Figure 1. Age 6 months.
Figure 2. Cryostat sections of deltoid muscle obtained at age 9 months show random atrophy, marked fiber hypertrophy, and endomysial fibrosis. Note nucleomegaly with pale chromocenters resembling viral inclusions and small eosinophilic sarcoplasmic inclusions (hematoxylin-eosin, original magnification ×250).
Figure 3. Note the extent of atrophy and hypertrophy. Large aggregates of lymphocytes are present. Some fibers are "disintegrating" with vacuolar degeneration and loss of sarcoplasmic detail (hematoxylin-eosin, original magnification ×100).
Figure 4. Widespread granular appearance of Z-bands appear as small densities. The myofilamentous assembly is normal between. Mitochondria are unremarkable (uranyl acetate-lead citrate, original magnification ×10 000).
Figure 5. Age 6 years.
This patient, to our knowledge, represents the longest surviving patient with hypertonic muscular dystrophy (HMD), originally reported in 1994 in a Canadian Cree Indian population.1 Her rigidity progressed until she could only move her eyebrows, and she became too stiff to ventilate. She died of respiratory failure at age 10¾ years. She had continued to be active in school and extracurricular activities until that time. Case 8 of a recent report1 showed no progression beyond age 18 months. That patient died at age 3½ years (Elizabeth Gibbings, MD, oral communication, June 1991). As in previous cases, our patient's rigidity became evident after the neonatal period.1- 3 The muscles remained rigid despite sequential motor unit blockade with curare, pancuronium, and total anesthetic nerve block. The fibrillation potentials on EMG resemble that seen in previously reported cases. Normal cognitive development and nerve conduction velocities further support the concept that the central and peripheral nervous systems are normal in HMD. Autopsy studies on previous cases support these findings as well.1 Creek and Cree Indians are from geographically distinct regions. However, Creek Indians traded in regions that may have been inhabited by the Cree. We cannot, therefore, rule out a genetic transmission similar to those reported.
Features of HMD include progressive muscular dystrophy with granular transformation of Z-bands, best seen on longitudinal sections. This leads to disorganization of the adjacent myofilaments spanning several sarcomeres. A primary but segmental biochemical abnormality at the level of the Z-band organizational proteins might explain this phenomenon. Recent evidence suggests that the giant protein, titin, plays a major role in the development and subsequent arrangement of the myofilaments. During early muscle embryogenesis, this high-molecular-weight protein forms a punctate staining pattern by immunohistochemical analysis. On maturation, this protein is thought to unfold and ultimately span the region between the Z-line and M-line, evolving into a cross-striated pattern.2,3 It may play a role in maintaining muscle elasticity and normal ultrastructure.3 Alternatively, gene defects leading to loss of integrity in myofilament organization may contribute to muscle rigidity. The progressive muscle destruction may ultimately be due to a link to the membrane structural protein via the dystrophin axis. Further immunohistologic and population genetic studies using molecular techniques may help elucidate the pathophysiologic characteristics of this rare disease.
Accepted for publication June 3, 1999.
We thank Thomas O. Crawford, MD, for sharing his records and his support; Mr and Mrs Don Harper for their support and photographs; and Peter Steele, PhD, for doing the electron microscopic preption.
Reprints: Gail D. Cawkwell, MD, PhD, Pfizer Inc, 235 E 42nd St, 219/4/34, New York, NY 10017.
Pathological Case of the Month. Arch Pediatr Adolesc Med. 2001;155(7):854. doi:10.1001/archpedi.155.7.853