Over the years, infectious diseases have been brought under control due to the development of powerful antibiotics. This has resulted in increasing the average life span by several decades. The increased life span provides an opportunity for genetic diseases to clinically manifest themselves. In addition development of new technologies and diagnostic procedures enable early diagnosis of a large number of genetic diseases. The increasing awareness about genetic diseases amongst the medical practitioners and common man has also led to renewed emphasis on their diagnosis and management, wherever possible. Further, the Human Genome Project has provided tremendous impetus to the science of genetics and its futuristic applications.

Traditionally, hereditary conditions have been classified under three major categories - chromosomal disorders, single gene disorders and multifactorial disorders.

Chromosomal disorders involve numerical aberrations or structural aberrations. This could be in the form of an addition of a whole or a part of a chromosome. This results in trisomy. The chromosomal aberration could also be in the form of a deletion of a whole or a part of a chromosome. This causes monosomy. A classic example of a trisomy. The chromosomal aberration could also be in the form of a deletion of a whole or a part of a chromosome. This causes monosomy. A classic example of a trisomy is Mongolism and that of a monosomy is Turner Syndrome. Table 1 shows the load of a variety of genetic diseases, which are encountered, in clinical practice. They usually result in a loss or a gain of several functions and lead to a devastating outcome. In single gene disorders a single genetic entity is affected leading to a loss of a unit function. Multifactorial disorders involve more than one genetic entity leading to a disease, which in general is more severe than a single gene disorder. A fourth category of ‘acquired somatic genetic disease, has now been added. Not all genetic errors are present from conception. Many billions of cell divisions occur in the course of an average human lifetime. During these divisions there is a possibility for both single gene mutations to occur, because of DNA copy errors, and for numerical chromosomal abnormalities to arise as a result of errors in chromosome separation. These errors are now known to play a significant role in causing cancer and they probably also explain the rising incidence with age of many other serious illnesses as well as the aging process itself.

Diagnosis of the genetic disease is the first step. This step is complicated because of several factors. A genetic disease is episodic in nature. This means that the disease may not manifest all the time. The sample collection from the patient, therefore, becomes critical as the sample has to be preferably collected during the episode. As this is usually difficult, analysis has to be carried out on at least two or three samples collected at various times. One of these samples has to be a fasting sample.

There are a variety of approaches to the diagnosis of genetic disease. A patient with gross structural features would require chromosomal analysis. He will also require a large number of biochemical tests. Karyotyping or chromosomal analysis would require a good tissue culture facility, a sophisticated microscope with photographic attachment. Biochemical investigations range from simple chemical tests to using highly sophisticated equipments such as HPLC, GC-MASS, fluorimeter, etc. with a number of other instruments, which are routinely required. Molecular diagnosis requires PCR, RT-PCR, a variety of electrophoresis gadgets, transilluminater, gel documentation system, etc. The laboratory set-up is capital intensive. In addition to the laboratory a geneticist also requires a facility where samples for prenatal diagnosis could be collected. This includes an operation theatre for the collection of chorionic villi, amniotic fluid, abortus material and ova for IVF. Preimplantation genetic analysis can also be done in the same set-up.

Once the diagnosis of the disease is established the next step is to do the management of the patient if the disease is manageable. A sizeable proportion of Inherited metabolic Diseases (IMDs) is manageable. A basic concept in the inborn errors is that the biochemical abnormality produces the clinical abnormality. If so, correcting the biochemical imbalance will improve the clinical condition. The IMD could be due to the substrate accumulation leading to the generation of toxic metabolites. Restricting the input of the accumulating substrate and the disposal of the toxic metabolites would help the patient. The metabolic block will also result in the reduction of the product. Supplementation of the depleted product will lead to the correction of the metabolic imbalance.

Several enzyme proteins are inactive by themselves (apoenzymes) but get catalytic activity when combined with a vitamin as a cofactor (coenzyme). The inactivity of the enzyme could be due to unavailability of the cofactor. In such cases the vitamin can be supplied in the diet to correct imbalance.

Let us see one such example from our department.

Coenzyme binding
If the coenzyme is in short supply apoenzyme will not gain catalytic activity till the concentration of the coenzyme is adequate. Increasing the concentration of the coenzyme several fold results in restoring the normal metabolic balance. This is accomplished by supplementing the diet with large quantities of the coenzyme.1

This situation may arise if the bound coenzyme is irreversibly lost, as the mechanism for its recycling has become defective. A classic example of the loss of coenzyme is when biotinidase enzyme becomes defective.2,3 All apocarboxylases bind covalently with biotin. An enzyme called Holocarboxylase synthetase catalyses this reaction. The bound biotin is released from the Holocarboxylase by the action of biotinidase when the reaction catalyzed by a carboxylase is over. A defective biotinidase is unable to release the bound biotin, which thus goes out of circulation and is excreted in urine as biocytin. This loss of coenzyme, biotin, is replenished by adding large quantities of biotin to the diet. All carboxylases require biotin as a cofactor. Lack of biotin, therefore, affects their function leading to a disease called multiple carboxylase deficiency (MCD).4

In this disease the patient suffers from total alopecia with erythematous patches all over, ataxia, multiple seizures, episodic metabolic acidosis, muscular hypotonia with elevated excretion of several organic acids. Biotinidase deficiency usually presents in infants after three months of age.

A six-month-old child, SS, was admitted to our hospital with multiple seizures and hypotonia. Four older siblings of the child had died between three months and six months of age for which the diagnosis of the cause of death remained unknown. Analysis of the urine for organic acids showed elevated levels of 3-methyl crotonyl glycine, 3-hydroxyisovaleric acid, methyl citric acid and 3-hydroxypropionic acid. The child had elevated blood levels of lactic and pyruvic acid. The child was put on 5 mg BD of biotin. The convulsions stopped on the third day. The child showed normal activity for his age and was discharged from the hospital.

Four years later the boy was readmitted to our hospital with total alopecia, large erythematous patches around the waist, convulsions and inability to walk and understand simple commands. The boy was brought to this stage as his daily dose of biotin was stopped for two months. Analysis of his urine sample gave the typical biochemical picture of biotinidase deficiency. SS was put back on a higher dose of 10 mg BD of biotin. SS, before and after the management, is shown in Figs. 1 to 7.

Figs. 1 - 7 : Progression of clinical manifestations in a patient with Biotinidase deficiency. Figs. 1 and 2 show the patient at 4 months and 3 years of age. Figs. 3 and 4 show the patient after Biotin was withdrawn for 2 months. Figs. 5 and 6 show the same patient 2 months and 8 months after Biotin supplement. Fig. 7 shows the patient at 18 years of age.

Stimulation of alternative pathways can be achieved by certain nutritional supplements.⁶ Detoxification of toxic metabolites is yet another way of correcting the imbalance.⁷

Nutritional management remains the principal component of the treatment of many IMDs of amino acid, organic acid, carbohydrate and fatty acid metabolism.^8-11 While some sources of energy and amino acids are restricted, adequate intake of energy and amino acids must be provided to have normal or near-normal development of the patient. Energy requirements increase when the intake of intact protein is replaced by an equivalent of L-amino acids.¹² If the amino acids are administered in one single dose, they are oxidized to a greater extent than when the same dose is divided over 24 hours. Nitrogen balance improves considerably when L-amino acids are given in several doses with a small quantity of intact protein.¹³

Dietary restrictions required to correct imbalances in metabolism that occur in IMDs also require the use of elemental medical foods. Consequently they should be designed to supply 80 to 100% of all the required major trace elements, vitamins, essential amino acids, fats and carbohydrates. Several companies have come out with a number of formulations each designed for a specific IMD.¹⁴ Such facilities also should be made available.

Despite these advances a lot more needs to be done in terms of running screening and management programmes at various levels, if the Indian society is to be freed of the impending burden of genetic disease. Hard figures on the overall incidence or prevalence of inherited metabolic diseases (IMDs) in India are difficult to get as no systematic surveys have been done. Indian data on IMD is, therefore, scanty. In 1980 there were 77 genetic centres in the country, which were involved in providing some kind of genetic service to the patients.¹⁵ Only 22 of these centres were attached to the hospitals. The rest were located in the university departments of zoology or anthropology or psychology. Psychology departments provided IQ tests and analyzed the patient through the psychological point of view. Genetic services in zoology and anthropology departments provided only chromosomal analysis. Out of the 22 centres, which are attached to hospitals, most provided a small mix of metabolic work-up to patients. In all of these centres the major thrust is on looking for numerical or structural chromosomal abnormalities. Not much attention is given to metabolic work-up of the patient. Even today there are very few centres in India that provide reasonably comprehensive genetic metabolic tests. A majority of the genetic centres work on projects, which are funded by a Government or a semi government agency and, therefore, have their emphasis laid on basic research, which is not directly related to the diagnosis and management of genetic disease.

There are a limited number of studies on the frequency of metabolic disorders among subjects with mental retardation.¹⁶ According to the study carried out by the Indian Council of Medical Research (ICMR) in five centres to determine genetic aetiology of mental retardation. 43% of 1314 cases had metabolic disorders.17 Of these, 0.5% was found to have amino acid disorders. Previous study on 4461 symptomatic patients showed that the commonest amino acid disorders were hyperglycinaemia (55), homocystinuria (32), alkaptonuria (18) and maple syrup urine disease (15).18 Other metabolic studies on mental retardation in the All India Institute of Medical Sciences (AIIMS), Delhi and KEM Hospital, Mumbai revealed that common disorders were mucopolysaccharidosis (37%), Lysosomal enzyme disorders (24%), Wilson disease (14%), glycogen storage disease (4%) and galactosaemia (5%).19 The incidence of congenital hypothyroidism is higher than the West due to the high prevalence of iodine deficiency in many parts of India.20 A small Parsi community has a very high prevalence of G-6-PD deficiency. This is so because of the high incidence of consanguineous marriages in this community. According to the ICMR multicentric study about 5% of genetic causes resulting in mental retardation are due to IMD. Studies carried out earlier in 1984 on the clinical, biochemical and cytogenetic studies in mental retardation have quoted a figure of 0.5 to 2.5%.21 Sindhi and Lohana Communities have a high incidence of thalassaemia, which is significantly higher than what is observed in the general Indian population (Table 1).

Table 1 : Total load of genetic disease. The bracketed figures indicate that they are, at best, gross approximations

The data available from screening programmes carried out in western countries is restricted to only a few selected disorders such as phenylketonuria (PKU), maple syrup urine disease (MSUD), hypothyroidism, etc. The actual incidence of IMD as a group is estimated to be about 1 to 2 per cent of live births.22 A break down of the total frequency of IMDs is shown in Table 1. This is only a crude estimate and tells us very little about the burden on the community or its health services. Many of the conditions are lethal at birth or in early life while some only appear later in life.

Another approach to assessing the incidence of IMD is to analyze the frequency of genetic diseases and congenital malformations among patients in paediatric hospitals. A study of this type was done in Montreal.23 They analyzed a sample of 12801 admissions to a paediatric hospital between 1969 and 1970. Genetic admissions accounted for 11.1% and congenital malformations 18% of the total. Their overall estimate was that, about a third of all admissions were for diseases with a genetic component. They also found that 70% of the patients with multiple admissions had genetic illnesses or congenital malformations. This study provides clear evidence that genetic diseases put serious burden on the health services. Subsequently, several studies have confirmed these findings and, in addition, have shown that genetic disease is the important cause of death under the age of 15 years.
Enzyme replacement therapy has been in practice for some time.24 the conceptual and technological revolution in the realm of DNA has raised the real possibility of direct gene replacement in human genetic diseases. In fact gene therapy has been done for a few diseases.25 This therapeutic avenue, which would have been considered extremely visionary, is now a real possibility. This will provide us with the ultimate weapon to treat inherited metabolic diseases.

Human genetics is in a revolutionary phase worldwide, emerging as a core area of biological sciences and human health. The modern genetics is going to find its way to every nook and corner of the practice of medicine, human evolution, history, anthropology, forensic science, etc. This is going to revolutionize clinical practice in the coming years. Every few weeks new study reports of a possible link between a gene and human behaviour appear. Indian population, which represents 1/6th of the world population, provides a goldmine for genetic studies.

A broad-based, comprehensive programme will diminish IMD-related morbidity, mortality and handicap to an acceptable level. Even an orthodox country like Saudi Arabia has realized the importance of screening programmes and has now made it mandatory for couples to undergo genetic investigations before conception. At the medical level services developed should have a general appeal. A number of newly developed tests and modalities have much wider applications in the field of IMDs and physicians should find them instrumental in diagnostic work-up of their patients. Private practice in genetics is an intellectual intensive, lucrative and rewarding commercial activity providing high entry barriers and hence very little competition. A number of IMDs are still not included in the present screen that is used in our genetic centres. The possibilities are enormous. The field is wide open. A variety of clinical material is available for diagnosis, management, genetic counseling and research. The future is inviting.

References

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Head, Genetic Department, Bombay Hospital Institute of Medical Sciences, Bombay Hospital, Mumbai - 400 020.