ANOTHER LOOK AT G6S
by Karen Bailey, Calm & Gentle Dairy Goat Farm
September 15, 2008
My first introduction to G6S was in a buck born years before I ever heard about G6S. Ringo was one of triplets. His brother died during the difficult birth. He and his sister Rose were beautiful, the prettiest kids I had ever raised. Due to my inexperience Rose went down with coccidia and I almost lost her. She recovered but with the stunted growth of a coccidia survivor. Ringo continued to grow and at about a year old was the pride of my eyes. He was so tall, well filled out, and as healthy as could be. A few months later I went out to feed him in the morning and he was down thrashing around in convulsions. He had been perfectly fine the night before.
I called the vet. The vet, not knowing exactly what was wrong tried the shotgun approach - banamine for pain (in case of Enterotoxemia or Urinary Calculi ), an antibiotic (in case of infection), and thiamine (in case of Goat Polio). Within 20 minutes Ringo seemed to come to himself, stood up, shook himself, and peed. So we continued him on thiamine through the course of treatment and he seemed to be fine. A month later he started staggering around, was treated with thiamine, got better, but seemed to have lost condition. Every month, then in intervals of 3 weeks, then every other week he would have an episode, and his condition continued to get worse. His appetite continued to be good and he did go into rut and bred a few does, but he got skinny, his hair became rough and dry looking, his eyes looked sunken, and he continued to need the thiamine treatment more and more often. Finally I realized that although treating him got him back on his feet, he wasn't getting any better, but worse with each incident. I had him put down.
Two years later I came across an article about G6S. I wondered if that is what could have been wrong with him. I had blood tests done on his sister, and his daughters. His daughters were indeed Carriers, every one of them. Thankfully his sister was Normal. Ringo's parents were both gone by then, but I now suspected they both were Carriers. All daughters and half siblings to Ringo were eventually culled from my herd, and I checked the G6S status of all the other non-related goats that had been brought into my herd. Most had been already tested by the breeder I bought them from, and the rest I tested. I now had a G6S Normal herd.
More recently I contacted another breeder and reserved a buck kid from some breeding she was doing using AI to bring forward some really nice older genetics. There were twin bucks, and I decided to buy them both. Since the other breeder had never tested for G6S, I had them tested myself. With great shock and dismay I discovered that both kids were G6S Affected. At first I seriously considered putting them down immediately, after all, when told of the test results, the other breeder was willing to replace them or refund my money. But I had chosen them because I truly felt that they would contribute greatly to my herd. I really didn't want to lose their genetics.
After much thought I decided to proceed in this manner: First, if they lived until breeding age, I would use them to three does I knew to be G6S Normal. All kids from those breedings would be Carriers, so I would keep only one or two doe kids, culling anything else. Next I would breed the carrier doe(s) to a G6S Normal buck and test all the resulting kids for G6S. In this generation I would cull all carriers and keep only G6S Normal, bringing my herd back to G6S Normal status.
In order to put this into action, I wanted to know more about G6S and what exactly was happening in the body. I wanted to know if there was anything I could do to prolong the lives of my Affected bucks, at least until they had produced doe kids. I began to research all the available information about G6S. There have been many studies on G6S in Nubian dairy goats because G6S also afflicts a small percentage of the human population, and the dairy goats became the study model for understanding the human condition. In humans G6S is called Sanfilippo syndrome (type D).
So what is this condition referred to as G6S? It is a deficiency of the enzyme called N-acetylglucosamine-6-sulfate. G6S is a lysosomal storage disease. A what? I needed a more detailed explanation to understand this. So the following explanation, as I relay what I understand of it, may seem simplistic if you're a doctor or a veterinarian, but my goal is to explain this to fellow Nubian dairy goat breeders, as well as to myself.
Every body part and system in the body is made up of cells. Each cell in the body has a specific job to do, with many intricate, mostly biochemical, steps to do that job. G6S is not localized in any one cellular system, but it affects every cell in the body simultaneously.
One protein type molecule called heparan sulfate is found on and within each cell wall. In normal cellular activity heparan sulfate is used by the cell, then broken down to be recycled. The enzyme that is supposed to break heparan sulfate down is G6S.
In a Normal presentation there are two copies of work orders and instructions to make the enzyme G6S, one on each DNA strand. In a Carrier for the G6S mutation there is one copy, and at that place on the corresponding DNA strand where there should be a second copy there is just coded nonsense. G6S is made by the good copy and supplies the cells, while the mutated copy just reads nonsense and the code is ignored. In a G6S Affected goat both places where the instructions should be coded are just nonsense and no G6S is produced.
When no G6S is produced the heparan sulfate simply cannot be broken down for recycling. Some of it is excreted from the body by way of the urinary system. The rest of it is stored in the cell. Eventually the buildup of heparan sulfate will cause the cell to be unable to do it's job.
Clinical symptoms shown by the Affected goat depend on which cells, within a system or group of cells forming an organ are put out of commission first. All of the following have been documented as symptoms of G6S: small stature, lack of muscling, immune system problems, heart problems, reproductive problems, neurological problems, pneumonia, and death before 3 to 4 years of age, sometimes before 2 months of age.
Fortunately there is a genetic test available to detect this G6S mutation. When a blood sample is submitted, the results will read Normal, Carrier, or Affected. From knowing the status of your goats, you can manage the problem and remove the G6S curse from your bloodlines. A tested G6S Normal goat bred to another G6S Normal goat will always produce G6S Normal kids. A G6S Normal goat bred to a G6S Carrier will produce both G6S Normal and G6S Carrier kids. When two G6S Carriers are bred together, there is a possibility of producing G6S Normal kids, G6S Carrier kids, and G6S Affected kids. G6S Affected goats should not be used unless bred to a G6S Normal goat, and only with the knowledge that all the resulting kids will be Carriers.
The problem I see in not testing is that even if you manage to dodge the bullet and never have a symptomatic G6S Affected goat that you know of, not every time, but more often than not, when Carriers are bred to each other, more Carriers are produced, not to mention the less frequent but possible Affected kids. This mutation can spread throughout the Nubian gene pool making the incidence of Affected goats more likely. Speaking from personal experience, it is heartbreaking to see a promising young goat go down with this and die, there being nothing you can do for them. By conscientiously testing for G6S and selecting for G6S Normal goats, the Nubian breed will ultimately be improved in the succeeding generations.
Sources and Further Reading
1) A Genetic Defect and its Management, Author: Dagny Vidinish.
2) What is G-6-S??, by Jessica Howard, Jekuthiel's Nubians.
3) Sanfilippo Syndrome: Current knowledge and perspectives for therapies, This publication is based on interviews lead in 2006 by Elise Peltekian, PhD, and Karen Aiach, Alliance Sanfilippo, President. It has been fully elaborated by Dlise Peltekian., December 2006.
4) Mucopolysaccharidosis Type III, Author: Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor of Pediatrics, Department of Pediatrics, Olive View-University of California Los Angeles Medical Center, Article Last Updated: Apr 24, 2008.
5) Determination of the molecular defect of caprine N-acetylglucosamine 6-sulfatase deficiency, Author: Leipprandt, J.R. ; Jones, M.Z. ; Cavanagh, K.T. [Michigan State Univ., East Lansing, MI (United States)][and others], Publication Date 1994 Sep 01.
6) Morphological, biochemical and molecular biology approaches for the diagnosis of lysomal storage diseases, by Christopher D. Warren, Joseph Alroy.
7) Determination of genotypic frequency of caprine mucopolysaccharidosis IIID, by Heidi M. Hoard, Jeffrey R. Leipprandt, Kevin T. Cavanagh, Nancy K. Truscott, Beverly A. L.Levene, Karen H. Friderici, Margaret Z. Jones.
8) Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics.
[My paper] M Z Jones, J Alroy, J C Rutledge, J W Taylor, E C Alvord Jr, J Toone, D Applegarth, J J Hopwood, E Skutelsky, C Ianelli, D Thorley-Lawson, C Mitchell-Herpolsheimer, A Arias, P Sharp, W Evans, D Sillence, K T Cavanagh
Department of Pathology, Michigan State University, East Lansing 48824, USA.
9) Caprine mucopolysaccharidosis-IIID: clinical, biochemical, morphological and immunohistochemical characteristics.
[My paper] M Z Jones, J Alroy, P J Boyer, K T Cavanagh, K Johnson, D Gage, J Vorro, J A Render, R S Common, R A Leedle, C Lowrie, P Sharp, S S Liour, B Levene, H Hoard, R Lucas, J J Hopwood
Department of Pathology, Michigan State University, East Lansing 48824, USA.
10) Caprine mucopolysaccharidosis IIID: a preliminary trial of enzyme replacement therapy.
[My paper] E Downs-Kelly, M Z Jones, J Alroy, K T Cavanagh, B King, R E Lucas, J C Baker, S A Kraemer, J J Hopwood, Division of Human Pathology, College of Human Medicine and College of Osteopathic Medicine, Michigan State University, East Lansing 48824, USA.
11) Caprine mucopolysaccharidosis IIID: fetal and neonatal brain and liver glycosaminoglycan and morphological perturbations. [My paper] Margaret Z Jones, Joseph Alroy, Erinn Downs-Kelly, Rebecca E Lucas, Stacey A Kraemer, Kevin T Cavanagh, Barbara King, John J Hopwood, Division of Human Pathology, Colleges of Human and Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, USA.
12) Michigan State University, Margaret Z. Jones, M.D., Final Report, September, 2001.