensory cortex) that is involved in generating the prominent action myoclonus characterizing the disorder. The LBD findings highlight sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli, which fit with a more severe impairment of inhibitory mechanisms.

A neurophysiological study of myoclonus in patients with DYT11 myoclonus-dystonia syndrome

Mutations in the ϵ‐sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus‐dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11‐MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 ± 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo‐rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a “startle‐like” muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long‐loop reflexes were normal, as was silent period and long‐term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short‐term intracortical inhibition revealed subtle impairment, and event‐related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11‐MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11‐MDS may justify the involvement of different brain areas.

The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome

A few patients with mutations in the microtubule‐associated protein tau gene (MAPT), affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17T), may clinically present with a corticobasal syndrome (CBS). We report a case of apparently sporadic CBS bearing a mutation in the MAPT gene so far associated with frontotemporal dementia (FTD) phenotype. The patient is a 41‐year‐old man with progressive asymmetric signs of cortical and basal ganglia involvement consistent with CBS. Magnetic resonance imaging showed asymmetric cortical atrophy and unusual corticospinal tract hyperintensity in T2‐weighted images. Genetic testing revealed a heterozygous G to C mutation at the first base of codon 389 of the MAPT gene, changing glycine to arginine (G389R), in the patient and his unaffected elderly father. In conclusion, the MAPT G389R mutation shows phenotypic variability resulting in both FTD and CBS. The mutation also demonstrates incomplete penetrance. Corticospinal tract degeneration is an exceptional finding.

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.

Phenomenology of psychogenic movement disorders in children.

Psychogenic movement disorders are heterogeneous and diagnostically challenging. Despite the growing literature on adult forms, clinical features in children have received relatively little attention. We retrospectively reviewed medical records and video of patients <18 years diagnosed with a psychogenic movement disorder at our institute between 2007 and 2010. We identified 14 patients (6 males and 8 females) with a mean onset age of 11.5 years. Levels of diagnostic confidence were documented (2 patients), clinically established (8 patients), and probable (4 patients). A single movement disorder was present in 10 patients (71%); 4 patients (29%) presented an association of two or more movement disorders. Eleven patients presented other medically unexplained symptoms associated with their movement disorders. Five patients, among 6 with chronic occurrence, performed a polymyographic study showing significant modifications of frequency, amplitude, and distribution of electromyographic activity, related to distracting maneuvers. The present series represents 5% of all movement disorders observed in the considered period and 32% of nonorganic neurological manifestations. The most frequent movement disorders were tremor (36%) and dystonia (29%). We describe two phenotypes not previously reported among psychogenic movement disorders: myoclonus and association of myoclonus with dystonia. We remark on the presence of psychogenic symptoms associated with movement disorders (79%) as being one of the most useful clinical clues as well as on the value of polymyographic study in chronic psychogenic movement disorders, which provide evidence of the inconsistency of movement disorders.