Diagnostic reasoning in neurogenetics: a general approach

Establishing the definitive diagnosis of a neurogenetic disease is usually a complex task. However, like any type of clinical diagnostic reasoning, an organized process of development and consideration of diagnostic hypotheses may guide neurologists and medical geneticists to solve this difficult task. The aim of the present review is to propose a general method for diagnostic reasoning in neurogenetics, with the definition of the main neurological syndrome and its associated topographical diagnosis, followed by the identification of major and secondary neurological syndromes, extraneurological findings, and inheritance pattern. We also discuss general rules and knowledge requirements of the ordering physician to request genetic testing and information on how to interpret genetic variants in a genetic report. By guiding the requests for genetic testing according to an organized model of diagnostic reasoning and with the availability of specific treatments, clinicians may find greater resoluteness and efficacy in the diagnostic investigation, shortening the struggle of patients for a definitive diagnosis.

Keywords:
Neurology; Genetics, Medical; Diagnosis

Authorship

Helena Fussiger

conceptualization

writing

Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Programa de Pós-Graduação em Medicina: Ciências Médicas, Porto Alegre RS, BrazilUniversidade Federal do Rio Grande do SulBrazilPorto Alegre, RS, BrazilUniversidade Federal do Rio Grande do Sul, Faculdade de Medicina, Programa de Pós-Graduação em Medicina: Ciências Médicas, Porto Alegre RS, Brazil

http://orcid.org/0000-0002-6566-8293

José Luiz Pedroso

writing

review

editing

Universidade Federal de São Paulo, Departamento de Neurologia, Unidade de Ataxias, São Paulo SP, BrazilUniversidade Federal de São PauloBrazilSão Paulo, SP, BrazilUniversidade Federal de São Paulo, Departamento de Neurologia, Unidade de Ataxias, São Paulo SP, Brazil

http://orcid.org/0000-0002-1672-8894

Jonas Alex Morales Saute

conceptualization

writing

review

editing

Hospital de Clínicas de Porto Alegre, Centro de Pesquisa Clínica, Neurogenética, Porto Alegre RS, BrazilHospital de Clínicas de Porto AlegreBrazilPorto Alegre, RS, BrazilHospital de Clínicas de Porto Alegre, Centro de Pesquisa Clínica, Neurogenética, Porto Alegre RS, Brazil

Hospital de Clínicas de Porto Alegre, Serviço de Genética Médica, Porto Alegre RS, BrazilHospital de Clínicas de Porto AlegreBrazilPorto Alegre, RS, BrazilHospital de Clínicas de Porto Alegre, Serviço de Genética Médica, Porto Alegre RS, Brazil

Hospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, BrazilHospital de Clínicas de Porto AlegreBrazilPorto Alegre, RS, BrazilHospital de Clínicas de Porto Alegre, Serviço de Neurologia, Porto Alegre RS, Brazil

Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, BrazilUniversidade Federal do Rio Grande do SulBrazilPorto Alegre, RS, BrazilUniversidade Federal do Rio Grande do Sul, Faculdade de Medicina, Departamento de Medicina Interna, Porto Alegre RS, Brazil

http://orcid.org/0000-0003-1141-6573

Address for correspondence Jonas Alex Morales Saute (e-mail: jsaute@hcpa.edu.br).

Conflict of Interest

The authors have no conflict of interests to declare.

SCIMAGO INSTITUTIONS RANKINGS

Figures | Tables

Figures (3)
Tables (1)

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Figure 1
Major groups of neurogenetic conditions according to the topographical diagnosis.

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Figure 2
General models of monogenic and multifactorial diseases. The gray shape indicates the effect of the environment on the risk of developing a particular condition. Reddish forms indicate variants in genes that confer risk, and yellow forms indicate variants in genes that confer protection for a given condition. The thickness of the shapes indicates the size of the variant’s effect on the development of the phenotype. Abbreviation: CNS, central nervous system.

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Figure 3
Organizing diagnostic hypotheses and ordering tests in neurogenetics. Abbreviations: aCGH, array comparative genomic hybridization; ES, exome sequencing; GS, genome sequencing; MLPA, multiplex ligation-dependent probe amplification; NGS, next-generation sequencing; PCR, polymerase chain reaction.

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Table 1
Fundamental questions when obtaining family history

Figure 1 Major groups of neurogenetic conditions according to the topographical diagnosis.

Figure 2 General models of monogenic and multifactorial diseases. The gray shape indicates the effect of the environment on the risk of developing a particular condition. Reddish forms indicate variants in genes that confer risk, and yellow forms indicate variants in genes that confer protection for a given condition. The thickness of the shapes indicates the size of the variant’s effect on the development of the phenotype. Abbreviation: CNS, central nervous system.

Figure 3 Organizing diagnostic hypotheses and ordering tests in neurogenetics. Abbreviations: aCGH, array comparative genomic hybridization; ES, exome sequencing; GS, genome sequencing; MLPA, multiplex ligation-dependent probe amplification; NGS, next-generation sequencing; PCR, polymerase chain reaction.

Table 1 Fundamental questions when obtaining family history

Is there family recurrence? The recurrence of similar and unusual conditions in the same family is a fundamental clue for the diagnosis of genetic conditions. When encountering recurrence, try to collect information about as many affected family members as possible.

Sometimes, it will be necessary to examine these family members to confirm the reliability of the information. Remember that the family history of common illnesses, such headache, hypertension, diabetes mellitus, and late-onset dementia, should be evaluated very cautiously, because in most cases this information will not be relevant enough to modify the diagnostic suspicion.

Is there consanguinity? When collecting the family history, watch out for consanguineous marriages in the family of the proband (suggesting an autosomal recessive inheritance), and try to define the degree of kinship.

Geographic isolates? The proband’s place of birth, and their parents and grandparents may also be of relevance to the diagnosis, both because of the possibility of some form of more frequent condition in that region (such as founder effect of Machado-Joseph disease in Southern Brazil,³⁰30 Souza GN, Kersting N, Krum-Santos AC, et al. Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions. Clin Genet 2016;90(02):134–140 familial amyloid polyneuropathy in Rio de Janeiro,³¹31 Cruz MW. Regional differences and similarities of familial amyloidotic polyneuropathy (FAP) presentation in Brazil. Amyloid 2012;19(Suppl 1):65–67 and families with amyotrophic lateral sclerosis related to the VAPB gene in the Southeastern Region of the country³²32 Nishimura AL, Mitne-Neto M, Silva HC, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 2004;75(05):822–831,³³33 Chadi G, Maximino JR, Jorge FMH, et al. Genetic analysis of patients with familial and sporadic amyotrophic lateral sclerosis in a Brazilian Research Center. Amyotroph Lateral Scler Frontotemporal Degener 2017;18(3-4):249–255), and to reveal potential distant unknown consanguinity.

Possibility of hidden recurrence?

-Early death of the parent: pay attention to the age of death of the parents. Remember that the early death of one of the parents (before the expected age of manifestation of the disease) can hide the family history of the condition.

-Doubtful paternity: doubtful paternity can also hide family history. We must bear in mind the possibility of doubtful paternity and, if there is subsequent confirmation of a genetic condition in which this scenario is possible, the matter must be approached carefully, at the right time and conditions. Remember that dubious parenting is not of medical interest itself, and its search can lead to family conflicts.

All of the aforementioned data will assist in establishing the likely inheritance mechanism. However, we emphasize that the absence of these factors does not exclude the possibility of genetic conditions for several reasons (examples: de novo variants, which are new spontaneous variants emerging from a germline cell of one of the parents or in the fertilized egg; incomplete penetrance, which means that not everyone who has a given genotype will express the phenotype; variable expressivity, which means that subjects with the same genotype may have different disease severity or different clinical pictures; common frequency of carriers of pathogenic variants for some autosomal recessive diseases in the general population, as spinal muscular atrophy; compound heterozygosity for recessive disease etc.). Therefore, clinicians should refrain from saying that the family history is negative, but should rather inform the answers to the questions raised above.

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[1] Address for correspondence Jonas Alex Morales Saute (e-mail: jsaute@hcpa.edu.br).