LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES QUEBEC COOPERATIVE STUDY OF FRIEDREICH'S ATAXIA Familial Spastic Ataxia Associated With Ehlers-Danlos Syndrome With Platelet Dysfunction C. Chouza, J.L. Caamano, O. De Medina, J. Bogacz, C. Oehninger, R. Vignale, G. De Anda, E. Novoa, R. De Bellis, H. Cardozo, B. Crispino, S. Romero, H. Correa, S. Feres ABSTRACT: Four members of a family with consanguineous relationships, the proband and his three children (2 sons and 1 daughter) are affected with Familial Spastic Ataxia and with Ehlers-Danlos' Syndrome with platelet aggregation dysfunction. In the four cases, this exceptional association appears remarkably homogeneous both in clinical and laboratory studies. The two syndromes are of dominant-autosomic transmission and probably originated in a new mutation which presumably maintained a genetic linkage. Spastic ataxia is characterized by a precocious onset and a slow evolution. The first-born son shows a dominant pyramidal syndrome with mild ataxia suggesting that it is a transitional form of familial spastic paraplegia. The Ehlers-Danlos syndrome pertains to form II or "mitis" with moderate skin hyperelasticity and joint hypermobility. The abnormal platelet aggregation curves have the same profile in all the patients. The first-born son also presents a mitral valve prolapsus as we may find either in Ehlers-Danlos syndrome or in spastic ataxia. The neurophysiological, tomographical, histological, ultrastructural and biochemical studies attempt to accomplish a better definition of these associated nosological entities. RESUME: Dans une famille avec des rapports de consanguinite, quatre de ses membres, le "proband" et ses trois enfants (deux hommes et une femme) sont atteints d'une ataxie spastique et du syndrome d'Ehlers-Danlos avec deficit d'agrdgation des plaquettes. Cette extraordinaire association montre des aspects cliniques et de laboratoire tres homogenes dans les quatre cas. Les deux syndromes se transmettent d'une maniere autosomale dominante et originent probablement dans une nouvelle mutation qui maintient peut-etre un lien gfinetique. L'ataxie spastique se caracterise par un debut tres pr6coce et une lente Evolution. L'aine montre un syndrome pyramidal dominant avec une 16gere ataxie, ce qui suggere une forme transitionnelle avec la paraplegie spastique familiale. Le syndrome d'Ehlers-Danlos correspond a la forme II ou "mitis" avec une hyperelasticity moderee de la peau et une hypermobilite articulaire. Les courbes anormales d'agregation des plaquettes ont le meme profit chez tous les patients. L'aine' montre un prolapsus de la valve mitrale tel que nous pouvons le trouver dans le syndrome d' Ehlers-Danlos ainsi que dans l'ataxie spastique. Les dtudes neurophysiologiques, tomodensitometriques, histologiques, ultrastructurelles et biochimiques essaient de deTmir le mieux possible cette association d'entites nosologiques. Can. J. Neurol. Sci. 1984; 11:541-549 The Ehlers-Danlos' Syndrome (Ehlers, 1901; Danlos, 1908) and cardiac defects. Some forms of the syndrome are accompanied or hyperelastic cutis is a disorder of the connective tissue by hemostatic disturbances. With a significant incidence of 10 produced by a biochemical disturbance of collagen, of hereditary to 20% (Aita, 1972), Ehlers-Danlos' syndrome is associated nature and usually of dominant autosomic transmission. The with various neurological syndromes such as mental deficiency, clinical expression comprises thin, soft, hyperelastic and frail marked hypotonia, epilepsy, multiple neurofibromatosis (Good­ skin with defective cicatrization associated to articular hyper­ man et al., 1962), acute multiple brachial neuropathy (Kayed mobility and the risk of luxation. Arachnodactyly, muscular and Kass, 1979) and, exceptionally, to spino-cerebellar degen­ hypotonia, Kypho-scoliosis and cutaneous molluscum pseudo- eration (Aita, 1972). tumours are frequent components of the syndrome. Some of We present a family with a consanguineous relationship whose the complications we may observe are multiple arterial aneurysms proband and three children sufferfrom spastic ataxia of precocious and dissecting aortic ectasis. Various congenital malformations onset associated to Ehlers-Danlos syndrome with platelet may appear such a hypertelorism, epicanthus, syndactylism aggregation dysfunction. To our knowledge this is the first From the Neurological Institute, Dermo-Syphilopathy Department and Hematology Department, University School of Medicine, Montevideo, Uruguay Reprint requests for the complete supplement (Phase 3, Part 3) to: Prof. Andrt Barbeau, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7 Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.164, on 04 Oct 2021 at 13:56:29, subject to the Cambridge Core terms of use, available at 541 https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100035010 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES report of this kind of association. This unusual nosologic presentation is transmitted in dominant autosomic form and its clinical and laboratory data are of remarkable homogeneity in the four patients. CLINICAL STUDY The family lives in the city of San Carlos some 140 kilometers' distance from Montevideo, Uruguay's main city. We can see in the family pedigree (Fig. 1) a consanguineous relationship between the proband's parents and also between the proband and her first husband. The proband (Case 1) and her three children (Cases 2, 3 and 4) are affected. There are no previous known cases of these diseases in the family. The neurological examination was completed with the Ataxias' Scale of Pourcher and Barbeau (1980), rating the Total Score (maximum of 138) and the Functional Staging (0-5) in each case. AUTOSOMAL DOMINANT SPASTIC ATAXIA FAMILIAL PEDIGREE [SPASTIC ATAXIA. EHLERS-OANlOS • 6^ aSYNDROM E WITH PLATELET DYSFUNCTION P4<ZP Figure 2 Figure 1 CASE REPORTS Case 1: The proband (Fig. 2) N.P. 38 years old. Female. Caucasian. Left-handed. When she was 3 years old her left foot progressively became deformed in varus; the same symptom appeared in her right foot 3 years later accompanied by weakness of both feet, unsteadiness of gait and repeated falls. At the age of 7 she noticed incoordination of movement and tremor, and at age 13 she had dysarthria and progressive ataxia of gait; two years later she needed help for walking. These symptoms had a slow progression and, at present, the patient uses a wheel-chair although sometimes she may walk some steps with the aid Figure 3 of a special walking cane. Past history: BK pleuritis when 15 years old. Physical examination: Tall and thin with long arms and fingers. Epicanthus. Skin: Thin, soft, diffuse choroiditis. Visual field with colours: normal. Bilateral rotatory hyperelastic, folding easily (Fig. 3). The translucency of the skin permits nystagmus in primary position. Transient convergent strabismus. Irregular visualization of the superficial vascular system. Multiple molluscum. conjugate pursuit ocular movements in lateral gazes. Enhanced mandibular Large "cafe au lait" spot on cervical left side. Torpid post-traumatic reflex. Upper limbs: hyperextensibility and muscle hypotonia. Normal lesions in lower limbs. Joints: Hyperextensibility most marked in distal muscle strength and tendinous reflexes. Cerebellar incoordination of joints. Mild dorso-lumbar scoliosis. moderate degree. Normal sensitivity. Lower limbs: extension and internal Neurological examination: Normal intellect. Mild dysarthria. Severe rotation with pes equinus-varus. Severe spasticity with marked tendinous myopia, higher on the right eye. Fundus: severe myopic signs with hyperreflexia and intense Babinski. Weakness and coordination are Downloaded542 from https://www.cambridge.org/core. IP address: 170.106.35.164, on 04 Oct 2021 at 13:56:29, subject to the Cambridge Core termsFamilial of use, availableSpastic at Ataxia — Chouza et al. https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100035010 LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES Figure 4 Figure 5 difficult to evaluate because of the spasticity. Vibratory sensation Physical examination: Long and thin upper limbs. Skin: Hyperextensible within the limits of normality. Very difficult gait with help. Total score with easy and elastic folding. Visible cutaneous blood vessels on trunk (Pourcher-Barbeau Scale): 75. Functional stage: IV. and limbs (Fig. 5 & 6). Pigmented flat nevus on back and right upper Case 2: (Fig. 4) L.C. 15 years old. Male. Caucasian. Left-handed. limb. Joints: Hypermobile. Delay in attainment of motor behaviour. When 3 years old he started Neurological examination: Marginal intellect (WISC = 73). Moderate left varus pes and at the age of 6 varus also appeared on his right foot, dysarthria and hypophonia. Fundus: normal. Enhanced mandibular thus determining slowly progressive disturbances of gait. Two years reflex. Upper limbs: Hyperextensibility and hypotonia. Mild hyporeflexia. ago dysarthria and moderate loss of strength in the lower limbs. The Mild-moderate cerebellar incoordination. Lower limbs: Bilateral pes patient walks without help. cavus. Hyperextensibility. Mild spasticity and hyperreflexia. Bilateral Physical examination: Tall and thin. Hypertelorism. Defective dental Babinski. Mild weakness. Mild cerebellar incoordination. When the implantation. Skin: Translucent with visible blood vessels. Hyperex- patient stands up, we observe: hyperlordosis, "Tendinous dance" of tensible with