Linda A. Specht

Infantile phosphofructokinase deficiency with arthrogryposis : Clinical benefit of a ketogenic diet

We report a 2-year-old boy with phosphofructokinase deficiency presenting in the newborn period with congenital arthrogryposis and severe myopathy, who has had significant improvement on a ketogenic diet since its institution at 4 months of age. We provide a rationale for use of this treatment and hypothesize it may be beneficial in other patients with phosphofructokinase deficiency and progressive muscular involvement. Confirmation awaits further clinical trials in carefully selected patients.

Cognitive dysfunction as the major presenting feature of Becker's muscular dystrophy

We report four patients, currently aged 15, 17, 19, and 42 years, with X-linked dystrophinopathy who presented with mental retardation (IQ range, 60-68) and psychiatric disturbance in the absence of muscle weakness. All patients had elevated serum creatine kinase and dystrophic changes on muscle biopsy. There were alterations in the size and abundance of dystrophin on immunohistochemistry and immunoblotting in all cases, consistent with a molecular diagnosis of Beckers muscular dystrophy. Two patients had deletions of the dystrophin gene on DNA analysis. These findings suggest that Beckers muscular dystrophy may be associated with a predominantly neuropsychiatric presentation and that dystrophinopathy should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males. Serum creatine kinase may provide an adequate screening test in this clinical situation. NEUROLOGY 1996;46: 461-465

Orthopedic deformities in Emery-Dreifuss muscular dystrophy.

Orthopedic deformities in Emery-Dreifuss muscular dystrophy are discussed based on a study of four patients and an extensive literature review. The condition is characterized by slowly progressive humeroperoneal muscle weakness; ankle equinus, elbow flexion, and neck extensor muscle contractures; paravertebral muscle tightness; and cardiac abnormalities involving bradycardia and atrioventricular conduction defects. Tendo Achilles lengthening is warranted, since patients remain ambulatory for several decades. Scoliosis occurred in three patients but stabilized in the absence of treatment. Recognition of the condition is important to allow for heart pacemaker insertion because the usually asymptomatic cardiac abnormalities are associated with a high incidence of sudden death in mid-adult life.

Childhood onset oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy is an inherited disorder, usually autosomal dominant, which typically becomes symptomatic during the fifth decade of life with slowly progressive ptosis and dysphagia; childhood onset has not been reported. A 13-year-old female of French-Canadian descent developed nasal speech and strabismus at 5 years of age; there was no family history of neuromuscular disease. Ptosis and mild facial and proximal muscle weakness were present by 9 years of age. Over the next 4 years, the patient developed dysphagia, palatal paralysis, weight loss, decreased ocular motility, scoliosis, shortness of breath, and obstructive apnea. Tracheostomy and gastrostomy were required. Creatine kinase and repetitive facial nerve stimulation were normal. Edrophonium testing was negative and electromyography revealed myopathic motor units in the iliopsoas muscle. A preponderance of type I fibers and scattered atrophic and angulated muscle fibers were present in 3 muscle biopsies. The clinical presentation and findings are consistent with childhood onset oculopharyngeal muscular dystrophy.

Differential glucocorticoid effects on the fusion of Duchenne/Becker and control muscle cultures: pharmacologic detection of accelerated aging in dystrophic muscle.

We report that the glucocorticoid methylprednisolone (Mepd) enhanced myogenesis in normal primary human muscle cultures, but inhibited myogenesis of most Duchenne/Becker muscle cultures. A decline in the magnitude of myogenic stimulation by Mepd correlated with age in a random group of control patients, including some with neurologic diseases other than Duchenne/Becker dystrophy. A case of Duchenne muscular dystrophy from an exceptionally young patient yielded a muscle culture that was myogenically stimulated by Mepd. These results suggest that continuous cycles of degeneration and regeneration of dystrophic muscle in vivo may result in a change of the glucocorticoid response of the muscle progenitor cells. The glucocorticoid effects suggest caution in the long-term clinical use of these agents for muscle disease such as Duchenne muscular dystrophy.

Prediction of dystrophin phenotype by DNA analysis in Duchenne/Becker muscular dystrophy

Allele-specific molecular diagnosis of Duchenne and Becker muscular dystrophies (DMD and BMD) has been largely dependent upon muscle biopsy for dystrophin protein assay. We performed lymphocyte DNA mutation analysis by polymerase chain reaction on 14 boys presenting with a clinical picture compatible with DMD or BMD. DNA analysis revealed that 12 of 14 boys had a deletion of the dystrophin gene, thus establishing the diagnosis of DMD/BMD. Furthermore, genotypes for 9 of 12 deletion patients permitted prediction of the specific allelic disorder (i.e., DMD or BMD). Subsequent dystrophin testing confirmed all of the DNA-based diagnoses. We propose that DNA mutation analysis be included in the initial evaluation of patients suspected of having DMD/BMD, thus potentially eliminating the need for muscle biopsy in the majority of patients.

Locomotor problems in infantile facioscapulohumeral muscular dystrophy: Retrospective study of 9 patients

A retrospective study of 9 patients with infantile facioscapulohumeral muscular dystrophy defines orthopedic deformities and progression. Patients presented in the early months of life with facial diplegia. Sensorineural hearing loss occurred in 8 out of 9 with a mean onset at 5 (2-9) years. Walking began at the normal time, but worsened progressively, which was due mainly to gluteus maximus muscle weakness. Scapular winging, extreme lumbar lordosis, and foot drop were characteristic. The majority of patients (in this and other series) lose walking ability in the second decade. Efforts to control lumbar lordosis by bracing while the patients were still walking were ineffective. Control of lumbar lordosis after the patients are wheelchair-dependent is important.

Defective dystrophin in Duchenne and Becker dystrophy myotubes in cell culture.

We examined normal and dystrophic human myotubes in cell culture for expression of dystrophin, the protein product of the Duchenne muscular dystrophy locus. Dystrophin levels in developing myotubes detected by Western blotting increased after 24 hours and reached maximum levels after 10 days in fusion medium. We did not detect dystrophin in myotubes cultured from Duchenne myoblasts (7 cases). Myotubes from a Becker muscular dystrophy patients biopsy produced a lower molecular weight (approximately 408 kd) dystrophin, which was the same size in a whole muscle preparation from the same biopsy. This 408-kd dystrophin was the expected size for this Becker patient whose DNA was deleted for exons 45-48 of the Duchenne gene. This cell culture system will allow a detailed analysis of the effects of potential pharmacologic agents on steady-state dystrophin levels.

In Situ Hybridization of Somatostatin and Vasoactive Intestinal Peptide mRNA in the Rat Nervous System

Expression of neuronal genes encoding specific neurotransmitters is one of the major events that occurs in the developing nervous system. The signals that regulate the expression of neurotransmitter genes during development are poorly understood. Identification of the signals and mechanisms that regulate neuronal phenotypic expression during development will be facilitated by knowing when neurotransmitter genes are activated.

Increase in fetal breech presentation in female carriers of Duchenne muscular dystrophy

Female carriers of Duchenne muscular dystrophy (DMD) may demonstrate elevated serum creatine kinase (CK) and reduction of muscle dystrophin in all muscle types. We hypothesized that decreased dystrophin in uterine or pelvic girdle musculature might affect the obstetrical performance of females heterozygous for a dystrophin mutation. We reviewed the outcome of 34 deliveries resulting in 35 children from 13 women who were mothers of males attending a muscular dystrophy clinic. Obstetrical performance was examined retrospectively by chart review and patient contact. Of 35 children, 6 (17%) were delivered in the breech position, which is a fivefold increase above the national standards for term pregnancies. Of the six infants with breech presentation, two were males affected with DMD, one was a female heterozygote, one was a male who died perinatally, and the carrier status of the other two females is unknown. Most DMD affected males (12/14) were delivered in the vertex position. Thus, it is likely that maternal, rather than fetal, muscle weakness was the significant factor in determination of fetal position at term. We speculate that subtle changes in uterine or pelvic girdle muscle tone may contribute to a higher rate of fetal breech position in carriers of the DMD gene.