Final Diagnosis

Duchenne Muscular Dystrophy

Patient Follow-up

After the diagnosis of DMD was made, the patient was started on Prednisone 0.75 mg/kg/day and a proton pump inhibitor for GI prophylaxis. The patient was also evaluated and followed by our cardiology and pulmonary team. He continued to deteriorate over the years and lost ambulation by 10 years of age after a fall and subsequent femur fracture. He was unable to stand to bear weight, with or without assistance. He was unable to go from a supine to a sitting position without assistance and required pillows for support when pulled to sit. He could assist with dressing himself, brushing his teeth, and feeding himself independently. The patient developed progressive upper extremity weakness at age 16 years. He also developed obstructive sleep apnea and restrictive lung disease, requiring non-invasive ventilation overnight. He had dilated cardiomyopathy. Echocardiogram showed normal ventricular systolic function and under filled ventricles. He took Lisinopril, Carvedilol and Spironolactone. He had a hiatal hernia and required a GT and Nissen. He had not developed neuromuscular scoliosis.

Discussion

DMD is an X-linked recessive disease caused by mutations in the dystrophin gene with an incidence of 1 in 3,500–5,000 live birth males [1–3]. Dystrophin is an intracellular cytoskeletal protein that stabilizes the plasma membrane and stabilizes the dystrophin glycoprotein complex, preventing degradation of the muscle fiber. Loss of these membrane proteins causes degeneration of the muscle fibers resulting in elevated CK level and muscle weakness. DMD is characterized by progressive muscle weakness and degeneration of skeletal and cardiac muscles. Weakness starts at the hip and progresses to involve the whole lower extremities. Patients stop ambulating between 10 and 15 years of age. Then, truncal weakness followed by upper extremity weakness develops. Physical examination is notable for proximal more than distal weakness, hypotonia, decreased reflexes, abnormal waddling gait, increased lordosis, difficulty running and jumping, calf pseudohypertrophy, macroglossia, and positive Gowers’ sign. Duchenne boys usually present with symptoms around age 2–5 years, become wheelchair bound by age 12–15 years, and die around age 30 years due to cardiac or respiratory muscle weakness and complications [4]. Our patient had a typical presentation of DMD.

Differential diagnosis includes limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, spinal muscular atrophy, mitochondrial or other metabolic myopathies. Once the clinical features are apparent to help narrow the diagnosis, genetic testing is performed looking for deletions, duplications or sequence alterations in the dystrophin gene. In a small percentage of patients, no known pathogenic variants can be found as seen in our patient, whose dystrophin gene test only showed a DNA sequence variant of unclear significance, a muscle biopsy is necessary. Biopsy shows chronic active myopathy with near complete absence of dystrophin protein expression by immunohistochemistry (IHC), which confirms the diagnosis of DMD. This case illustrates the shift in diagnostic paradigm for muscular dystrophies in the genetic era. Clinically prototypical cases of dystrophies are usually diagnosed by paneled genetic analysis. The pathologists nowadays are more likely to encounter muscle biopsies from patients whose initial genetic testing did not match the clinical impression, or genetic testing identified a variant of uncertain significance, or the patient had late onset or unusual clinical features that mimic acquired myopathies. The hallmarks of muscular dystrophy are chronic myopathic changes, which are sometimes referred to as “dystrophic” changes . Those changes, however, are nonspecific and do not distinguish dystrophy subclasses. Immunohistochemical stains can serve as surrogate markers for some underlying mutations when the mutations result in loss of normal protein expression. We typically perform an IHC panel including beta-spectrin (sarcolemma integrity control), dystrophin epitopes (rod domain, carboxy terminus and amino terminus), sarcoglycans (alpha, beta, gamma and delta), caveolin-3, dysferlin, merosin (80 KDa and 300 KDa), alpha-dystroglycan, collagen IV, collagen VI and emerin, on any pediatric muscle specimen with chronic myopathic changes.

DMD management involves a multidisciplinary approach involving experts in different medial fields, including neurology, cardiology, pulmonology, orthopedic surgery, endocrinology, dietitian, physical and occupational therapies. Glucocorticoids are the mainstay of the treatment in DMD to maintain the motor strength and to delay the loss of ambulation [5, 6]. The only FDA approved medication is Exondys, an antisense oligonucleotide for exon 51 skipping. This therapy is applicable to only 13% of patients with DMD [2–4]. Therapeutic approaches that are currently under exploration include gene transfer (micro-dystrophin), exon skipping, trans-splicing, genome editing, stop codon read-through and cell replacement therapy [7, 8].

Pearls