Friedreich’s ataxia
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Friedreich’s ataxia, a spinocerebellar degeneration, is an autosomal recessive disease of the cerebellum, spinal cord, and peripheral nerves. Symptoms generally begin before puberty and include an ataxic gait, dysarthria, loss of reflexes, and variably nystagmus, kyphoscoliosis, and pes cavus. Heart disease usually develops, death often resulting from heart failure or dysrhythmia. Diabetes occurs in about one third of patients. Most are wheelchair bound within 15–20 years of the onset.
Nikolaus Friedreich described the disease in 1863.1 He described six patients in two families.2 He added three other patients in the 1876/1877 papers.3 A typical patient, Charlotte L, aged 49, had had symptoms from the age of 18 and was admitted to hospital in 1862. By 1876 she could not walk; she showed nystagmus, nodding tremor of the head, poor balance, and kyphoscoliosis. Her legs were paralysed, the feet in equinovarus; sensation in the legs was impaired.
Friedreich found:
"Speech is to a large extent distorted, more than at discharge from the clinic thirteen years ago. The patient articulates so badly, that one often hardly understands the words... And the pupils no abnormalities... The locomotor coordination of the upper limbs is impaired to the highest degree, much more than at the first visit in the clinic...writing has become almost impossible; directing the spoon to the mouth...happens with many additional movements deviating from the correct line and from the target. Closing the eyes does not increase the ataxic symptoms... Stronger stimuli at the sole of the foot generate rather brisk reflexes; yet the tendon reflexes of Erb are absent."
He differentiated the early age of onset, hereditary tendency, slow progression, and the absence of sensory loss in the early stages, from tabes dorsalis.4
The four patients’ postmortems showed degeneration of the dorsal columns. Microscopy showed neurogenic atrophy and demyelination. Clarke’s column and the hypoglossal nuclei were degenerate. Friedreich shrewdly observed fatty degeneration of the heart in three cases, which he associated with the tendency of the patients to collapse.
His belief that he had discovered a new disease was contentious. Several thought it was a variant of tabes or multiple sclerosis.1,2 But, Gowers acknowledged "familial locomotor ataxy or Friedreich’s disease" in 18805 and in his Manual (1886) commented on 65 cases in 19 families: "the family tendency of the disease...shown by the affection...of brothers and sisters",6 and mentioned 57 cases reviewed by Everett Smith in 1885.7 One year later, Bury summarised 100 published instances.8
The approval of Friedreich’s conclusions, however, had to await Charcot’s demonstration9 of a young sufferer from a hereditary ataxia, which did not conform to diagnoses of tabes or multiple sclerosis.
Nikolaus Friedreich was born in Würzburg in 1825, son of Johannes Baptist Friedreich (1796–1862) and grandson of Nikolaus Anton Friedreich, both professors of medicine in Würzburg. Friedreich
When the famous Virchow came to Würzburg, Friedreich became a devotee, and considered abandoning medicine for pathology. Virchow went to Berlin in 1857, thus Friedreich was appointed Professor of Pathological Anatomy at Würzburg, and, in 1858, to the Chair of Pathology and Therapy and Director of the medical clinic at Heidelberg, where he remained until he died.
Both physician and pathologist, Friedreich maintained a successful private practice. He believed "the principles of cellular pathology have become the cynosure in the labyrinth of pathological process". Enormous energy characterised his clinical and laboratory research; and many acclaimed his teaching ability. Kussmaul, Friedrich Schultze, and Erb were his acolytes. He published eight major treatises and 51 other works that included the first description of paramyoclonus multiplex (Friedreich’s disease), progressive muscular atrophy, heart disease, and possibly the first description of acute leukaemia (1857).
He was loyal to his friends but a sensitive10 and suspicious man, who habitually appeared miserable and oppressed. He died from a ruptured aortic aneurysm.
Several genes code for autosomal dominant cerebellar ataxia (ADCA) and a few for autosomal recessive ataxias. The gene for Friedreich’s ataxia was mapped to chromosome 9 in 1988. The frataxin gene codes for a 210 amino acid protein of unknown function; the mutation is an unstable expansion of a GAA repeat in the first intron inherited from both parents.11 Friedreich’s ataxia results from lack of frataxin in cells of the brain, nerves, heart, and pancreas. The gene encoding this protein is susceptible to a particular kind of DNA mutation, a triplet repeat expansion. Most are homozygous for the GAA expansion. The clinical features relate to the number of GAA repeats; formes frustes carry less repeats than typical patients.12
REFERENCES
Friedreich N. Ueber degenerative atrophie der spinalen Hinterstr?nge. Virchow’s Arch path Anat 1863;26:391–419, 433–59, and 1863;27:1–26.
Keppel Hesselink JM. A discussion from the previous century: multiple sclerosis or tabes dorsalis; or Friedreich’s disease? Ned Tijdschr Geneeskd 1986;130:2353–6.
Friedreich N. Ueber Ataxia mit besonderer Berücksichtigung der heredit?ren Formen. Virchow’s Arch path Anat 1876;68:145–245 and 1877;70:140–52.
Tyrer JH. Friedreich’s ataxia. In: Vinken PJ, Bruyn GW, DeJong JMBV, eds. Handbook of clinical neurology. Volume 21, System disorders and atrophies, part 1. Amsterdam: North-Holland Publishing Company, 1975:359–64.
Gowers WR. A family affected with locomotor ataxy. Clin Soc Trans 1880;14:27–36.
Gowers WR. A manual of diseases of the nervous system. Volume 1. London: Churchill, 1886:349–56.
Smith WE. Hereditary or degenerative ataxia. Six cases in one family. Death of one case, and autopsy. Boston Med Surg J 1885;113:361–8.
Bury JS. A contribution to the symptomatology of Friedreich’s disease. Brain 1886;9:145–77.
Goetz CG. Charcot the clinician. The Tuesday lessons. New York: Raven Press, 1987:141–63.
Erb W. Heidelberger Professoren aus dem 19 Jahrhundert. Volume 2. Heidelberg: Winter, 1903 (Biographical account).
Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;271:1423–7.
Brice A. Unstable mutations and neurodegenerative disorders. J Neurol 1998;245:505–10.(J M S Pearce)
Friedreich’s ataxia, a spinocerebellar degeneration, is an autosomal recessive disease of the cerebellum, spinal cord, and peripheral nerves. Symptoms generally begin before puberty and include an ataxic gait, dysarthria, loss of reflexes, and variably nystagmus, kyphoscoliosis, and pes cavus. Heart disease usually develops, death often resulting from heart failure or dysrhythmia. Diabetes occurs in about one third of patients. Most are wheelchair bound within 15–20 years of the onset.
Nikolaus Friedreich described the disease in 1863.1 He described six patients in two families.2 He added three other patients in the 1876/1877 papers.3 A typical patient, Charlotte L, aged 49, had had symptoms from the age of 18 and was admitted to hospital in 1862. By 1876 she could not walk; she showed nystagmus, nodding tremor of the head, poor balance, and kyphoscoliosis. Her legs were paralysed, the feet in equinovarus; sensation in the legs was impaired.
Friedreich found:
"Speech is to a large extent distorted, more than at discharge from the clinic thirteen years ago. The patient articulates so badly, that one often hardly understands the words... And the pupils no abnormalities... The locomotor coordination of the upper limbs is impaired to the highest degree, much more than at the first visit in the clinic...writing has become almost impossible; directing the spoon to the mouth...happens with many additional movements deviating from the correct line and from the target. Closing the eyes does not increase the ataxic symptoms... Stronger stimuli at the sole of the foot generate rather brisk reflexes; yet the tendon reflexes of Erb are absent."
He differentiated the early age of onset, hereditary tendency, slow progression, and the absence of sensory loss in the early stages, from tabes dorsalis.4
The four patients’ postmortems showed degeneration of the dorsal columns. Microscopy showed neurogenic atrophy and demyelination. Clarke’s column and the hypoglossal nuclei were degenerate. Friedreich shrewdly observed fatty degeneration of the heart in three cases, which he associated with the tendency of the patients to collapse.
His belief that he had discovered a new disease was contentious. Several thought it was a variant of tabes or multiple sclerosis.1,2 But, Gowers acknowledged "familial locomotor ataxy or Friedreich’s disease" in 18805 and in his Manual (1886) commented on 65 cases in 19 families: "the family tendency of the disease...shown by the affection...of brothers and sisters",6 and mentioned 57 cases reviewed by Everett Smith in 1885.7 One year later, Bury summarised 100 published instances.8
The approval of Friedreich’s conclusions, however, had to await Charcot’s demonstration9 of a young sufferer from a hereditary ataxia, which did not conform to diagnoses of tabes or multiple sclerosis.
Nikolaus Friedreich was born in Würzburg in 1825, son of Johannes Baptist Friedreich (1796–1862) and grandson of Nikolaus Anton Friedreich, both professors of medicine in Würzburg. Friedreich
When the famous Virchow came to Würzburg, Friedreich became a devotee, and considered abandoning medicine for pathology. Virchow went to Berlin in 1857, thus Friedreich was appointed Professor of Pathological Anatomy at Würzburg, and, in 1858, to the Chair of Pathology and Therapy and Director of the medical clinic at Heidelberg, where he remained until he died.
Both physician and pathologist, Friedreich maintained a successful private practice. He believed "the principles of cellular pathology have become the cynosure in the labyrinth of pathological process". Enormous energy characterised his clinical and laboratory research; and many acclaimed his teaching ability. Kussmaul, Friedrich Schultze, and Erb were his acolytes. He published eight major treatises and 51 other works that included the first description of paramyoclonus multiplex (Friedreich’s disease), progressive muscular atrophy, heart disease, and possibly the first description of acute leukaemia (1857).
He was loyal to his friends but a sensitive10 and suspicious man, who habitually appeared miserable and oppressed. He died from a ruptured aortic aneurysm.
Several genes code for autosomal dominant cerebellar ataxia (ADCA) and a few for autosomal recessive ataxias. The gene for Friedreich’s ataxia was mapped to chromosome 9 in 1988. The frataxin gene codes for a 210 amino acid protein of unknown function; the mutation is an unstable expansion of a GAA repeat in the first intron inherited from both parents.11 Friedreich’s ataxia results from lack of frataxin in cells of the brain, nerves, heart, and pancreas. The gene encoding this protein is susceptible to a particular kind of DNA mutation, a triplet repeat expansion. Most are homozygous for the GAA expansion. The clinical features relate to the number of GAA repeats; formes frustes carry less repeats than typical patients.12
REFERENCES
Friedreich N. Ueber degenerative atrophie der spinalen Hinterstr?nge. Virchow’s Arch path Anat 1863;26:391–419, 433–59, and 1863;27:1–26.
Keppel Hesselink JM. A discussion from the previous century: multiple sclerosis or tabes dorsalis; or Friedreich’s disease? Ned Tijdschr Geneeskd 1986;130:2353–6.
Friedreich N. Ueber Ataxia mit besonderer Berücksichtigung der heredit?ren Formen. Virchow’s Arch path Anat 1876;68:145–245 and 1877;70:140–52.
Tyrer JH. Friedreich’s ataxia. In: Vinken PJ, Bruyn GW, DeJong JMBV, eds. Handbook of clinical neurology. Volume 21, System disorders and atrophies, part 1. Amsterdam: North-Holland Publishing Company, 1975:359–64.
Gowers WR. A family affected with locomotor ataxy. Clin Soc Trans 1880;14:27–36.
Gowers WR. A manual of diseases of the nervous system. Volume 1. London: Churchill, 1886:349–56.
Smith WE. Hereditary or degenerative ataxia. Six cases in one family. Death of one case, and autopsy. Boston Med Surg J 1885;113:361–8.
Bury JS. A contribution to the symptomatology of Friedreich’s disease. Brain 1886;9:145–77.
Goetz CG. Charcot the clinician. The Tuesday lessons. New York: Raven Press, 1987:141–63.
Erb W. Heidelberger Professoren aus dem 19 Jahrhundert. Volume 2. Heidelberg: Winter, 1903 (Biographical account).
Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996;271:1423–7.
Brice A. Unstable mutations and neurodegenerative disorders. J Neurol 1998;245:505–10.(J M S Pearce)