Multidisciplinary approach to genetic testing for hereditary neuromuscular diseases]

The benefit of genetic testing for hereditary neuromuscular diseases is accurate and rapid diagnosis. On the other hand, it raises several ethical, legal, and psychosocial issues because the test results may greatly influence the life plan or life style of the applicant. In particular, in case of predictive or prenatal genetic testing, or carrier detection for family relatives, careful genetic counseling and psychosocial support are needed for applicants. When requests for predictive or prenatal genetic testing, or carrier detection for healthy relatives are received, a multidisciplinary approach should be taken. A team that consists of a geneticist, neurologist, psychiatrist, psychologist, genetic nurse, and social worker should carefully conduct genetic counseling sessions. It is quite important to build effective communication and coordination of activities among the applicant, the applicant's family and members of the counseling team during pre-test counseling sessions. This will help applicants feel satisfied with their own decision as to whether they will receive genetic testing or not. Furthermore, it will help applicants cope with an unfavorable test result.     

Analysis of 14 individuals who requested predictive genetic testing for hereditary neuromuscular diseases]

Predictive genetic testing for hereditary neuromuscular diseases is a delicate issue for individuals at risk and their families, as well as for medical staff because these diseases are often late-onset and intractable. Therefore careful pre- and post-test genetic counseling and psychosocial support should be provided along with such genetic testing. The Division of Clinical and Molecular Genetics was established at our hospital in May 1996 to provide skilled professional genetic counseling. Since its establishment, 14 individuals have visited our clinic to request predictive genetic testing for hereditary neuromuscular diseases (4 for myotonic dystrophy, 6 for spinocerebellar ataxia, 3 for Huntington's disease, and 1 for Alzheimer's disease). The main reasons for considering testing were to remove uncertainty about the genetic status and to plan for the future. Nine of 14 individuals requested testing for making decisions about a forthcoming marriage or pregnancy (family planning). Other reasons raised by the individuals included career or financial planning, planning for their own health care, and knowing the risk for their children. At the first genetic counseling session, all of the individuals expressed hopes of not being a gene carrier and of escaping from fear of disease, and seemed not to be mentally well prepared for an increased-risk result. To date, 7 of the 14 individuals have received genetic testing and only one, who underwent predictive genetic testing for spinocerebellar ataxia, was given an increased-risk result. The seven individuals including the one with an increased-risk result, have coped well with their new knowledge about their genetic status after the testing results were disclosed. None of them has expressed regret. In pre-test genetic counseling sessions, we consider it quite important not only to determine the psychological status of the individual, but also to make the individual try to anticipate the changes in his/her life upon receiving an increased-risk or a decreased-risk result. Sufficient time should be taken to build a good relationship between the individual and his/her family and the medical staff during pre-test counseling sessions. This will help the individuals feel satisfied with their own decisions for the future, whether they receive genetic testing or not.     

Psychosocial impact of presymptomatic genetic testing for transthyretin amyloidotic polyneuropathy

Presymptomatic genetic testing of an untreatable disease raises clinical, ethical, legal and psychosocial questions. Investigations in specific disorders are needed to help in understanding the motivation for and the impact of genetic testing in the lives of persons at risk for these diseases. Here, we performed a longitudinal study to investigate the psychological consequences of presymptomatic genetic testing on people at risk for transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP). The aim of the present study was to provide possible guidelines for genetic counselling and psychosocial support. Impact of Event Scale Revised (IES-R), Hospital Anxiety and Depression Scale (HADS) and SF-36 questionnaires were administered to 18 asymptomatic subjects before, immediately after communication of the genetic test result and after 3, 6 and 26 months. Our findings showed evidence of anxiety, depression, avoidance of the disease, and psychological distress, especially for women, including those with a negative genetic test result (“survivor guilt”). A psychological support has to be provided before and continued at long term after presymptomatic genetic testing for TTR-FAP in people with positive result as well as in those with negative result.     

Electrodiagnostic testing in neuromuscular disorders

For the past approximately six decades, electrodiagnostic testing orelectrodiagnosis (EDX) has played an increasingly important role in the clinical evaluation of patients who have neuromuscular disorders. This in part is because of a greater understanding of the pathophysiology of these disorders. Also of importance is the development of the techniques themselves, beginning with basic needle electromyography (EMG) and electroneurography (or nerve conduction studies) (NCS) in the 1940s. Today the clinician has a larger menu of testing options, including somatosensory evoked potentials,quantitative EMG, single fiber EMG, and autonomic testing.The advent of computers has added speed and accuracy to testing     

Olfactory dysfunction in hereditary ataxia and basal ganglia disorders

In the present study the olfactory system of hereditary ataxia patients was tested using the smell identification test. Two previous findings suggested a possible olfactory impairment in these patients. First, an olfactory dysfunction has been found in different neurodegenerative diseases, and second, human functional imaging has shown cerebellar activation during olfaction. As an initial approach to determine if cerebellar ataxia impairs the olfactory process, cerebellar ataxia patients, along with basal ganglia patients, were tested. The results show an olfactory deficit in both basal ganglia and hereditary ataxia patients. Further exploration of the olfactory capacities in hereditary ataxia is necessary to elucidate the specific nature of the deficits.     

Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease

Molecular genetic advances have led to refinements in the classification of inherited neuromuscular disease, and to methods of molecular testing useful for diagnosis and management of selected patients. Testing should be performed as targeted studies, sometimes sequentially, but not as wasteful panels of multiple genetic tests performed simultaneously. Accurate diagnosis through molecular testing is available for the vast majority of patients with inherited neuropathies, resulting from mutations in three genes (PMP22, MPZ, and GJB1); the most common types of muscular dystrophies (Duchenne and Becker, facioscapulohumeral, and myotonic dystrophies); the inherited motor neuron disorders (spinal muscular atrophy, Kennedy's disease, and SOD1 related amyotrophic lateral sclerosis); and many other neuromuscular disorders. The role of potential multiple genetic influences on the development of acquired neuromuscular diseases is an increasingly active area of research.     

遗传性脊髓小脑型共济失调7型遗传学诊断及临床特征

目的研究中国人遗传性脊髓小脑型共济失调(SCA)7型(SCA7)的基冈突变和临床特征。方法应用聚合酶链反应(PCR)、聚丙烯酰胺凝胶电泳(PAGE)等技术对临床表现为SCA的92个家系112例患者和16例散发SCA患者的SCA7基因内CAG三核苷酸重复序列进行检测,对异常等位基因片段进行DNA测序,分析基因型和表型之间的关系,并与表型正常的家系成员和健康人对照。结果在1个SCA7家系的6位成员中检测出2例患者的SCA7等化基因内CAG重复数目为71;临床表现主要为共济失调、视力下降、黄蓝色盲及视网膜色素变性。该家系内表型正常的4位成员SCA7等位基因CAG重复数目为7～9,另126例临床表现为SCA的患者、71名表型正常的家系成员及60名健康对照者SCA7等位基因内CAG三核甘三酸重复数为6—21。结论CAG过度扩增为SCA7的致病原因,分子遗传学分析有助于SCA7的诊断;视网膜色素变性为SCA7的重要特征。     

Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy

We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia. Phenotypic analysis of the various SCA subtypes evidenced a marked heterogeneity of symptoms with a substantial overlap between different syndromes.     

Psychological consequences of genetic testing for spinocerebellar ataxia in the Japanese

To evaluate the psychological consequences of genetic testing for spinocerebellar ataxia (SCA), state and trait anxiety inventories (SAI and TAI) and social desirability scale (SDS) were assessed and analyzed in patients and their family members diagnosed with spinocerebellar ataxias such as spinocerebellar ataxia type 1 and Machado—Joseph disease (MJD). The results obtained prior to and after the genetic testing were compared to a control group that included more severe hereditary neurological disorders such as Huntington's disease and familial amyotrophic lateral sclerosis. Genetic counseling was undertaken during the study. Of the 62 total participants, 37 were diagnosed with SCA, and 25 as asymptomatic family members. The SCA patients had higher baseline SAI, TAI and SDS scores than their asymptomatic family members. Genetic testing did not significantly increase the scores for all the patients and their asymptomatic family members, whereas the SAI value was greatly reduced in those subjects who received negative results and were not carriers of the defective gene. Similar results were obtained even in the control group with more severe diseases except for a reduction of SAI values in the patients. Patients, their SCA asymptomatic family members, and the disease control generally had some apprehension for the testing, but, at the same time, were not so anxious if remedial or curative therapy was available. Furthermore, most participants in this study showed a high degree of acceptance and did not express much regret in undergoing the genetic testing regardless of having the disease or finding out the results of the predictive testing. These results suggest that the psychological health of the asymptomatic family members with negative results for SCA gene abnormality recovered after genetic testing, and genetic testing was not disadvantageous for the psychological well-being of the patients and even for those with positive predictive results.     

An autopsy case of hereditary ataxia (hereditary spastic ataxia)

An autopsy case of hereditary spastic ataxia is reported. There are four family members with similar symptomatology through three generations. A 36-year-old man developed atactic gait at the age of 22 years, with following dysarthria, scanning speech, pyramidal signs, dysmetria, dysdiadochokinesia, nystagmus and mild sensory disturbance. The clinical course was steadily progressive and terminated about 14 years after the onset. The gross examination showed smallness of the brain stem and spinal cord with marked symmetrical atrophy of the anterior and lateral columns, especially at thoracic level. Histologically, pronounced degeneration was found in the anterior and posterior spino-cerebellar tracts, spino-thalamic tracts, and spinal ganglia. The olivary nuclei, pons and cerebellum were spared. The dentate nuclei showed considerable loss of neurons with degeneration, however there were no clinical signs related to this pathology. This case is considered to fall in the group of hereditary spastic ataxia according to Greenfield's classification, however, there was no report on degeneration of the dentate nucleus in this disease for the present. Hereditary spastic ataxia is very rare disease and only four cases have well been documented in our country to the best of our knowledge. The presence of nystagmus and superficial sensory disturbance, and sparing of the posterior column of the spinal cord seems to be common clinico-pathology in Japanese cases, differing from those of foreign cases. The fact that reactive astrogliosis was immunohistochemistry demonstrated in the degenerative regions of the spinal cord and where is no discrepancy between degenerative and reparative processes as reported before is stressed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impacts of massively parallel sequencing for genetic diagnosis of neuromuscular disorders

Neuromuscular disorders (NMD) such as neuropathy or myopathy are rare and often severe inherited disorders, affecting muscle and/or nerves with neonatal, childhood or adulthood onset, with considerable burden for the patients, their families and public health systems. Genetic and clinical heterogeneity, unspecific clinical features, unidentified genes and the implication of large and/or several genes requiring complementary methods are the main drawbacks in routine molecular diagnosis, leading to increased turnaround time and delay in the molecular validation of the diagnosis. The application of massively parallel sequencing, also called next generation sequencing, as a routine diagnostic strategy could lead to a rapid screening and fast identification of mutations in rare genetic disorders like NMD. This review aims to summarize and to discuss recent advances in the genetic diagnosis of neuromuscular disorders, and more generally monogenic diseases, fostered by massively parallel sequencing. We remind the challenges and benefit of obtaining an accurate genetic diagnosis, introduce the massively parallel sequencing technology and its novel applications in diagnosis of patients, prenatal diagnosis and carrier detection, and discuss the limitations and necessary improvements. Massively parallel sequencing synergizes with clinical and pathological investigations into an integrated diagnosis approach. Clinicians and pathologists are crucial in patient selection and interpretation of data, and persons trained in data management and analysis need to be integrated to the diagnosis pipeline. Massively parallel sequencing for mutation identification is expected to greatly improve diagnosis, genetic counseling and patient management.     

Psychiatric implications of presymptomatic testing for Huntington's disease

Responses of 69 at-risk individuals suggest that potential for psychiatric problems exists for those testing positive for the Huntington Disease gene and for their relatives. Their families were found to have high rates of psychiatric dysfunctions and suicide. Poorly developed social support networks and the psychological defensive strategies of many at-risk people may also contribute to post-test psychiatric morbidity. The active involvement of mental health professionals is emphasized.     

What we do not know about pregnancy in hereditary neuromuscular disorders

Only sparse information is available concerning the relationship between pregnancy and hereditary neuromuscular disorders. This review deals with several issues like the effects of such conditions on female fertility (myotonic dystrophy type 1 and mitochondrial disorders), on the risk to the fetus (myotonic dystrophy type 1 and Charcot-Marie-Tooth disease), on the ability to carry pregnancy and its complications (markedly increased preterm labor in myotonic dystrophies and spinal muscular atrophy), on the labor and its possible need for interventions (myotonic dystrophy type 1, facioscapulohumeral dystrophy and Charcot-Marie-Tooth disease). It also discusses the question of pregnancy effects on the course of the inherited neuromuscular disorders (myotonic dystrophies, spinal muscular atrophy, facioscapulohumeral dystrophy, Charcot-Marie-Tooth disease, congenital myopathy and limb-girdle muscular dystrophy). The aim of this critical review is to point at pregnancy-related problems that need further research.     

脊髓小脑性共济失调的症状前诊断研究

目的:探讨脊髓小脑性共济失调的症状前患者分子遗传学诊断及其面临的有关问题。方法:对临床诊断为脊髓小脑性共济失调(SCA)患者进行基因诊断的同时根据申请者要求检测其家系“健康”个体,采用聚合酶链反应(PCR)对三核苷酸重复(TNR)片段进行扩增,聚丙烯酰胺凝胶电泳并计算其长度,推算正常和异常扩增等位基因内TNR重复拷贝数。结果:多数家系无症状患者均要求进行致病基因突变检测。通过基因检测诊断出6例SCA3、2例SCA1、2例SCA12症状前患者。结论:分子遗传学检测可作出可靠的症状前诊断。进行遗传咨询应考虑医学、伦理、法律及社会诸多问题。     

CDG (congenital disorders of glycosylation). Differential hereditary ataxia in adulthood diagnosis

Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem diseases due to different defects of enzymes or transport molecules involved in the synthesis of glycoproteins. CDG-la is the most common subtype, with cerebellar ataxia as the main neurological symptom. Currently there is little information about CDG-la manifestation in adulthood. Here we present two sisters in whom the diagnosis of CDG-la was made in the fourth decade of life and who to our knowledge are the oldest known patients with the disorder in Germany. The clinical course of the disease was typical, although less severe than previously described. The carbohydrate-deficient transferrin (CDT) level was increased but lower than in other CDG patients. Isoelectric focusing of transferrin revealed changes typical of CDG, whereas those of alpha 1-antitrypsin were only moderately pathologic. This might be due to the milder manifestation of the disease in our patients or it could be indicative of a stabilization of the disease after puberty. The CDG should be included in the differential diagnostic workup of hereditary cerebellar ataxia in adults.     

Lecithin therapy of hereditary ataxia

Eight patients with Friedreich's ataxia and eight others with syndrome of spino-cerebellar degeneration received oral lecithin (21 g daily) for a six-month period. No relevant clinical change was note either during or soon after treatment. Statistical analysis was also irrelevant in the total number of patients. Similar results emerged when grouping the patients at the stage of the illness (stage II in contrast with stage III-IV). The outcome of therapeutical trials in literature is discussed in comparison with results.     

Leucocyte fatty acid oxidation in hereditary neuromuscular disorders. A preliminary report

An attempt has been made to screen for an enzyme defect in the metabolic pathway involved in fatty acid oxidation (β-oxidation) using peripheral blood leucocytes from patients with various neuromuscular disorders. The widely-used technique of ¹⁴CO₂ trapping and subsequent scintillation counting was employed. In controls the values obtained were unrelated to age or sex. No significant difference was found between the values in patients with various forms of muscular dystrophy and in controls. However, in 2 patients with Duchenne muscular dystrophy the values were lower than in patients with other forms of dystrophy.