Question

A 32-year-old Caucasian man underwent testing for Huntington’s Disease. The patient was a lively and talkative child who completed high school with As and Bs and college with poor grades. At age 22 he became quiet and non-conversant. At age 24 he began work as a cook/dishwasher and displayed noticeable un-coordination. At age 28 he developed dysarthria, dysphagia, stiffness, slow ataxic gait, and dementia. There was no history of schizophrenia or depression and the neurological review of systems was negative. Both parents were in their late 60s and in excellent health, without signs of dementia. There was no history of any neurodegenerative disease and he had three sisters, aged 35-37, all in good health.

Laboratory Results:

Creatine phosphokinase: Normal

Vitamin E: Normal

Lactate: Normal

Pyruvate: Normal

Imaging Results:

MRI: Generalized, cerebral and cerebellar atrophy

​​Very mall caudate nuclei

HIstology Results:

Skin biopsy: Normal mitochondria

Bone Marrow and Enzyme Screen:

Human Granulocyte-Macrophage: Normal

Metachromatic Leukodystrophy: Normal

Krabbe’s disease: Normal

Physical examination:

Mini-mental status exam: 20/26

Cranial nerve exam: decreased upgaze, saccadic extraocular eye movement, dysarthria and hyperactive gag reflex

Strength: Normal

Gait: wide-based and ataxic

Molecular Test Results:

Diagnostic HTT molecular test for patient:

​​​1 band representing 23 CAG repeats

​​​1 band representing 49 CAG repeats

HTT molecular test for father:

​​​1 band representing 20 CAG repeats

​​​1 band representing 37 CAG repeats

HTT molecular test for mother:

​​​1 band representing 17 CAG repeats

Predictive HTT molecular test for sister:

​​​1 band representing 17 CAG repeats

​​​1 band representing 20 CAG repeats

1. Why did the patient show phenotypic traits while his parents and sisters did not?

2. If this patient has a child with an unaffected female, what are the chances that the child will have HD?

Answer 1

Question 1

The character of the genetic defect in Huntington’s disease explains many feature and nature of inheritance too. The responsible gene is located at 4p16 position and the prior cause of the disease is alteration/increase in the repetition of nucleic acid C, A and G in coding region. This CAG “triplet” is in normal condition will be repeated around 20 times whereas the expression of the disease occurs when this repetition exceeds 40 or more. In this particular case as the father exhibits a CAG repeats of 37 that symbolize the expression of the HD gene (genotype) in P generation although the reduced penetrance does not allow exhibiting the disease in father whereas F1 generation inherited the disease in their major phenotypic traits. Many research reports also suggested that the descendents of the persons in the range of 26-38 used to transmit the HD as a phenotypic trait as their genotypic expression for the HD gene is much higher than normal range.

Question 2

HD is a dominantly inherited desease. Hence, if this patient has a child with an unaffected female, the child will have a 50% chance of developing HD.

All are having two copies of each gene. Consider the father has HD and the mother doesn’t have that means mother has two good copies of the gene whereas father has one broken copy of the gene and one good copy. Hence, the child will get one of them randomly, thereby chances of getting the broken faulty copy are one in two or 50%.