Autosomal Recessive Disease

ATAXIA-TELANGIECTASIA

Syllaba and Hennery first reported three adolescent patients with progressive choreoathetosis and ocular telangiectasia in 1926, but it was not until 1964 that Martin recognized their clinical description as ataxia-telangiectasia (AT). y A second report in 1941 by Louis-Bar described a young boy with progressive cerebellar ataxia and extensive cutaneous telangiectasias; she identified the syndrome as one of the phakomatoses. y After the 1958 descriptions by Bean, y Boder and Sedgwick,y , [58] and Centerwall and

Miller, [5si AT became recognized as a distinct disease, and multiple reports appeared in the literature.

AT is an autosomal recessive disorder characterized by a constellation of signs and symptoms associated with progressive cerebellar dysfunction, conjunctival and cutaneous telangiectasias, severe immune deficiencies, premature aging, and a predisposition to cancer. y AT is inherited as a single mendelian locus on chromosome 11q22-23. Recent studies have identified the mutated gene in AT and its identification provides answers to the link between the mutated gene product in AT and the signaling pathways that regulate the cell cycle. y In the normal cell cycle, surveillance checkpoints are used to arrest cells during the cell cycle, allowing either completion of certain events that are required at that point or repair of damage. During these delay periods, damaged DNA can be repaired so that subsequent cycles can occur normally. Clinical and laboratory work has suggested that the AT gene product is involved in maintaining the integrity of chromosomal DNA and in signal transduction mechanisms that operate to regulate the cell cycle or DNA repair. The exact biochemical roles of the gene product in these processes, however, remain unknown.

AT occurs equally among the sexes and is reported in all races and in all parts of the world. The prevalence of this disorder ranges from 1 in 40,000 to 100,000 births. Although AT is a multisystem disorder, progressive neurological deterioration is the hallmark of the syndrome. y The early neurological features of AT are characterized by signs indicative of a progressive cerebellar degeneration, including ataxia and dysarthric speech. Ataxia is manifested by a swaying of the head and trunk and becomes apparent shortly after affected children begin to walk. It progresses and becomes severe enough to warrant the use of a wheelchair by 10 to 15 years of age. By this time, dyssynergia and intention tremor of the extremities interfere with normal activity. Speech is initiated slowly and slurred, and words are articulated poorly. Choreoathetosis can be present in older children and can even mask the ataxia. Myoclonic jerks, rigidity, dystonic posturing, muscular hypotonia, drooling, and arrest of cognitive development are also typical. These patients also have characteristic facies, described as relaxed, dull, sad, and inattentive when unstimulated. The examination also reveals oculomotor abnormalities, including slowly initiated voluntary horizontal movements of conjugate gaze with nystagmus-like jerks with fixation and refixation. The deep tendon reflexes are diminished, the plantar response is flexor, Romberg's sign is absent, and deep and superficial sensation is normal. Later neurological features may be dominated by spinal cord dysfunction, including abnormalities of position and vibratory sensation. Other patients demonstrate neuromuscular deficits with diffuse weakness, muscle atrophy, fasciculations, and absent tendon reflexes with intact sensory findings. Finally, in some patients there is a more mixed clinical picture including abnormalities of both sensory and motor function.

Non-neurological features vary and include vasculocutaneous, immunological, and neoplastic manifestations. The characteristic telangiectasias usually appear later than ataxia, typically at around 3 to 6 years of age in the region of the conjunctival angles of the eye. Once present, they steadily progress and spread in a symmetrical pattern across the exposed portion of the bulbar conjunctivae. These telangiectasias are bright red horizontal streaks that cause the eyes to look "bloodshot" and eventually involve the rest of the conjunctivae, eyelids, adjoining facial regions, external ears, neck, and antecubital and popliteal spaces. Rarely, the telangiectasias may be present on the dorsum of the hands and feet and on the mucosal surfaces of the palate. These abnormal vessels are not symptomatic and appear to be of venous origin, branching from subpapillary venous plexuses in the skin and dilated connecting venules in the conjunctivae.

Patients with AT also demonstrate progeric changes of the hair and skin, including early graying of the hair and atrophic, hidebound facial skin. Pigmentary changes are also frequent and consist of hyperpigmentation and hypopigmentation with cutaneous atrophy. A few patients may demonstrate partial albinism, vitiligo, and cafe au lait spots. Seborrheic dermatitis occurs in nearly all patients, and senile keratoses, atopic dermatitis, and eczema are also reported. Another prominent feature of AT is frequent sinopulmonary infections. These may range from infection of the ears, nose, and sinuses to chronic bronchitis and recurrent pneumonia. The latter two may result in bronchiectasis and pulmonary fibrosis. Chronic infections are typically due to common bacteria; however, they are sometimes poorly responsive to antibiotic therapy. The predisposition to infection is associated with the presence of an abnormal thymus and a marked deficiency of IgA, which is the predominant immunoglobulin in respiratory secretions. Neoplasms occur in an estimated 10 to 15 percent of patients with AT and are second only to pulmonary disorders as a cause of death. The most common neoplasms include Hodgkin's disease, malignant lymphomas, reticulum cell sarcoma, and histocytosarcomas. Various other tumors have been associated with AT, including medulloblastoma, basal cell carcinoma, acute lymphocytic leukemia, and gliomas, as well as others. These patients also have retarded somatic growth with dwarfing and various skeletal disorders. Endocrine abnormalities are also prominent, and female hypogonadism with sexual infantilism is found consistently. Male hypogonadism also occurs but is less prominent and is characterized by a delay in puberty, incomplete spermatogenesis, and decreased Leydig cells. Other studies report an unusual type of diabetes mellitus that appears in late adolescence as well as anterior lobe pituitary abnormalities.

The laboratory evaluation of patients with AT reveals normal results on routine studies of the urine, blood (except for lymphopenia), and spinal fluid. Although glucose studies may reveal evidence of an insulin-resistant diabetes mellitus, thyroid function studies are normal. Elevations in serum alpha-fetoprotein and plasma carcinoembryonic antigen are typically, but not invariably, present and are not required diagnostic criteria. Humoral or cellular immunological defects are also helpful in the diagnosis of AT, including low or absent levels of IgA, IgG2, and IgE, yet these are not invariable. Plain films of the skull may show decreased or absent nasopharyngeal adenoidal tissue, and CT and MRI studies of the head show cerebellar atrophy. Muscle and nerve biopsies may reveal evidence of denervation atrophy and axonal degeneration, respectively.

Treatment of patients with AT is supportive and includes

treatment of infections and the use of sunscreens to retard the cutaneous progeric changes. Early institution of pulmonary physiotherapy and physical therapy is important. Prenatal diagnosis is possible through the measurement of alpha-fetoprotein levels in amniotic fluid and the documentation of increased spontaneous chromosomal breakage of amniotic cell DNA.

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