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In-Depth Coverage of Issues Concerning the Global Sikh Community Including Self-Determination, Democracy, Human Rights, Civil Liberties, Antiracism, Religion, and South Asian Geopolitics
About Leukodystrophy
Leukodystrophy (leuko=white matter; dystrophy=degeneration) is a hereditary (i.e. genetic) degenerative nervous system disorder. Most of leukodystrophy's victims are children. As a result, most of the research on leukodystrophy that has taken place thus far has been in the context of Child Leukodystrophy.
Since the mid-1990s, Surendra's son, Puneet, has been interacting with several leading researchers worldwide in an effort to keep abreast of the latest findings in the area of Adult Leukodystrophy. His findings are continually reported on this page.
To learn more about leukodystrophy, visit the United Leukodystrophy Foundation.
About Genetics
Humans have trillions of cells, each of which has 23 pairs (i.e. 46) of chromosomes. The only exception are the sex cells - the ovum and the sperm - each of which contain only 23 chromosomes. Each chromosome has a D.N.A. (deoxyribonucleic acid) strand, a double-stranded helix linked via weak bonds between cytosine and guanine (C.G.) on the one hand and adenine and thymine (A.T.) on the other. These linkages are called base pairs (B.P.). The gene itself is a segment of a D.N.A. molecule and can have a few hundred to several million base pairs. The human genome (the complete set of human D.N.A.), for example, comprises some 30,000 genes which amounts to some three billion base pairs. The genetic instructions encoded in these pairs provide the rules for the creation of various proteins that perform most life functions. Except for mature red blood cells, all human cells contain a complete genome.
Each gene is an instruction for a particular characteristic or trait, such as blue eyes, blood type A, black hair, etc.
The evolution of species involves the discarding of selected genetic structures (or genes) and the formation of new ones. Interestingly, the rejected genetic structures remain available (although unused) and contain the organism's entire history of genetic evolution from lower life forms. Individual genes are responsible for observed phenomenon (disease or talent). Genetic disorders are the result of damaged genes. Genetic damage may either be inherited (e.g. breast cancer or leukodystrophy) or acquired (e.g. lung cancer, caused by excessive smoking).
For further information on genetics, consult Genomics 101: A Primer, maintained by the Human Genome Project. Especially useful is their Dictionary of Genetic Terms.
About Genetic Disease Inheritance Patterns
Although there are several genetic inheritance patterns, only the single-gene patterns are discussed here since it is assumed that all forms of leukodystrophy are controlled by a single pair of genes.
All genes (except those that make up the male sex chromosome) come in pairs, formed by putting together one gene from each parent. A genetic defect is typically the result of a non-matching pair.
A person carrying a defective gene is referred to as affected if diseased and carrier otherwise.
Genetic defects exhibit the following major inheritance characteristics:
Autosomal implies that the defect is gender-neutral, i.e. it impacts males and females equally. Of the 46 chromosomes that make up the human D.N.A., all except the two sex chromosomes (two X chromosomes in females and one X and Y chromosome each in males) are present in both males and females and are called autosomes. Diseases caused by genes contained in autosomes are termed autosomal.
Recessive implies that if one of the genes in the pair is defective, then the owner of the pair of genes is a carrier. If both genes in the pair are defective, then the owner of the pair of genes is affected. This can only happen if both parents of the affected person are at least carriers. Metachromatic Leukodystrophy (M.L.D.) is an example of an autosomal recessive form of leukodystrophy.
As illustrated below, the chances of two carriers of a recessive genetic defect producing an affected child are 1 in 4 (25%).
If we use N to reperesent a normal gene and D to represent a defective recessive gene, then the male parent's genes can be represented as NmDm and the female parent's genes can be represented as NfDf. A child of such parents can inherit any one of the following four combinations (additional permutations can safely be ignored): (1) NmNf, (2) NmDf, (3) DmNf, (4) DmDf.
Combination (1) will produce a normal (non-carrier) child (i.e. a 1 in 4 or 25% chance), combinations (2) and (3) will produce a carrier child (i.e. a 2 in 4 or 50% chance), and combination (4) will result in an affected child (i.e. a 1 in 4 or 25% chance).
Dominant implies that if one of the genes in the pair is defective, then the owner of the pair of genes is affected. This can happen even if only one parent is affected. Adult-onset Autosomal Dominant Leukodystrophy (A.D.L.D.) is an example of an autosomal dominant form of leukodystrophy. In 1999, linkage analysis localized A.D.L.D. to a 4cM region in chromosome 5q31 and the A.D.L.D. gene is being isolated through fine genetic mapping. It is much harder to isolate the gene, given that there are only 46 chromosomes and some 30,000 genes.
As illustrated below, the chances of inheriting a dominant genetic defect from one parent are 2 in 4 (50%).
Assuming that the male parent is affected, if we use N to reperesent a normal gene and D to represent a defective recessive gene, then the male parent's genes can be represented as NmDm and the female parent's genes can be represented as N1fN2f. A child of such parents can inherit any one of the following four combinations (additional permutations can safely be ignored): (1) NmN1f, (2) NmN2f, (3) DmN1f, (4) DmN2f.
Combinations (1) and (2) will produce a normal (non-carrier) child (i.e. a 2 in 4 or 50% chance) and combinations (3) and (4) will produce an affected child (i.e. a 2 in 4 or 50% chance).
Autosomal and dominant are mutually exclusive.
Although the above discussion has been presented from the perspective of defective genes, the inheritance patterns apply equally to normal genes. For example, the genes that result in blue eyes and blond hair are recessive and those that result in brown eyes and dark hair are dominant. Therefore the offspring of one blue-eyed, blond-haired parent and one brown-eyed, dark-haired parent is more likely to be brown-eyed and dark-haired.
X-Linked implies a gender-specific inheritance pattern. Although females inherit two X chromosomes (one from each of their parents), males inherit one Y chromosome (from their father) and one X chromosome (from their mother). The X and Y chromosomes both contain many genes that the other chromosome does not. Because males have only one X chromosome, they only have one set of the genes that reside there. Therefore, if a man inherits one recessive copy of a gene on his X chromosome, he develops that trait because he has no additional copies of that gene. Thus, men are more likely than women to get many disorders associated with the X chromosome. Diseases that are caused by mutations on the X chromosome are called X-linked diseases. Hemophilia, a blot clotting disorder, and color blindness are X-linked disorders that are far more common in men than in women.
For further details about genetic diseases, consult the standard textbook Thompson & Thompson Genetics in Medicine by Robert L. Nussbaum et al. When dealing with rapidly evolving areas of research such as this, it is always best to try and get the latest edition available. As of January 2004, the latest edition is the sixth.
Surendra's Symptoms
Surendra started to exhibit symptoms in the early-to-mid-1990s. The primary symptom was gradual deterioration of muscle control. Initially, the loss of muscle control meant reduced steadiness while walking. With the passage of time, walking became more and more of a challenge. When Surendra arrived in Mumbai on the occasion of Puneet's marriage (July 4, 1996) he was transported from the airport terminal to the parked car in a wheelchair. At that time he could walk only very short distances, and that too with support. Since then his dependence on the wheelchair steadily increased. Since 2002 or so he has been completely bed-ridden.
Another symptom, likely related to loss of muscle control, has been reduced control on speech as well as emotion.
Surendra's Diagnosis
Doctors in Australia have diagnosed Surendra's illness as Familial Leukodystrophy. This diagnosis was the first time that the disease afflicting the family actually received a name. Tests for the enzyme Arylsulphatase A (also spelt Arylsulfatase; see below) conducted in 1994 and 2002 show a normal activity level (typically measured in urine or blood samples).
Family Medical History
Family members that have perished to what is believed to be leukodystrophy include Surendra's father, Gurbachan, elder brother, Joginder (died in late 1996), and elder sister, Jaswant Kaur Sodhi (died in 1997). Jaswant's sons Gurpreet (Jugni) and Manpreet (Raja) began experiencing what are believed to be leukodystrophy symptoms in early 2002. Surendra's elder sister, Tej Kaur Bedi, died at an early age in a traffic accident. Tej's son, Har Kanwar (Gulu), began experiencing what are believed to be leukodystrophy symptoms in early 2002. Surendra's eldest brother, Rana, and his descendants appear to be free of symptoms.
Gurpreet's Diagnosis
Dr. Bal N. Apte, a human genetics expert in Mumbai, has diagnosed Gurpreet with M.L.D. (see above). The diagnosis is claimed to be supported by reduced activity levels of the enzyme Arylsulphatase A. Doctors have therefore prescribed medication and dietary changes designed to raise the enzyme's activity level. A reduction in this enzyme's activity level is said to cause the erosion of the mylin sheath that protects the nerves. The same diagnosis has been offered in the cases of Manpreet and Har Kanwar.
What Dr. Apte Requires in Order to Perform an Initial Diagnosis
One might ask, quite legitimately, "Why can't I get the enzyme test done where I live and simply send the results to Dr. Apte?"
Dr. Apte's reason for requesting a blood sample (as detailed below) is that he has devised a unique technique for measuring enzyme activity. However, pending the imminent publication of his paper detailing this technique, it would be inappropriate to disclose any further information about the methods he uses.
In order to perform an initial diagnosis, Dr. Apte requires a 10 milliliter (m.l.) sample of heparinised blood and a 50 milliliter (m.l.) sample of urine. The samples may be collected at any time of the day. The urine sample should be kept as cold as possible, preferably frozen. The blood sample should not be frozen but should be kept at a temperature of 4 to 6 degrees centigrade via the use of a good thermos.
The blood sample must reach Dr. Apte within 48 hours of being collected. He recommends the use of D.H.L. (a courier service) for expedient delivery to his office address as detailed below. Alternatively, if hand-delivering the samples, store the samples in a refrigerator (blood) / freezer (urine) until they can be delivered to his office, which opens at 9 a.m. on weekdays.
Dr. Bal N. Apte, M.Sc., Ph.D., F.R.S.H. (London)
Professor and Head Medical Geneticist
Department of Human Genetics
Room Number 15 (15th Floor)
Medical Research Centre (Rear)
Bombay Hospital
Mumbai, India 400 020
Bus: 22-206-7676 x 361
Res: 22-515-1226
Email: balnapte@hotmail.com
Remedies
Although Dr. Apte's prescriptions to each of the three above-mentioned affected individuals might vary based on individual levels of fitness and other accompanying disorders, the general flavor is similar. He has recommended complete restraint from high-protein foods such as non-vegetarian foods and milk products. He has also advised limited intake of sugar per session so that no more is injested than what the body can immediately process (this is, of course, standard dietary advice these days). He has provided a certain medication (more on this as the details come forth) in its raw crystal form as well as several vitamins from the B family. All three of the above-mentioned affected individuals have reported improvements in physical balance, gait, control on speech and emotion.
It is generally acknowledged that Dr. Apte's medication and treatment is aimed primarily at checking further deterioration. Not much hope is harbored that existing levels of deterioration can be reversed. It is, therefore, natural to be skeptical about reports of perceived improvement in symptoms.
Analysis
Given that the disease is clearly hereditary in nature, it seems unlikely that different members of the family should be inflicted by different strains of leukodystrophy. Consequently, one cannot help but wonder if Dr. Apte's diagnosis is too optimistic. Therefore, it would seem that the real test in these cases should be not whether the treatment results in raising the enzyme's (Arylsulphatase A) activity level but rather whether symptoms are reversed, or at least checked. It would conceivably require the passage of several months before conclusive change (or absence of change) in symptoms can be observed.
Discussion with Dr. Mahoney
On May 31, 2003 Puneet met with Dr. Apte (see above) and Dr. Maurice J. Mahoney, professor of genetics at Yale Univeristy. Dr. Mahoney performed the following calculation to determine the probability that four out of five of Gurbachan's (see above) offspring could be affected by a recessive genetic disorder.
Here, A represents the probability of a normal offspring and B that of an affected offspring. As demonstrated above, assuming carrier (rather than affected) parents, A=3/4 and B=1/4. In the expression (A+B)5, which expands to A5 + 5A4B + 10A3B2 + 10A2B3 + 5AB4 + B5, the term 5AB4 represents the probability we had set out to calculate. Substituting for A and B, we arrive at a probability of 1.5%.
Once we make corrections for the fact that Gurbachan was affected (rather than a carrier), and use A=2/4 and B=2/4, the probability evaluates to 15.6%.
To this already low probability when one adds the probability that two of Gurbachan's offspring, Tej and Jaswant, known to have affected offspring, both married spouses who were carriers (despite the fact that neither spouse was from within the family; one was a Bedi and the other a Sodhi), it seems safe to rule out a recessive genetic inheritance pattern and concentrate instead on dominant flavors of leukodystrophy, of which the only known one is A.D.L.D. (see above).
Dr. Mahoney referred Puneet to the following genetics experts:
Lamba Family's History of Leukodystrophy
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More
There's much more to come. I am studying medical history documents meticulously prepared by Gurpreet as well as medical reports for Gurpreet and Surendra. My findings will be summarized here. If you're interested in updates on the progress we're making as an extended family, please return to this page often. Also, please feel free to email me (puneet@sikhtimes.com) with queries, comments, and/or updates for inclusion on this page.