Autosomal Recessive Disorders

AUTOSOMAL RECESSIVE DISORDERS

Autosomal recessive disorders are those that are inherited by means of the autosomal genes. Being recessive, they are not necessarily clinically apparent when the gene is inherited because there will be another gene that will “cover” for the abnormal gene so that the individual won’t get the disorder until the person has two copies of the abnormal gene. This leads to the possibility of a carrier status, in which the person has the ability to pass on the gene but does not have the disease themselves. Two carriers will have a 25 percent chance of having a child with the disease.

These are the common autosomal recessive diseases:

· Cystic fibrosis—this is an autosomal recessive disease that involves a defect in the

CFTR gene on chromosome 7. Chloride ion transport fails to happen so there are excessively viscous mucous secretions. Children will have meconium ileus from thick meconium, respiratory bronchiectasis, pancreatic insufficiency, high sweat chloride concentration, and a high risk of Pseudomonas pneumonia infections.

· Fanconi anemia—this is an autosomal recessive pancytopenia, leading to both anemia and neutropenia. Children will have mental retardation, short stature, microcephaly, hypogenitalism, microphthalmia, and bony abnormalities.

· Hartnup’s disease—this is a defect in the gastrointestinal uptake of certain amino acids and niacin. It is autosomal dominant and leads to a syndrome typical of pellagra, with diarrhea, dermatitis, and dementia. They will have brain dysfunction with transient cerebellar ataxia.

· Kartagener’s syndrome—this is an autosomal recessive disorder that leads to a lack of motility of the cilia. It leads to recurrent sinus and lung infections and situs inversus due to impaired ciliary motion during embryogenesis. The thoracic organs will also be on the opposite side of the body with possible dextrocardia.

Males will be sterile because of a lack of ciliary motion.

· Pyruvate dehydrogenase deficiency—this is an autosomal recessive disorder and a deficiency of the enzyme pyruvate dehydrogenase. This causes lactic acidosis from a buildup of lactate and pyruvate in the bloodstream. The treatment is to

increase the amount of ketogenic nutrients in the diet (such as leucine and lysine) so that acetyl CoA can be increased in the cells.

· Xeroderma pigmentosum—this is an autosomal defect involving inability to adequately repair DNA. It leads to a high degree of excessive damage to skin as well as skin cancer. The skin will be dry with a high risk of pre-malignant and malignant skin cancers. There can be eye and nerve-related abnormalities as well.

· Congenital fructose intolerance—this is an autosomal recessive disease in which there is an aldolase B deficiency. This leads to a buildup of fructose-1-phosphate in the tissues so that both glycogenolysis and gluconeogenesis are impaired. This leads to severe hypoglycemia when fructose is in the diet. The treatment is to remove fructose from the diet.

· Galactosemia—this is an autosomal recessive defect in carbohydrate metabolism.

It results in an inability to convert galactose to glucose so that galactose accumulates in the tissues. More than one galactose enzyme may be defective.

Infants will have cataracts, failure to thrive, hepatic failure from cirrhosis that often leads to death. The treatment is to remove galactose from the diet.

· Cori’s disease—this is a glycogen storage disease and is autosomal recessive.

Glycogen cannot be broken down at its branch points so it builds up. This leads to hepatomegaly, stunted growth, and low blood sugar levels.

· McArdle’s disease—this is an autosomal recessive muscle phosphorylase deficiency so that skeletal muscle cannot be utilized. It is another glycogen storage disease. It leads to muscle cramps, weakness, easy fatigability, and myoglobinuria with exercise.

· Pompe’s disease—this is another glycogen storage disease involving alpha 1,4glucosidase deficiency states. Glycogen cannot be broken down, leading to hepatomegaly, cardiomegaly, and early death.

· Von Gierke’s Disease—this is an autosomal recessive glycogen storage disease, involving the inability to breakdown glycogen. There is severe fasting hypoglycemia and hepatomegaly from excessive amounts of glycogen in the liver.

· Von Willebrand disease—this is a type of hemophilia that has both autosomal dominant and autosomal recessive types. It leads to a defect in the initial formation of platelet plugs in the formation of blood clots and a shorter half-life of factor VIII in the bloodstream. This leads to an increase in bleeding. There are mild, intermediate, and severe types of the disorder.

· Ataxia-telangiectasia—this is an autosomal recessive immune deficiency state. It leads to telangiectasias of the face (enlarged facial capillaries), B cell deficiency and T cell deficiencies along with an IgA deficiency. Patients will have cerebellar ataxia.

· SCID (Severe combined immunodeficiency disease)—this is autosomal recessive and results from an adenosine deaminase deficiency and a decrease in DNA precursors. There are severe deficiencies of both cellular and humoral immunity secondary to impaired DNA synthesis. It can sometimes be treated with a bone marrow transplant.

· Gaucher’s disease—this is a lysosomal storage disease that is autosomal recessive.

The defect is in the level of glucocerebrosidase in the system so the glucocerebrosides will be increased in the lysosomes. There are three types, which can be extremely severe and seen in infancy or less severe and seen in adults.

· Niemann-Pick lipidosis—this is an autosomal recessive lysosomal storage disease. It is a defect in the sphingomyelinase enzyme so that sphingomyelin builds up in the phagocytes (in the lysosomes). These patients will die prior to the age of three from multiple organ problems.

· Hurler’s syndrome—this is an autosomal recessive lysosomal storage disease involving alpha-L-iduronidase deficiency so that mucopolysaccharides build up throughout the body. It leads to Gargoyle facies, mental deterioration, and death

by the age of 10. It is otherwise similar to Hunter’s syndrome but is different with respect to the way it is inherited.

· Tay-Sachs disease—this is a lysosomal storage disease that is autosomal recessive. It is secondary to a hexosaminidase A deficiency with accumulation of

GM2 ganglioside in the neurons. There is blindness, mental retardation, and CNS degeneration with death before four years of age.

· Albinism—this is an autosomal recessive defect of nitrogen metabolism. It involves a tyrosinase deficiency and an inability to make melanin from tyrosine.

It leads to lack of pigmentation, pink eyes in some cases, and an increased risk of skin cancer.

· Alkaptonuria—this is an autosomal recessive homogentisic oxidase deficiency so that phenylalanine and tyrosine do not get made. The urine turns dark with standing and there is pigmentation of fibrous and cartilaginous tissues. The cardiac valve can be involved but the disease otherwise isn’t severe.

· Homocystinuria—this is an autosomal recessive defect in cystathionine synthase so that homocysteine builds up in the body with a relative lack of cysteine. There is mental retardation, failure to thrive, and thromboembolic disease. It can be treated by giving cysteine and pyridoxine.

· Maple syrup urine disease—this is an autosomal recessive deficiency of branched chain keto-acid decarboxylase so that branched chain amino acids build up.

There can be CNS deterioration, mental retardation, and early death unless these amino acids are removed from the diet.

· Phenylketonuria—this is an autosomal recessive defect in phenylalanine hydroxylase. Phenylalanine can build up if not removed from the diet. The symptoms are CNS deterioration, hypopigmentation of the skin and eyes, with death if not treated.

· Glycolytic enzyme deficiencies—these are red blood cell diseases that involve a defect in any enzyme responsible for glycolysis in the red blood cells. RBCs rely