J. Neurol. 212, 281--284 (1976) © by Springcr-Vcrlag 1976
Short Communications
A Family with Amyotrophic Lateral Sclerosis and Parkinsonism Milton Alter a n d B l a n k a S c h a u m a n n The Epidemiology and Genetics Unit, University of Minnesota and the Neurology Service, Minneapolis Veterans Hospital, Minneapolis, 1Kinnesota 55417 Received November 2, 1975
Zusammen/assung. Bericht fiber einen 45j/~hrigen Mann mit der Kombination yon myatrophischer Lateralsklerose und Parkinson-Syndrom, dessen Vater ebenfalls diese Krankheitskombination aufwies. Die epidemiologische Bedeutung derartiger F~lle wird diskutiert unter Bezugnahme auf das geh~ufte Vorkommen auf den Marianen-Inseln und die Mitteilungen ffir das famili~re Vorkommen in Europa. Ein gemeinsamer genetischer Faktor wird ffir wahrseheinlich gebalten. Key words: Amyotrophie lateral sclerosis - - Parkinson disease - - Familial aggregation. A m y o t r o p h i c lateral sclerosis (ALS) a n d P a r k i n s o n disease (PD) are k n o w n to occur s i m u l t a n e o u s l y a m o n g some Chamorro i n h a b i t a n t s of G u a m a n d other M a r i a n a I s l a n d s (Stanhope e t al., 1972). Outside of the W e s t e r n Pacific Islands, t h e concurrence of ALS a n d P D seems to be rare. However, it has been observed to occur w i t h sufficient f r e q u e n c y to suggest some causal association. The following is a report of a p a t i e n t suffering from ALS whose f a m i l y h i s t o r y i n c l u d e d P D i n several of t h e i m m e d i a t e relatives.
Case Report Tn 1968, at age 45, the propositus noted progressive weakness and stiffness in the lower extremities. He had considerable difficulty in walking downstairs. Past history included hepatitis in 1953, repair of a right patellar injury while in the military service, and urinary tract difficulty dating back several years. An evaluation at ~orthern Pacific Hospital in St. Paul revealed a normal electroencephalogram, brain scan, and myelogram. The patient was diagnosed as having progressive lateral sclerosis and vitamin BI~ was started. Examination at the Minneapolis Veterans Administration Hospital in 1969 revealed a husky white male, 180 cm tall, weighing 91 kg. Blood pressure was 128/106 mm Hg. The gait was wide-based and waddling. Strength in the iliopsoas, hamstrings, and dorsiflcxors of the feet was decreased. The pectoral, biceps and triceps reflexes were absent. There was bilateral sustained ankle clonus, a Babinski and a Chaddock sign bilaterally and a Gordon sign on the left. The hemogram, sedimentation rate, VDRL, urine, and T 8 uptake were normal. On urinalysis, 31--50 white cells were found. Fasting blood sugar, blood urea nitrogen, electrolytes, serum glutamic oxylacetic transaminase, urine amylase and the 2-hour postprandial glucose were normal. Uric acid was 7.9 mg~o. Alkaline phosphatase was 9.5 international units. There was minimal narrowing at Ls---S1. Posterior spurring was seen on the cervical spine films. The chest and skull radiographs were normal. The electrocardiogram showed counter-clockwise rotation and probable isehemia. There was a high frequency hearing loss bilaterally. A spastic external anal sphincter was diagnosed. Electromyography showed fasciculations characteristic of ALS. A cervical myelogram showed blunting of the C8-~ root sheath compatible with a disc at this level. This was confirmed on a repeated myelogram 4 months later. The cerebrospinal fluid glucose and protein were normal.
282
M. Alter and B. Schaumann
The weakness progressed gradually so t h a t b y age 47 t h e p a t i e n t lost the ability to walk, t h o u g h he could still stand. His speech became more slurred. Fasciculations were noted on the right leg. Coordination was normal. His handwriting was good. Deep tendon reflexes were sluggish in t h e upper limbs a n d very active and equal in t h e lower limbs. Bilateral ankle clonus, greater on the right t h a n on the left, was present. Sensation was intact. There was impaired lateral m o v e m e n t of the eye, particularly to the left a n d he was unable to move the left eye medially all the way. There was a t r o p h y of the right side of the tongue with fibrillations. Swallowing a n d pharyngeal sensation were normal. Six years after t h e onset, white cells were again present on urinalysis. The electrocardiogram revealed nonspeeifie ST and T wave changes a n d myocardial ischemia could not be ruled out. Creatine phosphokinase (CPK) was 121 a n d lactic acid dehydrogenase (LDH) was 132. W h e n repeated, t h e CPK was 160 a n d the L D H was 104. The isoenzyme p a t t e r n of L D H was normal. B y this time, the weakness of the extremities progressed and speech was barely intelligible. The right side was still weaker t h a n the left. He h a d difficulty swallowing, especially liquids. Mental functioning remained intact. Extraocular movements were full. He h a d difficulty keeping his eyes closed. There was slight weakness of upward gaze bilaterally a n d decreased hearing for high-pitched sounds. He could not produce high-pitched sounds a n d could n o t elevate the palate. R i g h t masseter and neck muscles were weak. The tongue was atrophic, more on the right t h a n the left. Atrophy was present in all four extremities, especially distally. S t r e n g t h in the deltoid was 3 ~ 4 + compared to 1--2+ in the interossei on a 5 point scale. There was a terminal intention tremor. Decadron was administered a n d gradually tapered prior to discharge. Tendon reflexes in the upper extremities became brisk a n d remained brisk in the lower extremities with transient elonus a t t h e knee and sustained clonus in the ankles. Sensation was intact. I n June, 1975, he h a d to drink through a straw a n d he fed himself using the left (nondominant} hand. He was still able to walk occasionally using a crutch or walker, b u t usually was confined to a wheelchair. He h a d control of the bladder a n d bowels. A transient, horizontal diplopia which disappeared prior to admission was associated with a flu-like episode. On physical examination, the patient was alert a n d oriented. The blood pressure was 1461100 m m Hg, the pulse was 64 per minute a n d regular. Speech was markedly dysarthric a n d difficult to understand. The extraocular movements were intact. There was a n equivocal jaw jerk a n d negative snout response. There was weakness of the right face and probably of the left as well. The tongue fasciculated bilaterally b u t could be protruded in the midline. The hands were weaker t h a n the arms a n d showed wasting of t h e small muscles. The legs were markedly weaker t h a n the arms. Bilateral foot drop was present. Faseiculations were noted in the upper extremities, over the back and less prominently in the legs. The tendon reflexes were hyperactive and symmetrical. Tone was increased in the legs with sustained ankle clonus. There was a bilateral equivocal Babinski. Palmomental responses were present. The glabellar t a p reflex was positive. Sensation was normal. Laboratory studies were uuremarkable. The chest radiograph showed a prominent left ventricle. CSF glucose was 67 mg~o and the protein was 42 mg~/o. The agar gel electrophoresis showed no abnormal immunoglobulins. IgG was 3 mg~o with the normal range of 0--9. On urinalysis one white cell was found. The albumin was 13 mg~o with a normal range of 1 1 ~ 8 . An EMG was consistent with motor neuron disease. Polyphasie potentials were increased in the sternomastoid, deltoid, triceps, brachioradialis, first dorsal interosseous muscle, and rectus femoris. The semitendinous and tibialis anterior muscles also showed increased polyphasic potentials. Fibrillations were found in the deltoid, brachioradialis, first dorsal interosseous, a n d tibialis anterior muscles. The patient's father h a d been diagnosed as having ALS and PD. D e a t h occurred a t age 75. He h a d fascieulations, a t r o p h y of the thenar eminence, rigidity, a pill-rolling tremor, a staggering propulsive gait, and later developed a pseudobulbar syndrome. The symptoms of ALS were limited to the h a n d injured in a threshing machine prior to the onset of ALS. The h a n d was t h o u g h t to have healed completely. However, in view of this injury, it is probable t h a t the " A L S " in fact represented a t a r d y ulnar palsy. The patient's paternal uncle a n d paternal grandfather were also diagnosed as having PD. The patient has four daughters ages 26, 22, 17, and 15, a son 24 and two male grandchildren, ages 4 a n d 3 years.
Amyotrophic Lateral Sclerosis and Parkinsonism
283
Discussion Concurrent motor neuron disease and parkinsonism have been observed in some patients following encephalitis lethargiea or as part of neurological syndromes such as Shy-Drager syndrome or Creutzfeldt-Jakob disease. Simultaneous occurrence of ALS and P D without evidence of previous encephalitis is rare as is the familial aggregation of these disorders. Studies of the familial aggregation of neurologie disorders are of special significance because they m a y provide insights into genetic causes or predispositions or they may focus attention on shared environmental factors of etiologic or pathogenetic significance. I n addition, intrafamilial variation in expression of the disease m a y indicate the range in pleiotropism of a given genetic trait. Although the Guamanian ALS/PD complex is frequently familial in occurrence, the familial aggregation follows no simple genetic pattern and indeed m a y not be hereditary at all. Rather, environmental factors are suspected to account for the common familial occurrence. The ALS and P D of the Mariana Islands are believed to represent one neurological disorder with varying degrees of involvement of t h e upper and lower motor neurons, extrapyramidal system and higher cortical functions in different individuals (Mathai, 1970). The possibility that P D and ALS m a y represent a single disease entity even in non-Guamanian cases can also be considered as a few examples of concomitance of the disorders have been reported in the literature, several of them with familial occurrence. Van Bogaert and Radermecker (1954)described a family with 5 affected members in 3 generations. Two of them suffered from ALS, 2 others had P D and 1 had both disorders. Biemond and Beck (1955) reported 3 siblings suffering from a heterogeneous neurologic disorder, consisting of peripheral nerve, extrapyramidal and pyramidal components. The disorder was considered to represent the ALS/PD complex by Brait et al. (1973). Biemond and Sinnege (1955) encountered another family with 6 aifected individuals in 3 generations. Two of the patients complained originally of parkinsonian symptoms which were later accompanied by muscular atrophy. One of these patients also had a cerebellar ataxia. A mild static ataxia was observed in a third patient who later developed typical PD. Little information was available on the remaining 3 affected individuals apart from the fact t h a t they all died in middle age after a protracted disease which originated as walking disturbances and ultimately resulted in complete invalidism. The largest pedigree of a family suffering from various neurological disorders including ALS and P D was reported by Ziegler et al. (1972). Thirty one individuals of the kindred were affected, presenting either peripheral neuropathy, ALS, PD, spinocerebellar degeneration or various combinations of these disorders. Another f a m i l y including individuals with ALS, PD, and ataxia was described by Brait et al. (1973). The proband had both ALS and PD, while 2 other family members (the patient's sister and son) had ataxia without PD or ALS and 2 additional individuals (the patient's mother and maternal aunt) had impaired coordination and gait difficulty which worsened progressiveiy during their lifetimes. Our patient had pure ALS with no signs of either extrapyramidal or cerebellar involvement on physical examination while 3 of the patient's relatives suffered from PD.
284
M. Alter and B. Schaumann
I n view of the relative rarity of hereditary ALS and PD as separate entities, it seems unlikely that the two disorders in the above mentioned kindred were inherited independently. I t is more likely that signs of ALS and PD (and occasionally cerebellar ataxia as well) constitute a single neurologic syndrome with considerable variation in expressivity. Brait et al. (1973) offered the descriptive label "familial spinocerebellonigral amyotrophy" (SCNA) for this syndrome. With the possible exception of the kindred reported by Biemond and Beck (1955) in which only siblings were affected, the syndrome seems to be inherited as an autosomal dominant trait. The onset of the disease is usually in middle age, although an earlier onset, during the second decade of life, has been reported (van Bogaert and Radermecker, 1954). The initial symptoms vary greatly so that the disease m a y first present itseff as ALS or PD even within the same family. Independently of the original signs, the syndrome is characterized by its relatively benign course with protracted duration. Our patient's illness has already lasted 7 years. The syndrome of familial SCNA may be considerably more common than is indicated by the paucity of families reported in the literature. As has been pointed out previously (Brait et al., 1973), the signs of one disorder may mask or obscure the signs of the other and evidence of disturbance of other nervous systems must be sought carefully. I n addition, the possible hereditary character of both ALS and parkinsonism is often not appreciated because detailed inquiry into the family history of patients who have either of these disorders is not carried out. Such inquiries are certainly warranted and m a y reveal additional individuals within the same kindred suffering from either or both diseases.
References Biemond, A., Beck, W.: Neural muscle atrophy with degeneration of the substantia nigra. Confin. neurol. (Basel) 15, 142--153 (1955) Biemond, A., Sinnege, J. L. M. : Tabes of Friedreich with degeneration of the substantia nigra, a special type of hereditary parkinsonism. Confin. neurol. (Basel) 15, 129--142 (1955) Brait, K., Fahn, S., Schwarz, G. A. : Sporadic and familial parkinsonism and motor neuron disease. Neurology (Minneap.) 28, 990--1002 (1973) Mathai, K. V. : Amyotrophic lateral sclerosis and parkinsonism dementia in the Marianas. Amer. J. trop. Med. Hyg. 19, 151--154 (1970) Stanhope, J. M., Brody, J. A., Morris, C. E.: Epidemiologic features of amyotrophic lateral sclerosis and parkinsonism-dementia in Guam, Mariana Islands. Int. J. Epidemiol. 1, 199--210 (1972) Van Bogaert, L., Radermecker, M. A.: Scl6roses lat~rales amyotrophiques typiques et paralysies agitantes h$r~ditaires, dans une m~me famille, avec une forme de passage possible entre les deux affections. Mschr. Psychiat. Neurol. 127, 185--203 (1954) Ziegler, D. K., Schimke, R. N., Kepes, J. J., Rose, I). L., Klinkerfuss, G. : Late onset ataxia, rigidity, and peripheral neuropathy. A familial syndrome with variable therapeutic response to levodopa. Arch. Neurol. 27, 52---66 (1972) Milton Alter, M.D., Ph.D. Chief Neurology Service Veterans Administration Hospital 54th Street and 48th Avenue South Minneapolis, Minnesota 55417, USA
Short Communications
A Family with Amyotrophic Lateral Sclerosis and Parkinsonism Milton Alter a n d B l a n k a S c h a u m a n n The Epidemiology and Genetics Unit, University of Minnesota and the Neurology Service, Minneapolis Veterans Hospital, Minneapolis, 1Kinnesota 55417 Received November 2, 1975
Zusammen/assung. Bericht fiber einen 45j/~hrigen Mann mit der Kombination yon myatrophischer Lateralsklerose und Parkinson-Syndrom, dessen Vater ebenfalls diese Krankheitskombination aufwies. Die epidemiologische Bedeutung derartiger F~lle wird diskutiert unter Bezugnahme auf das geh~ufte Vorkommen auf den Marianen-Inseln und die Mitteilungen ffir das famili~re Vorkommen in Europa. Ein gemeinsamer genetischer Faktor wird ffir wahrseheinlich gebalten. Key words: Amyotrophie lateral sclerosis - - Parkinson disease - - Familial aggregation. A m y o t r o p h i c lateral sclerosis (ALS) a n d P a r k i n s o n disease (PD) are k n o w n to occur s i m u l t a n e o u s l y a m o n g some Chamorro i n h a b i t a n t s of G u a m a n d other M a r i a n a I s l a n d s (Stanhope e t al., 1972). Outside of the W e s t e r n Pacific Islands, t h e concurrence of ALS a n d P D seems to be rare. However, it has been observed to occur w i t h sufficient f r e q u e n c y to suggest some causal association. The following is a report of a p a t i e n t suffering from ALS whose f a m i l y h i s t o r y i n c l u d e d P D i n several of t h e i m m e d i a t e relatives.
Case Report Tn 1968, at age 45, the propositus noted progressive weakness and stiffness in the lower extremities. He had considerable difficulty in walking downstairs. Past history included hepatitis in 1953, repair of a right patellar injury while in the military service, and urinary tract difficulty dating back several years. An evaluation at ~orthern Pacific Hospital in St. Paul revealed a normal electroencephalogram, brain scan, and myelogram. The patient was diagnosed as having progressive lateral sclerosis and vitamin BI~ was started. Examination at the Minneapolis Veterans Administration Hospital in 1969 revealed a husky white male, 180 cm tall, weighing 91 kg. Blood pressure was 128/106 mm Hg. The gait was wide-based and waddling. Strength in the iliopsoas, hamstrings, and dorsiflcxors of the feet was decreased. The pectoral, biceps and triceps reflexes were absent. There was bilateral sustained ankle clonus, a Babinski and a Chaddock sign bilaterally and a Gordon sign on the left. The hemogram, sedimentation rate, VDRL, urine, and T 8 uptake were normal. On urinalysis, 31--50 white cells were found. Fasting blood sugar, blood urea nitrogen, electrolytes, serum glutamic oxylacetic transaminase, urine amylase and the 2-hour postprandial glucose were normal. Uric acid was 7.9 mg~o. Alkaline phosphatase was 9.5 international units. There was minimal narrowing at Ls---S1. Posterior spurring was seen on the cervical spine films. The chest and skull radiographs were normal. The electrocardiogram showed counter-clockwise rotation and probable isehemia. There was a high frequency hearing loss bilaterally. A spastic external anal sphincter was diagnosed. Electromyography showed fasciculations characteristic of ALS. A cervical myelogram showed blunting of the C8-~ root sheath compatible with a disc at this level. This was confirmed on a repeated myelogram 4 months later. The cerebrospinal fluid glucose and protein were normal.
282
M. Alter and B. Schaumann
The weakness progressed gradually so t h a t b y age 47 t h e p a t i e n t lost the ability to walk, t h o u g h he could still stand. His speech became more slurred. Fasciculations were noted on the right leg. Coordination was normal. His handwriting was good. Deep tendon reflexes were sluggish in t h e upper limbs a n d very active and equal in t h e lower limbs. Bilateral ankle clonus, greater on the right t h a n on the left, was present. Sensation was intact. There was impaired lateral m o v e m e n t of the eye, particularly to the left a n d he was unable to move the left eye medially all the way. There was a t r o p h y of the right side of the tongue with fibrillations. Swallowing a n d pharyngeal sensation were normal. Six years after t h e onset, white cells were again present on urinalysis. The electrocardiogram revealed nonspeeifie ST and T wave changes a n d myocardial ischemia could not be ruled out. Creatine phosphokinase (CPK) was 121 a n d lactic acid dehydrogenase (LDH) was 132. W h e n repeated, t h e CPK was 160 a n d the L D H was 104. The isoenzyme p a t t e r n of L D H was normal. B y this time, the weakness of the extremities progressed and speech was barely intelligible. The right side was still weaker t h a n the left. He h a d difficulty swallowing, especially liquids. Mental functioning remained intact. Extraocular movements were full. He h a d difficulty keeping his eyes closed. There was slight weakness of upward gaze bilaterally a n d decreased hearing for high-pitched sounds. He could not produce high-pitched sounds a n d could n o t elevate the palate. R i g h t masseter and neck muscles were weak. The tongue was atrophic, more on the right t h a n the left. Atrophy was present in all four extremities, especially distally. S t r e n g t h in the deltoid was 3 ~ 4 + compared to 1--2+ in the interossei on a 5 point scale. There was a terminal intention tremor. Decadron was administered a n d gradually tapered prior to discharge. Tendon reflexes in the upper extremities became brisk a n d remained brisk in the lower extremities with transient elonus a t t h e knee and sustained clonus in the ankles. Sensation was intact. I n June, 1975, he h a d to drink through a straw a n d he fed himself using the left (nondominant} hand. He was still able to walk occasionally using a crutch or walker, b u t usually was confined to a wheelchair. He h a d control of the bladder a n d bowels. A transient, horizontal diplopia which disappeared prior to admission was associated with a flu-like episode. On physical examination, the patient was alert a n d oriented. The blood pressure was 1461100 m m Hg, the pulse was 64 per minute a n d regular. Speech was markedly dysarthric a n d difficult to understand. The extraocular movements were intact. There was a n equivocal jaw jerk a n d negative snout response. There was weakness of the right face and probably of the left as well. The tongue fasciculated bilaterally b u t could be protruded in the midline. The hands were weaker t h a n the arms a n d showed wasting of t h e small muscles. The legs were markedly weaker t h a n the arms. Bilateral foot drop was present. Faseiculations were noted in the upper extremities, over the back and less prominently in the legs. The tendon reflexes were hyperactive and symmetrical. Tone was increased in the legs with sustained ankle clonus. There was a bilateral equivocal Babinski. Palmomental responses were present. The glabellar t a p reflex was positive. Sensation was normal. Laboratory studies were uuremarkable. The chest radiograph showed a prominent left ventricle. CSF glucose was 67 mg~o and the protein was 42 mg~/o. The agar gel electrophoresis showed no abnormal immunoglobulins. IgG was 3 mg~o with the normal range of 0--9. On urinalysis one white cell was found. The albumin was 13 mg~o with a normal range of 1 1 ~ 8 . An EMG was consistent with motor neuron disease. Polyphasie potentials were increased in the sternomastoid, deltoid, triceps, brachioradialis, first dorsal interosseous muscle, and rectus femoris. The semitendinous and tibialis anterior muscles also showed increased polyphasic potentials. Fibrillations were found in the deltoid, brachioradialis, first dorsal interosseous, a n d tibialis anterior muscles. The patient's father h a d been diagnosed as having ALS and PD. D e a t h occurred a t age 75. He h a d fascieulations, a t r o p h y of the thenar eminence, rigidity, a pill-rolling tremor, a staggering propulsive gait, and later developed a pseudobulbar syndrome. The symptoms of ALS were limited to the h a n d injured in a threshing machine prior to the onset of ALS. The h a n d was t h o u g h t to have healed completely. However, in view of this injury, it is probable t h a t the " A L S " in fact represented a t a r d y ulnar palsy. The patient's paternal uncle a n d paternal grandfather were also diagnosed as having PD. The patient has four daughters ages 26, 22, 17, and 15, a son 24 and two male grandchildren, ages 4 a n d 3 years.
Amyotrophic Lateral Sclerosis and Parkinsonism
283
Discussion Concurrent motor neuron disease and parkinsonism have been observed in some patients following encephalitis lethargiea or as part of neurological syndromes such as Shy-Drager syndrome or Creutzfeldt-Jakob disease. Simultaneous occurrence of ALS and P D without evidence of previous encephalitis is rare as is the familial aggregation of these disorders. Studies of the familial aggregation of neurologie disorders are of special significance because they m a y provide insights into genetic causes or predispositions or they may focus attention on shared environmental factors of etiologic or pathogenetic significance. I n addition, intrafamilial variation in expression of the disease m a y indicate the range in pleiotropism of a given genetic trait. Although the Guamanian ALS/PD complex is frequently familial in occurrence, the familial aggregation follows no simple genetic pattern and indeed m a y not be hereditary at all. Rather, environmental factors are suspected to account for the common familial occurrence. The ALS and P D of the Mariana Islands are believed to represent one neurological disorder with varying degrees of involvement of t h e upper and lower motor neurons, extrapyramidal system and higher cortical functions in different individuals (Mathai, 1970). The possibility that P D and ALS m a y represent a single disease entity even in non-Guamanian cases can also be considered as a few examples of concomitance of the disorders have been reported in the literature, several of them with familial occurrence. Van Bogaert and Radermecker (1954)described a family with 5 affected members in 3 generations. Two of them suffered from ALS, 2 others had P D and 1 had both disorders. Biemond and Beck (1955) reported 3 siblings suffering from a heterogeneous neurologic disorder, consisting of peripheral nerve, extrapyramidal and pyramidal components. The disorder was considered to represent the ALS/PD complex by Brait et al. (1973). Biemond and Sinnege (1955) encountered another family with 6 aifected individuals in 3 generations. Two of the patients complained originally of parkinsonian symptoms which were later accompanied by muscular atrophy. One of these patients also had a cerebellar ataxia. A mild static ataxia was observed in a third patient who later developed typical PD. Little information was available on the remaining 3 affected individuals apart from the fact t h a t they all died in middle age after a protracted disease which originated as walking disturbances and ultimately resulted in complete invalidism. The largest pedigree of a family suffering from various neurological disorders including ALS and P D was reported by Ziegler et al. (1972). Thirty one individuals of the kindred were affected, presenting either peripheral neuropathy, ALS, PD, spinocerebellar degeneration or various combinations of these disorders. Another f a m i l y including individuals with ALS, PD, and ataxia was described by Brait et al. (1973). The proband had both ALS and PD, while 2 other family members (the patient's sister and son) had ataxia without PD or ALS and 2 additional individuals (the patient's mother and maternal aunt) had impaired coordination and gait difficulty which worsened progressiveiy during their lifetimes. Our patient had pure ALS with no signs of either extrapyramidal or cerebellar involvement on physical examination while 3 of the patient's relatives suffered from PD.
284
M. Alter and B. Schaumann
I n view of the relative rarity of hereditary ALS and PD as separate entities, it seems unlikely that the two disorders in the above mentioned kindred were inherited independently. I t is more likely that signs of ALS and PD (and occasionally cerebellar ataxia as well) constitute a single neurologic syndrome with considerable variation in expressivity. Brait et al. (1973) offered the descriptive label "familial spinocerebellonigral amyotrophy" (SCNA) for this syndrome. With the possible exception of the kindred reported by Biemond and Beck (1955) in which only siblings were affected, the syndrome seems to be inherited as an autosomal dominant trait. The onset of the disease is usually in middle age, although an earlier onset, during the second decade of life, has been reported (van Bogaert and Radermecker, 1954). The initial symptoms vary greatly so that the disease m a y first present itseff as ALS or PD even within the same family. Independently of the original signs, the syndrome is characterized by its relatively benign course with protracted duration. Our patient's illness has already lasted 7 years. The syndrome of familial SCNA may be considerably more common than is indicated by the paucity of families reported in the literature. As has been pointed out previously (Brait et al., 1973), the signs of one disorder may mask or obscure the signs of the other and evidence of disturbance of other nervous systems must be sought carefully. I n addition, the possible hereditary character of both ALS and parkinsonism is often not appreciated because detailed inquiry into the family history of patients who have either of these disorders is not carried out. Such inquiries are certainly warranted and m a y reveal additional individuals within the same kindred suffering from either or both diseases.
References Biemond, A., Beck, W.: Neural muscle atrophy with degeneration of the substantia nigra. Confin. neurol. (Basel) 15, 142--153 (1955) Biemond, A., Sinnege, J. L. M. : Tabes of Friedreich with degeneration of the substantia nigra, a special type of hereditary parkinsonism. Confin. neurol. (Basel) 15, 129--142 (1955) Brait, K., Fahn, S., Schwarz, G. A. : Sporadic and familial parkinsonism and motor neuron disease. Neurology (Minneap.) 28, 990--1002 (1973) Mathai, K. V. : Amyotrophic lateral sclerosis and parkinsonism dementia in the Marianas. Amer. J. trop. Med. Hyg. 19, 151--154 (1970) Stanhope, J. M., Brody, J. A., Morris, C. E.: Epidemiologic features of amyotrophic lateral sclerosis and parkinsonism-dementia in Guam, Mariana Islands. Int. J. Epidemiol. 1, 199--210 (1972) Van Bogaert, L., Radermecker, M. A.: Scl6roses lat~rales amyotrophiques typiques et paralysies agitantes h$r~ditaires, dans une m~me famille, avec une forme de passage possible entre les deux affections. Mschr. Psychiat. Neurol. 127, 185--203 (1954) Ziegler, D. K., Schimke, R. N., Kepes, J. J., Rose, I). L., Klinkerfuss, G. : Late onset ataxia, rigidity, and peripheral neuropathy. A familial syndrome with variable therapeutic response to levodopa. Arch. Neurol. 27, 52---66 (1972) Milton Alter, M.D., Ph.D. Chief Neurology Service Veterans Administration Hospital 54th Street and 48th Avenue South Minneapolis, Minnesota 55417, USA
