Atypical mendelian inheritance and hereditary muscle disorders

Question 1

What is non-mendelian inheritance?

Answer 1

Non-Mendelian inheritance is any pattern of inheritance in which traits do not segregate in accordance with Mendel’s laws.

Question 2

Name some forms of non-mendelian inheritance?

Answer 2

De novo mutations, somatic or mosaicism.
Dynamic mutations and anticipation.
Genomic imprinting.
Mitochondrial inheritance.

Question 3

What is a trinucleotide repeat disorder (TNR)?

Answer 3

Trinucleotide repeat disorders (TNR) are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides (trinucleotide repeats) increase in copy numbers until they cross a threshold above which they become unstable. TNR commonly show anticipation, distinguishing it from classic mendelian inheritance.

Question 4

Names some examples of trinucleotide repeat disorders (TNRs).

Answer 4

Fragile X syndrome, myotonic dystrophy and Huntington’s disease.

Question 5

What gene is associated with fragile X syndrome?

Answer 5

The FRM1-gene (on the X-chromosome).

Question 6

In which sex has fragile X syndrome generally reduced penetrance?

Answer 6

In females.

Question 7

What is meant by FRM1 premutation? What can FMR1 premutations cause?

Answer 7

The CGG repeat expansion is within the premutation range (55-200).

FMR1 premutation can cause fragile X tremor/ataxia syndrome (FXTA) and premature ovarian insuffiency (POI) (menopause < 40 years of age).

Question 8

What is myotonia?

Answer 8

Inability of the muscles to relax after contraction.

Question 9

How is myotonic dystrophy inherited?

Answer 9

Autosomal dominant.

Question 10

What is the inheritance pattern of myotonic dystrophy ?

Answer 10

Autosomal dominant.

Question 11

True or false: All cases of myotonic dystrophy is associated with anticipation.

Answer 11

False. Only type 1 is associated with anticipation. Type 2, the congenital form, is not associated with anticipation.

Question 12

What is the pattern of inheritance for Huntington’s disease?

Answer 12

Autosomal dominant.

Question 13

What are signs/symptoms of Huntington’s disease? When is usually the onset of Huntington’s?

Answer 13

Irregular involuntary movement (chorea).
Dementia.
Cognitive and mental changes.
Gradual weight loss.
Onset is usually in adult life. Juvenile cases occur, but are seldom.

Question 14

What gene is associated with Huntington’s disease?

Answer 14

The HHT-gene.

Question 15

What is genomic imprinting?

Answer 15

An epigenetic phenomenon, involving DNA and histone methylations, that causes genes to be expressed in a parent-of-origin-specific manner. These epigenetic marks are established (“imprinted”) in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism.

Question 16

Name some examples of disorders involving genomic imprinting.

Answer 16

Angelman syndrome.

Prader-Willi syndrome.

Question 17

What are some signs/symptoms associated with Prader-Willi syndrome?

Answer 17

Neonatal hypotonia (“floppy infant”).
Failure to thrive / feeding difficulties early on.
Later excessive eating (insatiable appetite).
Slight mental retardation.

Question 18

What are some signs/symptoms associated with Angelman syndrome?

Answer 18

Normal at birth.
Seizures (with specific EEG pattern).
Microcephaly.
Ataxia.
Mental retardation.

Question 19

What is the pattern of inheritance for spinal muscular atrophy (SMA)? What type of mutation causes the disease?

Answer 19

Autosomal recessive.

It is caused by loss of function mutations, usually deletions, in the SMN1-gene.

Question 20

What is used to treat spinal muscular atrophy?

Answer 20

Nusinersen (Spinraza).

Question 21

What is the pattern of inheritance for Duchenne and Becker muscular dystrophy?

Answer 21

X-linked recessive.

Question 22

What are the differences between Duchenne and Becker muscular dystrophy?

Answer 22

Different mutations in the same gene cause either Duchenne or Becker muscular dystrophy.

Duchenne muscular dystrophy is characterized by creatinine kinase (CK) levels > 10x normal, a near total lack of dystrophin and a critical onset of disease at 2-3 years of age. (The disease is also associated with premature death around the age of 20 years.)

Becker muscular dystrophy is characterized by creatinine kinase (CK) levels > 5x normal, reduced levels of dystrophin, greater clinical variant and later onset of disease.

Question 23

What is Gowers’ sign?

Answer 23

Gowers’ sign is a medical sign that indicates weakness of the proximal muscles, namely those of the lower limb. The sign describes a patient that has to use their hands and arms to “walk” up their own body from a squatting position due to lack of hip and thigh muscle strength.

Question 24

What is the pattern of inheritance for facioscapulohumeral muscular dystropy (FSHD)?

Answer 24

Autosomal dominant (however 10-30 % of cases occur due to de novo mutations).

Question 25

What is characteristic for facioscapulohumeral dystrophy (FSHD) 1 in terms of onset of disease, progression and affected muscles?

Answer 25

Facioscapulohumeral muscular dystrophy (FSHD) 1 usually has it’s onset between the ages of 10 and 20 years. The disease is progressive. It affects muscles in the face, around the shoulder blades and upper arm, and is often asymmetric. (Moderate deafness sometimes occur.)

Question 26

What should be included in a clinical neuromuscular examination?

Answer 26

Muscle strength. 
Biochemical tests.
Electromyography (EMG). 
Nerve conduction velocity.
Muscle biopsy: Histology and immunehistochemistry.