Ataxia Telangiectasia

Ataxia-telangiectasia is a rare inherited disorder that affects the nervous system, immune system, and other body systems. This disorder is characterized by progressive difficulty with coordinating movements (ataxia) beginning in early childhood, usually before age 5. Affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The movement problems typically cause people to require wheelchair assistance by adolescence. People with this disorder also have slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia). Small clusters of enlarged blood vessels called telangiectases, which occur in the eyes and on the surface of the skin, are also characteristic of this condition.

In 1941, Madame Louis-Bar 1 described a patient with progressive cerebellar ataxia and telangiectasia of the skin and conjunctivae. Boder and Sedgwick in 1957 and 1958 2 reported eight cases with similar findings in association with frequent severe sinopulmonary infection. They proposed the name "ataxia telangiectasia" (A.T.). Wells and Shy 3 in 1957 described the choreoathetosis associated with this syndrome. Since that time, more than 150 cases have been reported or alluded to. 4 The recent admission of a patient with A.T. prompted review of this syndrome.

CASE REPORT
A 15-year-old boy was admitted recently to Henry Ford Hospital because of vomiting, gagging and generalized weakness of several days' duration. He was first seen at Henry Ford Hospital when he was 21/2 years old because of difficulty in walking.
Hyperemesis gravidarum occurred during the first five months of the mother's pregnancy. Gestation was full term with a normal, low forceps delivery. The neonatal period was uneventful. Development seemed normal until he was 18 months old, when the mother noticed he had difficulty in balance while walking. Between stable objects he walked rapidly, constantly grasping at something to avoid falling. Past medical history at that time revealed frequent colds and a poor appetite following colic during the first three months. Pertinent physical findings at the age of 2 1 /2 years were an expressionless facies with mouth held open, staring eyes, head tilted to the left while standing, walking or sitting, and an ataxic gait with loss of coordination of arm swing and leg motion while walking. CBC revealed a lymphopenia with a white blood count of 9,450. EEG was normal. The patient was discharged with a diagnosis of suspected cerebral palsy, athetoid type.
After that he was evaluated in a number of different places. At age 51/2 he suffered an episode of viral encephalitis requiring two weeks' hospitalization without apparent sequelae. While he was hospitalized it was noted that he had indistinct speech, appeared small, frail, and lethargic. When he was almost eight, involuntary twitching of the right hand began. It progressed to a twitching of the face and right leg and transient right hemiplegia. The diagnosis then was choreoathetosis and questionable convulsive disorder. Marked hyperref!exia of the lower extremeties was noted. When he was 10 the diagnosis of ataxia telangiectasia was made.
He was able to walk with crutches at the age of 10, having continued physical therapy twice a week since the age of seven. At the age of 13 he became bedridden. ln retrospect, his mother recalled that his eyes had been bloodshot since he was four.
Respiratory infections were treated early with antibiotics since he was three. In 1963, when he was l I years old, he was hospitalized with chickenpox and bilateral bronchopneumonia which, despite antibiotic therapy, left residual pulmonary fibrosis on chest roentgenograms. Chronic respiratory disease has persisted and remained a major problem since.
The patient attended kindergarten at the age of five, but failed after missing a great deal of school due to illness. Thereafter he was placed under a special schooling program and began receiving physiotherapy twice a week.
His second admission to Henry Ford Hospital at the age of 15 was prompted by vomiting, gagging and increased generalized weakness of two days' duration. Prior to admission he had been receiving Dilantin 15 mg t.i.d., Tetracycline 500 mgs b.i.d, Dimetapp and Quibron elixir, gamma globulin once a month and allergy vaccine every two weeks.
The physical examination revealed a cachectic, senile appearing boy in no acute distress. Weight was 56 pounds, height 55¥,i inches. The blood pressure was 110/ 80, pulse 80 and regular, temperature 100.4 and respirations 60 and regular. There was a masklike facies with stooped shoulders and head tilted forward and to the left (Fig 1). Peculiar eye movements were seen when the patient looked laterally. Hori zontal nystagmus with poor fixation were present along with the inability to converge. Telangiectasia of the bulbar conjunctivae and pinnae of the ears were present (Fig. 2). Auscultation revealed decreased breath sounds without rales.
o abnormality was noted on examination of the heart, abdomen and external genitalia. Extremities were thin with much muscle wasting and bilateral weakness. The right arm was weaker than the left. Athetoid movements and slurred dysarthric speech were present. He was bedridden and unable to walk. Dysdiadokokinesis was marked.
Laboratory: Hemoglobin 13.6 grams per cent, white blood count 17,900, differen tial -10 bands, 81 neutrophils, 4 lymphocytes, 5 monocytes, 1+ toxic changes and adequate platelets. Urinalysis and serum electrolytes were normal. Sputum culture showed numerous coliform bacilli and moderate candida albicans. Roentgenograms of the chest revealed fibrotic changes (Fig. 3). Roentgenograms of the paranasal sinuses showed opacification of the left maxillary antrum and the clouding of the right maxillary antrum of maxillary sinusitis (Fig. 4). Adenoid tissue was absent. Laminograms of both lungs revealed the infiltrative process of left lower lobe pneumo-

Figure 1
Ma k-like facies, stooped shoulders, and head tilted forward.   nia and an absent thymus. Antinuclear factor was absent. Ceruloplasmin 78 mgs per cent (normal 16-80), C-reactive protein positive I :8, serum complement titer 160 (50% Hemolysis) units/ ml (normal 175-225 units/ ml). Peripheral blood leukocytes were tested for their ability to produce interferon by an in vitro culture method. 21 A "good interferon response" was obtained, a titer I : 128 (normal response being titers of 1.32 or greater).
Serum viral neutralizing antibody titers, protein electrophoresis ( acetate method) and immunochemical analysis were determined the day prior to administering by vein fresh frozen plasma (250 units daily on two consecutive days) and I, 8 and 20 days thereafter (Tables I, IL lll). It was concluded that fresh frozen plasma and gamma globulin administration were of little value to the patient.

D1scuss10
Ataxia telangiectasia is a unique syndrome involving several systems of the body. Clinically, there is involvement of the central nervous system, conjunctiva, skin, upper and lower respiratory tracts and the lymphatic and immunological systems (Tables  IV, V).
Neurologically, cerebellar and extrapyramidal systems are the most severely affected. Cerebellar ataxia is usually the first symptom and occurs about the time the child starts walking. It affects station, gait and intention without any aggravating or relieving factors, with steady progression to complete incapacitation by early adolescence. Gait is seen as broad based, staggering and reeling, so severe as ataxia progresses that often the patient is bedridden early in ljfe. At autopsy! severe loss and degeneration of the Purkinje cells, and, to a lesser degree, similar changes of the basket and granule cells in the cortex of the cerebellar vermjs and neocerebellum (lateral lobes and dentate nucleus) are found.
The extrapyramidal symptoms of choreoathetosis m many cases are prominent and progressive, and appear later than the cerebellar ataxia. Peculiar conjugate eye movements occur. 6 These include a halting lateral gaze "hung up", so to speak, at   A decrease in the deep tendon reflexes is seen, and it progres,es many times to complete areflexia even with reinforcement. Plantar response is flexor. Speech is dysarthric and, with poor breath control, is sometimes explosive. Many times it is described as scanning, slurred or slow in character. 2 • 7 • 8 Drooling results from excessive salivation.
These patients have a characteristic facies and posture (Figs. J and 2). The facies is relaxed, dull, sad and seemingly inattentive in contrast to the alert, cheerful, sweet smile. Many times they have been described as the smallest child in the class, with a "poker face." 2 Posture is stooped with drooping forward of the shoulders and head. The head usually is tilted to one side (Fig. 2). Wasting of the face gives the appearance of premature aging. Initially hypertonia is seen, giving way to hypotonia on passive movements. The toes tend to curl under and the thumbs are adducted.

ATAXIA TELANGIECTASIA
No detectable mental changes appear in the early stages of A.T. Later, with deterioration of mentation and slowing of reactions, a lack of responsiveness is seen. Seizures are rare and the EEG shows no consistent or specific pattern of abnormality. Pneumoencephalographic studies reveal evidence of cerebellar atrophy. 2 Cutaneous and conjunctiva! telangiectasia are an intriguing part of the syndrome. The telangiectasia is a prerequisite for the diagnosis and usually appears later than the ataxia or choreoathetosis, at approximately four to six years. Thus, if there is no family history, the diagnosis may be delayed and labeled simply cerebellar ataxia or, at times, cerebral palsy. The telangiectasia occurs only in the bulbar portion of the conjunctiva (Fig. 1). Distribution on the skin includes the butterfly area of the face, eyelids, ear lobes, neck, antecubital and popliteal fossae, dorsum of the feet, hands, wrists and knees.
Other skin manifestations include pigmentary disturbances with a mottled pattern of hyperpigmentation and hypopigmentation with cutaneous atrophy and telangiectasia similar to poikiloderma in scleroderma or to advanced actinic or radiation dermatitis. Cases of partial albinism have been described. Reed, Epstein, Boder and Sedgwick 4 studied in detail skin manifestations of 150 patients with A. T. They found, in addition to the previously mentioned findings, that skin infection occurs commonly with nearly aU patients who have had impetigo at one time or another. Also, extensive warts commonly occur in most patients after the age of six. Seborrheic dermatitis is frequent and is more severe in patients with marked neurological damage. Follicular keratitis and dry skin are common, as well as hirsutism of the arms and legs in girls over 10. Diffuse graying of the hair occurs early but tends not to be progressive. Thus, with the skin changes, the premature graying of the hair and the masklike facies, the child appears old (Fig. 1).
Sinopulmonary infections are frequent, 2 , s , 6 occurring in approximately 85% of the cases; however, this is not indispensable for the diagnosis. These infections usually occur later than the neurological symptoms, around the age of four to six years. Otitis media is frequent. 2 Thus, recurrent sinusitis and bronchitis lead to bronchiectasis and pulmonary fibrosis. This is the usual cause of death which usually occurs during adolescence.
These patients have a uniform disposition and are commonly referred to as "ideal patients to take care of." Despite their morbid condition, their personality is such that they seldom complain and appear almost euphoric in spite of the poor prognosis and their great disability. Familial incidence is well-known and recently Tadjoedin and Fraser 9 analyzed the genetic aspects of the condition. Transmission was found to be that of autosomal recessive inheritance. As the disease progresses, it is found that these patients show stunted growth.
Investigation of the immunological abnormalities followed early reports of low gamma globulin and lymphopenia. 5 Peterson 1 0• 11 bas pointed out the close resemblance of patients with ataxia telangiectasia to neonatal thymectomized animals. At autopsy in most cases an immature thymus was present, on other occasions it was absent alto gether. Eisen 12 recently published immunological studies in six patients with significant findings of 1) decreased lymphoid tissue; 2) lymphopenia; 3) dysgammaglobulinemia ( diminished or absent immunoglobulin A (IgA); 4) absence of de'ayed hypersensitivity and 5) impaired homograft rejection. Patients with ataxia telangiectasia vary in their capacity to maintain skin grafts, manifesting either complete tolerance or prolonged rejection time. 13 Eisen demonstrated many of his above findings by the use of skin tests to histoplasmin, tuberculin, candida, trichophyton, streptokinase and strepto dornase antigens as well as passive transfer of delayed hypersensitivity, all of which were negative. First and second homograft rejections have been shown to be abnormal. 1 1 The first showed prolonged survival of approximate I y 24 to 60 days ( normal 10 to 14 days). Absence of any inflammatory reaction was apparent and the second homo graft was intact after 12 days with subsequent gradual progression of necrosis with scal ing. This abnormal homograft rejection is similar to rejection often seen in patients with Hodgkins disease. 1 5 These findings focused attention to the thymus gland and presented the problem of correlating the relationship of the immunological defects to the neuro logical abnormalities.
Karpati et a1 14 pointed out that the time relationship of the immunological and neurological abnormalities may be of importance, as demonstrated in one of their patients with A.T. Ataxia was clinically evident at 18 months and at that age she also had lymphopenia, absent IgA in her serum and absent delayed hypersensitivity. However, peripheral lymphoid tissue was normal and growth and development were otherwise normal for her age.
Recently, antiviral activity of nasal secretions has been found to be associated with lgA, the predominant immunoglobulin in the secretions. Therefore various studies of the immunoglobulins in A.T. nasal secretions have been done.1 6 It has been found that the pattern of neutralizing antibodies in these secretions parallels that of serum with markedly deficient or absent lgA in the nasal secretions. Bellanti 16 concluded that, although patients with A.T. lack the normal complement of lgA in nasal secretions, they do contain antiviral antibodies in association with other immunoglobulins.
McFarlin 17 found evidence to support the fact that lgA in saliva is produced locally and not transported from the serum in patients with A.T. In five patients he found that they all had no detectable serum lgA but had normal levels of saliva IgA. Also the deficiency of serum IgA can be explained as a defect in IgA synthesis, which is incomplete. Other mechanisms which contribute to this deficiency may be impaired IgA release or increased catabolism.
Thus it is seen that the major immunoglobulin defect is the deficient or absent IgA. However, decreased immunoglobulin G (lgG) is seen on occasion, and sometimes increased immunoglobulin M (lgM) and lgG. 18 The potential for lymphoreticular malignancy 1s high.11 Patients with A.T. have died with lymphosarcoma, reticuloendotheliosis, generalized reticulum cell sarcoma, Hodgkins disease and undifferentiated round cell sarcoma.

ATAXIA TELANGIECTASIA
Reed, Epstein, Boder and Sedgwick 4 reviewed the family history of 22 patients with A.T. They found 15 families with recurring history of cancer of all types. Six of the 15 families had members with lymphosarcoma (including Hodgkins disease) and leukemia. In 50% the history of cancer was remarkable because of its onset in young adults.
McKusick 19 recently described two patients found in the Old Order Amish, one with A.T. and the other with Swiss type agammaglobulinemia (SAG). Tracing their genealogies, they found a common ancestry in these patients. Also, it was found that two siblings of the patient with A.T. died early with a clinical picture consistent with Swiss agammaglobulinemia. Finding suggested, but did not prove, genetic identity of A.T. in one form of Swiss agammaglobulinemia. Clinical features of SAG include growth failure a sociated with serious infections usually in the first week of fungal, bacterial and viral etiology. Ulcerative colitis and malabsorption syndrome are often seen: Inheritance is autosomal recessive and some cases have been thought to be sex linked recessive. Gamma globulin levels are less than 25 mgs percent, and there is a distinct deficiency of lymphocytes in the blood, bone marrow and lymphoid organs. Peripheral blood shows less than 1,000 lymphocytes per cubic millimeter. These patients usually die in the first 18 months, despite gamma globulin replacement and thymic gland homotransplants. At autopsy, peripheral lymphoid tissue is poorly developed, lymphocytes are almost absent and no plasma cells are found. The thymus is primitive, small and many time undescended. Tonsils are ab ent.

SUMMARY
A patient with ataxia telangiectasia is presented with undetectable serum immuno globulin A, elevated immunoglobulin M and decreased immunoglobulin G. Serum viral neutralizing antibody titers and serum immunoglobulins were determined one day before, and one, eight and twenty days after, administration of fresh frozen plasma intravenou ly. It was concluded that fresh frozen plasma or gamma globulin would be of little value in treatment. Interferon response was good. The features of ataxia telangiectasia are discussed.