Key information to record on a pedigree includes [4]
Age and/or year of birth
Age and cause of death (year if known)
Relevant health information and age of diagnosis (e.g., chorea, onset age 40 years)
Ethnic background/country of origin for each grandparent
Any consanguinity (with degree of relationship noted, such as first cousins)
Unless three generations of family history are recorded, it is difficult to observe patterns of inheritance; a good rule of thumb is two generations “up” (parents, grandparents, aunts and uncles) and two generations “down” (first cousins, children, and grandchildren). Distinguishing full siblings from half-siblings is also important. An arrow is used to point to the proband (the first affected person in the pedigree) or the consultand (the person who is seeking medical advice, who may be affected or not). Ancestry of the grandparents is noted because some genetic disorders are more common in certain populations (an example is Machado-Joseph/SCA3 in the Azores, DYT3 dystonia in Filipino or HDL2 in Black Africans) or there may be common founder mutations making certain pathogenic mutations more likely to be identified. For example, the autosomal dominant Parkinson LLRK2 gene mutation G2019S is common in the Ashkenazi population and in North African Arabs, whereas the R1441G variant is more common in persons of Hispanic or Spanish descent [6, 11, 12]. The autosomal dominant TOR1A pathogenic mutation is associated with early-onset dystonia in the Ashkenazi population. If the parents of the person who is being evaluated for a movement disorder are closely related (such as first cousins), this can be a clue that an autosomal recessive movement disorder is in the differential diagnosis (see Table 19.1) [3, 8].
Table 19.1
Examples of inheritance patterns for several hereditary movement disorders, clues for recognizing patterns of inheritance, and variables that can mask recognition of these patterns
Inheritance pattern | Mode of transmission | Pedigree clues | Confounding factors | Disease examples |
|---|---|---|---|---|
Autosomal dominant (AD) | 50 % risk to each son/daughter (heterozygotes affected with disease) | Vertical transmission Male-male transmission Males/females affected (often with similar degree of clinical manifestations) Often variability in disease severity Homozygotes may be affected more severely than heterozygotes Homozygous state may be lethal | Reduced penetrance Can miss diagnosis in relatives if mild expression for disease New mutations may be mistaken for sporadic if small family size Gonadal mosaicism | Dopa-responsive dystonia DRPLAa Dystonia (early-onset primary dystonia) Huntington’s disease Huntington’s disease-like 2 Frontotemporal dementia with Parkinsonism-17 Neuroferritnopathy SOD-1 Related Amytrophic lateral sclerosis Spinocerebellar ataxias |
Autosomal recessive (AR) | 25 % risk to each son/daughter (homozygotes affected with disease) Parents “healthy” but mutation carriers (heterozygotes) | Usually one generation (horizontal transmission) Males/females affected Often seen in newborn, infancy, childhood Often inborn errors of metabolism May be more common in certain ethnic groups (e.g., Tay-Sachs disease and Ashkenazim) Sometimes parental consanguinity | May be mistaken as sporadic if small family size If carrier frequency high, can look like autosomal dominant | Ataxia-telangiectasia Ataxia with oculomotor apraxia Friedreich ataxia Hyperekplexia Lafora body disease Myoclonic epilepsy of Unverricht and Lundborg Neuroacanthocytosis Panthothenate kinase-associated neurodegeneration (PKAN) Parkin type of juvenile Parkinson’s disease (Park2) Tyrosine hydroxylase-deficient DRD Wilson disease |
X-linked dominant (XLD) | Heterozygous women affected with 50:50 risk to have affected daughter/50:50 chance for affected male (though lethal) | No male-to-male transmission Often lethal in males so see paucity of males in pedigree May see multiple miscarriages (due to male fetal lethality) Females usually express condition but have milder symptoms than males | Small family size | Rett syndrome |
X-linked (XL) | Women have 50 % chance for affected son/50 % chance for heterozygous daughter (usually unaffected) | No male-to-male transmission Males affected Females may be affected but often milder and/or with later onset than males | May be missed if paucity of females in female Lyonization | Adrenoleukodystrophy Fragile X syndrome Lesch-Nyan disease |
Mitochondrial | 0–100 % | No male transmission to offspring, only maternal transmission Highly variable clinical expression Often central nervous disorders Males and females affected, often in multiple generations | Generally considered rare | Mitochondrial encephalopathy with ragged-red fibers (MERRF) Mitochondrial encephalopathy, lactic acidosis, strokes (MELAS) Neuropathy with ataxia and retinitis pigmentosa (NARP) |
Multifactorial | Based on empirical risk tables | Males and females affected No clear pattern Skips generations Few affected family members | May actually be single gene | Schizophrenia Bipolar disorder Epilepsy |
Family history is dynamic—children are born, relatives die, and relatives become affected with new diseases over time. It is important to update family history every few years. Noting who recorded the pedigree, the reason it was taken (e.g., family history of Huntington disease, family history of Parkinson’s disease), and the date it was recorded is essential to note [4].
Patterns of Inheritance for Hereditary Movement Disorders
Movement disorders are inherited in many different patterns. Knowledge of these patterns can assist with differential diagnosis and of course be used for genetic counseling regarding chance of disease occurrence and recurrence. These basic inheritance patterns and examples of some of the hereditary movement disorders are summarized in Table 19.1.
Recognizing patterns of inheritance requires recognition of the phenotype (outward expression of the condition), which can be difficult for many reasons including reduced penetrance (not every person who has the pathogenic mutation(s) develops the condition) and variable expressivity (the relatives in the family may have very mild expression of the disease and therefore never be diagnosed with the hereditary movement disorders).
Autosomal Dominant
The majority of the currently recognized hereditary movement disorders follow this inheritance pattern. Autosomes refer to the 22 pairs of nonsex chromosomes, numbered from 1 to 22. With this pattern of vertical transmission, a person who has a disease-causing mutation has a 50:50 chance to pass the mutation to each son or daughter. Two major clues to autosomal dominant inheritance are recognition of the disease in more than one generation and male-to-male (i.e., father-to-son) transmission (mother-to-son transmission could be autosomal dominant or X linked). A person can have a new autosomal dominant deleterious mutation (the mutation occurred in the egg or sperm, and neither parent is affected) and thus be the first person with the disease in the family; their siblings would not be at risk for the disease, but he or she would have a 50 % chance to pass the mutation on to each son or daughter.
Gonadal mosaicism can occur with autosomal dominant conditions. This means that the mutation occurring in the testes or ovaries are mosaic for the pathogenic mutation and thus not all the progenitor cells have the mutation; the parent has no symptoms of the condition, but they are at risk to have children with the condition.
There are several autosomal dominant neurological disorders that show anticipation. This is where relatives with the disease have more severe manifestations and often earlier age at onset with each generation. A classic example of this is Huntington’s disease. Anticipation in Huntington’s disease is explained by instability in the CAG expansion which can expand over successive generations, and relatives with larger CAG repeats can have earlier onset of symptoms (Chap. 8). Other examples are HDL2 (Chap. 8) and some of the spinocerebellar ataxias (Chap. 11).
Autosomal Recessive
To have an autosomal recessive condition, the individual would have two pathogenic mutations, one inherited from each parent. The couple who each carry a mutation have a 25 % chance with each pregnancy to have an affected son or daughter. The person with the condition will always pass one copy of the pathogenic mutation to each offspring, but he or she would only have an affected child if his or her partner carried a mutation in the same gene. Usually, the likelihood that the offspring of an affected parent will have a child affected with the same condition is less than 1 %. The unaffected sibling of a person with an autosomal recessive condition has a 2/3 chance to be a carrier, but to have an affected child, their partner must also carry a pathogenic mutation for the condition, thus the a priori chance to have an affected child is usually in the range of 1 %.
Although it is rare for the offspring or unaffected siblings of a person with an autosomal recessive condition to in turn have a child affected with the hereditary movement disorder, it is important that carrier testing be offered to their partner. Some populations have a high carrier frequency for certain autosomal recessive disorders. A clue to a possible recessive disorder in the family includes if the parents are close “blood relatives” (such as first cousins). This is referred to as consanguinity. People who are closely related are more likely to have the same genetic variants in common [3, 8].
There can be hundreds of pathogenic changes in a gene. If the person carries the same allele, then this is referred to as homozygous. If the person carries two different copies of the same gene, then this is compound heterozygosity. Usually, the disease severity is not affected by whether a person is homozygous or a compound heterozygote, but there are some diseases where certain mutations may be associated with variable disease severity.
X-linked
With this pattern, the pathogenic mutation occurs on the X chromosome. Women generally do not show symptoms because the gene on the other X chromosome functions normally. If she has a male offspring, there is a 50 % chance he will inherit the pathogenic mutation and thus be affected, and for a female offspring, there is 50 % chance that she has the pathogenic mutation, but she often has no symptoms or mild symptoms. Many X-linked conditions have a high rate of new mutation (if the males have limited reproductive fitness).
Mitochondrial Inheritance
Mitochondria have their own genome with a circular DNA molecule A single cell can have hundreds of mitochondria. With mitochondrial inheritance, women are affected and can pass the mutation to sons or daughters; but sons cannot pass the mitochondrial mutation to their children. Depending on the number of mitochondria that are randomly included in the cytoplasm during meiosis, it affects the offspring’s mitochondrial DNA component. Thus, offspring of a woman with a mitochondrial disease can have marked variability in the disease expression, and the chance the offspring will be affected ranges from 0 to 100 %.
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