Neurogenetics (TRANSFERRED)

Question 1

Reference: Genetics residents in-training examination – Fall 2020

In the following scenarios associated with seizures, name the most likely diagnosis and one laboratory or clinical investigation you would order to confirm/support your diagnosis:

a) A 4-year old girl with ataxia, dysmorphism, developmental delay, inverted nipples, abnormal fat pads, and cerebellar hypoplasia on MRI. Her parents are first cousins.
b) A 3-year old boy presents with developmental delay and a history of febrile seizures that began at age 6 months and his seizures have evolved to include generalized tonic-clonic seizures, status epilepticus, and most recently myoclonic seizures.
c) A 2-year old girl presents with onset of progressive microcephaly, loss of skills, seizures, and hand wringing after previous normal development.

Answer 1

a) Congenital disorder of glycosylation – TIEF (Transferrin isoelectric focusing) or panel
b) Dravet – SCN1A or panel
c) MECP2 or FOXG1-related Rett syndrome– single gene, microcephaly or seizure panel

Question 2

Reference: Genetics residents in-training examination – Fall 2020

A 42 yo woman presents with myalgias and hand stiffness in the cold. Needle electromyogram demonstrates myotonic discharges. List 6 genetic causes of myotonia.

Answer 2

Myotonic dystrophy type 1
Myotonic dystrophy type 2
Myotonia congenita
Paramyotonia congenita
Hyperkalemic periodic paralysis
Schwartz-Jampel Syndrome
Acid maltase deficiency (Pompe)

Question 3

Reference: Genetics residents in-training examination – Fall 2020

A 30 year man presents with foot drop and high arches and a history of recurrent ankle sprains; nerve conductions studies show a length-dependent demyelinating sensorimotor polyneuropathy.

a) What is the most likely clinical diagnosis?
b) What is the mostly likely gene and genetic mechanism?
c) What disease is allelic with this gene and explain the mechanism?

Answer 3

a) CMT
b) PMP22 and duplication
c) HNPP: Hereditary neuropathy with liability to pressure palsies – and deletion

Question 4

Reference: Genetics residents in-training examination – Fall 2020

1. What are 3 common clinical features of Charcot Marie Tooth Disease?
2. What would be the top 3 genetic causes of CMT in Canada.
3. The most common changes in CMT on nerve conduction studies is: (circle one)
   demyelinating / axonal / intermediate

Answer 4

1. distal sensory loss and weakness
   deep tendon reflex abnormalities
   skeletal deformities (pes cavus, hammertoes, scoliosis)

2.
Over 90% of patients with Charcot-Marie-Tooth disease have a mutation in the PMP22, MFN2, MPZ, or GJB1 gene.

3. demyelinating

Question 5

Reference: Genetics residents in-training examination – Fall 2020

Differentiate between myotonic dystrophy type 1 and 2.

Mutated gene
Mutation type
Anticipation
Age of onset
Congenital form
Facial weakness
Distal weakness
Cataracts
Balding
Cardiac arrhythmias
Gonadal failure
Hypersomnia

Answer 5

Mutated gene:
DMPK
ZNF9

Mutation type:
CTG repeats
CCTG repeats

Anticipation:
yes
No/rare

Age of onset:
0 to Adult
8 to 60 years

Congenital form:
Yes
No

Facial weakness:
Common
No (very rare)

Distal weakness:
Common
Rare

Cataracts:
+
+ some

Balding:
+
No/rare

Cardiac arrhythmias:
+
occasional

Gonadal failure:
+
rare

Hypersomnia:
+
No/rare

Question 6

Reference: Genetics residents in-training examination – Fall 2020

1. What are 3 common early clinical features consistent with Oculopharyngeal muscular dystrophy?
2. Describe the inheritance pattern of OPMD

Answer 6

1.
ptosis
dysphagia
proximal weakness

2.
OPMD is both dominant (Dominant OPMD 11 to 18 GCG trinucleotide repeats in PABPN1 and recessive (11-13 GCG trinucleotide repeats in PABPN1)