Sex-Linked Hereditary Ataxic Diplegia, the Borderland Between Cerebral Palsy and Pelizaeus-Merzbacher Disease

THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES

H. G. DUNN, MARGARET W. THOMPSON, ELIZABETH BANDLER and L. G. ANDREWS

SUMMARY: After a review of the litera described in three previous reports in the The importance of genetic factors ture concerning hereditary cases of literature. No evidence of linkage with in the etiology of cerebral palsy is cerebral palsy, a family is reported in other sex-linked disorders has been still somewhat controversial, though which ataxic diplegia appears to be inh found, Xg" typing showed that recombi erited as a sex-linked and probably re nation between the Xg locus and the occasional cases have a clear family cessive condition occurring in 3 males in locus for hereditary ataxic diplegia has history of similar disability. With successive generations. This ataxic dip occurred once out of three possible op regard to spastic forms, Pas kind and legia, occurring after an unremarkable portunities. In the absence of Stone in 1933 were able to analyze perinatal course, is associated with mild neuropathological findings or specific 152 families in the literature, in to moderate mental retardation, congen biochemical tests, the differential diag whom familial cases had been de ital nystagmus and significantly small nosis from Pelizaeus-Merzbacher dis scribed. Among these, spastic stature and prevents the acquisition of ease cannot be made with certainty. The paralysis had been found in two gen free walking. Associated extrapyramidal differentiation from other progressive erations in 32 instances and in 3 or features may gradually become more sex-linked neurological disorders is dis more generations in 13 instances. marked, while the nystagmus may sub cussed. The literature has also been re side. The condition is similar to that viewed by Rhein (1916), Bell and Carmichael (1939), Polani (1963), In gram (1964) and Glenting (1970). The RESUME: Apres une revue de la litera s'attenuer. La condition est presque exact frequency of hereditary cases ture sur les cas hereditaires de paralysie similaire a celle decrite dans trois rap is hard to determine since the mere cerebrate, la cas a"une famille, dans ports anterieurs de la litterature. Aucune occurrence of cerebral palsy in sibl laquelle une ataxie diplegique appardit evidence n'a ete donnee du lien avec les defacon hereditaire a etre liee au sexe et autres desordres lies au sexe. Un typage ings may be due to environmental probablement chez 3 males de 3 Xg " montrait que la recombinaison entre factors like prematurity or maternal generations successives, est rapporte. le locus Xg et le locus pour I'ataxie toxemia, rather than genetic causes. Cette ataxie diplegique survenant apres diplegique est survenu une fois sur trois Also, the frequency depends on the une periodeperinatale peu remarquable, possibilites. En /'absence de constata- definition of the cerebral palsy syn est associee a un retard mental leger, a tions neuropathologiques ou de tests drome; as most recent authors insist un nystagmus congenital, a une petite biochimiques speciaux, le diagnostic that this should strictly exclude any taille et ne permet pas /'acquisition differentiel de maladie de Pelizaeus- progressive lesions, conditions like d'une demarche libre. Les signes ex- Merzbacher ne peut pas etre fait avec hereditary spastic paraplegia cannot trapyramidaux associes peuvent certitude. La differentiation des autres be considered in this context (Mac- graduellement devenir plus marques desordres neurologiques lies au sexe est pendant que le nystagmus peut aussi discutee. Keith et al 1959, Bax 1964, Glenting 1970). In surveys of cerebral palsy the prevalence of the condition in sibl ings has been found to range from about 3% to 5% (Blumel et al 1957, Mitchell 1961, Ingram 1964). The prevalence in all relatives in direct descent of the grandparents has been found to be about 10% (Ingram 1964, Glenting 1970). In general, cerebral palsy tended to affect members of From the Division of Neurology, Department of the family in a horizontal rather than Pediatrics, University of British Columbia; the De vertical direction on the pedigree, partment of Medical Genetics, University of To ronto; and the G. F. Strong Rehabilitation Centre, thus suggesting mostly recessive in Vancouver. B.C. heritance. However, environmental Reprint address: Dr. H. G. Dunn, 715 West 12th factors could then not be excluded, Avenue, Vancouver, B.C., Canada V5Z 1M9 and Glenting (1970) noted that the

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incidence of consanguinity among with ataxic forms of cerebral palsy importance, there were 10 with con parents was only 1.2%, compared to often had defects of vision, eye genital non-progressive ataxia and 2.1% among the general population. movements, hearing and speech, mental retardation, and 3 with ataxic A closer investigation of etiological and Ingram noted that only 36% of diplegia. The ataxia and mental re possibilities in his survey showed those with ataxia and 21% of those tardation appeared to be inherited as that a tendency to premature birth with ataxic diplegia had normal intel an autosomal recessive condition; in might be related to the condition, but ligence. He concluded that a de one of the 3 families with ataxic that otherwise birth factors could velopmental malformation of the diplegia, the disease appeared to be not be considered significant. He brain was probably more important due to a dominant gene, possibly concluded cautiously that genetic than birth injury in the majority of with varying expressivity. One fam factors might well be responsible for patients with ataxic forms of cere ily with only a brother and sister some cases of spastic cerebral palsy, bral palsy. Such a malformation affected by ataxic diplegia was sub and that some familial cases might (sometimes associated with hyd be part of hereditary syndromes. rocephalus) might then be geneti sequently published in detail by Twin studies (Gedda 1955, Hansen cally determined or due to Hagberg et al (1970), since the pa 1960, denting, 1970) and the finding teratogenic factors in early pre tients were also found to have defi of chromosome defects among pos gnancy. In 1964, Ingram mentioned cient cellular immunity. sibly 1% of cerebral palsied patients that among 12 patients with ataxic We report a family in whom ataxic with severe mental retardation (Po- diplegia, 5 had a family history of diplegia appears to be inherited as a lani 1963) point towards the same possible significance. In 2 of these sex-linked and probably recessive conclusion. Neuro-pathological the mother also had ataxic diplegia, condition. We have found only three studies demonstrating developmen suggesting that the disease was inh previous reports in the literature tal brain defects in familial cases erited in a dominant manner. In their concerning this mode of inheritance would be of great value in supporting Swedish survey, Gustavsson and his in ataxic diplegia, and in all three the hereditary nature of the condi collaborators (1969) collected 43 families the clinical picture was re tion but have rarely been available families in whom more than one markably similar to that in our pa (Paskind and Stone 1933, Christen- member had cerebral palsy, and tients (Wolfslast 1943, Blumel et al sen and Melchior 1967). In a these included 16 families with iden 1957, Baar and Gabriel 1966). How Swedish survey, Gustavsson et al tical syndromes and a history of ever, the condition may also be clin (1969) concluded that about 1.5% of normal pregnancy, delivery and ically indistinguishable from all cases of cerebral palsy were inh perinatal period. Among these 16 Pelizaeus-Merzbacher disease with erited as an autosomal recessive, families, which were of main genetic a very slow course. while other modes of inheritance were rarer. In ataxic forms of cerebral palsy PEDIGREE OF M. FAMILY

the proportion of hereditary cases IRISH MOHAWK INDIAN ENGLISH ENGLISH appears greater than in the purely spastic type. Ingram (1962) sug i> 4 gested that two major categories of ataxic cerebral palsy could be de fined, namely "ataxia" and "ataxic SCOTTISH diplegia." The former tends to be 0+ Q+ i. accompanied by persistent 3 4 5 6 hypotonia dating from birth, while the latter shows some features of spastic diplegia associated with the ataxia. In an analysis of 29 patients with congenital ataxia and 33 pa o+ n6 7 - tients with ataxic diplegia, Ingram found that about one-half of each group had been delivered normally after normal pregnancies and that one-half of the mothers' previous IV i in. pregnancies had resulted in abor 12 3 4 5 / 7 8 9 10 11 12 tion, perinatal or infant death, or the birth of an abnormal child. Also, • = AFFECTED WITH ATAXIC DIPLEGIA about 20% of the ataxic children had associated major developmental + = Xg(a+) malformations. Skatvedt (1958) had - = Xg(a-) previously pointed out that patients Figure 1. Pedigree of patients' family.

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CASE 1 (IV. 6) having a D.Q. of 65-75 on the same test a CM., a Canadian boy, is the younger year earlier. Chromosome analysis then of 2 children, and hjs older sister and showed him and his mother to have a parents are healthy (Fig. 1). The pre normal karyotype. gnancy was unremarkable. He was deli Physical examination at 3 years 10 vered normally 2 days after term, and months showed an auburn-haired, fairly though the cord was said to have been alert and happy but irritable little boy. tight around the neck, he cried well and His length of 92 cm was about 3 S.D. obtained an Apgar score of 8 at 1 minute. below the mean, and his weight of 14.5 The birth weight was 7 lbs. 8 ozs. (3,403 kg was satisfactory for the length-age. g.). After discharge from hospital at the The head circumference of 48.5 cm was age of 5 days, he had some projectile about 2 S.D. below the mean. He had a vomits and cried excessively, but gained slight anti-mongoloid slant of the pal weight satisfactorily. pebral fissures and an inexpressive fades (Fig. 2), with excessive drooling. About one week after birth the infant The hands were mostly fisted but at was first noted to have "wobbly eyes." times adopted an "avoidance" position. He smiled in response at 5 months, and The dermatoglyphs on the hands showed mental retardation was suspected at 8 a radial loop on the right middle finger months when he first learned to roll and double axial triradius and concomit over. At 15 months he began to crawl. ant Au/Ldr pattern in the right hypothe- He said the first words with meaning at nar area and were otherwise unremarka IV2 years. He learned to remain sitting ble (Table I). He sat with a long C unsupported at 20 months, to pull him kyphosis, and the hip adductors, hamstr Figure 2. Photograph of Case 1 at 6% self to sitting at 22 months and to stand ings and heelcords were tight. years. ing at 3 years. After that he began to take steps with support, but he never learned The boy appeared right-handed. His The optic fundi were normal apart to walk freely without supports or ap speech consisted mostly of single words from mild pallor of the optic discs. The pliances. which were poorly articulated. On the Gesell scale of behavioral development range of eye movements was full, but At W2 years cerebral palsy was diag he had mastered all the non-motor items there was a fine pendular and somewhat nosed, and physiotherapy was arranged. at the 18 months' level except toilet rotary nystagmus, noticeable on forward At 3 years he was temperamental and control by day. He also accomplished gaze, with superadded jerk component easily frustrated and obtained a D.Q. of about half the expected non-motor skills on lateral gaze. The mouth was often 52 on the Cattell Infant Intelligence at the 2-year level but hardly any beyond open, facial movement restricted. He Scale, whereas he had been assessed as that. appeared to hear satisfactorily, and the

Digital patterns and ridge counts Palms Soles 5 4 3 2 1 (L) Total (R) 1 2 3 4 5 Axiaj triradius (atd) Hypothen. Then Ii 12 13 14 Hal II.3, father of Case 2 U U U U U W W U W U (L) t' (36°), ' (32°) AU/AC O O Ld D Ld 13 13 14 12 15 67 154 87 18 19 13 21 16 (R) t' (38°) LU/AC O 0 Ld O Ld

II.4, mother of Case 2 U U U U U U R U W W (L) t' (42°) Au/Ac O 0 V O Ld 17 17 13 12 16 75 159 84 16 15 13 17 23 (R) t' (42°) Au/Ac O 0 0 Ld W

II.6, Case 3 U W U W U W W W W U (L) t' (51°) Ld/AC O 0 0 Ld 14 15 14 11 18 72 140 68 20 14 11 12 11 (R) t' (36°) Ar/0 O 0 0 Ld — III.4, mother of Case 1 U U U U W R U W (L) t (35°) O O 0 0 Ld /Ld O/O u u d U d 17 16 9 11 19 72 147 75 18 13 11 17 16 (R) t (38°) O O 0 0 L /L L

III.5, sister of Case 2 W W U W W W W W (L) t' (41°) Au/Ac O 0 0 Ld Ld w u d d 24 23 13 20 21 101 196 95 20 21 12 21 21 (R) t' (37°) AU/AC O 0 0 L L

III.7, Case 2 U W W W U W W R W U (L) t' (46°) AU/AC O 0 0 Ld W 17 25 24 17 24 107 218 111 27 21 21 21 21 (R) t' (40°) AU/AC O 0 Ld O O/O

U d IV.6, Case 1 U U U R U W R R U U (L) t (36°) A /AC O 0 o( L O/O 13 12 4 2 15 46 129 83 21 13 13 19 17 (R) t (38°), t (38°) Au/Ldr O 0 Ld O O/O

IV.7, son of III.5 U U R R U U R U U U (L) f (58°) AM/A= O 0 0 Ld Ld u c , d 17 19 4 17 12 69 153 84 19 15 12 22 16 (R) t' (55°) A /A O 0 0 Ld L

Table I — Dermatoglyphic patterns

228 - NOVEMBER 1974 Sex-Linked Hereditary Ataxic Diplegia

remaining cranial nerves were unre crawling but only a "bunny hop." When at that age showed poorly regulated and markable. supported in the standing position, the sustained alpha rhythm of 8 to 9Vfe Hz The upper limbs were mildly hyper boy showed marked truncal ataxia and and also much 4 to 7 Hz activity of low tonic, with excessive resistance to pas tended to stand on tiptoe or on the inner voltage in both occipital leads. Thus the sive supination. Seizing of objects was borders of the feet. He took a few steps record was somewhat dysrhythmic in the awkward and jerky, with primitive with "scissoring." waking state, whereas the sleep record spreading of fingers. The tendon reflexes At 5 years, he was examined by an was unremarkable. The following inves were present symmetrically, and no sen ophthalmologist who noted that he could tigations had normal results: urine os sory defect was demonstrated. Sitting find a 6 mm white ball almost anywhere molality and tests for specific gravity, balance was poor, unless he sat between in space, indicating generally satisfac reducing sugars and protein; urine his flexed legs, and there was slight tory vision and visual fields. There was screening for excessive amounts of keto truncal tremor and head titubation. no marked unilateral suppression on test acids or mucopolysaccharides and for ing with the Worth 4-color elimination abnormal amino acids (on two- The lower limbs were moderately dimensional paper chromatography); hypertonic with brisk tendon reflexes dots. The presence of a fine pendular type of nystagmus in the direction of complete blood count, assay of Factors and bilateral sustained ankle clonus. The VIII and IX, and of glucose-6-phosphate plantar and Chaddock responses were gaze was confirmed, and a jerk compo nent appeared to develop on peripheral dehydrogenase (by Brilliant Cresyl Blue extensor on both sides. When one ankle method); serum levels of calcium, phos was elevated in the Collis test, the oppo gaze. Cycloplegic refraction revealed moderate bilateral hyperopic astig phate, alkaline phosphatase, uric acid site leg tended to remain adducted and and protein, and electrophoretic pattern often extended. There was no proper matism. Funduscopy showed no abnor mality apart from a localized whitish of proteins. The mother's blood count, appearance of both optic nerve heads serum calcium, phosphate, alkaline attributed to gliosis. Corrective glasses phosphatase and uric acid levels were o were prescribed. also normal. The blood grouping of the family is shown in Table II, and the Investigations: X-ray examination of MSNs MsNs serum immunoglobulin levels are listed P+ the left hand and wrist indicated a sig in Table III. P+ nificantly retarded bone age of 2 years at CDe Ce ce. ce a chronological age of 3 years 10 months. Later, at 7 years, pure tone screening Lu bb Lu ab Films of the skull and pelvis showed no at 15 db showed hearing within normal Fy ab Fy ab abnormality. An electroencephalogram limits in both ears. Electronystagmo- Jk ab Jk ab Xga+ Xga+ Age IgG (mg.%) IgA (mg.%) igM (mg.%) Le a-b+ Le a+b- (yrs) II.3, father of Case 2 86 1700 (710-1540) 670 (60-490) 45 (37-204) 1 II.4, mother of Case 2 67 1400 (710-1540) 490 (60-490) 215 (42-261) MSNs MSMs P + P + II.5, sister CDe. ce CDe. ce of Case 3 65 1250 (710-1540) 410 (60-490) 252 (42-261) Lu ab Lu ab Fy ab Fy aa II.6, Case 3 45 1700 (710-1540) 280 (60-490) 100 (37-204) Jkbb Jk bb Xga+ Xg a+ III.3, father + + Le a-b Le a-b of Case 1 38 650-700 (710-1540) 426 (60-490) 87 (37-204)

All O; K-k+Kp(a-b+); LW+Gy III.4, mother (a + ) Wiel-Vw-Fy(ab-I-) of Case 1 36 650-700 (710-1540) 170 (60-490) 110 (42-261) Parents Be(a- ) Bi(a-) Wr(a-) Reid- Di(a - ) Mf - Bu(a -) Sm + D + mem III.7, Case 2 25 1250 (710-1540) 300 (60-490) 145 (37-204) bers also Holl+ Hart+ ; mother of proband D - and Holl - Hart- HI.8, son Note on Xg factor: While all 4 members of II.5 40 890 (710-1540) 180 (60-490) 120 (37-204) of this family, the affected maternal IV.5, sister uncle, both maternal grandparents and 85 (48-368) the maternal grandmother's sister are Xg of Case 1 10 600-650 (720-1600) 120 (36-256) (a+), Case 3 (II.6) is Xg (a -), as shown IV.6, Case 1 4V2 500-550 (550-1490) 344 (36-232) 74 (36-204) in Fig. I. Thus recombination between 550-600 (550-1490) 29J) (36-232) 80 (36-204) the Xg locus and the locus for hereditary 450-500 (620-1550) 310 (46-284) 43 (36-208) ataxic diplegia has occurred once out of 6V2 three possible opportunities. Note: Underlined values are outside normal range for age of patient. Table II Blood group studies in M Table III Serum immunoglobulin levels in members of family (normal range for age family according to Allansmith et al [1968] in brackets)

iDunn et al NOVEMBER 1974 - 229

graphy (Dr. R. P. Gannon) showed some I.Q. score was about 38. The Peabody ent fall in ability was considered to be large amplitude saccades with the eyes Picture Vocabulary Test showed voc that the later tests were more heavily open and closed, and a slow right- abulary recognition corresponding to an weighted with tasks requiring abstract beating nystagmus with the patient blind I.Q. of 66. He could then walk short thinking, and it was not thought that folded in the dark. Gaze testing did not distances precariously in his braces with there was any real fall in ability. By the demonstrate any significant nystagmus, a paraplegic walker. His truncal ataxia, age of 14 years, a mixed form of cerebral but both command and pursuit move titubation of the head and palsy had been diagnosed with spasticity ments were performed poorly. Superim choreoathetosis were accompanied by (chiefly in the legs), ataxia and athetosis, posed on all the eye movements was a considerable intention tremor and were and mild secondary flexion contracture fine oscillation of roughly sinusoidal pat worse on walking. of the hips and knees. Glasses were tern with a frequency of about 4 per prescribed for a refractive error. second, not significantly affected by eye CASE 2 (III.7) This lad was reported to be a good, opening or closure. Caloric responses to D.C., the maternal uncle of Case 1 irrigation at 30 and 44 C. showed that steady worker in the cerebral palsy (see Fig. 1), also had a normal pre-natal workshop, but was very dependent and both labyrinths were functioning nor and birth history. His birth weight was mally, but while a right-beating nystag had difficulty with fine hand movements. about 6 lbs. 5 ozs. (2,863 gm) at term. He was wheelchair-bound, but he could mus was induced normally from either Nystagmus was noted during the first 6 ear, any induced left-beating nystagmus transfer to and from bed and toilet, months, and then the mother became crawled and got around on his knees at was either distorted or absent, thus indi concerned at his failure to learn how to cating extreme directional preponder home. He had some limited ability to remain sitting. He always used his hands read, write and do simple arithmetic, but ance, presumably of brain stem origin. better than his legs. At 3 years he was Electronystagmography also demon added little to this in his teen years. At 19 diagnosed as having cerebral palsy and years he was discharged from the cere strated a significant positional nystag had become fully toilet-trained. At 5 mus and directional preponderance to bral palsy center and continued to attend years he began to attend a cerebral palsy a sheltered workshop. At 24 years he the right in the proband's healthy sister center, where he received (IV.5) but not in the mother (III.4). was admitted to a residence for hand physiotherapy. At 8-9 years he had icapped persons in Ontario. Like his Conduction in the motor and sensory learned to walk with crutches. Bilateral maternal uncle (Case 3) he was said to fibers of the right median nerve and in subtalar arthrodeses were then per be fond of music. the motor fibers of the right lateral pop formed, but he gradually lost his ability liteal nerve was normal. Electro to walk freely. He managed to feed him Physical examination at the age of 22 myography of the right tibialis anterior self with a spoon, though unsteadily, and years showed a pleasant, well- muscle was unremarkable apart from he was described as cheerful and relating nourished, dull lad with brown hair and features consistent with an upper motor well to other children. He formed long blepharitis (Fig. 3). His height of 153 cm neuron lesion. Lumbar puncture showed sentences, but articulated poorly. He was significantly small (more than 4 S.D. clear colorless fluid with an opening was thought to have an I.Q. of 77 on the below the mean). The head circumfer pressure of 180 mm, white blood cells 3 Stanford-Binet scale at the age of 7 ence of 55 cm was within normal limits. per cu mm (75% polymorphonuclears), years, but of only 52 at nearly 11 years, Many teeth had been filled; the lower red blood cells 120 per cu mm, protein 19 and a full-scale I.Q. of only 46 (Verbal wisdom teeth had erupted. The der- mg per 100 ml and gamma globulin 1.6 Score 53, Performance Score 44) on the matoglyphs showed a radial loop in the mg per 100 ml (8.5% of total protein), Wechsler Intelligence Scale for Children right middle finger (as in Case 1) and an glucose level normal, V.D.R.L. non- at HV2 years. The reason for this appar- unusually high digital ridge count (as in reactive, colloidal gold curve 112110. his sister III.5) but were otherwise nor mal (Table I). The finger joints were Course. A diagnosis of ataxic diplegia unusually extensible, the operated feet with mild mental retardation, congenital were somewhat fixed in mild pes planus. nystagmus and significantly small stature There were moderate flexion contrac was made. The boy continued to make tures at the hips and knees, and the hip slow progress in his physical and mental adductors were tense, with intertrigo of development while attending a pre the left groin. The spine showed slight school class and receiving physiotherapy dorsal kyphosis. The deltoids, biceps and speech stimulation. He gradually brachii and thigh muscles were well- developed some choreo-athetoid move developed, whereas the calves were ments of the hands, whereas the nystag small. The heelcords were only moder mus diminished. At 4 years sitting bal ately tight, and both ankles could be ance had improved, and below-knee dorsiflexed passively beyond 90c. braces were used. At 4 years 3 months he achieved an I.Q. score of 48 on the D. C. was right-handed and right- Stanford-Binet (Form L-M) test. At 5 eyed. His speech consisted of sentences, years he was fitted with above-knee but was uttered slowly and monoton braces, as his attitude of hip and knee ously with staccato quality. He was able flexion had increased. At 6V2 years a to add small numbers, to print slowly proximal hamstring release operation and to draw simple big figures clumsily, was performed. At 7 years he was begin but he could not name coins. Stereog- ning to form 3-word sentences. At 7 nosis was only fair in both hands. He years 5 months his abilities were increas Figure 3. Photograph of Case 2 at 25 also had some apraxia, e.g. for rubbing ing very slowly, and the Stanford-Binet years. his hands when washing with soap.

230 - NOVEMBER 1974 Sex-Linked Hereditary Ataxic Diplegia

Visual acuity appeared satisfactory Little is known about A.D.'s delivery, toward the right in the dorsal and toward with glasses, and color vision was but he was evidently considered healthy the left in the lumbar region, while the grossly intact. The optic fundi were initially and was brought to Canada at legs were both held together toward the normal apart from mild pallor of both the age of one year. He was slow to talk left side. The hips and knees exhibited optic discs. There was fixation nystag and never learned to walk freely, but as a flexion contractures. As in Case 2, the mus, and jerk nystagmus was noted in boy got around with a walker, dragging deltoid and biceps brachii muscles were the directions of lateral gaze; pursuit his feet. He spoke mostly in single well-developed and strong, whereas the movements of the eyes were saccadic words, but managed to form short sen calves and forearms were thin. The heel- but appeared conjugate. The face was tences, especially when excited. Until cords were tight and shortened, the feet somewhat inexpressive. Hearing was the age of about 10 years he was noted to flat, with flexed toes. The dermatog- normal for whisper and wrist watch. have an "eye wobble." He did not at lyphs were unremarkable and did not Otherwise, apart from dysarthria and tend any pre-school or school, became show a radial loop on the right 3rd digit slow protrusion of the tongue, the cranial wheelchair-bound and gradually de as in Cases 1 and 2. The hands were nerves appeared intact. veloped a moderate spinal deformity and elongated, fingers hyperextensible. The The upper limbs were mildly hyper flexion contractures. heart and lungs were normal, B.P. tonic with fair power and brisk tendon At 33 years he was admitted to a 100/60. The left testis was undescended. reflexes. Arm and hand movements were residential institution for the aged and A.D. was friendly and appeared mod slow and ataxic with dysmetria and ac handicapped in Ontario. On admission it erately orientated but dull. He was tion tremor. He was able to throw a ball, was noted that he was an "imbecile" and right-handed and right-eyed. His speech but could not catch it. Grasp and pinch unable to read, but had toilet control, was slow and slurred and consisted were strong. The outstretched hands was able to feed himself solids, used mostly of single words. He understood showed some athetoid posturing. No crayons and knew colors. The blood colors and other simple concepts like sensory defect was demonstrable apart pressure was 110/60, and a chest x-ray "up" and "down." He used his hands from slightly impaired stereognosis and showed no abnormality. fairly well, whereas the legs were stiff in doubtful vibration sense in the fingers. Physical examination at the age of 42 flexion. No asymmetrical tonic neck re The abdominal skin responses were ab years showed a crippled man who was sponse could be demonstrated. sent. The lower limbs were markedly greying prematurely and appeared to The optic fundi were normal apart hypertonic, with grossly exaggerated have moderate acne rosacea and knee and ankle jerks, sustained ankle from mild pallor and cupping of the blepharitis (Fig. 4).His length of about discs. The eyes followed poorly in pur clonus, crossed adductor responses, ex 132 cm was significantly small. The head tensor plantar and Chaddock responses, suit, but the eye movements appeared circumference of 52 cm was near the coordinated, and no nystagmus was evi and diminished power, especially in lower limit of the normal range for an muscles below the knees. He managed to dent. Opticokinetic nystagmus could not adult. The teeth consisted mostly of be elicited. The pupils appeared normal. stand and turn unsteadily with support carious stumps. In addition to the and with the legs flexed and adducted, Facial expression was somewhat re blepharitis he had a small marginal stricted. Chewing and lip closure ap but had very little ability to make move corneal ulcer and circumcorneal injec ments of progression. peared slow. The gag response was tion in the left eye. The tongue appeared brisk. The tongue was protruded centr The only investigations performed on somewhat prominent. The spine exhi ally to a moderate extent. Otherwise the D.C. were for Xg blood factor and serum bited marked kyphoscoliosis, convex cranial nerves appeared intact. immunoglobulins. He proved to be Xg (a4) like both his parents. The im The upper limbs were slightly hyper munoglobulin levels are listed in Table tonic, biceps and supinator jerks brisk. III. Power was fair, but hand movements were slow with mild dysmetria and poor CASE 3 (II.6) coordination of fingers. Position and A.D., maternal great-uncle of Case 1 touch sensation in the fingers appeared and maternal uncle of Case 2 (Fig. 1) was intact, vibration sense doubtful. Abdom born in Lancashire, England, in 1928. inal and cremaster skin responses could His father and mother are reported to not be elicited. have been in good health and to have The lower limbs were markedly hyper died at 72 and 71 years, respectively. tonic, especially the hip adductors and According to his older sister (II.5) the heelcords. Spontaneous clonus of the mother was one of 8 children, including whole legs was observed at times. Flex only one male, and there was no nervous ion contractures at the hips and knees disease among any of these or among restricted even passive movements, and their offspring, except that one sister's the ankles could not be dorsiflexed daughter died of meningitis. However, it beyond 90c. The knee and ankle jerks may be noteworthy that 3 of the were very brisk, with sustained ankle mother's sisters, though married, had no clonus and crossed adductor responses. children. A.D.'s father was evidently the The plantar and Chaddock responses 7th son among 10 children, and again were extensor. A.D. had to be held in the there was no family history of nervous standing position and was unable to take disease except that one of his sisters had any steps. He appeared quite unsteady a retarded son who did not have cerebral on his feet; the heel-shin test could not palsy. be performed. Pain, touch and position

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sense in the toes appeared intact, while German family. The proband was extremely active gag response and vibration sense was doubtful. noted at the age of 9 months to have spastic tongue. Athetotic move This man was seen by an ophthal horizontal-rotary nystagmus, a ments and marked cerebellar signs mologist who considered his eye move "weak neck," inability to remain were present in the upper limbs. The ments full and adequately coordinated. sitting, flexor hypertonus and in spinal fluid was evidently normal, The presence of fairly severe squamous creased tendon reflexes (particularly with a protein level of 40 mg.%. blepharitis with marginal ulceration of in the legs). Later, he exhibited mild Skull films showed a very small the left cornea was confirmed. The cor- neae were otherwise clear and the an head tremor and dysarthria, and at 6 cranium with poor development of terior chambers of average depth. The years was able to get around with a frontal fossa. An electroencephalog pupils and their light reaction were con walker, but was still unable to stand ram was reported as very abnormal, sidered normal, reaction to accommoda freely. A pneumoencephalogram with severe cerebral dysrhythmia tion could not be tested. After instillation was reported to show cortical at but without any focal changes. The of mydriatic the lenses were seen to be in rophy. His older brother, aged 10 younger brother, aged 12 years, was normal position, media clear. There was years, presented similar findings and similarly affected and was thought to mild pallor and cupping of the optic also bilateral choreoathetosis, inabil have I.Q.s of only 20 and 18 on the nerve heads, resembling in mild form the ity to sit freely, ankle clonus and Stanford-Binet and an I.Q. of 26 on changes seen in patients with long extensor plantar responses. Neither the Columbia Scale. His spinal fluid standing glaucoma. The retinal vessels was similarly normal, while an elec appeared grossly normal, and the intra this brother nor an affected cousin, ocular pressure felt normal to fingers, aged 19 years, received any school troencephalogram was said to be but accurate tonometry was impossible. ing, but the cousin did know his age within normal limits. The blood and weight. An affected retarded levels of glucose-6-phosphate de On investigation this man proved to be maternal uncle, aged 43 years, was hydrogenase and plasma fibrinogen Xg (a—), whereas his sister (II.5) was Xg concentration were checked in both (a+) like Cases 1 and 2. The serum in an institution and also exhibited immunoglobulin levels are listed in Table head shaking, nystagmus, dysarthria brothers and were normal; both boys III. and ataxia of both arms as well as were Xg(a-). The authors state that "spastic paraplegia" with secondary the affected males in the family ap contractures. Blumel and her as peared normal at birth and subse DISCUSSION sociates (1957) reported 4 affected quently developed signs of cerebral The clinical features of our three males in 2 generations in a Mexican palsy; the mother was able to predict patients may be summarized as fol family. The proband was a full-term this because the eyes were unsteady lows: child who had no difficulty at or after and shaky. The age of onset was birth. He passed his milestones of under 1 year in all affected males, 1. Non-progressive or slowly prog development with delay and at 10% and they were all retarded and had ressive ataxic diplegia after unre years was still unable to stand freely. similar physical findings. There was markable perinatal course, with He had slight nystagmus and essen no sign of color blindness. Thus, inability to walk freely without tially spastic paraplegia. His there was no evidence of any as supports or appliances, ultimately younger brother had a similar condi sociated sex-linked disorder. making the patient wheelchair- tion with definite lateral nystagmus bound. Sometimes mild as and was considered spastic with It is evident that all these cases in sociated extrapyramidal features, cerebellar pathway involvement. the literature fit into the same sex- e.g. choreoathetosis of hands, The maternal uncle was said to have linked syndrome, though no details titubation of head, static truncal the same type of cerebral palsy, in of stature, optic fundi, dermatog- tremor. cluding eye involvement. Baar and lyphic patterns or bone age were Gabriel (1966) published a brief ac reported. It is also of interest that 2. Non-progressive or slowly prog count of the most extensively af none of these patients had any seiz ressive mild to moderate mental fected family, in which 13 males in 5 ures, whereas children with ataxic retardation. generations had a condition which diplegia who have had difficulties at 3. Congenital nystagmus, rotary or the authors termed sex-linked spas birth often exhibit neonatal convul pendular or jerky, often subsiding tic paraplegia. As noted by Knox sions (Ingram, 1964). with age. (1967) it is clear from the description that all four limbs were affected, but The family described by Johnston 4. Significantly small stature. (Re the legs more than the arms, and and McKusick (1962) is different, tarded bone age also demon thus the term diplegia would be more since the affected males initially had strated in Case 1.) appropriate. The proband, a boy of a pure spastic paraplegia which grad 5. Slight gliosis of optic nerve heads 14 years, was wheelchair-bound and ually spread over many years to in without definite optic atrophy. was found to have an I.Q. of 35 on volve the upper extremities, brain the Stanford -Binet and an I.Q. of 36 stem, optic nerves and cerebral cor In reviewing the literature we en on the Columbia Scale. He also had tex. Nystagmus was variable, and countered three reports of similar marked dorsal kyphoscoliosis, nys there was evidently no gross mental families. Wolfslast (1943) described tagmus, impaired facial movements, retardation, at least among the chil 5 affected males in 2 generations in a dren.

232 - NOVEMBER 1974 Sex-Linked Hereditary Ataxic Diplegia

The question may next be asked almost total cerebral demyelination gene, and here also the clinical pic whether this sex-linked ataxic dip and complete failure of psychomotor ture was different. Finally, Malamud legia is really a non-progressive con development, with death before the and Cohen (1958) described an un dition qualifying for the term cere age of 8 years. Recently, Seitel usual syndrome of cerebellar ataxia bral palsy. The mother of our prob berger (1970) added a third type of with sex-linked inheritance which and and other intelligent observers the disease which is a transitional was characterized by a marked clini have not been convinced that the form between the classical and con- cal change from initial cerebellar to patients show intellectual deteriora natal categories. In this type the extrapyramidal manifestations with tion, and the increasing physical dis longest survival was to the age of 18 dementia. Autopsy in one case ability may be due largely to con years 10 months. However, occa showed a degenerative process in tractures. The falling I.Q. scores are sional cases of Pelizaeus- volving both the cerebellum and also of doubtful significance. On the Merzbacher disease with very slow basal ganglia in addition to the red other hand, it must be admitted that evolution have been recorded. Thus nucleus, optic tracts and thalamus. the patients appear to make little a patient described by Blackwood Again, the clinical course in that physical or intellectual progress and Cumings (1954, Case 2) began family was more rapid after more after the age of about 10 years. Also, like a congenital case but lived to the normal initial development than in while the nystagmus tends to di age of 41 years, when the diagnosis our family. minish, the extrapyramidal features was confirmed by autopsy. Another As has been pointed out previ may gradually increase. The spinal male patient with superadded prop ously with regard to sex-linked men fluid in our Case 1 and in the two ortional dwarfism, testicular atrophy tal deficiency (Allan et al. 1944, brothers described by Baar and Gab and tapeto-retinal degeneration sur Dunn et al. 1963), it is generally riel (1966) did not show any excess vived to 42 years (Luthy and Bis- impossible to distinguish categori of protein, and in our patient the choff 1961). One of Tyler's (1958) cally between sex-linked recessive level of gamma globulin was also patients with the classical type of the and autosomal dominant male- normal, while the colloidal gold disease is reported to have lived to limited transmission when the dis curve of 112110 may be described as the age of 51 years. The heredity and ease is so severe as to prevent the of doubtful significance. Thus a clinical features in the families de reproduction of affected individuals. slowly progressive disorder cannot scribed by Batten and Wilkinson However, Johnston and McKusick be excluded, but, in the absence of (1914) and by Tyler (1958) showed a (1962) noted with respect to sex- neuropathological studies and of any considerable resemblance to those linked spastic paraplegia that male- definite evidence of demyelination in reported here, though the affected limited autosomal dominant inheri the brain or peripheral nerves, it males were usually more severely tance seemed less plausible, because seems legitimate to retain the condi handicapped and died earlier. Thus there was no obvious mechanism by tion among the cerebral palsy syn it is hard to exclude the possibility which the neurological manifestation dromes for the present. that our patients and the similar ones of the autosomal gene could be li in the literature may have mited to males. In any case, it seems Wolfslast (1943) was concerned Pelizaeus-Merzbacher disease, un about the differential diagnosis from important to look for associated less neuropathological studies be sex-linked defects attributed to ab Pelizaeus-Merzbacher disease, come available or some appropriate which is considered to be a de normal genes on the X chromosome. biochemical test for that disorder is In the present family there is no generative disorder and is usually discovered. inherited as a sex-linked recessive evidence of color blindness, condition in males. In the classical In their review of spastic ataxia hemophilia, Christmas disease, form of that disease the clinical fea Bell and Carmichael (1939) encoun glucose-6-phosphate dehydrogenase tures can also be described as an tered only two reports of families deficiency, nephrogenic diabetes in ataxic diplegia with superadded head suggesting a sex-linked inheritance. sipidus or any other sex-linked dis tremor, bradylalia, athetotic move The cases described by Turner and order with which the ataxic diplegia ments and other extrapyramidal Roberts (1938) are suggestive of might be linked. Searching for an manifestations, and with pallor of Friedreich's ataxia, and those de association with an abnormal der- the optic discs and secondary scribed by Mastin (1887) were matoglyphic pattern, we were in skeletal abnormalities. Usually, nys somewhat similar, though associated terested to note that Cases 1 and 2 tagmus does not commence before with dementia and not with nystag both had a radial loop pattern on the the 3rd month of life, and the course mus. The manifestations and course right middle finger, but this was not is more distinctly progressive, lead of the illness in both these reports found in Case 3 and the presence of ing to death in the second decade are notably different from those in a radial loop on the left middle finger (Diezel and Huth 1963, Ford 1966, our patients. Nayrac et al. (1957) of the unaffected boy IV.7 suggests Seitelberger 1970). A congenital described a family in which that this may be a familial trait unre ("connatal'') form was described by Friedreich's ataxia with optic at lated to hereditary ataxic diplegia. Seitelberger (1954), and in this form rophy and mental retardation was We also looked for an associated the nystagmus and other features are thought to be inherited by an au abnormality of serum immunoglobu noticeable from birth, but there is tosomal but sex-influenced recessive lins, but Table III shows that no

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clear pattern emerges. The IgG level ACKNOWLEDGEMENTS GLENTING, P. (1970). Etiology of Congeni is low in Case 1 and in his mother We wish to express our gratitude to Dr. J. tal Spastic Cerebral Palsy, with special re and sister, but also in his father, R. Miller for his advice on genetic aspects, to ference to the significance of genetic and Dr. Bruce Chown and Miss Marion Lewis for prenatal factors. Copenhagen: F.A.D.L.s whereas it is high in Case 3 and in their studies of blood groups and factors in the Forlag. the father of Case 2. The IgA level is family, to Dr. J. Mashal for referring the GUSTAVSSON, K.-H., HAGBERG, B., and somewhat high in Case 1 and in his patient to us, to the Department of Biomedi SANNER, C. (1969). Identical syndromes unaffected maternal grandfather cal Communications, University of British of cerebral palsy in the same family. Acta II.3, but not in the other patients. A Columbia, for help with the illustrations, and Paediatrica Scandinavica 58, 330-340. to members of the family for their cooperation more notable marker may be the in the investigations. HAGBERG, B., HANSSON, O., LIDEN, presence of positional nystagmus S., and NILSSON, K. (1970). Familial and directional preponderance in the ataxic diplegia with deficient cellular im REFERENCES munity. Acta Paediatrica Scandinavica, 59, proband's sister, but this was not 545-550. found in the mother, and before it is ALLAN, W., HERNDON, C. N., and HANSEN, E. (1960). Cerebral Palsy in Den accepted as a sign of heterozygosity DUDLEY, F. C. (1944). Some examples mark. Copenhagen: Munksgaard. in children (possibly disappearing of the inheritance of mental deficiency: INGRAM, T. T. S. (1962). Congenital ataxic later) it will have to be confirmed apparently sex-linked idiocy and mic syndromes in cerebral palsy. Acta Paediat and checked in other members of rocephaly. American Journal of Mental rica, 51, 209-221. affected families. Deficiency, 48, 325-334. ALLANSMITH, M., McCLELLAN, B. H., INGRAM, T. T. S. (1964). Paediatric Aspects of Cerebral Palsy. Edinburgh and London: The data in Fig 1 would fit the BUTTERWORTH, M., and MALONEY, J. K. (1968). Development of immunoglobu Livingstone, pp. 245-272. possibility of the gene for sex-linked lin levels in man. Journal of Pediatrics, 72, JOHNSTON, A. W., and McKUSICK, V. A. hereditary ataxic diplegia and the a 276-290. (1962). A sex-linked recessive form of spas allele Xg being on the same BAAR, H. S., and GABRIEL, A. M. (1966). tic paraplegia. American Journal of Human chromosome in Cases 1 and 2, while Sex-linked spastic paraplegia. American Genetics, 14, 83-94. Case 3 may represent a crossover Journal of Mental Deficiency, 71, 13-18. KNOX, E. G. (1967). Sex-linked paralysis. event causing the gene for the dis BATTEN, F. E., and WILKINSON, D. Developmental Medicine and Child ease and the Xg allele to be as (1914). Unusual type of hereditary disease Neurology, 9, 105-106. sociated on the same chromosome. of the nervous system (Pelizaeus- LUTHY, F., and BISCHOFF, A. (1961). Die Merzbacher), aplasia axialis extra-corticalis Pelizaeus-Merzbachersche Krankheit. Ihre While the sample is too small to congenita. Brain, 36, 341-351. Zuordnung zu den Leukodystrophien, an allow any conjecture about the dis BAX, M. C. O. (1964). Terminology and Hand von drei eigenen familiaren Fallen. tance between the two loci con classification of cerebral palsy. Develop Acta Neuropathologica, 1, 113-134. cerned, the data are recorded here mental Medicine and Child Neurology, 6, MacKEITH, R. C, MacKENZIE, J. C. K., for the use of future investigators of 295-297. and POLANI, P. E. (1959). The Little Club like families. BELL, J., and CARMICHAEL, E. A. (1939). memorandum on terminology and On hereditary ataxia and spastic paraplegia. classification of cerebral palsy. Cerebral In practice, the most important Treasury of Human Inheritance, 4, 140-281. Palsy Bulletin, 5, 27-35. point at present is that any child with BLACKWOOD, W., and CUMINGS, J. N. MALAMUD, N., and COHEN, P. (1958). congenital ataxia or ataxic diplegia (1954). A histological and chemical study of Unusual form of cerebellar ataxia with sex- must be considered to have a possi three cases of diffuse cerebral sclerosis. linked inheritance. Neurology, 9, 261-266. Journal of Neurology, Neurosurgery and MASTIN, W. M. (1887). Two generations of ble genetic defect, particularly if Psychiatry, 17, 33-49. hereditary or congenital ataxia: a clinical pregnancy and delivery were unre BLUMEL, J., EVANS, E. B., and EGGERS, contribution. The Medical News (Philadel markable . In the case of a boy with G. W. N. (1957). Hereditary cerebral palsy. phia), 51, 225-229. ataxic diplegia the possibility of sex- Journal of Pediatrics, 50, 454-458. MITCHELL, R. G. (1961). In: Cerebral Palsy linked inheritance must be consi CHRISTENSEN, E., and MELCHIOR, J. in Childhood and Adolescence. J. L. Hen dered, particularly in the presence of (1967). Cerebral Palsy — A Clinical and derson, ed. London: Livingstone, pp. congenital nystagmus, and the fam Neuropathological Study. Clinics of De 25-167. velopmental Medicine No. 25, London: NAYRAC, P., GRAUX, P., FRANCOIS, P., ily history must be investigated ac Heinemann, pp. 37-39, 111-112. and RABACHE, R. (1957). Maladie de cordingly. If the history is positive DIEZEL, P. B., and HUTH, K. (1963). Friedreich avec atrophie optique et for sex-linked inheritance of the Pelizaeus-Merzbachersche Erkrankung mit imbecillite touchant de fagon elective les condition, the mother must be a familiarem Befall. Deutsche Zeitschrift fur garsons d'une fratrie. Revue neurologique, heterozygote and any subsequent Nervenheilkunde, 184, 264-287. 97, 295-306. children would have a 50% chance of DUNN, H. G., RENPENNING, H., GER- PASKIND, H. A., and STONE, T. T. (1933). RARD, J. W., MILLER, J. R., TABATA, Familial spastic paralysis. Archives of having the disease if they are males T., and FEDEROFF, S. (1963). Mental Neurology and Psychiatry, 30, 481-500. and of being heterozygote carriers if retardation as a sex-linked defect. Ameri POLANI, P. E. (1963). Causes of "cerebral they are females. If the family his can Journal of Mental Deficiency, 67, palsy" of pre- and perinatal origin. Modern tory is negative or the patient is a 827-848. Problems in Paediatrics VIII. Bibliotheca girl, the defect may be due to a FORD, F. R. (1966). Diseases of the Nervous Paediatrica, 81, 11-31. recessive autosomal gene, with its System in Infancy, Childhood and Adoles RHEIN, J. H. W. (1916). Family spastic 25% chance of recurrence in subse cence. 5th edition. Springfield, 111.: C. C. paralysis. Journal of Nervous and Mental quent siblings. Genetic counselling Thomas, pp. 754-756. Diseases, 44, 115-144, 224-242. GEDDA, L. (1955). Little's syndrome of SEITELBERGER, F. (1954). Die should be given accordingly. familial type. Acta Genetica, 5, 370-376. Pelizaeus-Merzbachersche Krankheit.

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Wiener Zeitschrift fiir Nervenheilkunde, 9, SKATVEDT, M. (1958). Cerebral Palsy: A TYLER, H. R. (1958). Pelizaeus-Merzbacher 228-289. Clinical Study of 370 Cases. Acta Paediat- disease. A clinical study. Archives of SEITELBERGER, F. (1970). Pelizaeus- rica Supplement 111. Neurology and Psychiatry, 80, 162-169. Merzbacher Disease. Chapter 10 in: WOLFSLAST, W. (1943). Eine Sippe mit Leucodystrophies and Poliodystrophies; in TURNER, E. V., and ROBERTS, E. (1938). recessiver geschlechtsgebundener spas- Handbook of Clinical Neurology, ed. I. J. A family with a sex-linked hereditary ataxia. tischer Diplegie. Zeitschrift fiir Vinken and G. W. Bruyn. Amsterdam: Journal of Nervous and Mental Diseases, menschliche Vererbungs-und North Holland Publishing Co., 10, 150-202. 87, 74-80. Konstitutions-Lehre, 27, 189-198.

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