Neurogenetics is a broad and important topic for the neurology board, RITE, and shelf exams. Genetics of various disorders will be covered in other topic chapters in more depth. In this chapter, we will discuss the fundamentals of genetics, and touch upon the genetic inheritance patterns and disorders that are the most frequently tested. It is important to understand genetics concepts and inheritance patterns, as well as memorize some key chromosomes and genes, which we have included both in this chapter and in the chapter flashcards.

Author: Steven Gangloff, MD

Neurogenetics is a broad and important topic for the neurology board, RITE, and shelf exams. Genetics of various disorders will be covered in other topic chapters in more depth. In this chapter, we will discuss the fundamentals of genetics, and touch upon the genetic inheritance patterns and disorders that are the most frequently tested. It is important to understand genetics concepts and inheritance patterns, as well as memorize some key chromosomes and genes, which we have included both in this chapter and in the chapter flashcards.

Author: Steven Gangloff, MD

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Table of Contents

Definitions

Genotype

  • The markup of a set of two genes. For example “B” and “b” where each letter represents a given allele for a gene. A capital letter indicates a dominant allele while a lowercase represents a recessive allele.

Phenotype

  • The physical presentation of the genotype. For example, for eye color, one may write the dominant allele for brown eyes as “B” and the recessive allele for blue eyes as “b”. In this scenario, the genotype for a heterozygote would be written as “Bb,” while the phenotype would be “brown”.

Homozygous

  • Both alleles are the same. Example: BB

Heterozygous

  • Each allele is different. Example: Bb

Mendelian Patterns of Inheritance

  • Humans have 23 pairs of chromosomes (46 total).
  • Each gene has two copies, one on each chromosome.
    • This second copy can be identical or different. These are called alleles.
  • Genes are segments of DNA that are transcribed into RNA and then translated into protein.
  • Whether a genotypic allele is expressed (i.e. seen “phenotypically”) depends on the protein that is transcribed by the gene.
  • Each chromosomal copy is obtained from the male and female haploid cells (sperm and egg, respectively), which combine by a somewhat random shuffling process known as recombination.
  • Because diploid organisms like humans have 2 copies of each allele, every haploid (sperm and egg) has a 1 in 2 chance of holding any given allele.
  • When the sperm fertilizes the egg, a 46 chromosome diploid embryo is made. Usually, one 1 of the 2 alleles will be seen phenotypically (they can also be expressed together, but we will discuss this later). This is the foundation of mendelian genetics.

Autosomal dominant

  • An autosomal dominant allele will “overpower” a recessive allele for expression as the phenotype.
    • In autosomal dominant diseases, therefor, Only one mutated copy of an allele is required to express the mutated phenotype.
  • These are usually “gain of function” mutations.
  • The risk of inheritance in an offspring is 50% if one parent is affected.
  • The inheritance pattern is described as “vertical” on the pedigree chart (no generations are skipped).
  • Some of the most commonly tested autosomal dominant disorders include…

TSC mutation. Autosomal dominant with variable penetrance. Read more→ 

NF1 and NF2 are autosomal dominant with complete penetrance but variable expression. NF1 is caused by neurofibromin gene mutation on chromosome 17. NF2 is caused by merlin gene mutation on chromosome 22. Read more→

HD gene. CAG trinucleotide repeat, ≥40 repeats. Autosomal dominant. This disorder is also listed under “anticipation” mutations. Read more→ 

DMPK gene, CTG repeat, >50 repeats. Autosomal dominant. This disorder is also listed under “anticipation” mutations. Read more→ 

CNBP gene, CCTG tetranucleotide repeat, >75 repeats. Autosomal dominant. This disorder is also listed under “anticipation” mutations. Read more→ 

TITF1 (a.k.a. NK2 homeobox-1, NKX2-1). This encodes thyroid transcription factor 1 (TTF-1).

Ryanodine calcium channel (RYR1). Read more→ 

SLC2A1 mutation results in inability to transport glucose into the brain, which results in low CSF glucose, while lactate is low-normal. Read more→

Trinucleotide expansion (CAG) of the ATN1 gene, causes late-onset ataxia, myoclonic epilepsy, and dementia, most commonly in Japanese. Read more →

Mutations of transthyretin (TTR), apolipoprotein A-1, or gelsolin proteins cause a length-dependent polyneuropathy and autonomic dysfunction.
Apolipoprotein A-1 can also cause multiorgan dysfunction due to amyloid deposition. Read more →

PABPN1 mutation. Onset in age 40’s with ptosis, progressing to dysphagia, then proximal muscle weakness.

Chromosome 17 deletion, including PAFAH1B1. Presents with lissencephaly, intellectual disability, developmental delay, seizures, spasticity, and hypotonia. Facies of prominent forehead, midface hypoplasia, micrognathia, and thick upper lip are seen.

VHL (a tumor suppressor) gene mutation causes numerous hemangiomas throughout the body, including the CNS. This disorder technically requires a mutation in both alleles for phenotypic presentation, but a single mutation is considered autosomal dominant because all patient’s will develop the second mutation in some cells via sporadic mutations throughout their life, and thus will all have phenotypic expression. Read more →

Ryanodine receptor mutation. Presents with muscle rigidity, hyperthermia, autonomic instability, and rhabdomyolysis after administration of anesthesia (usually succinylcholine). Read more →

Peripheral myelin protein (PMP22) duplication on chromosome 17p. Read more →

SCN4A voltage-gated sodium channel mutation, causes episodic weakness before age 10.

CACNA1S encodes L-type voltage-gates calcium channels. Mutation causes episodes of weakness lasting hours to days.

SCN4A sodium channel mutation causes episodic weakness triggered by cold. Read more →

CLCN1 chloride channel mutation. Read more →

GTP cyclohydrolase I (GCH1), chromosome 14. Read more→

Type I is caused by a mutation in the voltage-gated potassium channel (KCNA1), and episodes last minutes. Type II is caused by a mutation in the voltage-gated calcium channel (CACNA1a), and episodes last hours to days. Read more→

Autosomal Recessive

  • Both copies of the allele must be mutated in order to express the mutated phenotype.
  • These are usually “loss of function” mutations.
  • The risk of inheritance in an offspring is 25% if both parents are asymptomatic carriers.
    • Population genetics equations can be used to calculate risk if only one parent is a carrier and one is unknown, but this is beyond the scope of neurologic examinations.
  • The inheritance pattern is described as “horizontal” on the pedigree chart (some generations are skipped).
  • Most diseases are autosomal recessive, and for this reason, it is easiest for exams to memorize which diseases are inherited by other means, and suppose that all the rest are likely autosomal recessive.

X-linked

  • The mutated allele is on the X chromosome.
  • In X, X females, only one X is expressed, while the other is randomly silenced as a Barr body on a cell-by-cell level. Often, the result is that most women are “asymptomatic carriers” or have only mild symptoms for X-linked disorders.
    • This Barr body phenomenon is often what causes mosaicism.
  • X, Y males have a higher chance of expressing a mutated phenotype because only one X chromosome is present.
    • However, in some X-linked disorders, you will see that living affected men are actually less commonly seen since some unopposed X chromosome mutations can be fatal in early development. 
  • X-linked disorders can be dominant or recessive as well.

X-linked dominant:

    • The most commonly tested X-linked dominant neurologic disorders are:


 

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Table of Contents

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