One of the major effects of infantile Refsum Disease (as well as the other peroxisomal biogenesis disorders) is the combination of significant audiory and visual impairments. These sensory losses vary in severity from child to child, and these diseases do not necessarily lead to total deafness and/or total blindness. In fact, it is entirely possible that the child will retain some useful vision and hearing. However, in combination, these impairments of the distal senses cause serious developmental delay in the child; affecting cogntive and social development, orientation and mobility, and the acquistion of communication and language.
The disabling condition caused by combined hearing and visual losses is deafblindness (or deaf-blindness, equally correct). A deafblind child cannot be thought of as blind and also deaf, nor as deaf and also blind. She is deafblind. Deafblindness is a unique disability; it has its own concepts and terminology, its own methods of assessment and education, and its own modes of communication which distinguish it from blindness and deafness understood separately.
It is not a medical concept, the ophthalmologist and the audiologist observe within their respective spheres, and the strictly medical literature never refers to deafblindness. It's a developmental concept, and without it the nature of the disability cannot be understood.
Overview on Deaf-Blindness - Barbara Miles
This paper is a good introduction to the subject; covering basic definition, legal definition, major causes of deafblindness, communication systems, orientation and mobility, and the planning and methods of education. Includes a good basic reference bibliography.
The Deafblindness WWW Resource - James Gallagher
A well-maintained site in the UK with information on terminology, Internet resources, relevant journals and periodicals, conferences and learning courses, awareness and training videos, equipment (both existing and under development) of special use to deafblind people, communciation systems and methods, computer and Internet access, and organizations of and for deafblind people, their families, and professionals working with them. Global in scope, and with an extensive (basically searchable) bibliography.
The DB-LINK site at Monmouth, Oregon - Randy Klumph
Information relating to practices, programs and services for children and youth who are deaf-blind; early intervention, education, communication, health, technology, parent, family and social support, and legal issues. A co-operative effort of the American Association.of the Deaf-Blind, Helen Keller National Center, Perkins School for the Blind, and the Teaching Research Division of Western Oregon University. Extensive bibliographic and reference information.
American Association of the Deaf-Blind
Helen Keller National Center, Sands Point, New York
(Perkins School for the Blind, Waterton, Massachusetts)
The Hilton/Perkins Program provides consultation, technical assistance and training for the development of programs and services for children who are deafblind or multi-hadicapped blind. Assistance is available to programs serving infants, toddlers, and school-aged children in the United States and in developing countries.
Scottish Sensory Centre (University of Edinburgh)
For everyone who is involved in the education of children and young people with sensory impairment, the young people themselves, and their families. Information, articles, and refererence materials relating to developments and effective practices in the education of children with sensory impairments - blind, deaf, and deafblind.
Sense UK (London, England)
National Deafblind and Rubella Association of the United Kingdom, the world's largest organization working with and campaigning for deafblind people and those who share their lives.
Organizations of and for Deafblind People Throughout the World
A comprehensive list of organizations worldwide providing services and resources to deafblind people and their families
Deafblind International is a worldwide association promoting services for deafblind people. Its objects include furthering the idea of deafblindness as a unique disabling condition, fostering civil rights and equality of opportunity for deafblind people, the development of networks of and for deafblind people, their families, and the professionals working with them, and the promotion of services and opportunities which lead to self-determination and a high quality of life.
USA Organizations for Deafblind People
A comprehensive list of public and private organizations and agencies in the USA which provide services and information regarding deafblindness.
New York Institute for Special Education (Bronx, New York)
NYISE is a private, non-profit school with programs for children who are blind or visually impaired, learning disabled, or developmentally delayed. The NYISE website includes numerous links to resources and information relating to the education of blind, deaf, or deafblind children, braille and other reading codes, eye disease, national and international organizations and schools, adaptive and assistive technologies, and universal access.
HOME Project (Center on Self-Determination, Oregon Health Sciences University)
The purpose of the HOME project is to develop an assessment tool for use by parents to evaluate their children who are deafblind, in order to plan for appropriate intervention strategies in home, school and community. This project actively solicits and involves parents as partners in model development and field testing, recognizing them as the best source of information regarding the skills and capabilities of their children.
Deafblind Children Home Page
Family-oriented, stories of other children with deafblindness, and links to various sources of information.
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FAMILY SUPPORT GROUPS
By no means exhaustive, this list reflects countries currently represented on the [IRD list], our informal group of families throughout the world having children with peroxisomal biogenesis disorders.
Asociation de Padres de Personas con Sordoceguera de la Republica Argentina
La Rabida 2550 - San Isidro, (1643) Buenos Aires, Argentina
AV Lacerda Franco, 252 - Cambuci
Sao Paulo - SP, 01536-000 Brazil
telephone and fax: +55-11-270-5283
Canadian Deafblind and Rubella Association - National
350 Brant Avenue, Brantford, Ontario, Canada N3T 3J9
Foerdergemeinschaft fur Taubblinde e.V.
Basteistrae 83a, D-53173 Bonn, Germany
telephone: +49 0228-956-37-63
fax: +49 0228-956-37-65
Anne Sulivan Foundation for Deafblind People
40 Lower Drumcondra Road, Dublin, Ireland
telephone: +353 1-830562
New Zealand -
Deafblind New Zealand
Box 109-583, Newmarket, Aukland, New Zealand
telephone: 64 09-524-8598
Deafblind South Africa
125a Tulbagh Street,
Worcester 6850, Republic of South Africa
United Kingdom -
National Deafblind and Rubella Association of the United Kingdom
11-13 Clifton Terrace, Finsbury Park, London, England N4 3SR
telephone: 44 0171-272-7774 (voice)
44 0171-272-9648 (text)
fax: 44 071-272-6012
National Family Association for Deaf-Blind
111 Middle Neck Road
Sands Point, New York 11050
telephone: (800) 255-0411 ext 275
The hearing impairment or deafness associated with the peroxisomal biogenesis disorders (PBDs), as well as adult Refsum disease and some of the other single-enzyme disorders, is among the least-understood aspects of these diseases. There is no lack of documentation of the existence of such impairment - nearly all descriptions of these disorders and individual case studies include mention of sensorineural deafness. (Actually, the medical literature uses a variety of terms - "sensory deafness", "neurosensory deafness", "sensorineural hearing loss", "sensory neural hearing loss", "sensorineural hearing deficit", and so on. These all amount to the same thing and this page will use the term "sensorineural deafness"). Most of the time this deafness is specified as being bilateral (that is, affecting both ears, and probably always the case anyway, whether specified or not); and with degree of deafness ranging from moderate to profound. Occasionally, quantified data - "confirmed 70-decibel hearing impairment bilaterally".
There is, however, a significant gap between the recognition of sensorineural deafness as being typical in these diseases and an actual understanding of the pathology involved, or in what manner the PBDs cause such pathology. It is, in fact, remarkable how little is known about the subject and the general lack of study relating to it.
Sensorineural deafness is one of four types, or classifications, of deafness. These classifications are reflective of the anatomy of the ear, and the role of each part in the cascade of processes which make up the sense of hearing. In schematic, the ear consists of three parts, named (simply enough), the outer, middle, and inner.
The outer ear consists of the part we see sticking out from a person's head (the pinna) and the ear canal (external acoustic meatus) leading to the eardrum (tympanic membrane). The purpose of the outer ear is to funnel the environmental vibrations which we will come to perceive as sound (but which really aren't "sound" at all yet - simply vibrations in the air) to the tympanic membrane, which is itself then set into corresponding vibration. The tympanic membrane is the interface between the outer and middle ear. The middle ear is an air-filled chamber (the tympanic cavity) containing three small bones (the ossicles: malleus, incus, and stapes - the hammer, the anvil, and the stirrup). These bones are connected in a chain running the length of the middle ear, the handle (manubrium) of the hammer being attached to the inner side of the eardrum, set in motion by the vibrations of the eardrum, and transferring this motion mechanically from one ossicle to the next. The base of the third ossicle (stirrup or stapes) is called the foot plate. The foot plate fits into and seals an opening into the inner ear, the oval window (fenestra vestibuli, also called fenestra ovalis); the foot plate of the stapes is the interface between the middle and inner ear. The inner ear is known as the labyrinth (complex and maze-like, hence the name) and consists of two nested parts, the bony (osseus) labyrinth and within it, the membranous labyrinth. The space between the osseus labyrinth and the membranous labyrinth is filled with a fluid called perilymph, and the membranous labyrinth is filled with a fluid called endolymph. The oval window opens into a chamber called the scala vestibuli, which lies between bone and membrane and is filled with perilymph. The motion of the foot plate of the stapes, acting somewhat as a diaphragm, sets up hydraulic waves within the perilymph, which in turn propagate throughout the labyrinth, and in so doing set up corresponding waves - translations of that energy - in some of the internal membranes, and within the endolymph.
Within the membranous labyrinth are six structures which derive information
from these waves: five of them are specialized to the sense of balance
(vestibular function), and the sixth - the cochlea - to the sense of hearing.
The cochlea can be thought of as a cone, hollowed from solid bone in the
skull (the temporal bone), which spirals and decreases in diameter from
its base to its apex. This needs to be remembered, but visualization comes
easier thinking of it stretched out, and of a constant diameter. Running
the length of this tube are two membranes, and so forming three chambers
or passageways within (running the length) of the cochlea. The first of
these (the upper, viewed in section) is the scala vestibuli - which the
oval window opens into - lying between the temporal bone and Riessner's
membrane. The second (the lower) is the scala tympani, which lies between
(roughly) the opposite wall of the of the temporal bone and the basilar
membrane. Both the scalal vestibuli and the scala tympani contain perilymph,
lying between bone and membrane. The scala vestibuli and the scala tympani
are not closed systems, the names are used to distinguish one side from
the other and their different functions; Reissner's membrane and the basilar
membrane join each other somewhat short of the apex of the cochlear bone,
and the area where the scala vestibuli and the scala tympani are continuous
is called the helicotrema, and perilymph (or the waves within it) travel
directly from one side to the other. At the base of the scala tympani is
the round window, a membrane-covered opening back into the middle ear,
which serves to regulate the pressure within the inner ear created at the
oval window by dispersing that energy back into the middle ear.
Running the length of the basilar membrane are the cells which transduce mechanical energy into electrical. These are the hair cells, so called because each one has a very fine hair-like structure protruding from it. The overall arrangement of the cells - the tissue formed - is the sensory epithelium. The hair cells are arranged along the length of the basilar membrane in parallel rows, usually one inner and three outer. The "hairs" (cilia plural, cilium singular) of the hair cells extend into the scala media, with the bases of the hair cells oriented toward the basilar membrane, and resting upon and within a framework of supporting (and non-sensory) cells. At their bases the hair cells join to nerve fibers which carry the electrical output to the brain. (This works in both directions, information is also sent from the brain to the hair cells). Leaving each hair cell, these single nerve fibers cable together to form the cochlear nerve, which in turn joins with a similar nerve coming from the vestibular organs of the inner ear, and together forming cranial nerve VIII, which goes into the brain itself. The cells making up these nerves are called ganglion cells - a general term for nerve cells which lie outside the brain and central nervous system. The hair cells are covered over by another structure - the tectorial membrane - in such a way that the cilia of the outer hair cells are embedded within it and the cilia of the inner hair cells are affected by its motion, but not directly attached. [animated diagram - about 2 minutes to load]
The movement of the foot plate at the oval window causes waves within the perilymph.. The basilar membrane responds to these by taking on a wave motion of its own, the hair cells attached to it being displaced through three dimensions with the passing of the wave. The tectorial membrane is also in motion, but not in unison with the basilar membrane, and so the relative difference in the motions of these two surfaces causes twists and turns and bends in the cilia - mechanically: shearing action. This motion of each cilium causes each hair cell to undergo chemical and electrical changes which in turn generates an electrical impulse to the nerve fiber attached to it, and these impulses make their way collectively to the brain where they are perceived as sound.
Malformation or dysfunction of either (or both) the outer and middle ears is known as conductive deafness; of the inner ear, sensorineural deafness; of the nervous system from the organ of Corti to the brain, central auditory deafness; and the fourth type, a mixture of conductive and sensorineural, is called mixed deafness.
Sensorineural deafness is so called because it occurs in the cochlea or organ of Corti, the interface between the sensory input of the wave information coming from the outside world, and the neural output to the VIII cranial nerve and the brain. In fact, nearly all sensorineural deafness is really sensory in nature; the dysfunction occurs on the sensory side of the interface. Sensorineural deafness generally results from an inability of the organ of Corti to properly transduce mechanical input into electrical output.
The anatomy and chemistry of the inner ear, the cochlea, and the organ of Corti is of course very complex, and there are varying theories just how it all works: the nature of the waves, how they propagate, the resulting motion of the cilium, the process within the hair cell from mechanical, through chemical, to electrical energy. Within the scope of this page it has only been intended to give a very rough (and please note - greatly oversimplified) description.
The cochlea is very small, tucked well away in the skull, and the events occuring within it are happening on cellular and molecular scales. The cochlea, the organ of Corti, and their processes are not subject to direct observation. In the peroxisomal diseases this is probably the main reason that the ophthalmology and eye disease is so much better understood than the cochlear dysfunction.
In 1987 a post-mortem report was published by a Dr Torvik and others in Norway.(1) The deceased was a 12 year-old boy who had been dignosed with IRD and who had died of pneumonia. As part of this autopsy the cochlea was examined. Dr Torvik reported: "Organ of Corti. Sections through the inner ear showed good preservation of ganglion cells and nerve fibers. The sensory epithelium and the stria vascularis showed severe atrophy." There is one other known (or at least published) case of an autopsy in which the cochlea was examined(2), in this case a 19 month-old boy who had been diagnosed with neonatal adrenoleukodystrophy (NALD) and had also died of pneumonia. (At the time this article was written (1976) there was no disease called NALD, nor any understanding of it as a peroxisomal disorder. This article uses the term adrenocerebroleukodystrophy, which (in restrospect) is recognized as having been what is now called NALD). This report noted atrophy of the sensory epithelium and the tectorial membrane, partial collapse of Reisner's membrane, and widespread degeneration of ganglion cells. The fact that there are only these two reports is double-edged. There is insufficient evidence to state conclusively that they reflect the typical pathologies in these diseases; but on the other hand they represent nearly the sum total of certain knowledge on the subject, and it probably is a fair assumption that these are the typical pathologies.
Atrophy of the ganglion cells, sensory epithelium, tectorial membrane and/or stria vascularis is sufficient to cause sensorineural deafness. Essentially, these cells are dead, and there is no normal functioning of the cochlea without them.
In 1998 Drs James Powers and Hugo Moser published a paper(3) in which the various neurological and sensory pathologies of the peroxisomal diseases were examined and classified. In addition, they develop a hypothesis as to the cause of these pathologies. Included in this are the cochlear pathologies and their possible cause; this may be the only published paper which specifically addresses the subject.
They postulate that in some of the peroxisomal disorders there is a process of of degeneration of specialized sensory cells ("selective neuronal degeneration"), affecting the ganglion cells and sensory epithelium of both the retina and the cochlea. Some of the neurological pathologies of the the peroxisomal disorders are due to basic malformations that occur in the brain and CNS of the developing fetus - these are called neuronal migration defects. Neuronal degeneration is different in that the original formation is correct and degeneration occurs post-natally. In both the visual and auditory imapirments associated with these diseases the concept of such a degeneration conforms to the observed progressive nature of the impairments.
As a working hypothesis, Drs Powers and Moser attribute all neurological pathologies of the peroxisomal disorders (neuronal migration defects, defects of myelination, and neuronal degeneration) to "abnormal fatty acids, particularly very long chain fatty acids and phytanic acid, [which] accumulate in the peroxisomal disorders and are incorporated into cell membranes resulting in a perturbation of these membranes' microenvironments and the dysfunction, atrophy and death of vulnerable cells".
It might be noted that the tectorial membrane, stria vascularis, and the other membranes of the cochela are not made up of neuronal cells. Therefore, this hypothesis does not (strictly speaking) account for the the atrophy of these cells. In a sense it doesn't need to, since atrophy of gangion cells and hair cells is itself sufficient to account for sensorineural deafness. It may be a reasonable assumption that the degenerative process caused by the accumulation of VLCFAs in the sensory cells is also at work in the cells making up these other parts of the cochlea.
1. Infantile Refsum's Disease; a generalized peroxisomal disorder
Case Report with postmortem examination
Torvik et al.
Journal of the Neurological Sciences (Elsevier) 85: 39-53 (1988)
2. Cochlear nerve degeneration coincident with adrenocerebroleukodystrophy
Igarashi et al.
Archives of Otolaryngology 102: 722-726
3. Peroxisomal Disorders: Genotype, Phenotype,
Major Neuropathologic lesions, and Pathogenesis.
Brain Pathology 8: 101-120 (1998)
Medical articles which note the existence of sensorineural deafness in these diseases are too numerous to mention. In fact, it would be difficult to find an article which didn't note it.. Some examples of typical case reports will be found in the following:
Dysmorphic syndrome with phytanic acid oxidase deficiency,
abnormal very long chain fatty acids, and pipecolic acidemia:
Studies in four children
Budden, Kennaway, Buist, Poulos, Weleber
Journal of Pediatrics, Vol. 108, No. 1, January 1986
Infantile Refsum disease; an inherited peroxisomal disorder
Comparison with Zellweger syndrome and neonataladrenoleukodystrophy
Poll-The et al.
European Journal of Pediatrics 146: 477-483 (1987)
Treatment of infantile phytanic acid storage disease;
clinical, biochemical and ultrastructural findings
in two children treated for 2 years
Robertson et al.
European Journal of Pediatrics 147: 133-142 (1988)
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Hearing Science, Otology, and Deafness
Hearing and Balance - John Brugge
Comprehensive treatment of the entire process of the perception of sound. Included are description and explanation of sound transmission, the anatomy and function of the parts of the ear, disorders of those parts and the resulting types of deafness, the relation of hearing impairment to language acquisition, and the tests used to gauge hearing.
The Search for the Mechanisms of Hearing - Peter Dallos
Development, structure and functioning of the cochlea and organ of Corti
A Brief Introduction to the Inner Ear
Kresge Hearing Research Institute, University of Michigan Medical School
Cochlear Biophysics - Baylor College of Medicine
Hearing and Hair Cells - John Oghalai
Mechanisms of Transduction and Ion Channel Regulation in Hair Cells -
The electrical environment within the cochlea
Heridtary Hearing Loss and Deafness overview - GE Green and others
Descriptions of the various genetic defects which cause deafness, the types of deafness which result, and the tests used to assess extent of hearing loss.
Pediatric Hearing Loss - Shannon Esse and Linda Thibodeau
Anatomy and mechanics of the ear; types of hearing loss; testing and diagnosis; speech, language, and communication; types of hearing aids; educational placement; legal issues; family issues.
Hearing Loss - Pamela Feibig
Sensorineural Hearing Loss - Peter Grant
An overview of the literature on sensorineural hearing loss, with extensive references and bibliography
Hearing Evaluation in Children
The two following are descriptions of the ARB hearing test, the test most likely to be used in determining hearing levels in children diagnosed with peroxisomal disorders:
Auditory Brainstem Response
Brainstem Evoked Response Audiometry
- - -
Otolaryngological Resources on the Internet
National Institute on Deafness and Other Communication Disorders, NIH
Hugh Sasse's Deafness Resources Page
Hugh Sasse's Blindness Resources Page
Genetic Diseases of the Eye
(Traboulsi, editor) Oxford University Press, 1998
Chapter 33, Peroxisomal Disorders
The Peroxisome and the Eye
Folz and Trobe
Survey of Ophthalmolgy, Vol. 35, No 5, 353-368
Ocular Histopathologic and Biochemical Studies of the
Cerebrohepatorenal Syndrome (Zellweger's Symdrome) and its
Relation to Neonatal Adrenoleukodystrophy
Cohen et al.
American Journal of Ophthalmology, 96:488-501, 1983
Tapetoretinal degeneration in the cerbro-hepato-renal
Garner et al.
British Journal of Ophthalmology, 66, 421-431, 1982
Ocular Manifestations of Conradi and Zellweger Syndromes
Kretzer et al.
Metabolic and Pediatric Ophthalmology
Vol. 5, 1-11, 1981
Zellweger Syndrome: Lenticular Opacities Indicating
Carrier Status and Lens Abnormalities Characteristic
Hittner et al.
Archives of Ophthalmology
Vol. 99, 1977-1982, November 1981
Cerebro-hepato-renal Syndrome of Zellweger:
Ocular Histopathologic Findings
Haddad et al.
Archives of Ophthalmology
Vol. 94, 1927-1930, November 1976
Cerebro-hepato-renal (Zellweger's) Syndrome:
Stanescu and Dralands
Archives of Ophthalmology
Vol. 87, 590-592, May 1972
A syndrome of ocular abnormalities, calcification of cartilage,
and failure to thrive
Punnett and Kirkpatrick
Journal of Pediatrics
Vol. 73, No. 4, 602-606, Ocotber 1968
Ocular Histopathologic Studies of Neonatal
and Childhood Adrenoleukodystrophy
Cohen et al.
American Journal of Ophthalmology, 95:82-96, 1983
Ocular Pathologic Findings in Neonatal Adrenoleukodystrophy
Glasgow et al.
Ophthalmology, Vol 94, No. 8, 1054-1060, August 1987
Ophthalmic Manifestations of Infantile Phytanic Acid
Weleber et al.
Archives of Ophthalmology, Vol. 102, 1317-1321
Hyperpipecolic acidemia associated with hepatomegaly,
mental retardation, optic nerve dysplasia and
progressive neurological disease
Thomas et al.
Clinical Genetics, 8:376-382, 1975
Ocular Involvement in Chondrodysplasia Punctata
Levine et al.
American Journal of Ophthalmology
Vol. 77, No. 6, 851-859, June 1974
Dysplasia epiphysialis punctata with ocular anomalies
British Journal of Ophthalmology, 54, 755-758, 1970
Peroxisome bifunctional enzyme deficiency with
associated retinal findings
Al-Hazza and Ozand
Ophthalmic Genetics, Vol 18, No. 2, 93-99, 1997
Ocular Findings in Primary Hyperoxaluria
Small et al.
Archives of Ophthalmology
Vol. 108, 89-93, January 1990
Optic Atrophy in Primary Oxalosis
Small et al.
American Journal of Ophthalmology
Vol. 106, No. 1, July 1988
Ocular Involvement in Primary Hyperoxaluria
Meredith et al.
Archives of Ophthalmology
Vol. 102, 584-587, April 1984
Ophthalmic manifestations of primary oxalosis
Fielder et al.
British Journal of Ophthalmology, 64, 782-788, 1980
"Flecked retina" - an association with
Gottlieb et al.
Journal of Pediatrics
Vol. 90, No. 6, 939-942, June 1977
Heredopathia Atactica Polyneuritiformis:
Phytanic-Acid Storage Disease, Refsum's Disease:
A Biochemically Well-defined disease with a
Specific Dietary Treatment
Archives of Neurology
Vol. 38, 605-606, October 1981
Brainstem Auditory, Visual and Somatosensory
Evoked Potentials in Leukodystrophies
Markand et al.
Electroencephalography and Clinical Neurophysiology
Correlation of phenotype with genotype
in inherited retinal degeneration
Daiger et al.
Behavioral and Brain Sciences, 18:452-467, 1995
The Inherited Neurodegenerative Diseases of Childhood:
Journal of Child Neurology
Vol. 2, 82-97, April 1987
The retinal pigment epithelium:
a versatile partner in vision
Journal of Cell Science, Supplement 17, 189-195, 1993
Localization of Nonspecific Lipid Transfer Protein
(nsLPT = Sterol Carrier Protien 2) and Acyl-CoA Oxidase
in Peroxisomes of Pigment Epithelial Cells of Rat Retina
Deguchi et al.
Journal of Histochemistry and Cytochemistry
Vol. 40, No. 3, 403-410, 1992
Peroxisomes in Pigment Epithelium and Muller Cells of
Amphibian Retina Possess d-Amino Acid Oxidase
as well as Catalase
Beard et al.
Experimental Eye Research, 47, 343-348, 1988
Microperoxisomes in Retinal Epithelium and
Tapetum Lucidum of the American Opossum
Hazlett et al.
Experimental Eye Research, 27, 343-348, 1978
Studies on Microperoxisomes:
VII. Pigment Epithelial Cells and
Other Cell Types in the Retina of Rodents
Leuenberger and Novikoff
Journal of Cell Biology
Vol. 65, 324-334, 1975
Microperoxisomes in retinal pigment epithelium
Robison and Kuwabara
Vol. 14, No. 11, 866-872, November 1975
The dolichol pathway in the retina and its involvement
in the glycolysation of rhodopsin
Biochimica et Biophysica Acta