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Hereditary amyotrophic lateral sclerosis
Journal of the Neurological Sciences, 1981, 50 : 201-206
201
© Elsevier/North-Holland Biomedical Press
HEREDITARY AMYOTROPHIC LATERAL SCLEROSIS
R. ALBERCA, J. M. CASTILLA and A. GIL-PERALTA
Department of Neurology, Ciudad Sanitaria Virgen del Rocio, and Department of Neurophysiology, University Hospital, Sevilla (Spain) (Received 21 August, 1980) (Revised, received 1 October, 1980) (Accepted 14 October, 1980)
SUMMARY
A Spanish family transmits, as an autosomal dominant trait, a form of amyotrophic lateral sclerosis characterized by an unusually prolonged evolution of the disease in all affected members. Precocity and persistence of muscle cramps, presence of unilateral proximal segmental myoclonus and early abolition of ankle jerks are other clinical features conspicuous in this family. This type of hereditary ALS of non-Chamorro origin and prolonged evolution is rare.
INTRODUCTION
The number of well-documented published cases of non-Chamorro familial amyotrophic lateral sclerosis is low. These observations are heterogeneous and they can be grouped in 3 different types according to the clinical evolution and the morphopathological findings (Horton et al. 1976). One type is characterized clinically by an unusually prolonged evolution of the disease and only 3 such families have been reported (Horton et al. 1976). However, it is unknown whether this type of familial ALS is also heterogeneous as some other families recently reviewed (Gim6nez-Roldfin and Esteban 1977) present with great intrafamilial variation of the evolution of the disease. We present a Spanish family in which ALS is transmitted as a dominant autosomal trait. In all patients the disease has an extraordinarily prolonged evolution and the patients lead active lives for many years after the onset of symptoms. The object of this article is to discuss the reasons which support the existence of a Correspondence and reprint request to : Dr. R. Alberca, Servicio de Neurologia, Centro de Diagn6stico y Tratamiento, Ciudad Sanitaria "Virgen del Rocio', Avenida Manuel Siurot, s/n. Sevilla, Spain.
202 type o f familial A L S o f n o n - C h a m o r r o origin characterized by the exceptionally p r o l o n g e d course o f the disease. STUDY OF THE FAMILY In this family there are 13 affected m e m b e r s (Fig. 1), of which 7 have been examined. Five o f them (II-3, 1I-5, III-5, 111-6, III-9) present the developed clinical picture a n d 2 have muscle c r a m p s a n d fasciculation (III-13) or only muscle c r a m p s (III-16). In 4 p a t i e n t s (II-3, II-5, 111-6, III-9) a complete study has been carried out a n d r o u t i n e investigations were n o r m a l . E M G , carried o u t on several muscles of the extremities, showed in the 4 cases a n e u r o g e n i c pattern. M o t o r a n d sensory c o n d u c t i o n velocities in a r m a n d leg nerves were n o r m a l . Muscle biopsy showed n e u r o g e n i c a t r o p h y in the 4 cases (Fig. 2). Case 1 (111-9)
For 3 years this 34-year-oldmale had suffered daily painful muscle cramps in the lower extremities that intensified after exercise, during cold weather, and at night. He also experienced continuous muscular twitches which even moved fingers and toes. Occasionally he had noticed sudden jerks which displace the right arm. On examination continuous, diffuse fasciculation could be seen in the muscles of the trunk and extremities and myokymia in gastrocnemius, increasing after exercise and accompanied by continuous movement of the toes. The right gastrocnemius was slightly atrophic. In the right arm there was arrhythmic segmental proximal myoclonus of a very low frequency, not influenced by any stimulus and displacing proximal arm segments (Fig. 3). The rest of the examination was normal. For 2 further years the patient has been examined periodically and at the last examination there was slight bilateral atrophy of gastrocnemius, paresis and amyotrophy of intrinsic musculature of left hand and slight paresis of proximal left arm muscles. Fasciculation was present in the chin muscles. Deep reflexes were easily elicited in the arms but the ankle jerks were now abolished. The patient continues working as a mechanic.
II
III
16 ml' O NOI:~AL MALE:FEMALE
-l-
DIED CRANPS
AFFECTEDBY HISTORY Fig. 1. Genealogical tree of family.
203 1.0.
llI- 9
/......... i
IS.
#0,
•
.
/'5
o
II: . . . .
II- 5
;---'~ /
.
\
I
(0
~0
,,10
/o0
30
40
IrO
IlO
*1o
~
40
~10
I~0
f#O
MO
Fig. 2. Histogram of gastrocnemius biopsy from cases III-9 and 1I-5 shows chronic neurogenic atrophy.
,, J,. J-
l II
Deltoideus
k
w
,1 1
/I
t i'*
L
1-
L
]
L Biceps brach.
t,,..,..
11
Fig. 3. EMG, case 111-9. Tracing for triceps brachii during rest shows the potentials which accompany the segmental myoclonus, together with denervation activity and frequent fasciculations in all muscles. Case 2 (II-3)
This 57-year-old female has had muscle cramps since age 38 and weakness of the legs of imprecise, later onset. At age 54 leg paresis became important, and she noted the appearance of diffuse fasciculation and sudden involuntary movements which displaced the left arm. At age 56 she needed aid to walk and had speech and swallowing difficulties. At this age examination showed a bulbar syndrome with amyotrophy and fasciculation of the tongue, myokymia of the cheeks, paresis and amyotrophy of intrinsic musculature of the hands, and discrete paresis of proximal and distal leg
204 muscles. There was generalized fasciculation and myoclonus similar to that already described. Jilw reflex was easily elicited and deep reflexes were enhanced in the arms and abolished in the legs. Plantar reflexes were indeterminate. Four months later she could hardly speak and dysphagia was important. Seven months later she was readmitted with a serious respiratory insufficiency and died in a few hours. Permission for autopsy was not given. Case 3 (iii-6)
This 39-year-old male stated that since age 25 he suffered, in succession, from muscle cramps, weakness of the legs, diffuse muscle twitches, and finally loss of strength in the hands. On examination at age 31 there was amyotrophy and asymmetric paresis of distal arm muscles and slight paresis of distal leg muscles. Fasciculation could be seen in muscles of the trunk, extremities, and chin. Jaw, bicipitak tricipital and styloradial reflexes were enhanced; patellar reflexes were normal and ankle jerks abolished. Left Babinski sign was positive. On the last visit at 39 the patient continued to lead an active life. There was now paresis and asymmetric amyotrophy of proximal arm muscles and the distal amyotrophy of legs had become more evident. Babinski sign was positive bilaterally. Case 4 (II-5)
This 60-year-old male suffered from muscle cramps and diffuse fasciculation since age 24, together with sudden involuntary movements of the right arm and a loss of strength of imprecise distribution and onset. At age 53 there was paresis of hands and fatigue on walking. At age 58 he was still working and examination showed paresis and asymmetric amyotrophy of moderate intensity in proximal and distal muscles of all 4 extremities. There was continuous fasciculation in the muscles of trunk, extremities, and chin, and myokymia in the left cheek. Jaw jerk and deep reflexes were enhanced, but the ankle jerks were abolished. Plantar reflexes could not be evaluated. On successive visits during 18 months there has been no clear progression of the clinical picture. Case 5 (III-5)
This male has had muscle cramps since age 30, paresis and distal leg amyotrophy since age 34, and loss of strength since age 37. At a later date fasciculation developed in the muscles of the trunk and extremities. At age 44 the patient was still active and examination showed asymmetric amyotrophy and paresis of the intrinsic musculature of the hands and slight paresis and amyotrophy of the musculature of anterolateral compartment of the legs. There was fascicutation in trunk, extremities, and face muscles: The jaw jerk was normal, deep arm reflexes were enhanced, patellar reflexes weak and ankle jerks abolished. The left plantar reflex was indeterminate and the right one flexor. Case 6 (Ili-13)
This 29-year-old male complained of muscle cramps and twitches, onset date not known precisely. On examination only fasciculation in the arm muscles was found. Case 7 (III-16)
This female complained of muscle cramps, onset date not known precisely, and examination, at age 23, is normal. Cases 1I-3 and 111-5 came independently to this hospital without mentioning the existence of a familial disease. Case II1-9, the propositus, told of the familial antecedents. Case 11-2, the apparently healthy mother of 4 affected cases, died accidentally before age 30. Cases I-3, 1-5, and II-6 died in their 6th decade, other data unknown. Case II-1 is alive and ill at age 70, and cases III-I and Ill-3 are over 45 and lead active lives. Six members of the 4th generation below age 10 have been examined and found normal. DISCUSSION
Several members of this family present clinical signs of lower and upper motor neuron involvement and at least one of them died with a bulbar syndrome. These data suggest the diagnosis of amyotrophic lateral sclerosis, and the kinship study indicates that the disease is transmitted as a dominant autosomat trait. Although
205 4 affected siblings apparently lack an affected parent, this may be explained by the early accidental death of the mother. The muscle cramps and fasciculation of our patients should not be considered as incidental, benign findings, but as the onset of the disease, as demonstrated in case II1-9. These cramps affect all patients, persist during the whole evolution of the process, and are generally the most incapacitating symptom. Another conspicuous clinical finding is the unilateral segmental myoclonus. In the absence of polygraphic studies it is difficult to determine the pathogenesis of this myoclonus and to establish if it is similar to the mass contractions of sporadic ALS, attributed to gross fasciculation of motor unit groups (Bonduelle 1975). However, it is a common experience that the mass contractions of sporadic ALS appear in already developed cases and affect muscles with evident amyotrophy and paresis, while in our case they long preceded the paresis and amyotrophy. On the other hand, the term myoclonus is commonly used in a semiologic sense to designate involuntary movements of varied physiopathology. The myoclonus in our cases could have a spinal origin, although different from classical spinal myoclonus recently reviewed (Hoenh and Cherrington 1977). There are few reported ALS families of non-Chamorro origin and they form a heterogeneous group. Horton et al. (1976), following evolutive and morphopathological criteria, have subdivided this form of ALS into 3 types. The first 2 types, which comprise the largest part of the observations, are characterized clinically by rapid evolution of the disease as in classical sporadic ALS. In the 3rd type the course of the disease is unusually prolonged. According to these authors the reported families of this 3rd type are few (Dierssen 1959; Amick et al. 1971; family 12 of Horton et al. 1976) and there is only 1 autopsy verification (Horton et al. 1976) which showed the findings already described by Hirano et al. (1967). Our observation supports the existence of a type of non-Guamanian familial ALS with prolonged evolution and 2 other families (Espinosa et al. 1962; Metcalf and Hirano 1971) also probably belong to this group, in spite of some atypical findings. In the family of Espinosa et al. (1962) 4 members underwent a prolonged evolution and only 1 male died in 2 years. All the family members reported by Metcalf and Hirano (1971) presented with a prolonged course of the disease, but in 2 of them a glove and stocking superficial sensory impairment was found. However, the pathogenesis of the sensory involvement was not clear and the study did not include electrophysiological methods. If this group of families is accepted as representative of the prolonged-course type of hereditary ALS, then in all autopsied cases (Espinosa et al. 1962; Metcalf and Hirano 1971; Horton et al. 1976) sensory or spinocerebellar pathways were affected. Even in the case of Espinosa et al. (1962) with a short course, involvement of Clarke's column is described together with typical findings of ALS. The question arises as to whether there are any clinical data which could indicate the sensory involvement. Espinosa et al. (1962) call attention to the abolition of ankle jerks in their patients. The significance of this sign is difficult to evaluate in the other families discussed above, since all their members suffered important
206 paresis in lower extremities. In this sense, o u r f a m i l y is significant since the p a t i e n t s e x a m i n e d were at v e r y different evolutive stages. In the first case a b o l i t i o n o f the a n k l e j e r k s p r e c e d e d a n y paresis in the legs, a n d in the rest o f the cases a n k l e jerk a b o l i t i o n c o i n c i d e d with slight to m o d e r a t e paresis in the legs a n d with p y r a m i d a l signs a t higher levels. T h e e a r l y loss o f a n k l e j e r k s a n d the d i s p r o p o r t i o n between this a n d paresis c o u l d i n d i c a t e p a r t i c i p a t i o n o f the sensory c o m p o n e n t o f the stretch reflex. This p h e n o m e n o n c o u l d help to define this t y p e o f n o n - G u a m a n i a n heredi t a r y A L S with p r o l o n g e d course. ACKNOWLEDGEMENTS T h e a u t h o r s wish to t h a n k C. M o n t e r o , M. D., p a t h o l o g i s t , for his p e r m i s s i o n to c a r r y o u t the h i s t o g r a m s , a n d Prof. B o n d u e l l e a n d D r . G i m e n e z - R o l d f i n , M . D . , for p r o v i d i n g facilities for the l i t e r a t u r e survey. REFERENCES Amick, L.D., J.W. Nelson and H. Zellweger (1971) Familial motor neuron disease, non-Chamorro type Report of kinship, Acta neurol, scand., 47: 341-349. Bonduelle, M. (1975) Amyotrophic lateral sclerosis. In: P. H. Vinken and G. W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 22 (System Disorders and A trophies, Part II), North-Holland, Amsterdam, pp. 281 338. Dierssen, G. (1959) Un caso familiar de esclerosis lateral amiotr6fica, Rev. din. Esp., 73: 210-212. Espinosa, R.E., M.M. Okihiro, D.W. Mulder and G.P. Sayre (1962) Hereditary amyotrophic lateral sclerosis - - A clinical and pathologic report with comments on classification, Neurology (Minneap.), 12: 1-7. Gimenez-Rold~n, S. and A. Esteban (1977) Prognosis in hereditary amyotrophic lateral sclerosis, Arch. Neurol. (Chic.), 34: 706-708. Hirano, A., L.T. Kurland and G. P. Sayre (1967) Familial amyotrophic lateral sclerosis - A subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells, Arch. Neurol. (Chic.), 16: 232-243. Hoehn, M. M. and M. Cherrington (1977) Spinal myoclonus, Neurology (Minneap.), 27: 942-946. Horton, W.A., R. Eldridge and J.A. Brody (1976) Familial motor neuron disease Evidence for at least three different types, Neurology (Minneap.), 26: 460-465. Metcalf, C.W. and A. Hirano (1971) Amyotrophic lateral sclerosis - - Clinicopathological studies of a family, Arch. Neurol. (Chic.), 24 : 518-523.
201
© Elsevier/North-Holland Biomedical Press
HEREDITARY AMYOTROPHIC LATERAL SCLEROSIS
R. ALBERCA, J. M. CASTILLA and A. GIL-PERALTA
Department of Neurology, Ciudad Sanitaria Virgen del Rocio, and Department of Neurophysiology, University Hospital, Sevilla (Spain) (Received 21 August, 1980) (Revised, received 1 October, 1980) (Accepted 14 October, 1980)
SUMMARY
A Spanish family transmits, as an autosomal dominant trait, a form of amyotrophic lateral sclerosis characterized by an unusually prolonged evolution of the disease in all affected members. Precocity and persistence of muscle cramps, presence of unilateral proximal segmental myoclonus and early abolition of ankle jerks are other clinical features conspicuous in this family. This type of hereditary ALS of non-Chamorro origin and prolonged evolution is rare.
INTRODUCTION
The number of well-documented published cases of non-Chamorro familial amyotrophic lateral sclerosis is low. These observations are heterogeneous and they can be grouped in 3 different types according to the clinical evolution and the morphopathological findings (Horton et al. 1976). One type is characterized clinically by an unusually prolonged evolution of the disease and only 3 such families have been reported (Horton et al. 1976). However, it is unknown whether this type of familial ALS is also heterogeneous as some other families recently reviewed (Gim6nez-Roldfin and Esteban 1977) present with great intrafamilial variation of the evolution of the disease. We present a Spanish family in which ALS is transmitted as a dominant autosomal trait. In all patients the disease has an extraordinarily prolonged evolution and the patients lead active lives for many years after the onset of symptoms. The object of this article is to discuss the reasons which support the existence of a Correspondence and reprint request to : Dr. R. Alberca, Servicio de Neurologia, Centro de Diagn6stico y Tratamiento, Ciudad Sanitaria "Virgen del Rocio', Avenida Manuel Siurot, s/n. Sevilla, Spain.
202 type o f familial A L S o f n o n - C h a m o r r o origin characterized by the exceptionally p r o l o n g e d course o f the disease. STUDY OF THE FAMILY In this family there are 13 affected m e m b e r s (Fig. 1), of which 7 have been examined. Five o f them (II-3, 1I-5, III-5, 111-6, III-9) present the developed clinical picture a n d 2 have muscle c r a m p s a n d fasciculation (III-13) or only muscle c r a m p s (III-16). In 4 p a t i e n t s (II-3, II-5, 111-6, III-9) a complete study has been carried out a n d r o u t i n e investigations were n o r m a l . E M G , carried o u t on several muscles of the extremities, showed in the 4 cases a n e u r o g e n i c pattern. M o t o r a n d sensory c o n d u c t i o n velocities in a r m a n d leg nerves were n o r m a l . Muscle biopsy showed n e u r o g e n i c a t r o p h y in the 4 cases (Fig. 2). Case 1 (111-9)
For 3 years this 34-year-oldmale had suffered daily painful muscle cramps in the lower extremities that intensified after exercise, during cold weather, and at night. He also experienced continuous muscular twitches which even moved fingers and toes. Occasionally he had noticed sudden jerks which displace the right arm. On examination continuous, diffuse fasciculation could be seen in the muscles of the trunk and extremities and myokymia in gastrocnemius, increasing after exercise and accompanied by continuous movement of the toes. The right gastrocnemius was slightly atrophic. In the right arm there was arrhythmic segmental proximal myoclonus of a very low frequency, not influenced by any stimulus and displacing proximal arm segments (Fig. 3). The rest of the examination was normal. For 2 further years the patient has been examined periodically and at the last examination there was slight bilateral atrophy of gastrocnemius, paresis and amyotrophy of intrinsic musculature of left hand and slight paresis of proximal left arm muscles. Fasciculation was present in the chin muscles. Deep reflexes were easily elicited in the arms but the ankle jerks were now abolished. The patient continues working as a mechanic.
II
III
16 ml' O NOI:~AL MALE:FEMALE
-l-
DIED CRANPS
AFFECTEDBY HISTORY Fig. 1. Genealogical tree of family.
203 1.0.
llI- 9
/......... i
IS.
#0,
•
.
/'5
o
II: . . . .
II- 5
;---'~ /
.
\
I
(0
~0
,,10
/o0
30
40
IrO
IlO
*1o
~
40
~10
I~0
f#O
MO
Fig. 2. Histogram of gastrocnemius biopsy from cases III-9 and 1I-5 shows chronic neurogenic atrophy.
,, J,. J-
l II
Deltoideus
k
w
,1 1
/I
t i'*
L
1-
L
]
L Biceps brach.
t,,..,..
11
Fig. 3. EMG, case 111-9. Tracing for triceps brachii during rest shows the potentials which accompany the segmental myoclonus, together with denervation activity and frequent fasciculations in all muscles. Case 2 (II-3)
This 57-year-old female has had muscle cramps since age 38 and weakness of the legs of imprecise, later onset. At age 54 leg paresis became important, and she noted the appearance of diffuse fasciculation and sudden involuntary movements which displaced the left arm. At age 56 she needed aid to walk and had speech and swallowing difficulties. At this age examination showed a bulbar syndrome with amyotrophy and fasciculation of the tongue, myokymia of the cheeks, paresis and amyotrophy of intrinsic musculature of the hands, and discrete paresis of proximal and distal leg
204 muscles. There was generalized fasciculation and myoclonus similar to that already described. Jilw reflex was easily elicited and deep reflexes were enhanced in the arms and abolished in the legs. Plantar reflexes were indeterminate. Four months later she could hardly speak and dysphagia was important. Seven months later she was readmitted with a serious respiratory insufficiency and died in a few hours. Permission for autopsy was not given. Case 3 (iii-6)
This 39-year-old male stated that since age 25 he suffered, in succession, from muscle cramps, weakness of the legs, diffuse muscle twitches, and finally loss of strength in the hands. On examination at age 31 there was amyotrophy and asymmetric paresis of distal arm muscles and slight paresis of distal leg muscles. Fasciculation could be seen in muscles of the trunk, extremities, and chin. Jaw, bicipitak tricipital and styloradial reflexes were enhanced; patellar reflexes were normal and ankle jerks abolished. Left Babinski sign was positive. On the last visit at 39 the patient continued to lead an active life. There was now paresis and asymmetric amyotrophy of proximal arm muscles and the distal amyotrophy of legs had become more evident. Babinski sign was positive bilaterally. Case 4 (II-5)
This 60-year-old male suffered from muscle cramps and diffuse fasciculation since age 24, together with sudden involuntary movements of the right arm and a loss of strength of imprecise distribution and onset. At age 53 there was paresis of hands and fatigue on walking. At age 58 he was still working and examination showed paresis and asymmetric amyotrophy of moderate intensity in proximal and distal muscles of all 4 extremities. There was continuous fasciculation in the muscles of trunk, extremities, and chin, and myokymia in the left cheek. Jaw jerk and deep reflexes were enhanced, but the ankle jerks were abolished. Plantar reflexes could not be evaluated. On successive visits during 18 months there has been no clear progression of the clinical picture. Case 5 (III-5)
This male has had muscle cramps since age 30, paresis and distal leg amyotrophy since age 34, and loss of strength since age 37. At a later date fasciculation developed in the muscles of the trunk and extremities. At age 44 the patient was still active and examination showed asymmetric amyotrophy and paresis of the intrinsic musculature of the hands and slight paresis and amyotrophy of the musculature of anterolateral compartment of the legs. There was fascicutation in trunk, extremities, and face muscles: The jaw jerk was normal, deep arm reflexes were enhanced, patellar reflexes weak and ankle jerks abolished. The left plantar reflex was indeterminate and the right one flexor. Case 6 (Ili-13)
This 29-year-old male complained of muscle cramps and twitches, onset date not known precisely. On examination only fasciculation in the arm muscles was found. Case 7 (III-16)
This female complained of muscle cramps, onset date not known precisely, and examination, at age 23, is normal. Cases 1I-3 and 111-5 came independently to this hospital without mentioning the existence of a familial disease. Case II1-9, the propositus, told of the familial antecedents. Case 11-2, the apparently healthy mother of 4 affected cases, died accidentally before age 30. Cases I-3, 1-5, and II-6 died in their 6th decade, other data unknown. Case II-1 is alive and ill at age 70, and cases III-I and Ill-3 are over 45 and lead active lives. Six members of the 4th generation below age 10 have been examined and found normal. DISCUSSION
Several members of this family present clinical signs of lower and upper motor neuron involvement and at least one of them died with a bulbar syndrome. These data suggest the diagnosis of amyotrophic lateral sclerosis, and the kinship study indicates that the disease is transmitted as a dominant autosomat trait. Although
205 4 affected siblings apparently lack an affected parent, this may be explained by the early accidental death of the mother. The muscle cramps and fasciculation of our patients should not be considered as incidental, benign findings, but as the onset of the disease, as demonstrated in case II1-9. These cramps affect all patients, persist during the whole evolution of the process, and are generally the most incapacitating symptom. Another conspicuous clinical finding is the unilateral segmental myoclonus. In the absence of polygraphic studies it is difficult to determine the pathogenesis of this myoclonus and to establish if it is similar to the mass contractions of sporadic ALS, attributed to gross fasciculation of motor unit groups (Bonduelle 1975). However, it is a common experience that the mass contractions of sporadic ALS appear in already developed cases and affect muscles with evident amyotrophy and paresis, while in our case they long preceded the paresis and amyotrophy. On the other hand, the term myoclonus is commonly used in a semiologic sense to designate involuntary movements of varied physiopathology. The myoclonus in our cases could have a spinal origin, although different from classical spinal myoclonus recently reviewed (Hoenh and Cherrington 1977). There are few reported ALS families of non-Chamorro origin and they form a heterogeneous group. Horton et al. (1976), following evolutive and morphopathological criteria, have subdivided this form of ALS into 3 types. The first 2 types, which comprise the largest part of the observations, are characterized clinically by rapid evolution of the disease as in classical sporadic ALS. In the 3rd type the course of the disease is unusually prolonged. According to these authors the reported families of this 3rd type are few (Dierssen 1959; Amick et al. 1971; family 12 of Horton et al. 1976) and there is only 1 autopsy verification (Horton et al. 1976) which showed the findings already described by Hirano et al. (1967). Our observation supports the existence of a type of non-Guamanian familial ALS with prolonged evolution and 2 other families (Espinosa et al. 1962; Metcalf and Hirano 1971) also probably belong to this group, in spite of some atypical findings. In the family of Espinosa et al. (1962) 4 members underwent a prolonged evolution and only 1 male died in 2 years. All the family members reported by Metcalf and Hirano (1971) presented with a prolonged course of the disease, but in 2 of them a glove and stocking superficial sensory impairment was found. However, the pathogenesis of the sensory involvement was not clear and the study did not include electrophysiological methods. If this group of families is accepted as representative of the prolonged-course type of hereditary ALS, then in all autopsied cases (Espinosa et al. 1962; Metcalf and Hirano 1971; Horton et al. 1976) sensory or spinocerebellar pathways were affected. Even in the case of Espinosa et al. (1962) with a short course, involvement of Clarke's column is described together with typical findings of ALS. The question arises as to whether there are any clinical data which could indicate the sensory involvement. Espinosa et al. (1962) call attention to the abolition of ankle jerks in their patients. The significance of this sign is difficult to evaluate in the other families discussed above, since all their members suffered important
206 paresis in lower extremities. In this sense, o u r f a m i l y is significant since the p a t i e n t s e x a m i n e d were at v e r y different evolutive stages. In the first case a b o l i t i o n o f the a n k l e j e r k s p r e c e d e d a n y paresis in the legs, a n d in the rest o f the cases a n k l e jerk a b o l i t i o n c o i n c i d e d with slight to m o d e r a t e paresis in the legs a n d with p y r a m i d a l signs a t higher levels. T h e e a r l y loss o f a n k l e j e r k s a n d the d i s p r o p o r t i o n between this a n d paresis c o u l d i n d i c a t e p a r t i c i p a t i o n o f the sensory c o m p o n e n t o f the stretch reflex. This p h e n o m e n o n c o u l d help to define this t y p e o f n o n - G u a m a n i a n heredi t a r y A L S with p r o l o n g e d course. ACKNOWLEDGEMENTS T h e a u t h o r s wish to t h a n k C. M o n t e r o , M. D., p a t h o l o g i s t , for his p e r m i s s i o n to c a r r y o u t the h i s t o g r a m s , a n d Prof. B o n d u e l l e a n d D r . G i m e n e z - R o l d f i n , M . D . , for p r o v i d i n g facilities for the l i t e r a t u r e survey. REFERENCES Amick, L.D., J.W. Nelson and H. Zellweger (1971) Familial motor neuron disease, non-Chamorro type Report of kinship, Acta neurol, scand., 47: 341-349. Bonduelle, M. (1975) Amyotrophic lateral sclerosis. In: P. H. Vinken and G. W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 22 (System Disorders and A trophies, Part II), North-Holland, Amsterdam, pp. 281 338. Dierssen, G. (1959) Un caso familiar de esclerosis lateral amiotr6fica, Rev. din. Esp., 73: 210-212. Espinosa, R.E., M.M. Okihiro, D.W. Mulder and G.P. Sayre (1962) Hereditary amyotrophic lateral sclerosis - - A clinical and pathologic report with comments on classification, Neurology (Minneap.), 12: 1-7. Gimenez-Rold~n, S. and A. Esteban (1977) Prognosis in hereditary amyotrophic lateral sclerosis, Arch. Neurol. (Chic.), 34: 706-708. Hirano, A., L.T. Kurland and G. P. Sayre (1967) Familial amyotrophic lateral sclerosis - A subgroup characterized by posterior and spinocerebellar tract involvement and hyaline inclusions in the anterior horn cells, Arch. Neurol. (Chic.), 16: 232-243. Hoehn, M. M. and M. Cherrington (1977) Spinal myoclonus, Neurology (Minneap.), 27: 942-946. Horton, W.A., R. Eldridge and J.A. Brody (1976) Familial motor neuron disease Evidence for at least three different types, Neurology (Minneap.), 26: 460-465. Metcalf, C.W. and A. Hirano (1971) Amyotrophic lateral sclerosis - - Clinicopathological studies of a family, Arch. Neurol. (Chic.), 24 : 518-523.