New York University Medical Center
Frank Martiniuk, Ph.D.

A collaborative effort to test animal models with enzyme and gene replacement is underway. Dr. Martiniuk is sending the human gene and acid a-glucosidase to Australia to be tested in March on cattle affected by AMD. Peter Healy, D. V. Sc., Ph.D., Principal Research Scientist, Genetic Disease Laboratory at Elizabeth MacArthur Agricultural Institute in Camden, Australia, has four affected calves on which these reagents will be used. (December, 1996)

There are five main areas of research ongoing for glycogen storage disease type II or Acid Maltase Deficiency:

Basic studies in the molecular and biochemical defects in the GAA gene from patients and how these mutations relate to the clinical presentation. (see Research Participation below)
Determination of carrier frequency in the general population to estimate the prevalence of the disease.
Establishment of clinical protocols to investigate enzyme and gene replacement therapy in the USA.
Ongoing enzyme and gene replacement studies in a bovine model in Australia.
Clinical evaluation of high-protein/fat, low carbohydrate diet and submaximal exercise combined with ephedrine on halting or reversing affects of the disease. This is being done in collaboration with Dr. Alfred E. Slonim of North Shore University Hospital. (see Diet, Exercise, and Ephedrine Study below)
Research Participation

Title of Research Study:
Acid Maltase Deficiency: Molecular Analysis MDA

Project Director:
Frank Martiniuk, Ph.D., Dept. of Medicine
New York University Medical Center
and Bellevue Hospital Center

Frank Martiniuk, Ph.D., is undertaking a study to establishing cell lines in order to determine the mutations present at the acid maltase gene. He is asking for donations of blood and urine from patients of AMD. If parents of patients want to donate samples, that would be helpful, also. The purpose of the study is to understand the genetic reason for Acid Maltase Deficiency.

The potential benefits to you or to others:
There will be no direct benefit to patients or family members of patients outlined in this study. Information gained will be of benefit to others in the future. Hopefully, the study will clarify the disease and may be useful in planning for future offspring.

If you are interested in volunteering for this study, contact AMDA for consent forms and more information.

Diet, Exercise, & Ephedrine Study
Adult Form

A study entitled “Ephedrine, nutrition, and exercise therapy in late onset acid maltase deficiency,” is being undertaken under the direction of Drs. Slonim, Martiniuk, and Rom.

Alfred E. Slonim, M.D., is Director, Center for Inborn Errors of Metabolism, Associate Professor of Pediatrics, North Shore University Hospital, Manhasset, New York.

Frank Martiniuk, Ph.D., is Research Associate Professor at New York University Medical Center, Department of Medicine, Pulmonary Division, New York, New York.

William N. Rom M.D., M.P.H., is Chief, Pulmonary Division, New York University Medical Center, New York, New York.

The study is designed to examine whether a high protein, low carbohydrate diet, moderate daily aerobic exercise, and ephedrine is effective as long-term therapy for adult AMD patients.

The studies are being undertaken at North Shore University Hospital and in the Clinical Research Center at New York University Hospital (CRC-NYC).

An initial extensive clinical assessment of the patient is obtained. Then the patient is instructed and educated on how to adhere to this type of therapy.

Patient are to be reviewed every 6 months to assess whether or not this therapy causes an improvement in muscle function, or at least slows down the progressive muscle deterioration.

This therapy will not cure the disease, but it attempts to lessen the severity and slow the course of the disease, and improve the quality of life of patients.

During each admission, the patient undergoes a medical history, physical examination, and the following tests:

graded muscle strength
muscle strength by dynamometry
timed muscle function
video recording of patient’s muscle function
pulmonary function studies
chest X-ray
ECG and echocardiogram
magnetic resonance imaging (MRI) of thigh
nutritional assessment and therapeutic guidelines
metabolic exercise assessment and therapeutic exercise guidelines
blood for biochemical tests
two 24 hour urine collections for biochemical tests
blood for molecular genetic studies
body composition measurements
The drug ephedrine has been available for many decades, previously being used mainly for asthma. It has a few side effects and is contraindicated in patients with cardiovascular disease, hyperthyroidism, hypertension, and in elderly males with prostate enlargement.

This study commenced in July 1996. So far, 8 patients have undergone the first assessment studies and are continuing on the therapy.

The first two patients to complete 6 months of therapy are to be restudied during the later part of December 1996 or the early part of January 1997. From phone discussions with all the patients, the results have been encouraging. Most of the patients “feel better,” have more energy, walk further with more stability, and rise from a chair more easily.

Two of the patients have noticed that they are able to climb stairs more easily. There have been no significant side effects. However, two patients found it difficult to sleep at night and their evening ephedrine dose had to be discontinued.

An update on patients’ responses to this therapy should be available in April after retesting of values on patients during the first quarter of 1997. This evaluation will be a based on progress during the first six months of therapy.

Update on Diet, Exercise, & Ephedrine Study
April 9, 1997

This is an update of the collaborative study of “Ephedrine, nutrition and exercise therapy in late onset AMD” being conducted at North Shore and New York University hospitals. Information was provided by the office of Dr. Alfred E. Slonim.

Since the study began in July 1996, ten patients have been started on this protocol. Six patients have now completed 6 months of therapy. One patient has withdrawn form the study because of side effects of the ephedrine and has continued with the nutrition and exercise part of the protocol. Three patients are still to complete 6 months of therapy.

Of the patients who have completed 6 months of therapy, none have shown deterioration and four have shown 10-15% improvement in pulmonary function (VC and FEV¹). All the patients have shown small improvements in some of the graded muscle strength measurements (particularly peripheral muscles) and some of the timed function studies (particularly time to walk, to climb stairs, get up from a chair). Many of the patients found that they had considerable weight loss with the therapy. Patients are now advised to increase their caloric and protein intake, in anticipation of this side effect.

The patient who discontinued the ephedrine found that she had difficulty sleeping and developed a rapid pulse. One other patient reduced her ephedrine dose to 2 capsules/day because she had difficulty sleeping. All other patients tolerated the ephedrine well. Prior to therapy, three patients had bowel urgency with diarrheal stools soon after eating. With ephedrine this symptom disappeared or was greatly reduced.

Two patients were not started on the therapy because of severe respiratory insufficiency and sleep apnea. These patients may be considered for therapy when more patients have been studied.

In summary, the initial impression is that nearly all patients were modestly benefited by the therapy. Close adherence to all aspects of the therapy, i.e. nutrition and exercise as well as ephedrine, was essential to achieve any improvement.

Update on Diet, Exercise, and Ephedrine Study
April 1998

This is an update of the collaborative study of “Ephedrine, Nutrition and Exercise Therapy in Late Onset AMD” being conducted At North Shore and New York University Hospitals. Information was provided by the office of Dr. Alfred E. Slonim.

Since the study began in July, 1996, nineteen adult AMD patients have been started on this protocol. Nine (9) patients have now completed 12 months of therapy, including 5 patients who have received therapy for a least 1 1/2 years. Two patients have received therapy for greater than 6 months, and 7 patients have started therapy over the last 6 months. One patient discontinued therapy after 3 months because of side effects of the ephedrine. Of the 11 patients who have received therapy for more than 6 months, none have shown deterioration and 9 have shown small improvements in areas such as graded muscle strength, timed function studies and pulmonary function. As reported earlier, many of the patients experienced considerable weight loss after starting therapy, apparently due to the increased rate of metabolism induced by the exercise and ephedrine. Consequently, patients are now strongly advised to increase their caloric and protein intake by very large amounts to prevent this weight loss. Some of the patients are consuming greater than 3500 calories per day and in one case greater than 5500 calories per day, without evidence of excessive weight gain. Patients have all experienced an increase in their energy, allowing many of them to return to a full day of work and activity. This newly acquired energy seems to have contributed to the patients’ ability to comply fully to the therapy protocol. Most patients find complying with the daily exercise to be the most difficult part of the therapy. However, when patients do not exercise regularly, they find their energy level decreasing.

Three patients who had experienced bowel urgency and diarrhea prior to starting ephedrine therapy have shown much improvement in control of bowel function. Previously, their bowel dysfunction interfered with their ability to plan a normal day’s activity. However, since starting therapy they have been able to return to normal activities such as attending college and working a normal full day.

In addition to the above 19 patients, a further 6 patients are continued to be treated with nutrition and exercise therapy, but have not started ephedrine therapy as they have not met the criteria for inclusion in the study.

Ten childhood Acid Maltase Deficiency patients are also being treated at North Shore University Hospital. All of these patients have also received low dose ephedrine therapy. Initial impression indicates that the ephedrine has benefited these patients in a similar fashion to that observed in the adult patients. These patients have received ephedrine for less than 6 months, so that long term effects of this drug in this younger age group are not available.

In summary, the initial impression that nearly all the patients were benefited by this form of therapy has been maintained. The need to comply to all the aspects of the therapy, including nutrition, exercise and ephedrine has been re-enforced.

(December 1999—This study is still ongoing.)