Genetic Diseases

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Approximately 1 out of 50 live newborns has a serious congenital disease, 1 out of 100 a single gene disorder, and 1 out of 200 a chromosomal abnormality. Around 30% of hospitalizations of children is due to prenatal conditions, most of them genetic. Around 33% of perinatal mortality is due to genetic causes: in 30% of cases the cause is direct, while in 45% indirect. A study in British Columbia showed that at the age of 25 at least 1 out of 20 individuals suffers from a serious disease due to a dominant genetic cause, and as many as 60% of people will suffer of a serious disease due to a dominant genetic cause during their lifetime.

With rare exceptions the genetic diseases have no treatment. The prenatal and early postnatal diagnosis can in some diseases prevent damage due to faulty genes by giving an opportunity to institute preventive measures soon after birth. In all instances where such diagnostic measures are not available yet, the future of such patient entirely depends on fetal precursor cell transplantation.

There is an experience in clinical treatment by fetal precursor cell transplantation for some diseases, but more often not, particularly when it comes to very rare genetic diseases. Since animal models of 99.9% of genetic diseases do not exist, and the value of such models for evaluation of therapeutic possibilities of fetal precursor cell transplantation has always been suspect, there is only one way to handle such patients: propose to the parents or guardians to treat the patient once by fetal cell transplantation as a 'clinical trial of one'. Since fetal precursor cell transplantation is safer than taking aspirin, providing that fetal cell transplants were prepared ‘lege artis’, such an approach is not harmful to the patient. If there is no response, then fetal precursor cell transplantation is not repeated. If there is a positive response, then cell transplantation is carried out every 3 to 4 months until a team of experts in fetal cell transplantation and clinical genetics decides against the continuation of such treatment.

Every genetic disease is potentially treatable by fetal precursor cell transplantation. The problem is the selection of fetal precursor cell transplants to be used for treatment of patients with very rare diseases, where current medicine has too few data available. The more is known about the genetic disease, and the earlier after birth fetal cell transplantation treatment begins, the greater is the chance of success. At this moment the problem is a lack of education of parents of handicapped children, that results in delayed start of therapy.

Single gene abnormalities are characterized by an inheritance of simple mendelian type.

A certain phenotype is dominant if manifested even in heterozygote, and recessive if manifested in homozygote only but not in heterozygote. They are infrequent, and among them is an unknown number of ‘contiguous gene syndromes’. They are due to point mutations, that cause a change in the specific gene product, i.e. a structural or quantitative modification of synthesis of a polypeptide chain.

Total incidence of pathologic phenotypes in population is 0.6 – 0.8% . Around 25% of pathologic phenotypes of mendelian type is obvious already at birth, and as much as 90% by the end of puberty. In more than half of cases only one organ system is malformed or malfunctioning. Approximately 57% of single gene disorders shortens lifespan, and 69% reduces reproductive ability. Majority of so stricken struggle with defects that limit their schooling or work choices, mainly due to CNS damage.

Autosomal dominant (AD) type of inheritance is the most common. Variable expressivity and penetration of pathologic gene is typical. Usually it is due to neomutations which code non-enzyme protein, with the exception of porphyria, where each of 6 dominant forms is caused by a deficit of activity of one of series of enzymes involved in heme synthesis. Hereditary angioedema, and deficit of antithrombine, are likewise caused by enzymatic defect.

In the lists of genetic diseases, those marked with * are described in other parts of this book.

List of diseases with AD type of inheritance, and their incidence:

Familiar combined hyperlipidemia* 1:70 - 350

Familiar hypercholesterolemia (heterozygotes)* 1:500

Dominant otosclerosis 1:1000

Neurofibromatosis 1:2500

Noonan syndrome* 1:2500

Hereditary spherocytosis 1:5000

Dentinogenesis imperfecta 1:10000

Polyposis of colon* 1:10000

Marfan syndrome 1:25000 - 50000

Achondroplasia* 1:50000

Sturge-Weber syndrome 1:50000

Cornelia-de-Lange syndrome 1:50000

Tuberous sclerosis 1 :100000

Acute intermittent porphyria* 1 :100000

Neurofibromatosis, or von Recklinghausen disease, with ‘café-au-lait’ hyperpigmented spots, soft fibromas of skin, and multiple neurinomas along peripheral and cranial nerves, neurofibromas in the bone, intestines, endocrine glands, etc., often causing compression syndromes. Fetal precursor cell transplantation of diencephalon, liver, placenta, hypothalamus, medulla alba of brain, basal ganglia, is advised.

Tuberous sclerosis, or Bourneville-Pringle disease, is clinically characterized by a triad of mental retardation, epilepsy, adenoma sebaceum on the nose and cheeks, and ‘café-au-lait’ depigmented skin areas. Cachectic nanism with progeria facies due to the loss of subcutaneous fat, and premature graying of sparse hair, becomes obvious from 2nd to 4th year of life. There is a progressive mental retardation, intracranial calcifications, sensori-neural deafness, retinitis pigmentosa, with a ‘pepper and salt’ appearance of retina, optic nerve atrophy, and photosensitive dermatitis. Besides that there are skeletal abnormalities with disproportionately large hands and feet and flexion contractures of large joints. Patients survive until adulthood. Fetal precursor cell transplantation of placenta, liver, bone marrow, adrenal cortex, mesenchyme, exocrine pancreas, retina, is recommended.

Cornelia-de-Lange syndrome, is clinically characterized by a typical facies, short stature, microcephaly, micromelia, severe mental retardation and speech delay and normal life span.

Own experience with treatment of 8 years’ old male with Cornelia-de-Lange syndrome, with pronounced psychomotor delay at the level of imbecility, speech delay, seizures, severe myopic astigmatism, by human fetal cell transplantation of brain cortex, medulla alba of brain, frontal lobe of brain, mesencephalon, diencephalon, was positive as the patient’s height increased by 2.5 cm in 4 months, and the speech progressed to the level of speaking in phrases. The 2nd cell transplantation carried out 4 months later brought on another 2.5. cm growth in height and 1.0 kgm in weight, and noticeable improvement of self-care abilities. It should be noted that the treatment of this patient by fetal cell transplantation began very late. Treatment took place at the Endocrinology Research Center of Russian Academy of Medical Sciences in Moscow.

Autosomal recessive (AR) type of inheritance occurs in genetic diseases expressed in children of parents / heterozygotes that are phenotypically disease-free. AR diseases are often associated with inbreeding, and also among people living for generations in secluded areas, and so are limited to certain populations: cystic fibrosis in Caucasians, sickle cell anemia among blacks, Tay-Sachs disease among Ashkenazy Jews, etc.

List of diseases with AR type of inheritance, their incidence, and relation to populations:

Intestinal lactase deficit 1:10 in Caucasians

Thalassemias* very high in Mediterranean, African and Asian populations

Familial dysautonomy 1:100 Jews

Dubin-Johnson syndrome 1:1300 Iranian Jews

Cystic fibrosis* 1:2000 Caucasians

Gaucher disease type 1* 1:2000 U.S.Jews

Tay-Sachs disease* 1:3000 U.S. Jews

Alpha1 antitrypsin deficit* 1:3500

Congenital hypothyreosis* 1:4000

Cystinuria* 1:7000

Phenylketonuria* 1:10000

Congenital adrenogenital syndrome* 1:10000

Alkaptonuria* 1:19000

Hartnup syndrome 1:24000

Wilson’s 1:50000

Galactosemia* 1:60000

Cystinosis* 1:100000

Laurence-Moon-Biedl syndrome 1:100000

Maple-syrup-disease 1:160000

Xeroderma pigmentosum* 1:250000

Russell-Silver syndrome

Wilson’s disease, AR, disorder of copper metabolism, causes an accumulation of copper in liver, CNS, eye, kidney, heart, skeleton. From 40 to 60 % of copper is absorbed in stomach and upper duodenum. In liver the copper is built into ceruloplasmin and enters systemic circulation. One molecule of ceruloplasmin binds 6 – 7 atoms of copper. Copper is important for oxidation of plasma Fe2+. ATP-ase in the liver binds copper and removes copper ions into the bile. There is a lowered output of ceruloplasmin and thereby decreased elimination of copper through bile, and incorporation of copper into ceruloplasmin. As a result toxic free copper accumulates in liver, and other organs, and by binding with proteins, especially SH- groups, it supports the production of O2-radicals and lipid peroxidation.

Clinical symptoms start between 10 and 25 years of age, when chronic active hepatitis develops, that progresses into cirrhosis with hepatosplenomegaly and ascites. Defective copper pump in the liver leads to an accumulation of copper in other tissues, such as basal ganglia of brain, where it causes neuronal degeneration, with Parkinsonism-like clinical picture, and variety of nerve, neuromuscular and psychic disturbances. Copper accumulates also in erythrocytes, causing hemolytic anemia, and in kidneys. Copper deposits in the cornea are seen as golden or green Kayser-Fleischer ring. Free copper can be removed by penicillamine that chelates copper into urine, or chelation therapy. Fetal precursor cell transplantation of liver, retina, optic nerve, placenta, exocrine pancreas, intestine, is recommended.

Familial dysautonomy, or Riley-Day syndrome, has onset in infancy, with progressive degeneration of peripheral autonomous, motor and sensory nerves, and of CNS. Defect of swallowing reflex is observed first, followed by diminution of pain sensation and corneal reflex, dysarthria, ataxia, disturbed temperature control, hyperhidrosis, excessive salivation, cardiovascular dysregulation, taste defect. Death occurs during 2nd decade from lung infections.

Russell-Silver syndrome has onset in utero with growth retardation, that continues postnatally. There is an absolute lack of interest in food consumption. Head is of normal size, face is small and triangular, with a weak narrow chin, and there is a general asymmetry of the entire body with a hypotrophic right or left side, with resulting uneven length of extremities, clinodactyly of the 5th finger.

Our experience with treatment of a patient with Russell-Silver syndrome by human fetal cell transplantation was negative as 7 ½ years old male with oligophrenia at the level of debility, and severe seizure disorder, had two seizures after fetal cell transplantation of brain cortex, medulla alba of brain, temporal lobe of brain, frontal lobe of brain, and so any further treatment was stopped as this was quite unusual in our experience with treatment by fetal cell transplantation in children with genetic diseases. On the other side, the height and weight of the patients increased over the next 3 months, and overall there was a clinical improvement. The patient was hospitalized at the Endocrinology Research Center of the Russian Academy of Medical Sciences in Moscow.

X-linked recessive (XR) type of inheritance occurs predominantly in males, because in men with XY configuration of sex chromosomes one pathologic gene on chromosome X suffices for phenotypic expression. Classically, a pathologic gene transfers from the asymptomatic mother / carrier to 50% of her sons and to 50% daughters / asymptomatic carriers. Transfer from father to son is impossible, because father transfers to son his chromosome Y.

List of more common XR disorders:

Addison’s disease*

Agammaglobulinemia – type Burton, and Swiss type

Color blindness red/green

Muscular dystrophy Becker*

Muscle dystrophy Duchenne*

Diabetes insipidus renalis*

Fabry’s disease*

Hemofilia A and B*


Hunter’s syndrome (MPS type II)*

Lesch-Nyhan syndrome*

Lowe’s oculocerebrorenal syndrome*


Menkes’ disease

Non-spherocytic hemolytic anemia due to G6PD deficit

X-linked mental retardations*

Familial hyperuricemia

Ocular albinism, types I and II*

Syndrome of testicular feminization

Menkes’ disease, XR disorder of copper metabolism with incidence of 1:50000 of newborn boys, is due to a defective ATP-ase that binds copper, and removes copper ions from cells. There is an accumulation of copper in the intestine and other tissues, but not in the liver. It affects CNS, connective tissue and vascular system, and is fatal in infancy. There is a typical facies with full cheeks and fish-like mouth, microgenia, flat nose with short philtrum, minimal eyebrows, depigmented kinky hair ‘stiff like steel shavings’, microcephaly, mental retardation, seizures. Serum level of copper, and ceruloplasmin, are low. The activity of copper dependent enzymes: SOD and cytochrome oxidase is low. [230]

X-linked dominant type of inheritance occurs mostly in females, but when it happens in males then the course of disease is much more severe and usually lethal. Transfer from father to son is impossible because father transfers to son chromosome Y. Such disorders are rare.

Hereditary hypophosphatemic vitamin-D resistant rachitis, with a decreased reabsorption of phosphorus in proximal tubule of kidneys, and hypophosphatemia, decreased mineralization of bones, with bony defects, and retarded growth.

Others, such as Aarskog syndrome, Incontinentio pigmenti, Ornitintranscarbamylase deficiency, are all very rare.

Y-linked genetic disorders are unknown except for those causing infertility, since the sole gene on chromosome Y is ‘testis determining factor’ that determines the male sex.

Syndromes of defective DNA repair mechanism, also known as syndromes of spontaneous chromosomal instability:

Essential biological prerequisite for normal prenatal and postnatal development is the ability of organism to maintain a structural integrity of DNA, carry out DNA synthesis exactly, and continuously remove or repair changes of DNA caused by mutations and environmental cancerogens. Several diseases with defective DNA repair processes have been identified, with resulting hypersensitivity to various damaging factors, i.e. radiation of variable wavelength from UV to X-rays. In these cases there is a continuous ‘spontaneous’ disruption of structural integrity of chromosomes (that explains the name ‘syndromes of spontaneous chromosome instability), chomosomal tears and breaks, with eventual imperfect reconstruction of chromosomes, the consequence of which is a higher incidence of malignancy.

Xeroderma pigmentosum is AR disorder with incidence 1:250000. Hypersensitivity to sun rays is the main abnormality. In 80 – 90 % patients there is a faulty repair of DNA damaged by UV radiation, in remaining cases a defect of post-replication DNA repair after UV-radiation. Photosensitivity and photophobia appear between 6 months and 3 years of life. In the 1st stage there is a pronounced erythema after sun exposure with subsequent diffuse pigmentation. In 2nd poikilodermic stage a lentigo-like pigmentations, skin atrophy, teleangiectasias, angiomas, ectropion, develop. In 3rd precancerous stage tensile skin atrophy, senile keratoses, flat ulcers, appear. In 4th cancerous stage various skin cancers develop. Two thirds of patients die by the age of 20 from cancers or secondary infections.

Fanconi syndrome, or Syndrome of Fanconi anemia, is AR disorder with incidence of 1:350000 newborns, characterized by progressive panmyelophthisis. Besides pancytopenia, in 50% of patients there is a short stature, anomalies of radius and thumb, and microcephaly, in 20% mental retardation, in 7% deafness. Leukemias and other cancers develop frequently. Patients die young from bleeding, infections and other complications of panmyelophthisis.

Ataxia-teleangiectasia, or Louis-Bar syndrome, is AR disorder with incidence 1:40000 to 1:100000 of newborns. Oculocutaneous teleangiectasias appear in the first year of life, first on conjunctivas, later on the cheeks next to the nose, on auricles, gingivas, and elsewhere. When infant starts to walk, ataxia appears, and becomes progressively worse. Later on choreoathetosis, intentional tremor, dysarthria, are observed. At the age of 6 months recurrent respiratory infections begin, which become frequent between 3 and 8 years of age, often leading to bronchiectases, and all that leads to a suspicion of immunodeficiency disorder. Cancer development is frequent. There is a lack of IgA and IgE, decreased cell immunity, and increased level of Alpha-fetoprotein due to liver damage. Lifespan is shortened due to pathology of brain and lungs, as well as due to cancer.

Bloom syndrome is AR disorder with incidence 1:100000 newborns, most common in Ashkenazy Jews. In 1st year of life a typical teleangiectatic erythema of butterfly shape appears on face, that exacerbates following sun exposure. Growth delay begins already in utero. There is immunodeficiency with B-cells malfunction and recurrent infections. Cancer is frequent and is the main cause of death at young age.

Cockayne syndrome is a rare AR disorder with hypersensitivity to UV radiation and to chemical carcinogens.

Unstable trinucleotide repeats, one of the newest discoveries in genetics, are the cause of Syndrome of fragile chromosome X type A, also known as Martin-Bell syndrome, a single gene disorder with an incidence of 1:250 in males, and 1:2000 in females, the second most frequent specific cause of mental retardation after Down syndrome. The fragile chromosome X is found in males in 5 – 40% of cells, in females less often. Male patients are tall, have a long face with prominent mandible, long auricles which stick out laterally, and large testes. Mental retardation is accompanied in 10% of cases with epilepsy. Diagnosis is possible after 2 – 3 years of age.

Enzymopathies, or inborn errors of metabolism, is another way to group single gene disorders, more practical for a medical practitioner.

Metabolism consists of multiple biochemical steps, each one catalyzed by a specific enzyme. Any change of sequence of purine and pyrimidine bases in DNA causes a change of sequence of aminoacids in the protein portion of an enzyme that leads to a malfunction of the affected enzyme. There is a subsequent blockage in the metabolic pathway the outcome of which is that the substrate A, which should enter into a biochemical reaction with the enzyme X as catalyst to create a substance B, but has not done so due to the defect of enzyme X, has accumulated in the cell instead. The result of such accumulation can be:

  • substrate A by its sheer volume ‘crowds out’ all cell components, as is the case with ‘storage diseases’, such as glycogenoses, lipidoses;
  • substrate A becomes toxic in higher concentration, or solidifies because of low solubility, and thereby becomes harmful, I .e. cystine in cystinuria, uric acid in gout;
  • entry of substrate A into alternative metabolic pathway with enzyme Z as a catalyst creates a harmful metabolite E, as in phenylketonuria;
  • inhibition of metabolism of another enzyme Y, or of transport protein necessary for carrying other substances, such as substrate C;
  • a lack of substance B, the product of the original biochemical reaction, i.e. in glycogenosis there is a lack of glucose;

a lack of substance B can also raise the turnover of other enzymatic reactions, or it can disrupt a feedback mechanisms, such as when the lack of 21-hydroxylase stimulates secretion of ACTH-releasing factor from hypothalamus, and thereby of ACTH, and that then leads to an increased secretion of various precursors of cortisol, with resulting adrenogenital syndrome.

In order to elucidate the preceding explanation, look at the metabolic pathway A-B-C-D-E-F-G and assume that there is a deficiency of an enzyme that converts C into D. That reduces the production of D, E, F, and finally of G, the end product, but increases the level of C, later on also of B, and perhaps even A. If C, B, or A, are toxic in high concentrations, or can be converted into toxic compounds by other metabolic pathways, a pathological condition will develop, a disease, and perhaps death.

Because of their enormous importance the enzymes are produced in excessive quantities and for that reason enzymopathies are clinically apparent only in homozygotes where both alleles are abnormal.

A lack of an amino acid, due to poor nutrition, defect of transport protein, or defect of production of urea, cause serious disturbances as a rule. An excess of aminoacids is usually harmful as well.

Phenylketonuria (PKU), AR disorder with incidence 1:10000, is caused by a diminished activity of phenylalanine hydroxylase, an enzyme that turns L-phenylalanine into tyrosine in the liver. Abnormal concentration of phenylalanine causes damage of cells of developing CNS that leads to severe mental retardation and seizures. When plasma concentration of phenylalanine reaches certain level, it starts to break down via secondary pathways, mostly to pyruvate, that appears in urine, and inhibits transport of other amino acids so that they cannot enter brain cells in sufficient quantities. Lack of melanine, produced from tyrosine, disrupts pigmentation and triggers photosensitivity. Onset is at birth, blond hair, blue eyes, eczema and typical mouse odor of urine, are typical clinical findings. Screening eliminates most of such patients as candidates for fetal precursor cell transplantation as they stay well by following a strict non-phenylalanine diet.

But in malignant form of phenylketonuria with defective synthesis of tetrahydropterine (BH4), a co-factor of phenylalanine hydroxylase, that causes deficit of hydroxylation of phenylalanine, tyrosine and tryptophan, and thereby a decreased production of neurotransmitters dopamine, noradrenaline, and serotonine, not even strict diet can prevent CNS damage, unless the patient received missing neurotransmitters, i.e. DOPA, 5-hydroxytryptophan, and BH4. In these 2 – 3 % of patients with PKU fetal precursor cell transplantation has to be considered.

Alkaptonuria, also known as ochronosis, AR disorder with incidence of 1:10000 to 1:100000, is due to a lack of homogentisate-1-2-dioxygenase, that leads to an accumulation of homogentisic acid in the organism, a normal product of metabolism of phenylalanine and tyrosine. The elimination of homogentisic acid causes dark color of urine. Onset is at birth. Deposits of excess of ochronotic pigment in various connective tissues: sclera, cartilage, tendons, intima of larger vessels, endocardium, lungs, tympanic membrane, etc. are typical clinical signs. There is an increased incidence of kidney and prostatic stones, starting in childhood, and disabling arthropathy of spine and large joints, appearing after 20 years of age, that make a timely treatment of this disease by fetal precursor cell transplantation mandatory.

Albinism, oculo-cutaneous, or ocular, is a group of genetic disorders of melanocyte system of eye and skin, mostly AR, but also XR, or AD, with an inborn lack or paucity of pigment melanine in skin, hair, eyes, that leads to white skin, red iris, photophobia, nystagmus and decreased vision. The onset is at birth.

Hyperglycinemia due to faulty propionyl-CoA-carboxylase, Hyperoxaluria , Maple sirup disease with defects of multiple enzymes for decarboxylation of valine, leucine, isoleucine, Homocystinuria, Cystinosis due to transport defect, Hyperprolinemia caused by faulty prolin-dehydrogenase, which is also also the cause of Alport syndrome, are other enzymopathies involving amino acids.

A lack of carbohydrates occurs in the following genetic disorders.

Galactosemia, AR disorder of galactose metabolism with incidence of 1:62000, is divided into three types.

In Type I, or classical galactosemia, defect of galactose-1-phosphaturidyltransferase blocks a conversion of galactose to glucose. The accumulation of toxic galactose becomes apparent from the moment that newborn ingests milk for the first time. There is an immediate vomiting, unwillingness to drink, diarrhea, hypoglycaemic attacks, and subsequently cachexia, icterus, hepatomegaly, cataracts, seizures, and mental retardation develop. Screening for enzymes in erythrocytes, trophoblast, prevents death, but even galactose-free diet cannot stop long term complications, i.e. poor growth, neurologic and speech abnormalities, mental retardation, so that fetal cell transplantation should be strongly considered.

Types II and III are due to absence of different enzymes. Type III is a major problem, because insufficient intake of galactose leads to an insufficient production of UDP-galactose, and that causes already in 2nd year of life severe mental retardation and sensori-neural deafness, since galactose is an essential structural component of the brain.

Hereditary fructose intolerance, due to a defect of fructose-1-P-aldolase; splitting of fructose from fruits is blocked, and fructose-1-phosphate accumulates, which triggers in the liver an inhibition of activity of fructose-1,6-P2-aldolase, that in turn causes hepatogenic hypoglycemia, and can cause acute liver failure, or cirrhosis.

Glycogenoses: Glucose is stored in muscles and liver as glycogen. Its breakdown generates glucose that can be used in liver or in other organs. If splitting of glycogen is blocked, it accumulates and hypoglycemia develops. The causes are various enzymatic defects, and each is responsible for a different type of glycogenosis:

Type Ia, named after von Gierke, with locus in the liver;

Type Ib due to defect of microsomal glucose-6-phosphate-translocase;

Type II, named after Pompe, with anorexia, hepatomegaly, muscle dystrophy, cardiomegaly and respiratory muscle weakness, death in the 1st year of life;

Type III, the most common, named after Forbes and Cori, with locus in the liver;

Type IV, named after Anderson, where an abnormal form of glycogen is stored in brain, heart and peripheral muscles, liver, with liver failure, and death already in childhood;

Type V, named after McArdle, with locus in peripheral muscles;

Type VI, named after Hers, with locus in the liver;

Type VII, named after Tarui, in which skeletal muscle glucose cannot be used for energy;

Type VIII, named after Huijing, with locus in the liver.

Lesch-Nyhan syndrome, XR disorder, a hypoxanthine-guanine-phosphoribosyltransferase deficiency, ‘children’s gout’, causes a premature appearance of gout with urolithiasis and pronounced brain dysfunction, e.g. choreoathetosis, paralysis of cranial nerves, mental retardation with self-mutilation.

Hyperhomocysteinemias, caused by an absence of cystathionine-ß-synthase (CBS) and 5,10-methylene-tetrahydrofolate-reductase, lead to an accumulation of homocystein, an important lipid-independent factor of atherosclerosis, which due to its toxic effects causes:

1/ direct damage of endothel,

2/ changes of oxidation/reduction in blood vessel wall,

3/ disturbance of thrombin/antithrombin system in favor of thrombogenesis.

In clinical practice it causes a premature arteriosclerosis and its complications, as well as spina bifida, and pathologic pregnancies.

Severe hyperhomocysteinemia is the ‘classical’ homocystinuria, AR disorder, with an incidence of 1:130000, with onset at 2 – 30 years of life, where a lack of the same cystathionine-ß-synthase(CBS) causes:

- lens dislocation, myopia;

- marfanoid tall habitus with long fingers, osteoporosis, spine deformities;

- mental retardation, psychiatric disorders, seizures, EEG abnormalities;

- arterial and venous thrombosis. [234]

For single gene disorders, particularly when not sure of the exact nature, fetal precursor cell transplantation of liver, mesenchyme, adrenal cortex, placenta, brain cortex, medulla alba of brain, cardiomyoblasts, is recommended.

Lysosomal enzymopathies, is a group of inborn errors of metabolism, so named because the accumulation of complex macromolecules, resulting from a failure of normal degradation due to a defect of a specific enzyme, takes place in lysosomes. They are known also as ‘Lysosomal storage diseases’. Lysosomes are cell organelles that contain an abundance of acid hydrolases, which degrade proteins, nucleic acids, glycoproteins, acid mucopolysaccharides, glycogen, glycolipids, lipids, and peroxidase. In majority of these diseases the basic dysfunction is the genetically caused failure of synthesis of active forms of specific hydrolases in ribosomes, or of their protein activators.

A genetic heterogeneity, involvement of multiple organ systems, and great clinical variability is characteristic for lysosomal enzymopathies. Many of them are genetic diseases of connective tissue. So see also the chapter 'Diseases of locomotor apparatus’.

Clinically there is a big difference between enzymopathies causing abnormal metabolism of small molecules, i.e. aminoacids, and those causing abnormal metabolism of large molecules, i.e. glycosaminoglycans, sphingolipids, glycolipids, glycogen. In the first case the metabolism of mother can compensate the metabolic derangement of fetus, so that the abnormality becomes noticeable only after birth, while in the second case the abnormality becomes apparent already in utero.

Lysosomal storage begins in early fetal stage, but clinical manifestation starts during the first 2 years of life, or later. Clinical course is of variable severity, usually with with progressive CNS malfunction, dysostosis multiplex, i.e. dolichocephalia, ovoid vertebrae with hypoplasia, hypoplastic pelvis, flat acetabulum, wide diaphyses of long bones, wide ribs, abnormalities of metacarpal bones, as well as deafness, visual impairment, hepatosplenomegaly, skin abnormalities. A fatal outcome is common.

There are over 30 known lysosomal storage diseases. With the exception of XR disorders of Fabry’s disease and Hunter syndrome (MPS II), all remaining are AR disorders. The following three groups are based on the type of macromolecules accumulated in lysosomes.

A/ Mucopolysaccharidoses always include a serious skeletal dysplasia:

- Hurler syndrome, type IH, or ‘Gargoylism’, due to a defect of Alpha-L-iduronidase, is diagnosed before 2nd year; there is a typical facies like on antique water-fountains, dysostotic macrocephaly, kyphoscoliosis, nanism, early cataract, corneal opacities, hepatosplenomegaly, and mental retardation; death before 10 years of life;

- Scheie syndrome, type IS, due to a defect of Alpha-L-iduronidase, is diagnosed later; there are cataracts, normal intellect, and normal lifespan;

- Hunter syndrome, type II, due to a deficit of iduronate-2-sulphatase, is diagnosed before 4th year; clinical findings are somewhat similar as in Hurler syndrome, but much milder: a lesser degree of mental retardation, nanism; there are no cataracts, corneal opacities, or skeletal deformities; death before 15 years of life;

- Sanfillipo syndrome, type III, due to a deficit of heparan-N-sulphatase in type A, Alpha-N-acetyl-D-glucosaminidase in type B, Alpha-glucosamine-N-acetyltransferase in type C, N-acetylglucosamin-6-sulphatase in type D, is diagnosed after 2nd year, there is progressive dementia, nanism, disturbed behavior with aggressivity, some hepatomegaly, hypertrichosis, but no other physical abnormalities;

- Morquio syndrome, type IV, due to a defect of galactose-6-sulphatase in type A or of ?-galactosidase in type B, causes a nanism of various degree, cataract, thin dental enamel, progressive spine deformities, death in adulthood;

- Maroteux-Lamy syndrome, type VI, due to a deficit of N-acetylgalactosamine-4-sulphatase, causes a nanism of various degree, monster-like facies, typical kyphoscoliosis, corneal opacity, cardiopulmonary insuficiency, hepatosplenomegaly; intellect is normal, and lifespan nearly normal;

- Sly syndrome, type VII, due to a defect of Alpha-glucuronidase, can be present at birth as a fatal hydrops fetalis, or it appears in infancy as mental retardation, minor skeletal deformities, or it becomes apparent in teens as a moderate mental retardation.

Fetal cell transplantation of various parts of brain, eye, placenta, liver, mesenchyme, cartilage, osteoblasts, peripheral myoblasts, has brought only temporary improvements and retardation of progress of the disease. The lack of lysosomal enzymes can be positively influenced only for a short time and incompletely. But this statement is based on clinical experience of treating such patients too late. If the treatment starts immediately after birth then the the evaluation of possibilities of fetal cell transplantation can begin.

B/ Oligosaccharidoses are characterized by a disturbance of saccharide metabolism in glycoproteins and glycolipids, due to which there is an excessive accumulation of oligosaccharides in tissues and body fluids, and their excessive elimination in urine.

Glycoproteinoses are the most common among oligosaccharidoses:

- Mucolipidosis Type I, or ‘Pseudo-Hurler polydystrophy’, and Types II – III – IV, or ‘Sialidoses’, are due to a defect of N-acetylglusosamino-1-phosphotransferase;

- Glycoproteinsialidosis, known as ‘cherry-red-spot-myoclonus syndrome’;

- Aspartylglucosaminouria, a L-aspartylamido-?-N-GlcNAc-aminohydrolase defect;

- Fucosidosis, due to a defect of Alpha-L-fucosidase;

- Mannosidosis, due to a defect of Alpha-D-mannosidase.

Aspartylglucosaminouria, appears between 1 and 5 years of age, with mental retardation, speech impairment, cataracts, hepatomegaly, and the same bone deformities as in mucopolysaccharidoses.

Fucosidosis, is diagnosed in infancy by Hurler-like phenotype, muscle hypotonia, slowly developing spastic tetraplegia and decerebration rigidity, frequent respiratory infections, hyperhidrosis, cardiomegaly; death before 6 years of age.

Mannosidosis, becomes apparent between 1 and 3 years of age, with Hurler-like phenotype, muscle hypotonia, hepatosplenomegaly, cataracts, bone abnormalities, frequent respiratory infections, vacuolised lymphocytes.

C/ Lipidoses:

- Farber’s disease, or ceramidosis;

- Krabbe disease, or globoid leukodystrophy;

- Gaucher disease, types 1 – 2 – 3;

- Metachromatic leukodystrophy;

- Neimann-Pick disease, or sphingomyelin, or cholesterol, lipidoses;

- Fabry’s disease, glycosphingolipidosis, or angiokeratoma corporis diffusum;

- GM1 gangliosidoses, types 1 – 2 – 3, due to a defect of Alpha-D-galastosidase;

- GM2 gangliosidoses, and variants, due to deficits of hexosaminidase A that splits N-acetylgalactosamine off sugar chains attached to the complex lipids called gangliosides;

the variant B is Tay-Sachs disease;

- Wolman disease, due to a deficit of acid lipase;

- Neuronal ceroidlipofuscinoses, infantile, juvenile, adult.

Gaucher disease, defect of lysosomal Alpha-glucosecerebrosidase, as a result of which glucosecerebrosid accumulates in spleen, liver, and bone marrow in Gaucher cells. Clinically there is hypersplenism with thrombocytopenia, spontaneous fractures, pneumonias, cor pulmonale. There is:

- infantile type, onset by 3 months of age, with massive hepatosplenomegaly, dysphagia, digestive malfunction, cachexia, mental retardation, muscle hypertonia, opisthotonus, strabism, normal retina;

- juvenile type;

- adult type, onset at the age of 20, with massive splenomegaly, some hepatomegaly, hypersplenism with leukopenia, hemorrhagic diathesis, Perthes disease, bone pain.

Fetal precursor cell transplantation of liver, cardiomyoblasts, peripheral myoblasts, exocrine pancreas, intestine, is advised.

Our study of Gaucher’s disease, infantile type, was carried out at the Research Center of Pediatrics of the Russian Academy of Medical Sciences, and reported at the 1st Symposium on Transplantation of Human Fetal tissues in Moscow, December 4 – 7, 1995, under the title: “Treatment of Gaucher disease in children with the help of human fetal tissues”. The report deals with 6 children, from 6 to 13 years of age, 3 girls, and 3 boys, treated by infusions of human fetal hepatocytes. Diagnosis was confirmed in all 6 children by bone marrow biopsy and finding of typical cells filled with glucocerebroside. In two children a cytogenetic study to uncover the defect of glucocerebrosidase was done. The diagnosis was proven in all 6 children by DNA study to find a specific Gaucher’s disease allele. One child underwent splenectomy at the age of 4.

All children showed growth retardation, frequent intercurrent infections, bone lesions, hepatosplenomegaly, slight anemia, and thrombocytopenia.

During the first round of treatment, every child received 5 infusions of human fetal hepatocytes, one week apart. In one female patient fever and hallucinations appeared after the 4th infusion, which resolved in 3 days, and so no further treatment was given. Interestingly, this patient had the best clinical result of the whole group, i.e. decrease of size of liver and spleen by 6 cm, so that further treatment was not necessary. The second round of treatment began 4 months later, and consisted of 3 infusions, 7 – 12 days apart. Subsequently infusions were carried as necessary, every 6 – 8 weeks.

In one male patient signs of intrahepatic type of portal hypertension developed, and so further treatment was stopped: the result was not as good as in the remainder of the group, but there was an increased growth rate and subjective improvement.

There was a dramatic decrease of hepatosplenomegaly in 5 of 6 children during 6 months of treatment, but after the termination of infusions the hepatosplenomegaly re-appeared.

Bone pain disappeared in all 6 patients. X-ray findings remained unchanged. There was a marked growth spurt, and of physical development, and decreased frequency of intercurrent infections.

Gaucher’s disease is one of those where the exact nature of enzymatic defect has been known for some time, and the missing enzyme is commercially available for treatment. The sole problem is the enormous cost of such medication, prohibitive in most countries. The purpose of this study was to find an alternative, more affordable treatment.

Farber’s disease, with reddish subcutaneous lumps, swelling and rigidity of extremities, dysphonia, fever, sometimes also with CNS and cardiopulmonary symptomatology.

Krabbe disease, starting in infancy as a slowly progressing encephalitis-like condition, cerebral degeneration with spasms.

Metachromatic leukodystrophy, where the deficit of arylsulfatase A and variants causes demyelination, and storage of myelin breakdown products in CNS, liver and kidneys. Onset is in early childhood. There is muscle hypertonia, hyper-reflexia, delayed gross motor development, and eventually muscle atrophy of lower extremities, ataxia, dysarthria, progressive mental retardation, rigidity, blindness, deafness, loss of speech, total loss of contact with the world; death between 2 and 6 years of life. - There are also very rare juvenile and adult forms with chronic clinical course over many years. Fetal precursor cell transplantation of liver, placenta, intestine, exocrine pancreas, adrenal cortex, mesenchyme, spinal cord, peripheral myoblasts, is advised.

Niemann-Pick disease, is an accumulation of sphingomyelin and cholesterol in lysozymes, that becomes apparent at different age of the patient, with food refusal, vomiting, hepatosplenomegaly, mental retardation, red spots on retinal macula, muscle hypotonia, psychomotor delay,

  • type A (80% of cases), a defect of sphingomyelinase, with onset at 6 months of age, with severe developmental delay, hepatosplenomegaly, macular degeneration with blindness, death before 2 years of age;
  • type B, a defect of sphingomyelinase, is a storage disease without CNS involvement;
  • Type C, a defect of protein, very important in intracellular transportation and distribution of cholesterol, with onset in 2nd year of life, is the most common, with progressive gross motor and menta l retardation, death between 3 and 6 years of life;
  • Type D with onset in middle childhood and survival until 20 years of life.

Fabry’s disease, begins in teens, or early twenties, with diffuse teleangiectasias, diarrhea, kidney disorders, lower leg edema, corneal opacities , burning pain in fingers and toes. Fetal precursor cell transplantation of mesenchyme, placenta, liver, is advised.

Gangliosidoses, various defects of hexoseaminidase and its activator, or defects of ?-galactosidase, cause an accumulation of gangliosides that results in very serious brain dysfunction and death in childhood. It begins at 6 months of age, with psychomotor delay, blindness , nystagmus, decerebration state, mental retardation, macrocephaly, seizures. There are a few variants:

- GM1 Gangliosidosis, or ‘Pseudo-Hurler syndrome’, with muscle hypotonia, delayed motor development, neurologic defects, skeletal abnormalities.

- GM2 Gangliosidosis, with mental retardation, typical red spots on retinal macula, macroglossia, hepatosplenomegaly, limitation of joint motion, gross facial features, lymphocyte vacuoles.

A variant B is Tay-Sachs disease, where non-degraded lipid gangliosides accumulate in lysosomes, leading to cell death. Phenotypically there are severe neurological signs and symptoms, blindness, mental retardation, death in childhood.

Another variant O is Sandhoff syndrome, where non-degraded lipid gangliosides accumulate in brain, with progressive mental breakdown.

Fetal precursor cell transplantation of liver, placenta, mesenchyme, adrenal cortex, is advised.

Wolman ‘s disease, a defect of acid lipase leads to pathologic accumulation of cholesterol esthers, begins with vomiting, steatorhea, hepatosplenomegaly, liver cirrhosis, adrenal calcification, and causes death in the first 4 months due to cachexia; there is no CNS involvement; vacuolized lymphocytes are typical. [231, 234]

Peroxisomal enzymopathies, AR disorders with exception of adrenoleukodystrophies, that are XR disorders, are named after peroxisomes, cell organelles found in all tissues with the exception of erythrocytes. Peroxisomes produce oxidases, which in turn generate hydrogen peroxide, that is then reduced by catalase into water. Peroxisome enzymes fulfill multiple essential functions for the cell: synthesis of plasmalogel, dolichol, and cholesterol, Beta-oxidation of long fatty acids, production of hydrogen peroxide, degradation of all active kinds of oxygen, superoxide, etc. Since these enzymes are of vital importance for metabolism of lipids, particularly those in CNS, many of peroxisome disorders present a clinical picture of progressive psychomotor dysfunction.

Combination of craniofacial dysmorphism, i.e. high prominent forehead, wide fontanelles and cranial sutures, epicanthus, auricle deformities, gothic palate, with neurological findings, such as psychomotor retardation, hypotonia, absent or minimal reflexes, deafness, degeneration of white matter, abnormal EEG, etc., and with ophthalmological findings, such as cataract, chorioretinopathy, optic nerve dysplasia, and hepatomegaly with fibrosis/cirrhosis, short extremities, as well as the laboratory finding of a lack of peroxisomes and lamellar inclusions in hepatocytes, point to the diagnosis of peroxisomal enzymopathy.

Among these very rare disease, a few are somewhat more common:

- Adrenoleukodystrophy, neonatal, infantile, adolescent, or adult, characterized by adrenal gland dysfunction and generalized demyelination of CNS, invariably fatal;

- Zellweger syndrome, or cerebro-hepato-renal syndrome, due to a deficiency of pipecolate oxidase;

- Hyperoxaluria, types I and II, characterized by severe nephrolithiasis, and kidney failure;

- Chondrodysplasia punctata, rhizomelic type, characterized by pug nose, marked shortening of proximal limbs, death in infancy.

Zellweger syndrome, or cerebro-hepato-renal syndrome, a very rare disorder diagnosed at birth or early infancy, with typical facies: hypertelorism, flat nose, full cheeks, hypognathia, and extreme muscle hypotonia, areflexia, weak swallowing and suction reflexes, minimal gross motor development, mental retardation, hepatomegaly. [230]

Refsum disease, a deficiency of phytanic acid Alpha-oxidase, leads to a blockage of the breakdown of phytanic acid, that accumulates, and is progressively built into myelin, which causes polyneuropathies. It begins between 2 and 20 years of age, with night blindness, paresthesias, ataxia, pareses, painful attacks. [230, 234]

Fetal precursor cell transplantation of cartilage, mesenchyme, liver, kidney, medulla alba of brain, brain cortex, diencephalon, retina, optic nerve, is advised.

Mitochondrial Genetic Diseases

The most important function of mitochondrias, cytoplasmatic organelles with double membrane, is the production of energy necessary for cell metabolism by creation of ATP via oxidative phosphorylation system, or OXPHOS. Oxidative phosphorylation is carried out by five complexes of ‘respiratory chain cascade’, that are complexes of polypeptide enzymes located in the intermembraneous space in continuity with inner mitochondrial membrane, that handles the production of ATP. The first four complexes represent the respiratory chain proper and 5th complex is that of ATP-synthase. The number of mitochondrias in cytoplasm is commensurate to the energetic needs of the cell.

Mitochondrias contain also DNA organized into a separate genetic system, which is 10 – 20 times more vulnerable to mutations in comparison with nuclear DNA, but due to multiple copies of mitochondrial DNA in majority of mammal cells the impact of each mutation is substantially reduced.

OXPHOS processes are controlled to a great degree by nuclear genes, and mutation of nuclear genes and mitochondrial genes cause mitochondrial genetic diseases with autosomal inheritance.

Typical property of mitochondrial DNA is its exclusive transfer from mother, and for that reason is this type of inheritance called ‘maternal cytoplasmatic’. Only females can carry mutant gene from generation to generation.

During mitosis the segregation of mitochondrial genetic material is by a pure chance and thereby even minimal genotypic changes can cause major phenotypic changes, i.e. there is a ‘treshold effect’.

In summary, mitochondrial genetic diseases are characterized by

- maternal type of inheritance;

- segregation of mitochondrias during mitosis with ‘treshold effect’;

- signs of OXPHOS malfunction in those organs where it is of vital importance, and where mitochondrias are abundant, such as CNS, peripheral muscles, (including extraocular), heart muscle fibers, including those of the conductive system of the heart, liver and kidneys, deafness, retinitis pigmentosa, optic nerve atrophy;

- laboratory findings in muscle biopsy of ‘ragged red fibers (RRF)’, abnormal paracrystallic inclusions, abnormal mitochondrias, and lactic acidosis.

The basic difference between mitochondrial inheritance and X-linked dominant inheritance is that in the first group of diseases there is no transfer from father, and in the second group there is a pre-dominant incidence in female patients.

Clinically these diseases are extremely important in newborns and infants, where they sometimes masquerade as Reye Syndrome, or Sudden Infant Death Syndrome. In early stages the neuromuscular signs are present only in minority of patients. Diagnosis is difficult until signs of multiple organ involvement become apparent, i.e. simultaneous appearance of hepatomegaly and liver dysfunction, and malfunction of CNS, i.e. dementia, myoclonus, seizures, mental retardation, of kidneys, i.e. Fanconi syndrome, aminoaciduria, of heart, including arrhythmias, of hematopoietic system, and growth retardation. Extreme variability of clinical picture and course is typical for mitochondrial diseases: unusual combination of symptoms&signs, early onset with rapidly progressive course involving organs with seemingly no relationship from the viewpoint of embryology and biological functions.

Here is a brief description of some mitochondrial genetic diseases:

Kearns-Sayre syndrome begins before 20 years of age, with a typical ‘sleepy facies’ due to ophthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, cardiomyopathy with a pacemaker requiring arrhythmia, cerebellar syndrome, kyphoscoliosis, hyperlordosis, dry, ‘pellagra-like’ skin, high protein concentration in CSF.

Leigh disease, a neurodegenerative multisystem disease with great variability of clinical findings, starting before 2 years of age, with optic nerve atrophy, ophthalmoplegia, retinal degeneration, respiratory malfunction, ataxia, seizures, psychomotor retardation, typical findings on MRI of brain, and lactic acidosis. Myopathy is non-specific, and liver and heart are involved only occasionally. There is a sudden and unexpected worsening of clinical picture and metabolic parameters after infections. General condition is serious, the disease is fatal by 5 years of age.

Leber hereditary optic nerve neuropathy, acute or subacute painless loss of central vision caused by bilateral atrophy of optic nerve, beginning between 12 and 30 years of age, with typical retinal findings; it is a common cause of bilateral blindness of adolescents and young adults.

Myoclonic epilepsy with ragged red fibers, starting in late childhood to early adulthood, with characteristic progressive myoclonic epilepsy, slowly progressive dementia, deafness, ataxia, mitochondrial myopathy with RRF.

Mitochondrial encephalomyelopathy, commencing between 5 and 15 years of age, when in a previously perfectly normal child suddenly a cerebrovascular accident-like state develops with infarcts of brain cortex or subcortex proven by CT scan or MRI, which then subsides within hours or days. During the next episode of a CVA-like status additional neurological findings appear: ventricular dilatation, cortical atrophy, basal ganglia calcification. There is always mitochondrial myopathy.

Pearson syndrome with OXPHOS malfunction involves predominantly hematopietic stem cells in bone marrow: serious macrocytic anemia, requiring repeated blood transfusions, with variable degree of neutropenia and thrombocytopenia, appear already in early childhood. Marked variability of clinical findings and course is characteristic. Patients can die in early stage or a spontaneous improvement of pancytopenia is possible. Later on, a malfunction of additional organs becomes apparent, caused by defects of OXPHOS. There is growth retardation, progressive neurological disorders, mitochondrial myopathy, pancreatic malfunction, and lactic acidosis. [230]

As treatment of all mitochondrial genetic diseases fetal precursor cell transplantation of cardiomyoblasts, peripheral myoblasts, liver, placenta, intestine, mesenchyme, exocrine pancreas, is recommended, along with supplementation of enzymes of the respiratory chain, and neuro-muscular chain by Coliacron, a combination of succinate-dehydrogenase, NAD-kinase, Acetyl-CoA-synthetase, and Glutaminsynthetase, and high oral intake of Beta-linoleic acid and vitamin E for mitochondrial double membrane regeneration.

There are about 2,000 known genetic diseases, and many variants thereof, and only a few of them have any known treatment. Some of them have been treated with fetal precursor cell transplantation with success, but many others, particularly the rare ones, not yet, because no one has attempted to do it. Or at least no medical report has been written about it. 

Since fetal precursor cell transplantation is safe indeed, there is no harm to use it to treat an infant with a newly diagnosed genetic disease. There are only two possible outcomes: either there will be an improvement, or there will be no change in the condition of patient.  A  physician can learn about the benefit of fetal precursor cell transplantation for the treatment of that specific child with a rare genetic disease only by trial and error. There is no harm in trying in such case. If parents make a decision to treat their child, then fetal precursor cell transplantation must be carried out without delay.  [230]