Duchenne muscular dystrophy (DMD) -Prenatal Diagnosis & Genetic Counseling- Dr.Padmesh

1. PRENATAL DIAGNOSIS & GENETIC COUNSELING IN DMD
DNB Pediatrics Solved answers - Dr.Padmesh. V
INTRODUCTION:
-Duchenne muscular dystrophy is the most common hereditary neuromuscular disease.
-Its characteristic clinical features are progressive weakness, intellectual impairment, hypertrophy of the
calves, and proliferation of connective tissue in muscle.
-The incidence is 1 : 3600 liveborn infant boys.
-This disease is inherited as an X-linked recessive trait.
-The abnormal gene is at the Xp21 locus.
-Becker muscular dystrophy is the same fundamental disease as Duchenne dystrophy, with a genetic
defect at the same locus, but clinically it follows a milder and more protracted course.
- The molecular defects in the dystrophinopathies vary: intragenic deletions, duplications, or point
mutations of nucleotides. About 65% of patients have deletions, and only 7% exhibit duplications.
GENETIC COUNSELING IN DMD:
FIVE STEPS IN GENETIC COUNSELING:
1. Reaching at a DIAGNOSIS : 2. Risk Assessment, including risk of Recurrence;
3. Communication; 4. Discussion of Options; 5. Long term contact and support;
STEP 1.Reaching at a diagnosis:
1. First step is construction of a family tree:
-Pattern of inheritance can be obtained from Pedigree analysis.
-X-linked recessive,hence affects only males. Females are carriers.
2. History taking:
-Poor head control in infancy may be the 1st sign of weakness.
-Walks often at the normal age of about 12 mo, but hip girdle weakness may be seen in subtle
form as early as the 2nd yr.
-Progression of weakness continues into the 2nd decade.
-Death usually at about 18–20 yr of age. The causes of death are respiratory failure in sleep,
intractable heart failure, pneumonia, or occasionally aspiration and airway obstruction.

2. 3. Clinical Examination:
-An early Gowers sign is often evident by age 3 yr and is fully expressed by age 5 or 6 yrs.
A Trendelenburg gait, or hip waddle, appears at this time.
-Toddlers may assume a lordotic posture when standing to compensate for gluteal
weakness.
-Pseudohypertrophy of calves.
-Contractures (ankles, knees, hips, and elbows) -Scoliosis is common.
-Cardiomyopathy -Intellectual impairment
4. Investigations:
-Serum CK level is consistently greatly elevated in DMD, even in presymptomatic stages,
including at birth. Even asymptomatic carrier state of Duchenne dystrophy is associated with
elevated serum CK values in 80% of cases.
-Cardiac assessment by echocardiography, electrocardiography (ECG), and CXR.
-Electromyography (EMG) shows characteristic myopathic features but is not specific for
DMD. No evidence of denervation is found. Motor and sensory nerve conduction velocities are
normal.
- Cytogenetic analysis.
- Carrier testing
CONFIRMING THE DIAGNOSIS:
1.Blood polymerase chain reaction (PCR) for the dystrophin gene mutation.
2.Muscle biopsy
a. Dystrophin immunocytochemistry can be performed on muscle biopsy sections.
b. Muscle biopsy is diagnostic and shows the following characteristic changes:
-Myopathic changes include:
Endomysial connective tissue proliferation,
Scattered degenerating and regenerating myofibers,
Foci of mononuclear inflammatory cell infiltrates as a reaction to muscle fiber necrosis,
Mild architectural changes in still functional muscle fibers, and Many dense fibers.

3. STEP 2. Risk Assessment, including risk of Recurrence:
Despite the X-linked recessive inheritance in Duchenne muscular dystrophy, about 30% of
patients are new mutations, and the mother is not a carrier. Approximately 1/3 of cases are due
to new genetic mutations and only about 2/3 of cases occur by inheritance of the disease-
causing gene from the carrier mother.
- Only males affected.
-Recurrence risk
a. If the mother is a carrier,recurrence risk in her Child:
i. 50% risk to her son to receive the disease gene and express the disease.
ii. 50% risk to her daughter to receive the disease gene and become a carrier.
iii. Mother of a DMD patient, regardless of proven carrier status, has an empiric risk of 10–
30% of having an affected male fetus due to presence of maternal germinal mosaicism
b. Recurrence risk in Patient’s offspring:
i. Males with DMD: patient usually succumb or too debilitated to reproduce.
ii. Males with BMD may reproduce & recurrence risk is:
a) None of the sons will inherit the mutation
b) All the daughters are carriers
STEP 3. Communication:
-Counseling to be started as early as possible.
-Rapport with both parents and both parents must be present during counseling.
-Describe genetic basis of disease using simple language and visual aids.
-Natural History of the condition to be explained.
-Genetic aspects & recurrence risk.
-Options about Pre-natal diagnosis & prevention.

4. PRENATAL DIAGNOSIS:
a. In case of a known and readily detectable gene defect
i. Chorionic villi sampling for DNA analysis by Southern blot or PCR.
Amniocentesis and mutation analysis of amniocytes: Usually by multiplex PCR
ii. Preimplantation diagnosis: By single-cell PCR of blastomere or polar body
iii. Fetal nucleated erythrocytes from maternal blood analyzed by multiplex PCR.
iv. Confirmed in aborted fetuses with DMD by immunohistochemistry for dystrophin in muscle.
b. In case of unknown gene defect
i. Fetal sexing. Allow females to proceed to term
ii. Linkage analysis
iii. Fetal muscle biopsy for quantitative dystrophin analysis may serve as a diagnostic option.
STEP 4. Discussion of Options with NON DIRECTIVENESS:
Discuss about options available,like:
- Prenatal diagnosis - Abortion - Not having children - Adoption
STEP 5. Long term contact and support: Combined approach involving
-Parents -Genetic counselor -Family physician -Social worker -Other medical specialties
-Support groups
Management of DMD: Mainly supportive
1. Physical therapy
2. Treatment of dystrophic cardiomyopathy
3. Pharmaceutical agents (steroids)
4. Orthopedic surgery
5. Careful monitoring of pulmonary function & Ventilation for respiratory failure.
6. Genetic therapies in DMD: Use of viral and plasmid vectors to deliver dystrophin to
dystrophin–deficient muscle in vivo.
7. Corrective gene therapy

5. (Ref: Nelson, Atlas of Genetic Diagnosis & counseling by Harold Chen, IAP Textbook of pediatrics)
-Dr.Padmesh.

6. (Ref: Nelson, Atlas of Genetic Diagnosis & counseling by Harold Chen, IAP Textbook of pediatrics)
-Dr.Padmesh.