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adolescents: correlation with age, height, serum insulin-like growth fac tor I , a n d serum testosterone.’ Journal of Clinical Endocrinology and Metabolism, 67, 273-278.

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Skuse, D. H . (1985) “on-organic failure to thrive: a reappraisal.’ Archives of Disease in Childhood,

Turski, J . , Wolf, H., Otten, A , , Schiitz-Bolter, G. (1989) ‘Psychosozialer Minderwuchs.’ Social- padiatrie, 11, 425-429.

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60, 173-178.

Autosomal Dominant Familial Spastic Paraplegia: Description of a Large New England Family and a Study of Management

W. C. Cooley G . Melkonian C. Moses J. B. Moeschler

gressive weakness and spasticity of the lower extremities. Some of these disorders include involvement of other systems, such as visual impairment or ataxia, but the ‘pure’ form is limited to spastic paraplegia. Pure FSP is commonly called Strumpell’s familial spastic paraplegia, crediting another early description of this condition (Strumpell 1880). FSP may be inherited as an autosomal recessive, x-linked or, most commonly, an autosomal dominant trait (Bell and Carmichael 1939, Haldane 1941, Johnston and McKusick 1962). The ‘pure’ autosomal dominant form is referenced as #18260 in McKusick (1988). Many case reports have demonstrated the clinical heterogeneity from family to family.

We report here 16 individuals with autosomal dominant familial spastic paraplegia (ADFSP), from a large New England family traced back to 1853 over seven generations, with 71 apparently affected individuals (Cooley et al. 1990). Three cases are described, demonstrating the relative homogeneity of FSP within this family. A staging system is proposed for characterizing the natural history of FSP in this family and as a method of timing

Initially described by Seeligmiiller (1 876), the familial spastic paraplegias (FSPS) are a group of rare, genetically heterogeneous disorders characterized by slowly pro- therapeutic interventions.

Fig. I . Pedigree of family with autosomal dominant familial spastic paraplegia.

Results The family was studied by reviewing the medical records of 25 family members and examination of 16 individuals. We identified additional suspected cases by interviewing available family members. In all, we confirmed or suspected 71 family members to be affected, representing 41 per cent of the 173 individuals at risk (Fig. 1). There were 39 males, 31 females and one affected person of unknown sex; resulting in ma1e:female ratio of 1 -25:l (not significantly different from the expected 1:l ratio). The pedigree demon-

strates male-to-male transmission, ruling out x-linked inheritance. One instance of possible non-penetrance was noted in the pedigree (IV-9).

It was possible to examine the medical records of 25 individuals, of whom 16 underwent physical, neurological and orthopedic examinations, and functional assessments. No formal psychometric tests were carried out. All examinations were performed by the authors. The individuals examined or reviewed ranged in age from 10 months to 47 years (mean 12.7 years). The age at onset of disability 1099

TABLE I Clinical stages of ADFSP in present family

Stage Age Characteristics

Pre-symptomatic 0-12 mths Normal examination Pre-ambulatory 12-24 mths Long tract signs on examination;

rapid increase in spasticity

Ambulatory child 2-7 yrs Delay in walking (mean age 2 yrs); no further progression

School-age/adolescent 7-1 8 yrs Community ambulation; crutches occasionally

Adult > 18 yrs Community ambulation; adducted swing-through gait; crutches often; lower extremity pain; other systems not involved

Treatment

None Physical therapy; ?tone reduction casts; ?ankle-foot orthotics Physical therapy; tone reduction casts; serial casts for heel cords; ankle-foot orthotics; soft-tissue surgery Physical therapy; soft-tissue surgery common; casting/bracing as needed Physical therapy; outlined bracing; pain management if needed

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ranged from 10 to 34 months (mean 18 months). All were of average intelligence, had normal upper-extremity function, and no neurological findings except those related to spastic paraplegia. There was no ataxia or disturbance of vision. Community ambulation was attained by 24 of the 25 individuals reviewed. One male had spondylolithesis requiring surgery (VI-6), but none had scoliosis. One female child was found to have both FSP and achondroplasia (VI-7). Seven individuals have undergone soft-tissue orthopedic surgery (V-10, V-11, V-43, VI-5, VI-8, VI-11, VI-18), and two have had spine fusions, one with achondro- plasia (VI-7) and one with spon- dylolithesis (VI-6). Sexual, bladder and bowel function was normal in all individuals, except for one adult male with mild urinary incontinence (V-1 1). Following its onset in infancy, the spasticity has been non-progressive in this family. No pathological studies are available.

Orthopedically, FSP in this family resembles diplegic cerebral palsy, except that there is no compensatory tone overflow into the upper trunk, upper extremities and oral motor region. The lower extremities demonstrate muscle involvement, with spasticity and con- tracture, especially of the hip flexors,

hamstrings, hip adductors and gastroc- nemius soleus complex. The lower spine is affected primarily by iliopsoas involve- ment and secondarily by the gait pattern. Deformities occurring as a result of contractures included lordosis of the lumbar spine (resulting in spondylolithesis in one case), hip flexion and adduction, knee flexion and equinus ankle con- tractures. Valgus and varus deformities of the foot were also noted. Scoliosis, hip dislocation and dysplasia did not occur.

A review of the affected members of different ages, together with the longi- tudinal follow-up of several young children, has allowed us to characterize five stages of ADFSP in this family (Table I , Figs. 2 and 3).

Staging allowed the organization of ap- propriate therapeutic goals and methods by anticipating the likely evolution of the spastic paraplegia during the years ahead. Community ambulation with minimal equipment and maximum efficiency has been the therapeutic goal from an early age, and can be monitored through the stages we have characterized. Awareness of the pattern of inheritance of FSP within this family has allowed us to counsel affected members regarding the risk of bearing affected offspring.

We have been able to observe the children at risk closely during the pre-

0 E i

Fig. 2. (Clockwise from upper left) J.D., VI-3, aged I5 months; J.H., V-48, aged three years; A.H., V-47, aged four years; J .M., VI-5, aged five years.

symptomatic stage, and to establish an early diagnosis and treatment plan during the pre-ambulatory stage. Children free of signs of FSP by age three years have been assumed to be unaffected. During the ambulatory child stage, we have focused on ameliorating the effects of increased tone with physical therapy, casting, bracing and occasional soft-tissue surgery. By the school-age/adolescent stage, casting and bracing have been continued as needed, and commonly surgical intervention is necessary. Most of the adults in this family have not benefited from early, consistent or aggressive interventions, leaving many with swing-through gait requiring crutches for community ambulation. We hope that the outcome for the children we are following today will cause us to alter our description of the adult stage to one with less visible disability and less dependence on equipment for ambulation.

Fig. 3. (Clockwise from upper left) T.D., VI-9, aged 14 years (after soft-tissue surgery); C.D., VI-8, aged I 1 years; F.D., V-11, aged 35 years; E.D., V-IO, aged 25 years.

Physical therapeutic goals have been to maintain or improve muscle flexibility; to maintain a reciprocal gait pattern; to improve the quality and efficiency of gait; to improve functional mobility in all situations; and to improve upper-extremity function during movement. Since many of the children were not seen in our neuromotor clinic until after three years of age, it is difficult to predict the long-term consequences of early therapeutic interventions. However, eventually it should be possible to compare our younger patients with their parents, who received much less intensive treatment and monitoring.

Case reports CASE 1 E.D. (V-10, Fig. 1) was born in 1962 and was walking independently by age one year. His mother (IV-10) is reported to have ADFSP and is the only member of this family known to be wheelchair-dependent. His parents had noted gradual deterioration of his 1101

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walking ability by four years of age. He had orthopedic surgery at six years for release of hip adductors and medial hamstrings and lengthening of achilles tendons. Since that time he has required crutches for functional ambulation and has adopted a ‘swing through’ gait. At 27 years, upper-extremity function remains excellent. Contractures have limited his range of motion, primarily involving hip flexors, hip adductors and trunk rotators. He experiences some adductor spasm during sexual activity. There have been no problems with bowel or bladder function, nor with pain or muscle spasm. Mobility on stairs and ramps is adequate with crutches; he is able to drive a car and a motorcycle. Physical and neurological examination revealed him to be of average intelligence with abnormal findings limited to the hips and lower extremities. Muscle tone in his legs was increased at rest. Volitional activity produced a maximal increase in tone, predominantly extensor. Deep tendon reflexes were 3 + in the legs, compared with 2 + in the arms, with clonus demonstrable at both ankles. Protective responses were excellent in the upper extremities but nonexistent in the lower extremities.

CASE 2 C.D. (VI-11) was born in 1972 following an uncomplicated pregnancy, labor and delivery at 40 weeks gestation. His father (V-14) was known to have ADFSP. C.D. has had a completely uneventful medical history, except for aspects related to ADFSP. Onset was suspected at 15 months, when toe-walking and hip adduction were observed as he began to stand and walk with support. Independent walking occurred at 18 months, but his abnormal gait was characterized by hip flexion and adduction, knee extension and plantar flexion at the ankle. Therapeutic intervention was intermittent and inconsistent during early childhood. Throughout his school years he has required crutches for community ambulation. At 14 years of age he underwent soft-tissue surgery, including bilateral iliopsoas recession, adductor releases, medial hamstring lengthening and achilles tendon lengthening. There has been continued physical therapy since his surgery. He is able to a ride bicycle and requires no assistive devices for personal hygiene. C.D. has had no involvement of his upper extremities. His intelligence is normal, but he has received special educational services for a learning disability.

CASE 3 J .W. (VI-18) was born in 1985 to a mother with ADFSP (V-43). His mother had been relinquished for adoption as a young child and was not aware of the genetic implications of ADFSP. Pregnancy, labor and delivery at 42 weeks gestation were uncomplicated, with Apgar scores of 8 and 9. Birthweight was 4400g and the neonatal period was uneventful. His gross motor milestones were normal up to about 13 months of age, when he was first seen in our clinic for toe- walking and in-toeing. At that time he was cruising holding onto furniture and could stand without support for 15 seconds. Examination revealed mild internal rotation of the hips, plantar flexion at the ankles and forefoot adduction. There was no clonus or Babinski reflex. Muscle tone was mildly increased in the hip adductors and heel cords. Physical therapy was prescribed. By 19 months of age, spasticity was

significantly increased in the hip adductors and heel cords. His gait included hip flexion, persistent plantar flexion at the ankle, and high-guard posturing of the arms for balance. Ankle foot orthotics were prescribed, with continued physical therapy. At 23 months of age he had a four-minute generalized seizure associated with fever; a CT scan and several EEGs were normal. The seizure was not believed to be related to his spastic paraplegia. By three years of age, J.W. had findings typical of spastic paraplegia in this family, with lordotic posture, internal rotation at the hips, hyperextension of the knees, and internal rotation and plantar flexion of the ankles. The upper extremities were not affected and intelligence appeared to be normal. At 39 months of age he underwent bilateral percutaneous achilles tendon lengthening, following by casting, continued use of ankle-foot orthotics and physical therapy.

Discussion The prevalence of all hereditary spastic paraplegia syndromes is unknown. Skre (1974), in a review that failed to separate clinical types, found a prevalence of 12/100,000 for autosomal dominant forms and 1 *9/100,000 for autosomal recessive forms. In a review of 20 years experience at the Mayo Clinic, Stark and Moersch (1945) found that nearly 12 per cent of 60 ‘pure paraplegics’ had hereditary forms of the condition. We feel that a careful family history and examination of family members of those with paraplegia of uncertain etiology should be a routine procedure.

The relatively benign nature of ADFSP in most families has resulted in little clinicopathological correlation. In an exhaustive review, Schwartz (1952) found only seven satisfactory descriptions, including Strumpell’s original two in 1886. Available autopsy reports describe corticospinal tract degeneration increasing caudally, with posterior column de- generation increasing rostrally. The pathogenesis of ADFSP remains obscure. Since it has been reported to occur with the leukodystrophies, a metabolic defect has been postulated (Poser et af. 1957). ADFSP has also been classified among the hereditary spinocerebellar degenerations, with a ‘dying back’ of axons from their terminations to the cell body, which then dies. However, ADFSP shows none of the transsynaptic degeneration seen in some spinocerebellar degenerative diseases, and there is no evidence of depletion of the cells of origin of involved tracts. Since this condition involves the longest tracts in the

central nervous system, difficulty in maintaining fibres beyond a certain length has been suggested (Behan and Maia 1974). Accidental organophosphate poisoning has caused distal degeneration of long-tract fibres in man and similar changes have been achieved experimentally in chickens. Since organic phosphates may disrupt enzyme systems, an enzyme deficiency has been postulated (Behan and Maia 1974). In our family, the rapid changes during the period of myelinization raises the question of a defect in this process.

We found a high intrafamilial cor- relation between age at onset and natural history in our family. Holmes and Shaywitz (1977) found that 82 of 104 families had high intrafamilial consistency in age at onset, and that onset occurred in the same decade for 64 per cent of the families with ADFSP. Harding (1981), in a review of 22 families, noted a wide range of age at onset among families, but consistency within families. Both of these reviews found that interfamilial variability in clinical course was common, but that within-family expression tended to be quite homogeneous. Furthermore, Harding concluded that pure ADFSP was likely to be caused by more than one gene, and found a rough division between families with onset before age 35 and those with later onset. Harding’s observations suggest clinical differences between the groups, including more rapid progression, sensory loss and urinary symptoms in the late-onset group. Strumpell (1880) had originally proposed two groups based on age at onset; one with onset between three and five years of age, the other in the third decade.

Affected members of our family have a ‘pure’ form of familial spastic paraplegia, i.e. involvement of only the lower extremities. The pedigree demonstrates an autosomal dominant pattern of inherit- ance, with nearly complete penetrance. Onset is early, occurring by three years of age in all cases. Although onset was rapid, the spasticity was non-progressive during eight years of observation, although its functional consequences tended to increase with age, particularly when there had been no long-term orthopedic care. While many authors have commented on the extremely slow progression of FSP (Bickerstaff 1950), some have observed more rapid deterioration (Behan and Maia 1974). This is probably a result of the genetic heterogeneity of this condition. We feel that more aggressive surgical and non- surgical habilitative intervention for some of the youngest members of our family will result in more functional ambulation.

Accepted for publication 22nd February 1990.

Ackno wledgements Dr. Cooley’s participation in this project was supported by a grant from the Leopold Schepp Foundation. Dr. Moeschler’s participation was supported, in part, by the Jesse B. Cox Charitable Trust.

Authors’ Appointments *W. Carl Coolev. M.D.: John B. Moeschier, M.D.; Clinical Genetics and Child Development Center, Dartmouth Medical School, Hanover, New Hampshire 03756. Gregory Melkonian, M.D.; Colleen Moses, R.P.T.; Bureau of Special Medical Services, State of New Hampshire, Concord, New Hampshire.

*Correspondence to first author.

SUMMARY A large New England family with autosomal dominant familial spastic paraplegia (ADFSP) is described. In a pedigree of 173 family members, 71 affected individuals were identified. 16 cases examined by the authors are described with regard to the natural history of ADFSP in this family, and a staging system for following progress and planning interventions is proposed. Three illustrative cases are presented. In this family, ADFSP was found to have a homogeneous clinical course, with nearly complete penetrance. Onset, with involvement limited to the lower extremities, occurred by three years of age, after which no significant progression was noted. Early, aggressive habilitative care may result in more functional ambulation for the youngest family members.

RESUME Prise en charge de la paraplegie spastique familiale a transmission dominante autosomique: experience dans une grande famille de Nouvelle Angleterre L’article decrit une grande famille de Nouvelle Angleterre incluant des cas de parapltgie spastique familiale a transmission dominante autosomique (ADFSP). Dans I’anamnese de 173 individus, 7 1 apparaissaient atteints de I’affection. 16 cas examines par les auteurs sont dkcrits en fonction de l’histoire naturelle de I’ADFSP dans cette famille, et un systbme d’evaluation pour suivre les progres et pour prevoir les interventions est propose. Trois cas illustratifs sont present&. Dans cette famille,

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I’ADSFP est apparue avoir une evolution clinique homogene, avec une penetrance presque complete. Le debut, avec une atteinte limitee des extrCmites inferieures, survenait vers I’2ge de trois ans, apres quoi aucune progression significative n’etait notee. Des soins de reeducation precoces, intenses peuvant permettre d’atteindre une marche plus fonctionnelle.

ZUSAMMENFASSUNG Behandlung der autosomal dominanten familiaren spastischen Paraplegie: Erfahrungen rnit einer GroJfamilie in Neu England Es wird uber eine Gronfamilie in Neu England mit autosomal dominanter familiarer spastischer Paraplegie (ADFSP) berichtet. Im Stammbaum von 173 Personen waren 71 betroffen. 16 davon, die von den Autoren selbst untersucht wurden, werden mit der Anamnese der ADFSP in dieser Familie beschrieben, und es wird ein Protokoll vorgeschlagen, nach dem Fortschritte erfant und notwendige Interventionen geplant werden konnen. Drei anschauliche Falle werden vorgestellt. In dieser Familie hatte die ADFSP einen homogenen klinischen Verlauf mit nahezu vollstandiger Penetranz. Die Erkrankung begann bis zum dritten Lebensjahr und war auf die unteren Extremitaten beschrankt; danach fand keine signifikante Progression mehr statt. Durch eine friih beginnende, intensiv unterstutzende Betreuung konnte eine bessere funktionelle Ambulation erreicht werden.

RESUMEN Tratamento de la paraplejia espastia autosomica dominante familiar: experiencia con una gran familia de Nueva Inglaterra Se decribe una gran familia de Nueva Inglaterra con paraplegia espastica autosomica dominante familiar (PEADF). En una historia familiar de 173 individuos se identificaron 71 casos afectados. Se describen 17 casos estudiados por 10s autores con respecto a la historia natural de la PEADF en esta familia y se propone un sistema de internamiento para seguir el proceso y planificar las intervenciones. Se presentan tres casos ilustrativos de esta familia. Se ha116 que la PEADF tenia un curso clinic0 homogeneo, con una penetrancia casi completa. El inicio, con afectacion de extermidades interiores, tuvo lugar hacia 10s tres aiios de edad y a partir de entoces no se advirtio ninguna progresion significativa. Unos cuidados habilitadores precoces y agresivos pueden facilitar una deambulacion mas eficaz.

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familial spastic paraplegia: genetics and neuropathology.’ Journal of Neurology, Neuro- surgery and Psychiatry, 37, 8-20.

Bell, J., Carmichael, E. A. (1939) ‘On hereditary ataxia and spastic paraplegia.’ In Fisher, R. A. (Ed.) Treasury of Human Inheritance, Vol. 4, Part 3 . London: Cambridge University Press. pp.

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Cooky, W. C., Rawnsley, E., Melkonian, G., Moses, C., McCann, D., Virgin, B., Coughlan, J., Moeschler, J. B. (1990) ‘Autosomal dominant familial spastic paraplegia: report of a large New England family.’ Clinical Genetics, 38, 57-68.

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Poser, C . M., Dewulf, A,, Van Bogaert, L. (1957) ‘Atypical cerebellar degeneration associated with leucodystrophy.’ Journal of Neuropathology and Experimental Neurology, 16, 209-237.

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Skre, H. (1974) ‘Hereditary spastic paraplegia in western Norway.’ Clinical Genetics, 6 , 165-183.

Stark, F. M., Moersch, F. P. (1945) ‘Primary lateral sclerosis: a distinct clinical entity.’ Journal of Nervous and Mental Diseases, 102, 332-337.

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