Introduction to Neurogenetics

Introduction

Neurogenetics has evolved considerably over the last 25 years. Advancements in human genome sequencing have led to the identification of mutations that cause neurologic disease and to fundamentally new insights into disease pathophysiology. These advances, along with technological breakthroughs in gene therapy, have already translated genetic insight into disease treatments for previously incurable diseases, a process that will continue to accelerate. Given the increasing role genetic diagnosis and treatment are playing in neurological care, we aim to summarize basic genetic concepts and provide a framework for approaching both rare and common neurogenetic diseases.

Basic Concepts

The human genome is composed of over 3 billion DNA nucleotides organized into 23 pairs of chromosomes. Genes are sequences of DNA that are transcribed into RNA and translated into proteins. Although all cells contain the same DNA, gene expression is customized to the specific cell type and physiological stimulus. These complex gene expression patterns are controlled by gene enhancers, which are short, noncoding regions of DNA that recruit transcription factors required for gene activation of nearby protein-coding genes.

Humans inherit two copies of each gene, one from each parent. Rare genetic diseases often follow Mendelian inheritance patterns, in which the disease is the direct result of a single-gene mutation. Diseases that follow an autosomal dominant inheritance pattern require only one mutant allele and typically affect every generation of a family (e.g., neurofibromatosis, Huntington disease, and myotonic dystrophy). Autosomal recessive diseases require the inheritance of two mutant alleles, which often results in asymptomatic or mildly symptomatic carriers (e.g., Friedrich ataxia, Tay-Sachs disease). X-linked diseases are more commonly observed in males because they only have a single X chromosome, while females can be asymptomatic or mildly symptomatic carriers (e.g., Duchenne and Becker muscular dystrophy). Spontaneous mutations are not inherited but occur during development because of DNA replication errors. Somatic and germline mosaicism can occur when mutations occur in later stages of development, such that only certain cell lineages are affected by the mutation, while other cell and tissue types remain normal. Mosaicism may result in diverse phenotypes depending on where in the developmental process the mutation occurs. Mosaicism can also be observed in heterozygous females with X-linked mutations because X-inactivation randomly silences either the wild-type or mutant X chromosomes in each cell. Rare and phenotypically severe neurologic diseases can also be caused by mutations in the maternally inherited mitochondrial DNA.

The phenotypic severity of a genetic mutation depends on how the DNA sequence is altered. Point mutations occur when a single nucleotide is changed and can result in silent, missense, or nonsense mutations. Silent mutations, which are asymptomatic, do not affect the encoded protein because the mutated DNA sequence still codes for the wild-type amino acid. Missense mutations change a specific amino acid within a protein, and the phenotypic severity of this largely depends on how the amino acid change alters the protein’s function. A nonsense mutation results in a stop codon that terminates the translation of messenger RNA into protein. The severity of nonsense mutations depends on where in the protein the stop codon occurs, but they often result in severely truncated proteins. If more than a single nucleotide is mutated (e.g., insertions or deletions), a frameshift mutation can occur that disrupts the entire reading frame of the gene and usually results in severely dysfunctional protein. Several neurologic diseases, such as Huntington disease, are also caused by repeat expansions. Trinucleotide repeats often increase with each generation and are thought to result in progressively toxic RNA or protein products that correlate with disease severity. Lastly, noncoding DNA mutations may be significant if they prevent a transcription factor from binding to a gene regulatory element (gene promotor or enhancer) that is needed to activate the expression of a nearby gene. Distal enhancers can be at great distances from their target genes and form long chromatin loops to make contact with and regulate their expression.

The majority of common neurologic diseases are polygenic, caused by the summation of small effects from mutations in many genomic loci (e.g., Alzheimer disease, Parkinson disease, migraine). Genome-wide association studies (GWASs) have revolutionized the study of polygenic diseases. GWAS may identify genetic variation that is statistically more common in the disease of interest. Because multiple statistical comparisons are needed to study every genomic locus, large numbers of cases and controls are required to sufficiently power these studies. Initial GWASs were met with criticism because of insufficient sample sizes to detect susceptibility loci, but the ongoing development of collaborative international consortia has led to more recent high-quality studies.

Rare Genetic Diseases

Advances in DNA sequencing have resulted in the identification of numerous rare single-gene mutations in a wide spectrum of neurological diseases. Although these diseases are rare and may not be encountered in the primary care setting, collectively, they are not uncommon. Given recent improvements in gene therapy, it is important to recognize and refer these patients to specialists. The tables at the end of the manuscript serve as a reference and contain a detailed listing of rare monogenic neurologic diseases, organized by cellular function affected (see Tables 3.1–3.5 ). Below, we will review the key cellular processes that are disrupted in neurogenetic disorders to provide a framework for understanding their pathophysiology and clinical presentation.

Table 3.1

Major Neurometabolic Diseases With Causative Genes, Pathophysiology, and Phenotypic Features

Type	Disease	Genetics			Pathophysiology	Phenotypic Features
Type	Disease	Gene(s)	Location	Inherit	Pathophysiology	Phenotypic Features
Mitochondrial	MELAS	MTTL1	Mit.	M	Dysfunctional tRNA results in improper translation.	Seizures, ataxia, ischemic events, short stature, hearing loss, exercise intolerance, migraine.
	MERFF	MTTK	Mit.	M	Dysfunctional tRNA results in improper translation.	Seizures, ataxia, myoclonus, weakness, ptosis (may overlap with MELAS).
	LHON	MTND4 MTND1 MTND6	Mit.	M	Malfunctioning proteins involved in oxidative phosphorylation.	Subacute loss of central vision. 50%–85% of people with the mutation are asymptomatic.
Lysosomal	Gaucher disease (types 2 and 3)	GBA	1q22	AR	Glucocerebroside toxicity within cells secondary to abnormal β-glucocerebrosidase.	Type 2 may include brainstem dysfunction, apnea, hepatosplenomegaly, anemia, failure to thrive, thrombocytopenia, high mortality rate < age 2.
	Niemann-Pick disease	SMPD1	11p15.4	AR	Sphingomyelin excess due to abnormal sphingomyelinase.	Hepatosplenomegaly, cherry-red spot, and profound psychomotor regression; rare survival after age 2. Type B: without CNS involvement.
		NPC1	18q11.2	AR	Lipid accumulation due to dysfunctional lipid movement within cells.	Ataxia, supranuclear gaze palsy, dystonia, hepatosplenomegaly, interstitial lung disease.
		NPC2	14q24.3	AR
	Fabry disease	GLA	Xq22.1	XR	Glycosphingolipid excess in lysosomes due to α-galactosidase deficiency.	Classic: paresthesias, pain crises, GI manifestation, angiokeratoma, hypohidrosis, corneal/lenticular opacities, early death from renal or vascular Later onset: no vascular endothelial involvement, but develop cardiac and renal disease in maturity.
Metal metabolism disorders	Wilson disease	ATP7B	13q14.3	AR	Excess copper accumulation secondary to dysfunctional copper transporter ATPase 2.	Cirrhosis and neuropsychiatric symptoms (tremors, gait difficulty, mood disturbance), Kayser-Fleischer ring.
	Menkes disease	ATP7A	Xq21.1	XR	Maldistribution of copper (deficiency) in mitochondria, collagen, vascular tissue, and neuronal degeneration.	Presentation in neonate with hypothermia, feeding difficulties, seizures, palor, and kinky hair.
	PKAN	PANK2	20p13	AR	Lack of functional pantothenate kinase 2 disrupts the production of coenzyme A and results in iron deposition in the basal ganglia.	Neurodegeneration with brain iron accumulation, childhood-onset dystonia and pigmentary retinopathy, dementia, parkinsonism, and neuropsychiatric features.
Vitamin disorders	Holocarboxylase synthetase deficiency	HLCS	21q22.13	AR	Accumulation of abnormal urea cycle metabolites secondary to inability to utilize biotin.	Severe metabolic acidosis, feeding and breathing difficulties, hypotonia, lethargy in neonatal period.
Vitamin disorders	Pyridoxine-dependent epilepsy	ALDH7A1	5q23.2	AR	Accumulation of pyridoxine (B6).	Encephalopathy and seizures, intractable to antiepileptic drugs, treated with pyridoxine supplementation.
Lipid metabolism	Cerebrotendinous xanthomatosis	CYP27A1	2q35	AR	Lipid accumulation in brain parenchyma and myelin results in its destruction.	Defective bile acid synthesis—tendon/tuberous xanthomas, juvenile cataracts, nervous system dysfunction (epilepsy, movement disorders, peripheral neuropathy, dementia).
Urea cycle	Carbamoyl phosphate synthetase I deficiency	CPS1	2q35	AR	The enzyme is responsible for catalyzing entry of ammonia into the urea cycle.	Neonatal presentation starts secondary to hyperammonemia and includes poor feeding, vomiting, lethargy, seizures, coma, tachypnea, cerebral edema, and death if untreated. Treatments are sodium phenylacetate/benzoate and arginine. Partial deficiencies may present in adulthood in the setting of stress (e.g., surgery) and may present as encephalopathy, behavioral and psychiatric disorders, vomiting, alterations in consciousness.
	Ornithine transcarbamylase deficiency	OTC	Xp11.4	XR	The enzyme catalyzes production of citrulline from ornithine and carbamylphosphate in the liver and small intestine.
	Argininosuccinate synthase deficiency	ASS1	9q34.11	AR	The enzyme catalyzes conversion of citrulline and aspartate to arginosuccinic acid.
	Argininosuccinate lyase deficiency	ASL	7q11.21	AR	Catalyzes conversion of arginosuccinate to arginine and fumarate.
	Arginase deficiency	ARG1	6q23.2	AR	Catalyzes conversion of l -arginine into l -ornithine and urea.
	HHH	SLC25A15	13q14.11	AR	Ornithine translocase is a mitochondrial transporter.

AR , Autosomal recessive; CNS , central nervous system; GI , gastrointestinal; HHH , hyperornthinemia-hyperammonemia-homocitrullinuria; LHON , Leber hereditary optic neuropathy; mit. , mitochondria; M , maternal; MELAS , mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF , myoclonus epilepsy and ragged-red fibers; PKAN : pantothenate kinase–associated neurodegeneration; tRNA , transfer RNA; XR , X-linked recessive.

Table 3.2

Genetic Channelopathies With Principal Causative Genes and Key Phenotypic Features

Channel Affected	Disorder	Gene	Loc.	Inherit	Key Phenotypic Features
Sodium	Simple febrile seizures (part of GEFS+ syndrome)	SCN1A	2q24.3	AD	Seizures associated with fever in childhood. There is an overall benign course, although the risk of future epilepsy syndromes is increased.
	Dravet syndrome (or SMEI—severe myoclonic epilepsy of infancy) (part of GEFS+ syndrome)	SCN1A (in 80% of cases)	2q24.3	AD	Infantile-onset encephalopathy with epilepsy (tonic, tonic-clonic, or clonic seizures), typically presenting in the context of fever, continues to involve multiple seizure types and significant cognitive dysfunction. May have normal development in the first year of life, followed by regression.
	FHM3	SCN1A	2q24.3	AD	Attacks of migraine with fully reversible motor weakness and visual, sensory, or language problems.
Potassium	KCNQ2-related disorders (BFNE; NEE)	KCNQ2	20q13.33	AD	These are a continuum of disorders. BFNE—seizures starting within the first week of birth, normal interictal periods, and spontaneously disappearing by 1 year of age. NEE—In addition, patients have encephalopathy from birth and persist after seizures end (age 1–4 years) with moderate-severe developmental impairment.
Potassium	Episodic ataxia, type 1	KCNA1	12pq13.32	AD	Brief episodes of ataxia (minutes), provoked by exercise, with facial and hand myokymia. Treated with phenytoin.
Calcium	FHM 1	CACNA1A	19p13.3	AD	Attacks of migraine with hemiplegia that may be accompanied by vertigo or mild ataxia.
Calcium	Episodic ataxia, type 2	CACNA1A	19p13.3	AD	Episodes of ataxia for days and vertigo provoked by stress. Treated with acetazolamide.
AChR	AD familial nocturnal frontal lobe epilepsy	CHRNA4 , CHRNB2	20q13.33 1q21.3	AD	Nocturnal seizures during NREM sleep with tonic, clonic, and hyperkinetic movements, normal cognition, and development. Ictal EEG with bifrontal spike wave discharges.
GABA	Juvenile myoclonic epilepsy	GABRA1	5q34	AD	Myoclonic seizures, usually in the morning on awakening. Presentation starts in adolescence. Comorbid with absence seizures and generalized tonic-clonic seizures. EEG with 4–6 Hz polyspike wave complexes.
GABA	Childhood absence epilepsy	GABRG2, GABRA1, GABRB3	5q34 5q34 15q12	AD	Multiple daily absence seizures in developmentally normal children 4–10 years old; 3-Hz spike and wave pattern.

aSpinocerebellar ataxia 6 (SCA6) is also a notable channelopathy affecting P/Q type calcium channels; however, in this review, it has been classified along with the other SCAs as a repeat expansion disorder (see Table 3.4 ).

GEFS+ is a spectrum of seizure disorders that may be associated with fevers (simple febrile seizures are considered the mildest form, and Dravet syndrome is the most severe form). AChR , Acetylcholine receptor; AD , Alzheimer disease; BFNE , benign familial neonatal epilepsy; EEG , electroencephalogram; EIEE , early infantile epileptic encephalopathy; FHM3 , familial hemiplegic migraine type 3; GABA , gamma aminobutyric acid; GEFS+ , generalized epilepsy with febrile seizures plus; NEE , neonatal epileptic encephalopathy; NREM , non–rapid eye movement.

Table 3.3

Disorders of Gene Regulation With Major Causative Genes, Pathophysiology, and Phenotypic Features

Disease	Genetics			Pathophysiology	Phenotypic Features
Disease	Gene(s)	Location	Inherit	Pathophysiology	Phenotypic Features
Facioscapulohumeral muscular dystrophy—type 2	SMCHD1 DUX4	18p11.32 4q35.2	Digenic ^a	SMCHD1 protein affects DNA methylation in the D4Z4 region—preventing the normal silencing of the DUX4 gene.	Progressive muscle weakness and atrophy starting in face, scapula, and upper arms starting in adolescence may progress to lower extremity weakness and hearing loss.
Angelman syndrome ^b	UBE3A	15q11.2	Sporadic	Altered ubiquitin protein ligase results in altered proteostasis (rate of protein synthesis and degradation) at synapses.	Developmental delay, ataxia, epilepsy, microcephaly, happy demeanor, frequent smiling, laughter and hand-flapping movements, hyperactivity, coarse facial features, fair skin, light-colored hair, scoliosis.
Rett syndrome	MECP2	Xq28	XD	MeCP2 protein has various roles in transcription regulation.	Primarily in girls. Classic phenotype involves regression of normal development 6–18 months, with progressive dementia, motor loss, and stereotypies.
Rubinstein-Taybi syndrome	CREBBP	16p13.3	AD	CREB-binding protein important in gene regulation in many tissues (cell growth, division, and normal fetal development).	Short stature, moderate to severe intellectual disability, distinctive facial features, broad thumbs, increased risk of malignancies.
X-linked intellectual disability, Siderius type	PHF8	XP11.22	XR	Altered PHF8 protein (part of zinc finger proteins) is not able to bind chromatin, affecting chromatin remodeling, altering normal gene expression.	Only males are affected. Intellectual disability, cleft lip/palate, and developmental delay may have characteristic facial features (long face, sloping forehead, broad nasal bridge, prominent supraorbital ridge, upslanting palpebral fissures).
Early infantile epileptic encephalopathy 1	ARX	Xp21.3–XP22.1	XR	Altered transcriptional factor that is part of homeobox genes that act during early embryonic development to control cell differentiation.	Infantile spasms, developmental delay, and EEG with hypsarrhythmia pattern. Cases may evolve to LGS.