Neurogenetics for the Practitioner

Neurogenetics is a growing field, providing a clear link between clinical characteristics of phenotypes and exact molecular tests to reach a specific diagnosis. Neurogenetics for the Practitioner provides clinicians with a navigation tool to help diagnose and treat patients with neurological disorders using neurogenetics. The first section introduces the reader to an overview of genetic principles, including practical applications in relation to diagnosis and current limitations. Additional chapters highlight how to workup patients presenting with certain features including cerebral palsy/intellectual disability, congenital muscular dystrophy, cognitive decline/dementia, peripheral neuropathy, and paroxysmal disorder. The final section explores therapeutic strategies based on genetic interventions and genetic counselling options. Internationally contributed, this book will become the essential reference guide for neurologist.

• Reviews genetic testing for diagnostic confirmation, including carrier testing and prenatal diagnosis
• Explores various therapeutic strategies based on genetic interventions
• Discusses when a neurologic problem may have an underlying genetic cause

• Language: English
• Publisher: Academic Press
• Release date: Apr 24, 2024
• ISBN: 9780323958592

Book preview

Chapter 1 Introduction

Gregory M. Pastoresa; Stacey K.H. Tayb    a Emeritus, Medicine (Genetics), University College Dublin, Dublin, Ireland

b KTP-National University Children's Medical Institute, and Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

Abstract

The availability of genetic testing for diagnostic confirmation of certain conditions has transformed the practice of neurology, just as investigations into the etiology of several disorders has led to novel insights regarding molecular disease mechanisms. A by-product has been the ability to diagnose individuals at risk presymptomatically and the introduction of disease-specific therapies. This introductory chapter is an overview of certain genetic concepts and aims to illustrate how knowledge gained has been put into practice.

Keywords

Neurogenetics; Genetic counseling; Mendelian inheritance; Therapeutics

Overview

More than 80% of genes are expressed in the brain¹; so it should not come as a surprise that variations in multiple loci, ultimately leading to a disruption of biologic processes, can account for a neurologic phenotype, whether primarily or as an added feature of a systemic condition. Interestingly, similar clinical presentations can often be accounted for by defects in several distinct genes (i.e., locus heterogeneity), although recent studies indicate that these disease genes may be involved in similar or overlapping biological processes.²

Almost 6000 diseases are known to be associated with various defects of specific genes,³ although some may be considered as rare or infrequent; collectively these gene mutations account for a significant proportion of medical conditions that can lead to significant morbidity and untimely death. Most neurogenetic disorders have limited therapeutic options, a situation that is a source of deep frustration to both the clinician and the family. Yet reaching a genetic diagnosis has benefits: ending the diagnostic odyssey, obtaining closure for the families as well as gaining some measure of understanding the prognosis and management options. Moreover, genetic diagnosis is of great value in considering reproductive risk and life planning, although presymptomatic testing and carrier detection can be issues that lead to ethical dilemmas. Thus, offering genetic testing is ideally preceded by appropriate genetic counseling, during which a detailed pedigree (family tree) is obtained, and information regarding the test(s) requested and potential limitations is communicated.

Prior to the advent of large-scale next-generation sequencing, the search for the underlying basis of disease required the identification of large families segregating for an inherited neurologic condition. These studies involved linkage analyses, using an increasing number of probes that had been mapped to a particular chromosomal region.⁴ Occasionally, a chromosomal translocation that has resulted in the interruption of a relevant gene expedited the search. Examples of the latter are the localization and subsequent characterization of the gene defects causing neurofibromatosis type 1 (NF1) and Duchenne muscular dystrophy (DMD); wherein a translocation involving chromosome 17 and the X chromosome, respectively,⁵,⁶ were identified among affected individuals and their carrier mothers. (Incidentally, a valuable clinical clue was a history of recurrent miscarriages in these women.) The localization of the DMD gene was also facilitated by the recognition of an affected male with a small cytogenetically visible deletion incorporating Xp21.⁷ Today, the challenge does not appear to lie with sequencing long stretches of DNA,⁸ but with the interpretation of the clinical significance of the findings, especially if not previously described.

Historically, structural or numerical chromosomal defects such as Down syndrome (trisomy 21) and deletions and duplications were recognized in the era of karyotyping (i.e., examination of the number and structure of chromosomes in cells). Subsequently, it was recognized that single-nucleotide mutations or deletions of a gene or portions thereof could cause genetic disorders. The discovery of other types of molecular events, such as dynamic mutations resulting from trinucleotide repeat iterations,⁹ gene copy number variants,¹⁰ and other aberrations has helped to explain the basis of certain conditions wherein the search for traditional gene defects had proved elusive. (Incidentally, in this introductory chapter, the term mutation will be used when referring to a change associated with clinical significance, although the current preferred phrase is pathologic variant.¹¹)

Moreover, we have moved from basic Mendelian inheritance as a sole explanation for genetic disorders, to recognition of conditions associated with complex transmission (viewed as non-Mendelian traits), and which can implicate epigenetic factors in the evolution of the phenotype.¹² (Note: epigenetics relates to control of gene expression and function and mechanisms relevant to gene-gene and/or environmental interactions.¹³)

Apart from defects of nuclear genes, several syndromes have also been linked to mutations in mitochondrial genes associated with matrilineal transmission (i.e., through maternally-inherited mitochondrial DNA, mtDNA).¹⁴ MtDNA disorders often result in abnormal oxidative/energy metabolism and may manifest at the cellular level when the threshold of pathological mtDNA is breached, and cellular respiratory function is impaired. Note that mitochondrial dysfunction can result from defects of nuclear genes whose encoded proteins are localized and functional within the mitochondria; such cases would segregate in a Mendelian or autosomal pattern of segregation. Tissues with high energy demand often manifest dysfunction earlier, which is why individuals with severe mitochondrial disorders often present with an encephalopathy or myopathy phenotype. Genetic counseling can be particularly challenging in these disorders as the maternal level of heteroplasmy (i.e., the proportion of pathological mtDNA and wild-type mtDNA) is not predictive of the clinical phenotype in her offspring, on account of bottlenecks in mitochondrial segregation where the mutated alleles can vary widely between offspring.

Another instructive observation is the description of atypical cases; with features not encountered in most cases who display the most common classic clinical features. In some instances, these have been shown to result not from an expanded phenotype; but a consequence of the co-occurrence of additional mutations in another gene (e.g., digenic inheritance¹⁵), laying on another condition onto the primary diagnosis. (In the past, the term epistasis was used by some to describe some forms of digenic inheritance; but now epistasis is used to describe a broader category of locus-locus interactions in polygenic diseases, including but not limited to interactions of loci identified by genome-wide association studies.¹⁶) This issue is one among many that may confound genetic counseling, including the occurrence of sporadic or new mutations and somatic mosaicism (i.e., mutations that have arisen in a proportion of cells in the zygote postfertilization, rather than transmitted through the egg or sperm).¹⁷

As the molecular bases of disease were identified, it had been hoped this would enable a system of classification that would facilitate the approach to diagnosis and provide insights into disease mechanisms that would explain overlapping phenotypes, which in some cases have been attributed to various gene defects, perhaps through a convergent disease pathway.¹⁸ Although there has been increased understanding of cellular pathology, the mechanistic link between a gene defect and clinical expression for most disorders remains to be more fully elucidated. Importantly, it is expected this knowledge could ultimately allow the development of therapeutic strategies for these most challenging of clinical problems.

In some situations, a direct line can be drawn from implicated gene to disease; although it is evident that genetic contribution to some phenotypes is significant, a causal gene defect can still not be found for several conditions using current techniques. Thus, at present, investigations of disease propensity to establish risk scores are being undertaken in the hope that main genetic contributors to disease may be identified. For instance, there are active programs to search for shared genetic elements among families that show an aggregation of ischemic stroke.¹⁹ Interestingly, several genes that have been identified through these genome-wide association studies (GWAS), which contribute to such disorders as migraine, stroke, and others have proven in individual instances to have an impact, albeit a modest one.

On the other hand, it has become evident that among relatively common problems such as ataxia and epilepsy, a small number of cases can be accounted for by defects involving single genes with a major effect. This recognition indicates that certain diagnoses can harbor or be a reservoir of defective genes wherein genetic testing may allow an etiologic verdict. This, so-called needle in a haystack problem previously represented a major challenge, in an era when affected individuals were approached by targeting single or candidate genes. Not only was this a potentially expensive strategy, but one limited by the number of genes that could be examined at that time. For example, although mutations of the Fragile X gene (FMR1) account for a significant proportion of intellectual disability, defects of over 800 genes causing intellectual disability have been identified.²⁰ Thus, these conditions are now approached with a whole genome sequencing (WGS) strategy, followed by virtual exome reads; that is, limiting initial analyses to a list of relevant genes.²¹ (Exomes are regions of the genome encoding an amino acid sequence of a particular protein. Although they represent only a small proportion of the entire genome, a significant fraction of disease-causing alterations can be found in exomes and its adjoining intron, which in the latter can lead to aberrant splicing events.) This general scheme obviates the need for a hypothesis-driven, locus-based approach. However, it should be noted the yield of gene testing with current technology is not 100%—but ranging from 30% to 70%, depending on the indication.²² Thus, although a positive result can provide a causal diagnosis, a negative result does not necessarily exclude a genetic basis for the patient’s problem. The latter situation should call for genetic counseling regarding residual risk.

When there are associated features suggestive of a particular phenotype, rapid screening for microdeletions or genomic imbalance through chromosomal microarray (CMA)—looking at copy number variants (CNV) across the entire genome—may enable diagnosis within a short period (i.e., a more rapid turnaround time).²³ Model examples include Angelman and Prader-Willi syndrome; both mapped to 15q11.2-q13. Interestingly, studies involving patients with either Angelman or Prader-Willi syndrome have revealed other types of genetic modifications apart from deletion, such as the phenomenon of imprinting (i.e., an epigenetic alteration that causes genes within certain chromosomal regions to be expressed in a parent-of-origin-specific manner).²⁴

Furthermore, it has become evident that genotype (i.e., underlying gene defect) is often not perfectly concordant with phenotype (i.e., the spectrum of clinical manifestations). Thus, knowing the causal gene defect may not necessarily predict prognosis. A classic example is mutations in the X-linked adrenoleukodystrophy (XL-ALD) gene (ABCD1), wherein the same mutation among affected individuals, even within the same family, can lead to variable disease expression (i.e., phenotypic variability).²⁵ On the other hand, certain diseases show close genotype-phenotype relationships, such as mutations in the alpha-l-iduronidase (IDUA) gene where null defects present in homozygosity lead to a severe subtype—Hurler syndrome.²⁶ Knowledge of these genotype-phenotype correlations can be invaluable in clinical practice as routine biochemical testing in the case of lysosomal storage disorders (LSDs) does not enable prediction of disease severity. However, the presence of pathological mutations predicting a severe phenotype would lead the clinician, in the case of Hurler syndrome (mucopolysaccharidosis type IH), to choose hematopoietic stem cell transplantation (HSCT) over enzyme replacement therapy (ERT)—the standard of care for the intermediate (Hurler-Scheie) and attenuated (Scheie) subtypes. Thus, early genetic diagnosis is critical so the intervention can have a significant impact of cognitive function; thus, HSCT ideally should be undertaken in affected children diagnosed below 2 years of age.

Usually deleterious, inactivating defects are often associated with an early age at onset and more severe disease course; while mutations that result in impaired (but with residual) function of the encoding gene product usually leads to an attenuated, albeit not necessarily mild phenotype. Thus, knowledge of the nature of the mutation within a given gene could occasionally be provided during counseling sessions as one explanation for how a condition has manifested in a particular individual. There are several tools for characterizing the potential significance of a gene defect; for example, GeneMatcher is an open and collaborative data-sharing portal for novel disease genes and variants to help with identification of patients.²⁷ Clinicians are encouraged to submit cases to this site, to aid in refining the counseling process.

It has become clear that genetic testing may be an appropriate first-line approach for certain phenotypes, potentially shortening the delay in diagnosis, while also being cost-effective. As an example, one study has estimated that diagnosis could have been accelerated by 6–7 years and diagnostic costs reduced by an average of US$19,100 per family, had next-generation sequencing (NGS) been performed at the onset of symptoms in children with neurodevelopmental disorders.²⁸ Also, when certain mitochondrial defects are being considered, a genetic diagnosis may obviate the need for a muscle biopsy.²⁹

Beyond facilitating diagnosis, another application of genetic advances has come about to promote the understanding of disease, through the generation of animal models. Over time, it became apparent that some models did mimic the human phenotype, while others did not.³⁰ Moreover, it has been challenging to ascertain patterns of human behavioral changes and their corresponding animal correlate. These concerns have prompted investigations preferably designed with the use of large animal models, besides genetically manipulated mice. Such creatures (e.g., affected dogs and sheep) that occur spontaneously remain critical, not only for phenotypic characterization but also in terms of drug delivery studies and in preclinical trials investigating various therapeutic options to establish proof-of-concept.³¹ Furthermore, animal studies—involving both large and small models—also enable identification of the initial molecular and cellular events prior to onset of symptoms, and perhaps point to putative targets for intervention that may enable a more optimal outcome.

The ability to establish human cell lines [i.e., induced pluripotent stem cell (iPSC)] and iPSC-based disease modeling may be a more attractive approach, at least on the cellular level.³² In addition, such cells have provided an opportunity for high-throughput drug discovery. Screening of approved drugs that may be repurposed (or repositioned) to treat rare and common diseases may address a major gap in drug development, as data on drug toxicity profile have already been described.³³

In families with a single case, it had been assumed that the isolated event could be potentially sporadic (i.e., by chance), perhaps an autosomal recessive trait, or as in most instances viewed as an unexplained occurrence. When the patient was an infant or young child, families could not be counseled with confidence regarding recurrence risks or prognosis, except by relying on empiric data (e.g., available for club foot or talipes equinovarus arising from distal arthrogryposis and myelomeningocele).³⁴ Some structural abnormalities may be evident on ultrasonography, but occasionally at a late date into the pregnancy than hoped for. For some conditions, this situation has been changed dramatically by genetic investigations. Unanticipated was the occurrence of de novo mutations, as the basis of certain conditions (e.g., Dravet syndrome resulting from SCNA1 mutations). (Dravet syndrome is characterized by intractable, mainly clonic seizures precipitated by increased body temperature, with onset in the first year of life and subsequent appearance of multiple seizures types.³⁵) Of further interest with respect to this condition is the implication of other genes, accounting for similar encephalopathic features: SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2.³⁶ Identification of causal defect helps establish a conclusive diagnosis and in some instances can inform the choice of therapeutic agent. For example, three drugs (stiripentol, cannabidiol, and fenfluramine) have proven efficacy and safety as adjunctive therapies for treating pharmaco-resistant Dravet syndrome.³⁷ Indeed, elucidation of the genetic basis and neurobiology of epilepsies enables the development of better treatment strategies. Importantly, delineation of genes affecting drug pharmacokinetics and pharmacodynamics is important in understanding the interindividual variability in response to antiepileptic drug treatment.³⁸

The ability to efficiently and precisely read a gene sequence has unveiled a gap in knowledge—the presence of variants of unknown significance, where no functional studies have been undertaken, or no prior similarly affected individual has been identified. With uncertainty, it is important to continue to pursue careful clinical characterization of patients’ symptoms and signs, to add meaningful information toward a potential diagnosis of a genetic condition. Thus, classic neurologic examination of affected individuals remains a fundamental skill to be cultivated, especially for medical trainees learning to navigate the field of genetics in this era of rapid technological advancement.

Traditionally, homing in on a diagnosis relied on delineation of age at disease-onset and its evolution or course (i.e., acute, subacute, or chronic), with localization of the problem to a particular region within the nervous system (e.g., neuromuscular junction in congenital myasthenia³⁹), together with clues from extraneurologic features (e.g., café au lait spots in neurofibromatosis type 1⁴⁰), when present. The selective vulnerability to deleterious processes of certain neuronal populations sets the stage, in relation to phenotype; partly explained by the pattern of gene expression, but not in all instances. For instance, if one takes the case of amyotrophic lateral sclerosis (ALS), it has been noted that certain motor neuron subgroups (e.g., oculomotor, trochlear, and abducens nuclei) are relatively resistant to degeneration, even though pathogenic proteins are typically ubiquitously expressed.⁴¹ Thus, there must be modifiers that influence disease expression, beyond the primary gene defect. For ALS and other neurogenetic disorders, there is much that remains to be discovered, especially in relation to downstream molecular events, linking the initial insult with ultimate clinical expression.

Although genetic testing is increasingly becoming more cost-effective and accessible to patients, other complementary approaches offer the ability to achieve precision diagnosis; whilst investigations that disclose relevant biomarkers could prove to be valuable in monitoring of disease progression and/or measuring therapeutic response. Metabolomics and proteomics are such techniques that for certain diagnosis have led to the discovery of a biomarker useful in screening (e.g., oxysterols to identify cases of Niemann-Pick disease type C, NPC).⁴² Thus, discovery of a gene defect in some ways is just the first step in managing a patient, albeit foundational. Ultimately, it is the subsequent formal characterization of the mechanistic link to disease that will shed light on individualized targeted treatment. Perhaps, an even more valuable achievement would be the discovery of resilience or neuroprotective factors that would prevent the onset or evolution of disease altogether.

Historically, the genetic contribution to a particular condition was ascertained based on epidemiologic studies, such as examining the occurrence of a disorder among monozygotic twins compared with that among dizygotic twins. In some situations, a clear pattern of segregation may be evident. For instance, twin studies in schizophrenia have been central in establishing estimates for heritability and providing evidence for a genetic component in this disorder.⁴³

More recently, the search for genetic risk factors has involved genome wide association studies (GWAS), which has added validity due to large sample sizes. One such GWAS study has attempted to quantify the genetic sharing of 25 brain disorders in 265,218 patients and 784,643 control participants to assess their relationship to 17 phenotypes from 1,191,588 individuals.⁴⁴ Investigators noted that psychiatric disorders shared a common variant risk, whereas neurological disorders appear more distinct from one another and from psychiatric disorders. Significant sharing between disorders and several brain phenotypes, including cognitive measures, was also identified. These observations suggest that multiple genes may be implicated, but mostly associated with a minimal weight, perhaps partly clarifying why strategies aimed at identification of a single major gene defect have eluded several researchers, in particular those with an interest in the genetics of psychiatric disorders.

It has also been appreciated that certain recessive gene defects, which lead to specific phenotypes when present in homozygosity, can be associated with a risk for another entity when occurring as a heterozygous variant (e.g., GBA1 in Gaucher disease and Parkinson disease⁴⁵; TREM2 in Nasu Hakola disease and Alzheimer disease,⁴⁶ and HTRA1 associated with a higher burden of white matter hyperintensities in the general population⁴⁷). Insights drawn from these discoveries are anticipated to clarify some putative disease mechanism(s) that may be potentially treatable with pharmacologic agents.

Collecting detailed family trees (pedigrees) may reveal patterns of segregation, which may be consistent with autosomal dominant or recessive inheritance, or X-linked, or matrilineal transmission indicative of mitochondrial inheritance. Genetic counseling for single gene (monogenic) disorders is relatively straightforward. As noted, mtDNA defects whose expression is influenced by its segregation (homo- or heteroplasmy) and dependent on aerobic requirements of affected tissues are confounding factors when counseling families. Moreover, counseling for diseases attributed to polygenic or multifactorial inheritance can be challenging, although this may eventually be facilitated by research relating to the establishment of propensity risk scores (PRS).⁴⁸

Interpretation of the clinical significance of sequence variants can be labor intensive. Several publicly available databases, such as the Human Gene Mutation Database, ClinVar, Exome Aggregate Consortium, and the Genome Aggregation Database, are aids to assessment of variation in a gene sequence for its potential impact. These tools are used by clinical geneticists and reputable diagnostic laboratories, when providing support to clinicians who have requested testing for their patients. With regard to testing, academically-based diagnostic laboratories that have considerable clinical and technical experience and that often serve as reference laboratories should be the go-to sites for consultation; in particular, those that provide genetic counseling support to their clients, as interpretation of results may be occasionally perplexing for the uninitiated.⁴⁹ Interestingly, some specialists—such as neurologists, internists, and pediatricians—are now seeking dual training, encompassing their primary field of interest and genetics. Therefore, the field and practice of clinical genetics are undergoing a transformation, and it remains to be seen whether this may eventually be a specialty primarily supporting a diagnostic service, with patient management and follow-up directed by their primary care physician or specialist consultant.⁵⁰

A further notable development is the establishment of patient advocacy groups, which have not only been a major resource for affected individuals and their families but also now play a leading role in lobbying for healthcare funding and encouraging major investigations in the field.⁵¹ The latter is true, not only in terms of identifying patients who may be eligible to participate in clinical trials and through surveys that facilitate the characterization of disease expression but also by supporting drug development efforts. An example is the support given by the United MSD Foundation to academic centers that have shown an interest in conducting studies that focus on multiple sulfatase deficiency (MSD), an ultra-rare metabolic disease.⁵²

A major healthcare barrier for patients with rare disease relates to access to high-cost therapies, especially in jurisdictions with constrained healthcare resources. Although scientific evidence from clinical trials serves as the basis for drug approval, the patient voice is having an increased influence on legislation and the acceleration of the drug approval regulatory process.⁵³ An illustrative case is that of eteplirsen (Sarepta Inc., Boston, MA), a 30-mer phosphomorpholidate oligonucleotide treatment for Duchenne muscular dystrophy (DMD), an X-linked disorder, found in approximately 1/3500–1/5000 live male births.⁵⁴ Patient advocacy has resulted in accelerated approval of eteplirsen by the Food and Drug Administration (FDA), marking a landmark shift in FDA policy to consider patient perspectives in the drug approval process.⁵⁴

In certain cases, enigmas remain with respect to the phenomenon of penetrance, pleiotropy, variable expressivity and latency, and factors that may modify the pattern and severity of disease manifestations.⁵⁵ Penetrance refers to the observation that not all individuals who carry a specific gene defect necessarily express the condition; an all or none event—for example: familial dysautonomia, wherein only about 30% of carriers express the condition.⁵⁶ Pleiotropy is the phenomenon whereby a single gene influences two or more distinct phenotypic traits. For instance, mutations in VCP (which encodes the Valosin-Containing Protein) have been associated with three features: inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.⁵⁷ Variable expressivity relates to the range of clinical expressions among individuals who carry an identical mutation, as evident in X-linked ALD.⁵⁸ Latency refers to the late-onset expression of a genetic condition inherited from an affected parent, and thus present at conception, such as the development of inherited forms of early-onset Alzheimer disease.⁵⁹

With the ability to annotate an individual’s whole genome, two relevant issues have come up: (1) the handling of incidental or secondary findings; i.e., test results outside the scope of testing for a particular indication⁶⁰; and (2) how best to address genetic privacy concerns, especially in a time when records are kept electronically.⁶¹ An online public survey (n = 560) that looked at genetic literacy and broad public attitudes toward genetic tests in Singapore revealed: (a) broad public support for the use of genetic tests, (2) an average of almost 50% in genetic literacy, and (3) privacy concerns over data sharing and a desire for control over their genetic data.⁶² A separate data collection also was conducted, involving undergraduate students (n = 25) who underwent a genetic screen as part of a university class. In this group, the survey was undertaken before and after they received their test results. After taking a genetic test and receiving genetic test results, students reported less fear of genetic tests, while other attitudes did not change significantly.⁶² Also, a significantly higher proportion of participants discussed their test results with their families after receiving the results (80%) rather than before (52%). It is likely other groups may not share these positions or react differently; thus, attention should be paid to individual circumstances, cultural factors and other potential sensitivities around genetic testing.

On the therapeutic front, several challenges remain; most neurological disorders remain out of reach because of the complexity of neurological pathways and implicated structures, the lack of redundancy of postmitotic neuronal cells, as well as the presence of the blood-brain barrier that limits access of certain enzymes or drugs. However, it is clear we have moved from darkness to light, from nihilism to the promise of interventions that are genuinely transformative and can lead to a major impact on health and well-being. A great example is the success achieved with AAV9 vector delivery of the SMN gene sequence (as an RNA-targeted therapeutic), in dealing with infantile spinal muscular atrophy (SMA).⁶³ The ability to potentially correct defective genes by an editing process (through Crispr/Cas applications) introduces an altogether alternative strategy; by permanently silencing or correcting the disease-causing mutations, it may overcome key limitations of RNA-targeting approaches.⁶⁴ Meanwhile, a new therapeutic target class has emerged: long, noncoding RNAs (lncRNAs), which can be modulated using advanced oligonucleotide-based compounds that are often target-specific; with the potential of reducing off-target—possibly adverse—effects seen with chemical agents.⁶⁵ Moreover, oligonucleotides can be synthesized in a controlled chemical process; as opposed to the intricacy of large-scale production of biologics (e.g., recombinant enzymes). With several therapeutic opportunities, one can be genuinely optimistic about the future.

Clinical practice, not just among neurologists, is being transformed by genomic medicine; with a model of care (the 4Ps of precision medicine) aimed at being predictive, personalized (or individualized), preventive (which would be ideal), and participatory (i.e., engaging the patient in decisions made and delivering care tailored according to patient’s expectations or goals).⁶⁶ Although clinical geneticists may be seen primarily as assisting other specialities rather than as primary care providers, they can provide support in the management of affected individuals and their families through various ways, including the education of healthcare providers and patients regarding the interpretation of test results and delineating the significance of the findings in relation to potential risks for relatives. In the examination of complex patients, geneticists may also be able to help with integrating the various signs and symptoms toward a unifying diagnosis. For instance, an ophthalmologist may be referred a patient with visual problems found to be consistent with retinitis pigmentosa. As it happens, the patient may also have intellectual disability and obesity. Together with other findings such as renal anomalies, the clinical geneticist may suggest consideration of a syndrome diagnosis, possibly Bardet-Biedl syndrome (BBS). Interestingly, BBS is associated with extensive genetic heterogeneity, with at least 19 different genes implicated as contributing to disease expression.⁶⁷ It is an autosomal recessive trait, so there is a risk of recurrence in subsequent pregnancies. In this situation, aunts and uncles of a patient may want to know of their risk of having a similarly affected child, while the parents of an affected patient will want to know prognosis, management, and life expectancy. Providing counseling and support is what clinical geneticists and genetic counselors are trained for; thus, they should be viewed as genuine partners in health care. On the other hand, conditions that are clear-cut and relatively common (e.g., neurofibromatosis, Marfan syndrome) will likely be managed directly by the relevant subspecialist with some assistance from a geneticist, perhaps one with molecular subspecialty training and working with a diagnostic laboratory. In the latter setting, the geneticist may help laboratory scientist by directing their focus onto particular candidate gene, or contextualizing the results, based on information regarding the phenotype and family history.⁶⁸ Increasingly, artificial intelligence and machine-learning techniques are being employed to assist with understanding of disease processes.⁶⁹,⁷⁰

In an ideal world, genetic knowledge—as one piece of the puzzle—would be combined with intelligence gained from exploration of the patient’s milieu and other factors that influence disease expression. As targeted treatments are identified and incorporated into patient care, then the best outcomes could be achieved when the right patient is identified and disease-specific therapy provided in a timely fashion. In some cases, comprehensive care may necessitate adjunctive measures, such as physical and occupational therapy. There are also several patient advocacy and support groups that hold regular meetings, provide updates to its members and various resources to aid similarly affected individuals. Increasingly, patient advocacy groups are becoming actively involved in shaping research agendas and assist with study design and patient recruitment.⁷¹ By engaging multiple stakeholders in a collaborative research model, one can anticipate a greater chance of a successful outcome.

Neurogenetics: A brief historical perspective

N.B. The following is a brief account and a selective point of view, covering topics that are of memorable interest. It is not intended to be a comprehensive coverage of the field’s evolution.

The 19th century was a period during which several neurologic disorders were described and recognized as inherited traits. At this stage, the clinical manifestations noted among affected individuals were delineated, and their pattern of segregation described, way before knowledge of the underlying cause. In recognition of the contributions of key figures, diseases were given eponymous designations. An article from 1960 notes over 450 neurological eponyms.⁷² In some cases, the names of characters were drawn from the literature and mythical or biblical heroes.⁷³ As an example, Strümpell-Lorrain syndrome is a designation for hereditary spastic paraplegia (HSP), now recognized to be a heterogeneous group of neurodegenerative disorders presenting with spasticity and weakness of the lower extremities. Adolf von Strümpell (1853–1925) recognized its hereditary nature (1880), while Maurice Lorrain (1867–1956) described 29 affected families in his doctoral thesis (1898).⁷⁴

Through the years, discussions have been held regarding the appropriateness of using eponyms. For instance, Hallervorden-Spatz syndrome has been replaced by the term Neurodegeneration with Brain Iron Accumulation (NBIA). Julius Hallervorden (1882–1965) and Hugo Spatz (1888–1969) had been accused of roles in mercy killings associated with Nazi activities during World War II, which has prompted recommendations that their names be disassociated with the condition.⁷⁵

Early characterization of clinical presentations and disease course also was complemented by anatomic studies. For HSP, neuropathological investigations revealed axonal degeneration involving the lateral corticospinal tracts in both the cervical and thoracic spinal cord.⁷⁶ More recently, molecular investigations have shown HSP to be caused by over 60 distinct gene defects.⁷⁷ These discoveries have enabled elaboration of disease mechanisms, implicating a range of problems—from perturbations of axon transport to mitochondrial dysfunction.⁷⁸ It has been suggested that a functional convergence of deleterious events partly explains the overlap in phenotype. It is hoped that this knowledge would lead to development of targeted therapies.

Meanwhile, advances in radiology with the introduction of computerized tomography (CT) and magnetic resonance imaging (MRI) have facilitated diagnosis, and through pattern recognition enabled certain disease classifications. For instance, bilateral hypointensities in the globus pallidus noted on brain MRI among patients with the combination of extrapyramidal and pyramidal features point to NBIA.⁷⁹ Moreover, recent MRI applications (e.g., T2* and T2 fast spin echo brain MRI) have allowed differentiation of various subtypes of NBIA.⁸⁰

Over the last three decades, genetic investigations have played an increasing role. Prior to multiple parallel gene sequencing, linkage analysis was a technique used—in combination with other approaches—to map causal defects. Through this strategy, Huntington disease (HD) was mapped to human chromosome 4p in 1983. Keys to discovery include delineation of the phenotype and recognition of its autosomal dominant transmission; features recognized by George Huntington (1872). Highlights (reviewed by Bates, with citations of seminal papers⁸¹) include the identification of a high incidence of HD in two Venezuelan communities located near Lake Maracaibo. Nancy Wexler, a geneticist, found that the disease in this community likely originated with a single founder, suggesting that all affected individuals would carry the same original mutation. Initially, James F. Gusella and colleagues identified a DNA probe that showed a specific HD-associated restriction fragment length polymorphism (RLFP) pattern among affected individuals. Using human-mouse somatic cell hybrid lines, the probes were assigned to human chromosome 4. Various individuals came together to form the Huntington Disease Collaborative Research Group (HDCRG) and after 10 years of investigations, identified a gene sequence (IT15), which contained a repeated DNA element consisting of three nucleotides, CAG, repeated 21 times near the beginning of the gene. When evaluating unaffected cases, the group found that the number of CAG repeats varied from 6 to 35; while those with HD had 40 or more CAG repeats, which they ascribed to a phenomenon—instability of the trinucleotide repeat.⁸² Thomas Bird, a geneticist who had an interest in HD, is credited with establishing the first adult neurogenetics clinic in the United States.⁸³

Currently, there are more than 40 diseases that primarily affect the nervous system, caused by expansions of simple sequence repeats, including not only trinucleotide repeats but also tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions.⁸² In addition to HD, the list includes some of the most common genetic disorders seen by neurologists, including myotonic dystrophy (DM1 and DM2), Friedreich ataxia, and Fragile X syndrome.

Today, several neurogenetics unit have been set up worldwide. The experience of one country, Peru, has been well described; as a fully integrated service, encompassing clinical assessment and diagnosis, molecular genetic testing by international standards for accreditation, genetic counseling, and follow-up consultations.⁸⁴

Incidentally, just as interesting is the account of developments in pediatrics, and the specialty of medical genetics in particular.⁸⁵ With regard to the interplay between genetics and pediatric neurology, one would profit from reading the paper by Walter E Kaufmann.⁸⁶

In the genomic era, the discovery of the underlying defects that cause certain conditions has led to enhanced knowledge of pathogenesis, although much remains to be clarified. Take Friedreich Ataxia (FA), an autosomal recessive disease, characterized by progressive ataxia, absent deep tendon reflexes, and dysarthria.⁸⁷ Initial attempts to find specific biochemical abnormalities proved futile. Subsequent genetic studies revealed the pathogenic mutation in FA is a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 that causes a transcriptional defect of the frataxin gene.⁸⁸ Although frataxin has been identified as a mitochondrial protein, the pathogenesis of FA remains unclear as the cognate protein has multiple functions, including biogenesis of iron-sulfur clusters, iron chaperoning, iron storage, and control of iron-mediated oxidative tissue damage.⁸⁸

Among others, lessons learned thus far: Several neurogenetic disorders present a spectrum of features, delineated by age at onset, pattern of expression and rate of disease progression. An instructive example is neuronal ceroid lipofuscinoses (NCL), a group of neurodegenerative conditions associated with cognitive decline, progressive cerebellar atrophy, retinopathy, and myoclonic epilepsy.⁸⁹ Prior to the identification of causal gene defects, age at presentation led to a classification scheme: as congenital, infantile, late infantile, juvenile, and adult variants. All subtypes are morphologically characterized by loss of nerve cells, particularly in the cerebral and cerebellar cortices, and the cerebral and extracerebral formation of lipopigments that show distinct ultrastructural patterns (i.e., granular, curvilinear/rectilinear and fingerprint profiles).⁹⁰

The NCLs can be transmitted as an autosomal dominant or recessive trait, with defects in at least 13 distinct genes identified; the majority encode either a soluble or transmembrane protein localized to the endoplasmic reticulum or the endosomal/lysosomal organelles.⁹¹ Of interest is the current reliance on bioinformatics in combination with proteomic information to identify novel causes of NCL.⁹² In this regard, mass spectroscopy helps to identify or validate disease-causing mutations.⁹³ There is much that needs to be understood in terms of pathophysiology, so targeted therapies can be designed accordingly. Meanwhile, therapy has become available for one subtype (NCL type 2) by mean of intracerebroventricular administration of the recombinant enzyme (cerliponase alfa) to correct the deficiency of tripeptidyl peptidase 1.⁹⁴

Current outlook and future prospects

Parallel developments in relation to two aspects are a keen focus of investigations: (1) elucidation of pathophysiology and (2) development of therapeutic options.

It is evident that identification of the underlying gene defect, though it may lead to recognition of the initial insult to cells, is not sufficient. Studies have shown that the interruption of the gene product’s formation and function triggers a cascade of downstream events that ultimately lead to the varieties of clinical expression encountered in distinct neurogenetic disorders. Much has been learned from studies involving animal models of disease, as certain changes can be found before the onset of disease. The phenomenon of latency, as seen in delayed adult onset of inherited gene defects, remains incompletely understood. Meanwhile, certain observations have helped to partly explain the basis for vulnerability of certain neuronal populations, and also mechanisms of disease that may represent potential targets for therapeutic intervention.

Focusing on neurodegenerative diseases, it has been noted that the pathology associated with particular conditions only affects particular neurons (selective neuronal vulnerability⁹⁵); e.g., substantia nigra in Parkinson disease; pyramidal neurons in layer II of the entorhinal cortex in Alzheimer disease. With time, the pathology worsens and more regions are implicated in a stereotypical and predictable fashion. Pathology-mapping studies have suggested disease-specific proteins accumulate in regions of primary vulnerability, then spread to other areas of secondary vulnerability along anatomical connections.⁹⁶,⁹⁷

Delineation of shared molecular pathways has enabled the grouping of some diseases. A classic example is represented by the RASopathies; a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK (Ras/mitogen-activated protein kinase) pathway.⁹⁸ The RAS/MAPK pathway is a signal transduction cascade that is essentially involved with several cellular processes, such as proliferation, survival, differentiation, and metabolism. The central role of the pathway partly clarifies the multiplicity of conditions that can develop following its disruption; disorders implicated are neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, Costello syndrome, Legius syndrome, central conducting lymphatic anomalies syndrome, SYNGAP1 syndrome, and capillary malformation arteriovenous malformation syndrome (Fig. 1).⁹⁸ Although each syndrome has unique features, many have overlapping clinical characteristics (e.g., short stature, dysmorphic facial features, congenital heart disease, and intellectual disability).

Fig. 1

Fig. 1 RASopathies: protein defects and their associated developmental syndromes. (Source: Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009; 19(3): 230–236. Used with permission from Elsevier.)

Another set of conditions that can be partly grouped together are those associated with defects that incriminate autophagy, an intracellular pathway that mediates the lysosomal degradation of macromolecules and organelles. Disorders of the autophagy pathway include EPG5-associated Vici syndrome, WDR45-associated β-propeller protein-associated neurodegeneration, SNX14-associated autosomal-recessive spinocerebellar ataxia 20, ATG5-associated autosomal-recessive ataxia syndrome, SQSTM1/p62-associated childhood-onset neurodegeneration, and several forms of the hereditary spastic paraplegias (HSPs) (Fig. 2).⁹⁹ These conditions mostly are progressive and eventually involve pathology extending to multiple brain regions. As with the RASopathies, there are diagnosis-specific manifestations (e.g., storage disease in some subtypes), but also overlap in phenotype (e.g., intellectual disability, epilepsy).

Fig. 2

Fig. 2 Neurodegenerative diseases associated with defects in autophagy: conditions and their implicated protein defects. (Source: Zatyka M, Sarkar S, Barrett T. Autophagy in rare (non-lysosomal) neurodevelopmental diseases. J Mol Biol. 2020;432(8):2735–2753. Open Access with a CCYB license.)

Moving on to the therapeutic front, several approaches are under consideration. With regard to congenital disorders of autophagy, the modulation of autophagy is viewed as a promising strategy for the management of multiple human disorders, beyond those arising from single gene defects, as noted above.¹⁰⁰

There exist therapeutic options for several conditions, and these are covered in the relevant chapters. In the current era, it is clear that we have moved from nihilism to the possibility not only of treatment but of prevention as well.

Genes (and their products): Recent observations of interest

Gene size matters¹,¹⁰¹: there is a strong positive correlation between gene length, transcript length, and protein size. Among tissue-specific genes, the longest transcripts tend to be expressed in nerves and the brain. Bigger transcripts are often associated with neuronal development. Moreover, genes with longer transcripts tend to have a higher number of coexpressed genes and protein-protein interactions.

Repeat expansion disorders (Fig. 3): Affect about 1 in 3000 individuals; this is a clinically heterogeneous group, encompassing at least 40 conditions.¹⁰² Evaluation of 404 National Health Service (NHS, United Kingdom) patients presenting with neurologic problems revealed that whole genome sequencing (WGS) for the detection of repeat expansions had a high sensitivity (97.3%) and specificity (99.6%); correctly classifying 215/221 expanded alleles and 1316/1321 nonexpanded alleles, across 13 disease-associated loci (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP).¹⁰³ Using samples from 11,631 patients enrolled in the 100,000 UK Genomes Project (recruited in 2013–17), WGS identified 81 repeat expansions: 68 (full pathogenic range), 11 (nonpathogenic intermediate expansions or premutations), and two nonexpanded repeats (16% false discovery rate).¹⁰³

Fig. 3

Fig. 3 Repeat mutations and resultant disease. Their position within the relevant genes is shown on the schematic; e.g., intronic, exonic, etc.

Genetic modifiers: The search for factors that influence disease expression remains a focus of great interest, as such knowledge may lead to identification of the basis for neuronal toxicity and putative targets for intervention. Investigations undertaken in patients with Huntington disease (HD), which involved GWAS, has led to the identification of six DNA maintenance gene loci (among others) as modifiers, implicated in a two-step mechanism of pathogenesis: somatic instability of the causative HTT CAG repeat followed by the triggering of neuronal damage.¹⁰⁴ Combined with imputation using the Trans-Omics for Precision Medicine reference panel, genetic differences at HD modifier loci were revealed to have differential impact on phenotypes preferentially related to motor or cognitive manifestations.¹⁰⁴ The later observations suggest that not all HD modifier alleles impact equally the neuronal networks contributing to these phenotypes.

Human brain transcriptomics¹⁰⁵: analysis of polyadenylated messenger RNA and long noncoding RNA indicated that approximately 3% (n = 571) of all protein-coding genes and 13% (n = 87) of the long noncoding genes expressed in the human brain are enriched; by at least five times higher, when compared with the other analyzed peripheral tissues. Majority of the brain-enriched protein-coding genes identified were expressed in astrocytes, oligodendrocytes, or in neurons with molecular properties linked to synaptic transmission and brain development. Progress and new findings based on the analysis of brain transcriptional activity were underscored in a recent editorial in Genes (Basel).¹⁰⁶

Fig. 4 illustrates the structure of a typical gene and its immediate environ, with resultant mRNA.

Fig. 4

Fig. 4 Schematic: a typical gene and its immediate landscape, with resultant mRNA.* Legends/definition: 5′ cap —involved in ribosomal recognition of mRNA during translation into protein. CAAT/TATA box —noncoding consensus sequence, which signals the binding site for RNA transcription factors. Chromosome (not shown) —a threadlike structure of nucleic acids (paired across: adenosine-thymine; cytosine-guanine) and proteins (histones) found in the nucleus of cells. CpG island —a cytosine and guanine linked by a phosphate which represents a genetic hotspot for active methylation; involved with tissue-specific expression of a gene. Enhancer —region of DNA that can be bound by activators to increase the likelihood of gene transcription. Gene —basic unit of inheritance, encompassing both coding (exon) and noncoding (intron) sequences. Histone (not shown) —a protein that provides structural support for a chromosome. Methyl group —involved with directly turning genes on or off (via methylation of the cytosine ring) and affecting interactions between the DNA and relevant proteins. A second kind of epigenetic mark called histone modification affects DNA indirectly; through control of chromatic structure and gene transcription. Poly A tail —stabilizes mRNA and enabling its export from the nucleus. Promoter —an upstream region of DNA where proteins (such as RNA polymerase and transcription factors) bind to initiate transcription of that gene. Repressor —a DNA-binding protein that inhibits the expression of a gene by binding to a silencer; achieved by blocking the attachment of RNA polymerase to the promoter, thus preventing transcription of the gene into messenger RNA (mRNA). Silencer —a DNA sequence capable of binding transcription regulation factors (repressors) that prevent DNA transcription. Splice site —define exon-intron boundaries, an almost invariant sequence: donor —GT at 5′ end of intron; acceptor —AG at 3′ end; mutations in this region can lead to skipping of an exon, a shift in reading frame or premature termination of translation. Transcription —the process of making an RNA copy (i.e., mRNA) of a gene’s DNA sequence. Transcription factor (Tf) binding site —region of DNA with the promoter or enhancer section of a gene involved with regulation of its expression. UTR-untranslated region —section with a role in regulating the stability, function, and localization of mRNA.

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