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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 Strumpells 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
Fig. I . Pedigree of family with autosomal dominant familial
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
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
School-age/adolescent 7-1 8 yrs Community ambulation; crutches
Adult > 18 yrs Community ambulation; adducted swing-through
gait; crutches often; lower extremity pain; other systems not
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
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
We have been able to observe the children at risk closely during
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
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
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
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
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 Strumpells 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.
Hardings 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
Accepted for publication 22nd February 1990.
Ackno wledgements Dr. Cooleys participation in this project was
supported by a grant from the Leopold Schepp Foundation. Dr.
Moeschlers 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
RESUME Prise en charge de la paraplegie spastique familiale a
transmission dominante autosomique: experience dans une grande
famille de Nouvelle Angleterre Larticle decrit une grande famille
de Nouvelle Angleterre incluant des cas de parapltgie spastique
familiale a transmission dominante autosomique (ADFSP). Dans
Ianamnese de 173 individus, 7 1 apparaissaient atteints de
Iaffection. 16 cas examines par les auteurs sont dkcrits en
fonction de lhistoire naturelle de IADFSP dans cette famille, et un
systbme devaluation pour suivre les progres et pour prevoir les
interventions est propose. Trois cas illustratifs sont
present&. Dans cette famille,
IADSFP est apparue avoir une evolution clinique homogene, avec
une penetrance presque complete. Le debut, avec une atteinte
limitee des extrCmites inferieures, survenait vers I2ge de trois
ans, apres quoi aucune progression significative netait notee. Des
soins de reeducation precoces, intenses peuvant permettre
datteindre 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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