Collagen VI involvement in Ullrich syndrome: a clinical,genetic, and immunohistochemical study

BACKGROUND: Ullrich congenital muscular dystrophy (UCMD) is a form of merosin-positive congenital muscular dystrophy characterized by proximal contractures, distal laxity, rigidity of the spine, and respiratory complications. Recently, a deficiency of collagen VI on muscle and skin biopsy together with recessive mutations in the collagen 6A2 gene were reported in three families with UCMD. However, the clinical spectrum, frequency, and level of heterogeneity of this disorder are not known. Subjects and Methods: The authors studied 15 patients (aged 3 to 23.6 years) with a clinical diagnosis of UCMD. Linkage analysis to the three collagen VI genes was performed in all informative families (n = 7), whereas immunohistochemical analysis of collagen VI expression in muscle was performed in the remaining cases. RESULTS: An immunocytochemical reduction of collagen VI was observed in six patients. Three of the six patients belonged to informative families, and haplotype analysis clearly suggested linkage to the COL6A1/2 locus in two cases and to the COL6A3 loci in the third case. In the remaining nine patients, primary collagen VI involvement was excluded based on either the linkage analysis (four families) or considered unlikely based on normal immunolabeling of collagen VI. Age and presentation at onset, the distribution and severity of weakness and contractures, and the frequency of nonambulant patients were similar in the patients with and without collagen VI involvement. Distal laxity, rigidity of the spine, scoliosis, failure to thrive, and early and severe respiratory impairment were found in all patients by the end of the first decade of life, irrespective of their maximum motor functional ability or their collagen status. CONCLUSIONS: These results suggest that collagen VI involvement is relatively common in UCMD (40%); however, the role of this molecule was excluded in a number of cases, suggesting genetic heterogeneity of this condition.     

Somatization: a spectrum of severity

OBJECTIVE: The DSM-III-R diagnosis of somatization disorder requires that a patient have a specific number of medically unexplained somatic symptoms. This number of symptoms was developed by committee consensus, and it is not clear whether patients with this specific number of symptoms can be differentiated from patients with lower but still substantial numbers of somatic symptoms. METHOD: Fifty-one percent of 767 high utilizers of two primary care clinics were identified as distressed by an elevated SCL anxiety, depression, or somatization scale score or by their primary care physician. The Diagnostic Interview Schedule (DIS) was completed on 119 distressed high utilizers who were randomly assigned to an intervention group in a controlled trial of psychiatric consultation. The 119 distressed high utilizers were separated into four categories according to the number of unexplained somatic symptoms found on the DIS and were compared on demographic, psychiatric distress, disability, medical, and health utilization variables. RESULTS: The data suggest that many clinical and behavioral features of somatization are significantly more common in patients with four to 12 medically unexplained somatic symptoms rather than changing dramatically at the diagnostic threshold for somatization disorder. The data also showed that patients who meet the DSM-III-R criteria for somatization disorder are severely ill and have a high burden of psychiatric illness and disability. CONCLUSIONS: The results suggest that the DSM-IV somatoform disorders section should include somatization disorder, an abridged definition of somatization disorder often associated with anxiety and depression, as well as a type of somatization associated with an adjustment disorder.     

Collagen VI status and clinical severity in Ullrich congenital muscular dystrophy: phenotype analysis of 11 families linked to the COL6 loci

Ullrich's congenital muscular dystrophy (UCMD) is an autosomal recessive myopathy characterised by neonatal muscle weakness, proximal joint contractures and distal hyperlaxity. Mutations in the COL6A1, COL6A2 (21 q22.3) and COL6A3 (2 q37) genes, encoding the alpha 1, alpha 2 and alpha 3 chains of collagen VI, respectively, have been recently identified as responsible for UCMD in a total of 9 families. We investigated in detail the clinical and morphological phenotype of 15 UCMD patients from 11 consanguineous families showing potential linkage either to 21 q22.3 (6 families) or to 2 q37 (5 families). Collagen VI deficiency was confirmed on muscle biopsies or skin fibroblasts in 8 families. Although all patients shared a common phenotype, a great variability in severity was observed. Collagen VI deficiency in muscle or cultured fibroblasts was complete in the severe cases and partial in the milder ones, which suggests a correlation between the degree of collagen VI deficiency and the clinical severity in UCMD. No significant phenotypical differences were found between the families linked to each of the 2 loci, which confirms UCMD as a unique entity with underlying genetic heterogeneity.     

Collagen VI‐related myopathy: Expanding the clinical and genetic spectrum

Introduction: We aimed to analyze the clinical and genetic characteristics of collagen VI‐related myopathy. Methods: We analyzed the clinical course and mutation spectrum in patients with collagen VI gene mutations among our congenital muscular dystrophy cohort. Results: Among 24 patients with mutations in collagen VI coding genes, 13 (54.2%) were categorized as Ullrich type, and 11 (45.8%) as non‐Ullrich type. Congenital orthopedic problems were similarly observed in both types, yet multiple joint contractures were found only in the Ullrich type. Clinical courses and pathology findings varied between patients. Mutations in COL6A1, COL6A2, and COL6A3 were found in 15 (65%), 3 (13%), and 5 (22%) patients, respectively, without genotype–phenotype association. Five novel variants were detected. Discussion: We verified clinical heterogeneity of collagen VI‐related myopathy, which emphasizes the importance of genetic testing. Genotype–phenotype association or early predictors for progression were not identified. Multiple joint contractures predict rapid deterioration. Muscle Nerve 58 : 381–388, 2018     

Distal myopathy due to mutations of GNE gene: clinical spectrum and diagnosis

Distal myopathies are rare muscular disorders clinically characterized by a predominantly distal muscular involvement. Among recessive forms, the myopathy resulting from mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene, often designated as Nonaka myopathy, primarily affect young adults and are characterized by muscle wasting and weakness predominating on the anterior compartment of the leg, a remarkable quadriceps sparing and a frequent evolution towards ambulation loss after a few years. Finding rimmed vacuoles on muscle biopsy is a further argument for the diagnosis. However, the presentation and course may vary and we describe four patients who illustrate the clinical spectrum of the disease: the first patient had a classical form with progressive weakness over several years, the second one a rapidly progressive myopathy leading to ambulation loss within three years from onset, the third one a very slow course with no ambulation loss after several decades, and the last one a progressive form with misleading neurogenic features on the EMG. One of our four patients harbored a homozygous mutation, and three others were compound heterozygous, two of them displaying an original mutation: one had a c.2036 T>G (p.Val679Gly) substitution, the c.829 C>T (p.Arg277Cys) substitution.     

POMGnT1 mutations in congenital muscular dystrophy: genotype-phenotype correlation and expanded clinical spectrum

BACKGROUND: Muscle-eye-brain disease is a congenital muscular dystrophy with eye and brain involvement due to POMGnT1 mutations. OBJECTIVE: To describe the clinical and molecular features of 3 Italian patients with POMGnT1 mutations. DESIGN: Case reports. PATIENTS: One patient had muscle and brain abnormalities without eye involvement. Two patients had a classic muscle-eye-brain disease phenotype with different levels of clinical severity. RESULTS: Brain magnetic resonance imaging showed cortical malformation and posterior fossa involvement. Immunofluorescence for glycosylated alpha-dystroglycan performed on muscle biopsy specimens demonstrated an absent signal in 1 patient and reduced staining in 2 patients. Molecular analysis identified 5 mutations, 2 of which are novel. CONCLUSION: This article adds to what is known about the genotype-phenotype correlation and expands our awareness of the clinical spectrum associated with POMGnT1 mutations.     

The bipolar spectrum: a clinical perspective

The relative misdiagnosis and underdiagnosis of bipolar disorder is due in part to the 'soft' symptoms of bipolarity that characterize patients with non-classical bipolar disorder. While no agreement has been reached on the term for this group of patients, the most common classification used is 'bipolar spectrum', which shifts the emphasis in diagnosis away from polarity and toward other diagnostic validators. In order to recognize and properly treat patients with bipolar disorder, clinicians should focus on careful evaluation of patients with mixed anxiety/depressive symptoms or impulsivity conditions (substance abuse, borderline personality, bulimia, and attention deficit disorder). Furthermore, in the treatment of bipolar disorder, clinicians should also recognize that antidepressants can have a negative effect on patients by increasing the likelihood of more severe rapid cycling. While antidepressants may be useful in particularly difficult cases, emphasis should be placed on mood stabilizers for treatment of the bipolar spectrum.     

Epileptic olfactory auras: a clinical spectrum

Objective

To investigate the relative frequency of olfactory aura in a large number of patients with focal epilepsy, and examine the full clinical spectrum of epileptic olfactory auras (OAs) and their relationship to hemispheric lateralization and localization of epileptogenic focus.

Methods

This retrospective study was based on the medical records of 1384 patients with focal epilepsy. Of these, 71 (5.1%) patients were present with OAs, comprising 25 (35.2%) men and 46 (64.8%) women with a mean age of 35.43?±?12.89 years. These 71 patients were classified according to the clinical features of the OAs, and the electroencephalography and magnetic resonance imaging findings were examined.

Results

The relative frequency of OAs was 5.1% in the focal epileptic patients. The clinical spectrum of OAs in our cases was outlined as follows, complex OAs and elementary OAs. Elementary OAs were divided into three subgroups: elementary neutral OAs, elementary unpleasant OAs, and elementary pleasant OAs. In our cases, there was no difference between the right and left hemispheres in terms of lateralization of the epileptogenic focus. In all the 71 patients, the epileptogenic zone was most commonly localized in the temporal lobe (n?=?58; 81.7%).

Conclusions

The relative frequency of OAs in focal epilepsies is likely to be found higher than expected. Elementary OAs occur much more frequently than complex OAs. Among the elementary OAs, elementary unpleasant OAs and elementary neutral OAs are the most common types, whereas elementary pleasant OAs are extremely rare.

     

Sexual abuse of children: a clinical spectrum

This paper suggests that incest has been underestimated as a significant determinant of emotional disturbance, and that misuse of sexuality between parents and children can have detrimental consequences that parallel those resulting from other forms of child abuse. The spectrum of parent-child sexuality is classified into ten categories as a guide to the diagnosis, management, and prognosis of sexually abusive behavior.     

The spectrum of GNE mutations: allelic heterogeneity for a common phenotype

Hereditary inclusion body myopathy (IBM2) was mainly reported in Middle Eastern Jewish patients. Distal myopathy with rimmed vacuoles has been described as a worldwide distributed distal myopathy. Both diseases are caused by mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Herein we report two patients: an Egyptian Muslim patient with the “common” Middle Eastern mutation (M712T), rarely described in non-Jewish patients; and an Italian patient carrying a novel GNE mutation (L179F) in the epimerase domain. Our patients share common clinical and histopathological features, with some interesting aspects. The first patient presented a clinical deterioration during her first pregnancy confirming that an increased requirement of sialic acid during pregnancy may trigger a clinical worsening. The second patient showed a slowly progressive deterioration, different from other patients carrying mutations in the epimerase domain, who had a severe and rapid progression.     

Neuroleptic toxicity syndromes: a clinical spectrum.

The neuroleptic malignant syndrome (NMS) has undergone a number of changes since it was first described in the 1960s. This paper presents a review of these changes from the traditional approach of rigid categorization through the more flexible operational definitions to a spectrum of neuroleptic toxicity. This spectrum spans neuroleptic-induced extrapyramidal side effects, possible stages of neuroleptic toxicity, and the full blown neuroleptic malignant syndrome. Different theoretical concepts of the syndrome have contributed to diagnostic confusion among clinicians and thus to difficulties in management. The concept of a spectrum of neuroleptic toxicity provides a coherent theoretical base for understanding NMS and thus allows for more rapid identification of the potential threat of NMS. Three cases are presented and discussed to highlight the utility of the concept of a clinical spectrum.     

Periaxin mutations cause a broad spectrum of demyelinating neuropathies

Previous studies have demonstrated that apparent loss-of-function mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas neuropathy or severe demyelinating Charcot-Marie-Tooth disease. In this report, we extend the associated phenotypes with the identification of two additional families with novel periaxin gene mutations (C715X and R82fsX96) and provide detailed neuropathology. Each patient had marked sensory involvement; two siblings with a homozygous C715X mutation had much worse sensory impairment than motor impairment. Despite early disease onset, these siblings with the C715X mutation had relatively slow disease progression and adult motor impairment typical of classic demyelinating Charcot-Marie-Tooth neuropathy. In contrast, a patient with the homozygous R82fsX96 mutation had a disease course consistent with Dejerine-Sottas neuropathy. The neuropathology of patients in both families was remarkable for demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon. Our study indicates a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein.     

Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum

Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa‐induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X‐associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado–Joseph disease related to an abnormal CAG repeat expansion in ataxin‐3 (ATXN3) gene, Kufor–Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β‐glucocerebrosidase (GBA) gene and Chediak–Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.     

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations

The aim of the study was to determine the prevalence of MNGIE-like phenotype in patients with recessive POLG1 mutations. Mutations in the POLG1 gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase gamma essential for mitochondrial DNA replication, cause a wide spectrum of mitochondrial disorders. Common phenotypes associated with POLG1 mutations include Alpers syndrome, ataxia-neuropathy syndrome, and progressive external ophthalmoplegia (PEO). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, PEO and/or ptosis, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by TYMP mutations. Rare cases of MNGIE-like phenotype have been linked to RRM2B mutations. Recently, POLG1 mutations were identified in a family with clinical features of MNGIE but no leukoencephalopathy. The coding regions and exon-intron boundaries of POLG1 were sequence analyzed in patients suspected of POLG1 related disorders. Clinical features of 92 unrelated patients with two pathogenic POLG1 alleles were carefully reviewed. Three patients, accounting for 3.3% of all patients with two pathogenic POLG1 mutations, were found to have clinical features consistent with MNGIE but no leukoencephalopathy. Patient 1 carries p.W748S and p.R953C; patient 2 is homozygous for p.W748S, and patient 3 is homozygous for p.A467T. In addition, patient 2 has a similarly affected sibling with the same POLG1 genotype. POLG1 mutations may cause MNGIE-like syndrome, but the lack of leukoencephalopathy and the normal plasma thymidine favor POLG1 mutations as responsible molecular defect.     

Confirming an expanded spectrum of SCN2A mutations: a case series

Mutations in sodium channel genes are highly associated with epilepsy. Mutation of SCN1A, the gene encoding the voltage gated sodium channel (VGSC) alpha subunit type 1 (Nav1.1), causes Dravet syndrome spectrum disorders. Mutations in SCN2A have been identified in patients with benign familial neonatal‐infantile epilepsy (BFNIE), generalised epilepsy with febrile seizures plus (GEFS+), and a small number of reported cases of other infantile‐onset severe intractable epilepsy. Here, we report three patients with infantile‐onset severe intractable epilepsy found to have de novo mutations in SCN2A. While a causal role for these mutations cannot be directly established, these findings contribute to growing evidence that mutation of SCN2A is associated with a range of epilepsy phenotypes including severe infantile‐onset epilepsy.     

The fenfluramine challenge test in the affective spectrum: a possible marker of endogeneity and severity

In order to investigate the role of serotonergic mechanisms in depressive disorders, the fenfluramine challenge test was performed in 31 patients suffering from different types of depression. The strategy was to select a simple method (i.e., easier to perform than CSF studies for instance) to be applied to a wide range of patients, as close as possible to everyday cases in a clinical setting (i.e., not only to such severe or highly selected groups as is normally the case in biological research in psychiatry). The neuroendocrine test (which consisted of the measurement of variations in the secretion of prolactin, growth hormone and Cortisol after the administration of 60 mg dl-fenfluramine p. o.) did not correlate with symptoms of behavior patterns previously identified with a "serotonin deficit" (i. e., suicidal behavior or attempts, lowering of the control of impulses, sleep disturbances) but only with the severity of the diagnosis (in the DSM-III hierarchical scale) or with indexes of endogeneity (Newcastle scale). This fact could be explained by methodological artifacts (i. e., dlfenfluramine is not a clean probe, showing influence in the dopamine and noradrenaline metabolism; the absorption of fenfluramine was not controlled) or by the fact that the involvement of serotonin in affective disorders is not a selective, isolated dysfunction, but is integrated in more complex interrelationships. Nevertheless, our preliminary findings (even without the results of the comparison with a control group and the evaluation of a few more data and cases) do coincide with the absence of predictors or the lack of specific patterns of response of symptoms with new selective re-uptake blockers of serotonin antidepressants.