Search

With the passing of Lord Walton of Detchant—Dr. John Walton—on April 21, 2016, neurology lost one of the most distinguished figures of our specialty and the man who was arguably the founding father of clinical myology. John Walton was born in the United Kingdom in Co. Durham on September 16, 1922. He began his medical career at Newcastle Medical School in 1941, graduating after a course shortened by World War II in 1945. After serving in the Royal Army Medical Corps, he returned to Newcastle as a medical registrar. Inspired by Dr. Henry Miller to become a neurologist, he joined Prof. F.J. Nattras, who directed him to study all of the patients in the region with neuromuscular disorders. He often cited an incident from that time as being a defining moment in his career: meeting a family with 3 sons with Duchenne dystrophy, with the inevitable awful prognosis. The outcome of that work was the seminal publication “On the classification, natural history and treatment of the myopathies.”1 In the monograph “Polymyositis,” written jointly with Raymond Adams,2 he showed how careful clinical and pathologic assessment could help prevent misdiagnosis, previously common, as muscular dystrophy. Photograph courtesy of Green Templeton College, Oxford.

It is evident that diagnostic criteria used to select patients in a clinical trial must be carefully chosen. No matter how carefully the trial is conducted or how exact the outcome measures, unless one is certain that the patient population is homogeneous for the disease characteristic under study, the results will be ambiguous. Most commonly, the patient population is chosen on the basis of the clinical diagnosis. Trials are most common in diseases that have been easy for the clinician to recognize. Duchenne dystrophy, Guillain-Barre, and chronic inflammatory demyelinating neuropathy have been the subjects of well-known trials. Within the past few years, there has been a flurry of trials in ALS. This brief essay focuses on the way in which our use of diagnostic criteria has grown and examines the purpose of diagnostic criteria rather than repeating what is already extensively documented in the literature. [1,2] The application of the scientific method to clinical trials is relatively recent. Only two decades ago, numerous reports were accepted by journals documenting the apparent reversal of serious illness in isolated patients. These clinical descriptions were seldom malicious fabrications but rather honest attempts to describe phenomena that had deeply impressed the patient and the physician. If the lucky investigator happened to have such a patient on the nostrum of the week, a publication was guaranteed. Such reports were often accepted for publication on the premise that they held a flicker of hope in diseases that were otherwise fatal. Reviewers adopted the "who knows, there just might be something in it" approach. Uniformly, nothing came of these reports except a growing realization that there was more to the science of testing drugs than could be left to a neurologist's intuition. In the 1970s, there arose a groundswell that moved neurology into the clinical trials arena …

Carrier risk assessment for Duchenne muscular dystrophy (DMD) is necessary to counsel women at risks of developing cardiomyopathy and having a child with DMD. Comprehensive molecular testing for dystrophin gene mutations has only been available since 20031; women counseled earlier have outdated risk assessments. We present a 5-generation family in whom results of familial mutation testing for DMD newly identified 10 obligate carriers and 28 women at risk to be carriers for DMD.

The AAN Practice Parameter by Moxley et al. notes that class I trials in Duchenne dystrophy studying daily prednisone 0.75 mg/kg or deflazacort 0.9 mg/kg provide evidence of sustained improvement in strength and function. The Practice Parameter supports a recommendation of offering corticosteroid treatment to patients but with a balanced discussion of potential risks. see page 13 Weisskopf et al. prospectively studied over 400,000 US men and found that those who served in the military had a significantly increased ALS mortality. Veterans in this cohort had served in World War II, Korea, or Vietnam, but not in the Gulf War. ⇓ see page 32 The accompanying editorial by Beghi and Morrison notes that two epidemiologic studies in 2003 showed a twofold increased incidence of ALS in Gulf War veterans. The Weisskopf results argue against the role of unknown …

This issue’s paper by Nomori and Ishihara1 describes a novel method of respiratory support for patients with muscle weakness and ventilatory failure—the still-inevitable consequence of progressive weakness in Duchenne dystrophy, ALS, and many other neuromuscular diseases. …

A high incidence of mitral valve prolapse (MVP) has been reported in patients with X-linked Duchenne muscular dystrophy. In our study MVP was present in six of 22 Duchenne dystrophy cases (27%) followed in the Maryland General Hospital Muscular Dystrophy Clinic. In addition, seven carriers of Duchenne and X-linked benign (Becker) dystrophy had evidence of MVP. Autosomal dominant transmission of MVP was present in four families. The unusually high prevalence of MVP in families with X-linked muscular dystrophy may have potential value in the recognition of the carrier trait.

Compared with normal or denervated human muscle, long chain acyl CoA was increased in muscle from patients with Duchenne dystrophy. Free and short chain acylcarnitine were reduced in Duchenne muscle, whereas long chain acylcarnitine was preserved. The accumulation of long chain fatty acid derivatives may imply disruption of fatty acid oxidation.

A man with Duchenne muscular dystrophy fathered two living children. He was 1 of 10 affected males in 5 generations. Clinical and genetic patterns, muscle biopsies, autopsy results, and serum enzymes were all compatible with the diagnosis of Duchenne muscular dystrophy. History, blood typing, and karyotypes indicated that he was the biologic father. This report gives confirmatory evidence that Duchenne dystrophy is transmitted as an X-linked defect.

Clinical and genetic studies were made on progressive muscular dystrophy in six young girls. No chromosome abnormality was observed in these patients. The pedigree of one case implied a sex-linked recessive trait, and clinical features were identical with Duchenne dystrophy. The clinical manifestations of two sisters in another family were less severe than in their brother with Duchenne dystrophy. The clinical differences among these three cases are well explained by the Lyon hypothesis. Three other cases were compatible with childhood muscular dystrophy of autosomal recessive inheritance.

The intramembrane particle density in freeze-fractured muscle fiber plasma membranes did not differ in 4 patients with Duchenne dystrophy and 4 normal subjects. However, we confirmed reported loss of orthogonal arrays and increased density of caveolae in dystrophic muscle.

Study of creatine phosphokinase (CPK) isoenzymes using a quantitative column chromatographic technique showed that there was a significant difference in serum MB isoenzyme activity between patients with Duchenne muscular dystrophy (42 mU per milliter) and those with other kinds of neuromuscular diseases (8 mU per milliter). In the Duchenne patients, the serum MB isoenzyme activity did not correlate with clinical cardiac disease. Furthermore, skeletal muscle damage produced in the rat by aortic ligation and 5-hydroxytryptamine resulted in significant elevations of plasma MB isoenzyme activty. These studies suggest that the serum MB isoenzyme activity in the Duchenne muscular dystrophy patients is probably arising from skeletal, not cardiac muscle and may reflect a distinct pathogenesis from other kinds of neuromuscular disorders.

Only two (5.5%) of 36 possible of known carriers of the gene in Duchenne dystrophy showed increased lactate dehydrogenase isoenzyme 5 (LDH-5) (L/M) in serum, while creatine kinase (CK) was increased in ten (27.8%). LDH-5 and CK did not increase simultaneously; in all five known carriers CK activity was abnormal but LDH-5 was normal. In muscle biopsy, LDH-5 was reduced in patients with Duchenne dystrophy (25.6 +/- 11.5% of total, mean +/- SD; control 59.9 +/- 10.3%; p less than 0.01) and in two of nine possible carriers, but as a group the carriers did not differ from controls: (49.9 +/- 12.1%; p less than 0.05).

Serum levels of creatine phosphokinase (CPK) and pyruvic kinase (PK) were determined in 42 controls, 57 patients with various neuromuscular disorders, and 23 female relatives of Duchenne dystrophy patients. CPK and PK enzyme activities were increased in comparable numbers of muscle disease patients and female carriers; there was no advantage in the combined use of the two tests. We did not confirm earlier reports suggesting that determination of PK is more valuable than CPK in carrier detection.