LETTERS TO THE EDITOR
OCULOPHARYNGEALMUSCULAR DYSTROPHY AND MITOCHONDRIAL ABNORMALITIES We have paid particular attention to the article by Pauzner et They suggest that oculopharyngeal muscular dystrophy (OPMD) may be d u e to mitochondrial dysfunction on the basis of electron microscopy abnormalities found in 2 patients belonging to the same pedigree. They perform the diagnostic of OPMD according to clinical criteria: late adult onset of ptosis and disphagia and autosomal-dominant inheritance. We believe, in addition to clinical features, the main criteria to diagnose OPMD must include the following histopathological characteristics: presence of rimmed vacuola and intranuclear filaments. ',' Otherwise, it is very difficult to distinguish, solely on the basis of clinical grounds, between oculocraniosomatic syndrome (OCSS) and OPMD, because the former can also be manifested as a late onset progressive external ophthalmoplegia with dysphagia. We have studied a 71-year-old patient with late onset PEO and severe dysphagia. Histopathological subsarcolemmal oxidative accumulations (SOA) were found in muscle sections stained with SDH. Biochemical study showed combined defects of the respiratory chain. Large-scale mtDNA deletion was ruled out. Clinical and histopathological features could be consistent with OPMD except for the absence of autosomal-dominant inheritance while sporadic cases with OPMD have been described.6 On the other hand, SOA and combined defects of the respiratory chain are consistent with mitochondrial myopathy. In view of these facts, further support is needed to establish whether OPMD might be a clinical expression of mitochondrial dysfunction. Moreover, electron microscopy abnormalities have been described, as a nonspecific histopathological finding, in various neuromuscular disorders such as Duchenne muscular dystrophy, dermatomyositis, polymyositis, and glycogeno~es.~ Likewise, mitochondrial abnormalities might be the
Letters to the Editor
result of aging, a process in which mitochondrial function is i m ~ a i r e d . ~ Joaquin Arenas, PhD Rosa A. Huertas, PhD Yolanda Campos, BSc Ana Cabello, MD Eduardo Gutierrez, MD Centro de lnvestigacion Hospital 12 de Octubre Madrid, Spain Juan Bautista, MD Dolores Segura, MD Servicio de Neurologia y Neuropatologia Hospital Virgen del Rocio Seville, Spain 1 . Martin 11, Centerick C, Mercelis R: Nuclear inclusions in oculoph%ngeal muscular dystrophy. Muscle Nerve 1982; 5:735-737. 2. Pauzner R, Blatt I, Mouallem M, Ben-David E, Farfel Z, Sadeh M: Mitochondria1 abnormalities in oculopharyngeal muscular dystrophy. Muscle Nerve 1991;14:947-952. 3. Shy GM, Gonatas NK: Human myopathy with giant abnormal mitochondria. Science 1964;145:493-496. 4 . Tom6 FMS, Fardeau H: Ocular myopathies, in Engel AG, Banker BA (eds): Myology. New York, McGraw Hill, 1986, pp 1327- 1347. 5 . Trounce I, Byrne E, Marzuki S: Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in aging. Lancet 1989;i:637-639. 6 . Victor H, Hayes R, Adams RD: Oculopharingeal muscular
dystrophy: a familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 1962;207:1267- 1272.
OCULOPHARYNGEALMUSCULAR DYSTROPHY AND MITOCHONDRIAL ABNORMALITIES (A REPLY) We thank Dr. Arenas et al. for their interest in our study. We agree that, in sporadic cases, it may be difficult to distinguish between oculopharyngeal muscular dystrophy (OPMD) and the rarely occurring late onset oculocraniosomatic syndrome on clinical grounds. However, in our pedigree, the late adult onset which oc-
MUSCLE & NERVE
September 1992
1055
curred in all affected members and the autosomal dominant inheritance establish the diagnosis of OPDM.' We also believe that rimed vacuoles and intranuclear filamentous inclusions are the histopathological hallmark for OPMD. We can not rule out that such changes did occur in our patient, but because of a sampling error they were not detected. This possibility is supported by the recent finding of a new cluster of OPMD among Jews who emigrated from Bukhara to Israel.* Twentynine patients from 10 different families with typical OPMD were examined. The histopathological findings consisted of rimmed vacuoles and typical intranuclear inclusious, but no mitochondria1 abnormalities were detected. We believe that our family' belongs to the same cluster. Currently, we are investigating in these Bukharian Jews a possible biochemical defect in the mitochondrial respiratory chain which is not accompanied by morphological changes. We certainly agree with the comment that further support is needed to establish the role of mitochondrial dysfunction in the pathogenesis of OPMD. Finally, in contrast to the nonspecific changes mentioned by Arenas et al., the morphological abnormalities observed in our patient' in virtually all mitochondria examined, suggest that these abnormalities reflect a basic defect rather than nonspecific secondary change. R. Pauzner, MD 1. Blatt, MD M. Mouallem, MD Z. Farfel, MD M. Sadeh, MD Departments of Internal Medicine E and Neurology Sheba Medical Center Tel-Hashomer, Israel 52621 1 . Pauzner R, Bldtt I, Mouallem M, Ben-David E, Fdrfel Z, Sadeh M: Mitochondria1 abnormalities in oculopharyngeal muscular dystrophy. Muscle Nerve 1991;14:947-952. 2. Blumen SC: Oculopharyngeal muscular dystrophy among Bukhara Jews: a new cluster. Proc~rdzngcofthe Annual MePtzng 01 the Israel Neurolqgy Assoczatzon, Herzlia, 1990.
MOTOR NEUROPATHY WITH MULTIFOCAL PERSISTENT CONDUCTION BLOCKS Motor neuropathy with multifocal persistent conduction blocks (CB) was first described by Roth et aL8 Around the same time, Parry and Clarke independently made a similar ob~ervation.~ Since then, the disorder has received worldwide recognition. Implication of an immune mechanism is suggested, since many patients present with anti-GM ganglioside antibodies," and immunosuppressive therapy can be beneficial in certain case^.^.^ The first patient reported' died recently at the age of 59, after a 21-year evolution of the disease. The following remarks summarize and complete his history,
,
1056
Letters to the Editor
and discuss a number of points of interest. This man first complained of cramps in the right hand in 1969, at the age of 38. From 1974, progressive weakness of the right hand and leg extended gradually to the whole of the upper limb (1979), and then eventually to all four limbs. The patient has been quadriplegic since 1983. His weak muscles showed abundant fasciculations and myokymia, with little amyotrophy. There were no sensory deficits or symptoms except for painful cramps. Sphincter functions remained normal. Peripheral nerves were not thickened. Tendon reflexes were weak or absent with no upper motor neuron sign. The clinical diagnosis of motor neuron disease was revised after electrophysiological examination revealed numerous long-latency motor axon reflexes and multifocal proximal persistent CBs, with isolated and grouped fasciculation potentials originating distally on blocked axons. Over the years, new CBs developed and amyotrophy slowly increased with the progress of denervation. During the last few years, palsy extended to involve neck and tongue muscles, with fasciculations, resulting in difficulty of speech, mastication, and swallowing. AntiGM, antibodies, measured in March 1990 (Prof. A. J. Steck) were moderately elevated at a titer of 88 (normal
OCULOPHARYNGEALMUSCULAR DYSTROPHY AND MITOCHONDRIAL ABNORMALITIES We have paid particular attention to the article by Pauzner et They suggest that oculopharyngeal muscular dystrophy (OPMD) may be d u e to mitochondrial dysfunction on the basis of electron microscopy abnormalities found in 2 patients belonging to the same pedigree. They perform the diagnostic of OPMD according to clinical criteria: late adult onset of ptosis and disphagia and autosomal-dominant inheritance. We believe, in addition to clinical features, the main criteria to diagnose OPMD must include the following histopathological characteristics: presence of rimmed vacuola and intranuclear filaments. ',' Otherwise, it is very difficult to distinguish, solely on the basis of clinical grounds, between oculocraniosomatic syndrome (OCSS) and OPMD, because the former can also be manifested as a late onset progressive external ophthalmoplegia with dysphagia. We have studied a 71-year-old patient with late onset PEO and severe dysphagia. Histopathological subsarcolemmal oxidative accumulations (SOA) were found in muscle sections stained with SDH. Biochemical study showed combined defects of the respiratory chain. Large-scale mtDNA deletion was ruled out. Clinical and histopathological features could be consistent with OPMD except for the absence of autosomal-dominant inheritance while sporadic cases with OPMD have been described.6 On the other hand, SOA and combined defects of the respiratory chain are consistent with mitochondrial myopathy. In view of these facts, further support is needed to establish whether OPMD might be a clinical expression of mitochondrial dysfunction. Moreover, electron microscopy abnormalities have been described, as a nonspecific histopathological finding, in various neuromuscular disorders such as Duchenne muscular dystrophy, dermatomyositis, polymyositis, and glycogeno~es.~ Likewise, mitochondrial abnormalities might be the
Letters to the Editor
result of aging, a process in which mitochondrial function is i m ~ a i r e d . ~ Joaquin Arenas, PhD Rosa A. Huertas, PhD Yolanda Campos, BSc Ana Cabello, MD Eduardo Gutierrez, MD Centro de lnvestigacion Hospital 12 de Octubre Madrid, Spain Juan Bautista, MD Dolores Segura, MD Servicio de Neurologia y Neuropatologia Hospital Virgen del Rocio Seville, Spain 1 . Martin 11, Centerick C, Mercelis R: Nuclear inclusions in oculoph%ngeal muscular dystrophy. Muscle Nerve 1982; 5:735-737. 2. Pauzner R, Blatt I, Mouallem M, Ben-David E, Farfel Z, Sadeh M: Mitochondria1 abnormalities in oculopharyngeal muscular dystrophy. Muscle Nerve 1991;14:947-952. 3. Shy GM, Gonatas NK: Human myopathy with giant abnormal mitochondria. Science 1964;145:493-496. 4 . Tom6 FMS, Fardeau H: Ocular myopathies, in Engel AG, Banker BA (eds): Myology. New York, McGraw Hill, 1986, pp 1327- 1347. 5 . Trounce I, Byrne E, Marzuki S: Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in aging. Lancet 1989;i:637-639. 6 . Victor H, Hayes R, Adams RD: Oculopharingeal muscular
dystrophy: a familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med 1962;207:1267- 1272.
OCULOPHARYNGEALMUSCULAR DYSTROPHY AND MITOCHONDRIAL ABNORMALITIES (A REPLY) We thank Dr. Arenas et al. for their interest in our study. We agree that, in sporadic cases, it may be difficult to distinguish between oculopharyngeal muscular dystrophy (OPMD) and the rarely occurring late onset oculocraniosomatic syndrome on clinical grounds. However, in our pedigree, the late adult onset which oc-
MUSCLE & NERVE
September 1992
1055
curred in all affected members and the autosomal dominant inheritance establish the diagnosis of OPDM.' We also believe that rimed vacuoles and intranuclear filamentous inclusions are the histopathological hallmark for OPMD. We can not rule out that such changes did occur in our patient, but because of a sampling error they were not detected. This possibility is supported by the recent finding of a new cluster of OPMD among Jews who emigrated from Bukhara to Israel.* Twentynine patients from 10 different families with typical OPMD were examined. The histopathological findings consisted of rimmed vacuoles and typical intranuclear inclusious, but no mitochondria1 abnormalities were detected. We believe that our family' belongs to the same cluster. Currently, we are investigating in these Bukharian Jews a possible biochemical defect in the mitochondrial respiratory chain which is not accompanied by morphological changes. We certainly agree with the comment that further support is needed to establish the role of mitochondrial dysfunction in the pathogenesis of OPMD. Finally, in contrast to the nonspecific changes mentioned by Arenas et al., the morphological abnormalities observed in our patient' in virtually all mitochondria examined, suggest that these abnormalities reflect a basic defect rather than nonspecific secondary change. R. Pauzner, MD 1. Blatt, MD M. Mouallem, MD Z. Farfel, MD M. Sadeh, MD Departments of Internal Medicine E and Neurology Sheba Medical Center Tel-Hashomer, Israel 52621 1 . Pauzner R, Bldtt I, Mouallem M, Ben-David E, Fdrfel Z, Sadeh M: Mitochondria1 abnormalities in oculopharyngeal muscular dystrophy. Muscle Nerve 1991;14:947-952. 2. Blumen SC: Oculopharyngeal muscular dystrophy among Bukhara Jews: a new cluster. Proc~rdzngcofthe Annual MePtzng 01 the Israel Neurolqgy Assoczatzon, Herzlia, 1990.
MOTOR NEUROPATHY WITH MULTIFOCAL PERSISTENT CONDUCTION BLOCKS Motor neuropathy with multifocal persistent conduction blocks (CB) was first described by Roth et aL8 Around the same time, Parry and Clarke independently made a similar ob~ervation.~ Since then, the disorder has received worldwide recognition. Implication of an immune mechanism is suggested, since many patients present with anti-GM ganglioside antibodies," and immunosuppressive therapy can be beneficial in certain case^.^.^ The first patient reported' died recently at the age of 59, after a 21-year evolution of the disease. The following remarks summarize and complete his history,
,
1056
Letters to the Editor
and discuss a number of points of interest. This man first complained of cramps in the right hand in 1969, at the age of 38. From 1974, progressive weakness of the right hand and leg extended gradually to the whole of the upper limb (1979), and then eventually to all four limbs. The patient has been quadriplegic since 1983. His weak muscles showed abundant fasciculations and myokymia, with little amyotrophy. There were no sensory deficits or symptoms except for painful cramps. Sphincter functions remained normal. Peripheral nerves were not thickened. Tendon reflexes were weak or absent with no upper motor neuron sign. The clinical diagnosis of motor neuron disease was revised after electrophysiological examination revealed numerous long-latency motor axon reflexes and multifocal proximal persistent CBs, with isolated and grouped fasciculation potentials originating distally on blocked axons. Over the years, new CBs developed and amyotrophy slowly increased with the progress of denervation. During the last few years, palsy extended to involve neck and tongue muscles, with fasciculations, resulting in difficulty of speech, mastication, and swallowing. AntiGM, antibodies, measured in March 1990 (Prof. A. J. Steck) were moderately elevated at a titer of 88 (normal
