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Refsum's Disease—A Recently Characterized Lipidosis Involving the Nervous System
Combined Clinical Staff Conference at the National Institutes of Health
- DANIEL STEINBERG, M.D., PH.D.;
- FREDERIC Q. VROOM, M.D.;
- W. KING ENGEL, M.D.;
- JAN CAMMERMEYER, M.D.;
- CHARLES E. MIZE, M.D., PH.D.; and
- JOEL AVIGAN, PH.D.
- Requests for reprints should be addressed to Daniel Steinberg, M.D., Chief, Laboratory of Metabolism, National Heart Institute, Bldg. 10, Room 5-N-307, National Institutes of Health, Bethesda, Md. 20014.
Excerpt
Dr. Daniel Steinberg: About the time of World War II, a young Norwegian neurologist, Sigvald Refsum, became intrigued with four patients referred to the Neurology Department of the Rikshospitalet in Oslo. Two were a brother and a sister from one family, and the other two were cousins from a second family. The clinical features were unusual and shared a common pattern in all four subjects. Unable to fit the pattern into any previously described category, he reported his findings in 1945 (1), suggesting that these patients presented a new syndrome to which he eventually gave the name "heredopathia atactica polyneuritiformis"
Summario in Interlingua
Morbo de Refsum es un rar disordine neurologic que es transmittite geneticamente in un configuration recessive autosomal. Le major characteristicas clinic include retinitis pigmentose, hypertrophic neuropathia peripheric de character recidivante, ataxia cerebellar, marcatemente elevate nivellos de proteina in le liquido cerebro-spinal con dissociation albuminocytologic, e surditate neural.
Le diagnose differential es commentate, e studios special (electromyographia, electroretinographia, e velocitate del conduction neural) es reportate pro duo patientes con morbo de Refsum. Le alterationes histopathologic in patientes human es distinguite per (1) un conspicue accumulation de lipido in varie organos compatibile con un diagnose de lipidosis e (2) un atrophia irregular de musculos skeletic e del systema nervose central associate con "hypertrophic polyneuropathia interstitial." Nulle del varie alterationes es sufficientemente specific pro permitter un diagnose inequivoc.
Alte concentrationes de acido phytanic (acido 3,7,11,15-tetramethylhexadecanoic) ha essite incontrate tanto in le lipidos seral de patientes con morbo de Refsum (attingente usque a 500 vices le concentration de 2 µg/ml que es presente in normal sero human) como etiam in lor lipidos tissular (usque a 50 pro cento del total de acidos grasse). Nivellos normal de acido phytanic ha essite incontrate in seros ab patientes con un extense varietate de syndromes neurologic affin.
Il ha essite possibile, ni in animales experimental ni in patientes con morbo de Refsum, demonstrar un appreciabile biosynthese endogene per investigar le incorporation de acetato, de mevalonato, o de D2O in acido phytanic.
Tanto in animales experimental como etiam in patientes con morbo de Refsum, phytol dietari es ben absorbite e es un excellente precursor de acido phytanic. In animales experimental, le inclusion de alte concentrationes de phytol o de acido phytanic in le dieta resulta in un accumulation de acido phytanic in le sanguine e le tissus. Ben que un tal tractamento resulta in un arrestate crescentia e in un significative mortalitate intra plure septimanas, alterationes in le systema nervose simile a illos incontrate in morbo de Refsum ha non essite producite. Animales normal e humanos normal ha un forte capacitate pro metabolisar phytol e acido phytanic. Tamen, duo patientes con morbo de Refsum, studiate quando lor nivellos seral de acido phytanic esseva marcatemente elevate, monstrava un considerabilemente reducite intensitate del oxydation de oralmente administrate U-14C-phytol e un relentate elimination de marcate acido phytanic ab le compartimento del plasma.
Le elimination ab le dieta de alimentos que contine cognoscitemente phytol e acido phytanic ha causate un marcate reduction del concentration seral de acido phytanic in duo casos de morbo de Refsum. Ben que un del duo manifestava evidentia subjective e objective de melioration clinic, studios additional es requirite ante que le valor therapeutic del mentionate regime dietari pote esser asserite definitivemente. Tamen, un therapia dietari pare esser justificate in chimicamente diagnosticate casos e possibilemente etiam in apparentemente normal consanguineos de subjectos con elevate nivellos de acido phytanic e deberea esser instituite le plus precocemente possibile, i.e., ante que irreversibile alterationes morbide pote disveloppar se.
Le evidentia currentemente disponibile indica que le error metabolic in morbo de Refsum que causa le accumulation de acido phytanic jace in le circuito de su degradation. Un circuito major pro le degradation de acido phytanic (in le mus e in le ratto) es concernite initialmente con α-oxydation resultante in le formation de acido pristanic (acido 2,6,10,14-tetramethylpentadecanoic). Rationes justificante le postulato que le error metabolic concerne iste prime phase del degradation es commentate. Il pare que le degradation procede subsequentemente per successive β-oxydationes, resultante alternantemente in propionato e acetato, viste que le proxime intermediarios expectate in iste circuito—acido 4,8,12-trimethyltridecanoic e acido 2,6,10-trimethylundecanoic—ha essite trovate in le hepate murin como productos de acido phytanic. Le evidentia suggere que iste circuito es un circuito major—al minus in rodentes—sed que le utilisation de altere circuitos de degradation non es excludite. Le relation inter le accumulation de acido phytanic e le pathogenese del morbo hic discutite remane a elucidar.
Article and Author Information
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This is an edited transcription of a combined clinical staff conference at the Clinical Center, Bethesda, Md., by the National Heart Institute and the National Institute of Neurological Diseases and Blindness, National Institutes of Health, Public Health Service, U. S. Department of Health, Education, and Welfare.
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- Received November 15, 1966.
- Accepted November 28, 1966.
