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Refsum Disease

CMT4


Presentation

  • The purpose of this paper was to present the case of a 15-year-old female diagnosed with infantile Refsum disease (IRD) that presented with generalized enamel defects in the primary and permanent dentition.[ncbi.nlm.nih.gov]
  • The early presentation raises the possibility of in utero exposure to phytanate.[ncbi.nlm.nih.gov]
  • A 25-year-old woman with a diagnosis of infantile Refsum disease presented with progressively decreasing vision.[ncbi.nlm.nih.gov]
  • This paper presents a case history of a 12-year-old female patient with IRD who underwent dental rehabilitation in the operating room under general anesthesia and includes a 2-year follow-up.[ncbi.nlm.nih.gov]
  • A boy of 3 years and 8 months presented with facial dysmorphism, transaminitis, and psychomotor retardation. Biochemical analysis showed elevated PA and VLCFAs, with reduced PL in the serum.[ncbi.nlm.nih.gov]
Progressive Dementia
  • Discussion We report the very unusual case of a 72-year-old woman presenting with 2 years’ history of progressive dementia, walking problems, and diffuse leukoencephalopathy.[ncbi.nlm.nih.gov]
Anosmia
  • Besides tapetoretinal degeneration, additional symptoms are anosmia, skeletal malformations, chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, ichthyosis, and cardiac abnormalities.[ncbi.nlm.nih.gov]
  • Abstract Refsum disease is a peroxisomal disorder characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy, ataxia, and an accumulation of phytanic acid in plasma and tissues.[ncbi.nlm.nih.gov]
  • Abstract Refsum disease (RD), a neurological syndrome characterized by adult onset retinitis pigmentosa, anosmia, sensory neuropathy, and phytanic acidaemia, is caused by elevated levels of phytanic acid.[ncbi.nlm.nih.gov]
  • It is usually inherited and the condition can cause vision loss, and absence of smell (anosmia). It usually starts in early childhood to late adulthood.[wiki.ggc.usg.edu]
  • Anosmia is also considered an early symptom [Wierzbicki et al 2002].[refsumdisease.org]
Night Blindness
  • The authors report the case of a 14-year-old girl diagnosed because of night blindness. They treated her with a phytanic acid-poor diet and extracorporeal lipid apheresis. They used different methods over a 30-month period.[ncbi.nlm.nih.gov]
  • Typically, individuals with adult Refsum's disease experience night-blindness years before the progressive chnages changes of constricted visual fields and decreased central visual acuity appear.[refsumdisease.org]
  • Night blindness may be an early symptom. Diagnosis is made by demonstrating elevated plasma levels of phytanic acid or reduced phytanic acid oxidase activity in cultured fibroblasts.[aao.org]
  • The elder brother, aged 43, was myopic and developed night blindness and peripheral visual field loss at six years of age.[doi.org]
  • There is typical night blindness and visual field constriction. Rod ERG responses are usually subnormal. However, central acuity is also reduced due to a degenerative maculopathy. Cataracts and optic atrophy are common.[disorders.eyes.arizona.edu]
Hearing Impairment
  • We report the case of a 6-year-old boy who presented with developmental delay, ataxia, hypotonia, areflexia, vision and hearing impairment, dysmorphism, and hepatomegaly.[thieme-connect.com]
  • The visual and hearing impairments are less responsive to treatment. [ 11 ] Genetic counselling [ 5 ] Refsum's disease is inherited in an autosomal recessive manner.[patient.info]
  • The average daily intake of phytanic acid is 50-100 mg/day, and ideally this should be reduced to 10-20 mg/day.The neurological, cardiac and dermatological sequelae can be reversed by reduction of phytanic acid levels, but the visual and hearing impairments[path.upmc.edu]
Alopecia
  • Win32 Error Code 87 Aarskog syndrome Achondroplasia Achromatopsia Acoustic neuroma (and benign cranial nerve tumors) Adrenal hyperplasia Adrenoleukodystrophy Agenesis of corpus callosum Aicardi syndrome Alagille syndrome Albinism (& (hypopigmentation) Alopecia[kumc.edu]
Ataxia
  • A diet low in phytanic acid ameliorates polyneuropathy and ataxia and slows or even stops the other manifestations.[ncbi.nlm.nih.gov]
  • Major diagnostic clinical findings include retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, increased cerebrospinal fluid protein without pleocytosis, nerve deafness, and cardiac involvement.[ncbi.nlm.nih.gov]
  • Signs and symptoms include neurologic damage, cerebellar degeneration, and neuropathy An autosomal recessive familial disorder that usually presents in childhood with polyneuropathy; sensorineural hearing loss; ichthyosis; ataxia; retinitis pigmentosa[icd9data.com]
  • IRD patients present with multiple clinical manifestations, including: retinitis pigmentosa; nystagmus; sensorineural hearing loss; mental and developmental delays; neuromotor defects; and cerebral ataxia.[ncbi.nlm.nih.gov]
  • Ataxia. Friedreich ataxia is characterized by slowly progressive ataxia with mean onset between age ten and 15 years and usually before age 25 years.[ncbi.nlm.nih.gov]
Cerebellar Ataxia
  • Major diagnostic clinical findings include retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, increased cerebrospinal fluid protein without pleocytosis, nerve deafness, and cardiac involvement.[ncbi.nlm.nih.gov]
  • It causes retinitis pigmentosa, cataracts, a chronic polyneuropathy, cerebellar ataxia and cardiac arrhythmias amongst other clinical signs. By limiting dietary intake, plasma phytanic acid levels fall with an improvement in the neurological signs.[ncbi.nlm.nih.gov]
  • Besides tapetoretinal degeneration, additional symptoms are anosmia, skeletal malformations, chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, ichthyosis, and cardiac abnormalities.[ncbi.nlm.nih.gov]
  • ataxia Prende il nome da Sigvald Bernhard Refsum Controllo di autorità Q177809 Reasonator Scholia Statistica File nella categoria "Refsum disease" Questa categoria contiene 2 file, indicati di seguito, su un totale di 2.[commons.wikimedia.org]
  • Abstract Refsum disease is an autosomal recessive disorder characterized by retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia and increased cerebrospinal fluid protein.[ncbi.nlm.nih.gov]
Peripheral Neuropathy
  • Clinical features were characterized by neuroregression, retinitis pigmentosa, hearing loss, peripheral neuropathy and white matter signal changes on magnetic resonance imaging.[ncbi.nlm.nih.gov]
  • The body fluids must be assayed for phytanic acid whenever an atypical chronic peripheral neuropathy is observed.[ncbi.nlm.nih.gov]
  • Refsum disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an[ncbi.nlm.nih.gov]
  • In people with Refsum disease, phytanic acid can accumulate, leading to neurological problems vision loss, hearing loss, peripheral neuropathy, and neurodegeneration of the central nervous system. A.[chegg.com]
  • With treatment, symptoms of peripheral neuropathy and ichthyosis generally disappear. But, while treatment may prevent further deterioration of vision and hearing, it can’t undo damage to vision and hearing that has already occurred.[blog.imwithoutstress.com]
Nystagmus
  • IRD patients present with multiple clinical manifestations, including: retinitis pigmentosa; nystagmus; sensorineural hearing loss; mental and developmental delays; neuromotor defects; and cerebral ataxia.[ncbi.nlm.nih.gov]
  • Other symptoms may include rapid, jerky eye movements (nystagmus), floppy muscle tone (hypotonia) and lack of muscle coordination (ataxia), mental and growth retardation, mild abnormalities in the form and structure of the face (dysmorphia), enlargement[sharecare.com]
  • Refsum disease - a rare hereditary degenerative disorder characterized by retinitis pigmentosa, demyelinating polyneuropathy, deafness, nystagmus, and cerebellar signs. Synonym(s): heredopathia atactica polyneuritiformis ; Refsum syndrome[medical-dictionary.thefreedictionary.com]
  • Case Reports Patient 1 A 2-year 9-month-old girl with nystagmus, visual and hearing impairment, and developmental delay was evaluated for the possibility of multisystem genetic disorder.[ajnr.org]
Neurologic Manifestation
  • Disease definition Refsum disease (RD) is a very rare, clinically variable, multisystemic metabolic disease, characterized by anosmia, early-onset retinitis pigmentosa and possible neurological manifestations, including neuropathy, and cerebellar ataxia[orpha.net]
  • The cardinal neurological manifestations of the disease include a demyelinating neuropathy, pes cavus, cerebellar ataxia, sensorineural deafness, anosmia and cranial nerve involvement (5).There may be marked nerve hypertrophy.[path.upmc.edu]
  • The cardinal neurological manifestations of the disease include a demyelinating neuropathy, pes cavus, cerebellar ataxia, sensorineural deafness, anosmia and cranial nerve involvement. 7 There may be marked nerve hypertrophy.[academic.oup.com]

Workup

  • A metabolic workup disclosed very high plasma phytanic acid level (458 μmol/L; control Genetic analysis of the PHYH gene revealed a novel homozygous mutation in exon 1, c.42-60dup, a frameshift mutation resulting in a premature stop codon at position[ncbi.nlm.nih.gov]
  • Additional preoperative workup was performed. Funduscopy revealed retinitis pigmentosa ( Fig 3 ).[pediatrics.aappublications.org]
Abnormal ECG
  • Cardiomyopathy and conduction abnormalities. ECG changes are present. Ichthyosis, hyperkeratosis plantaris and palmaris may be seen.[patient.info]

Treatment

  • Subsequent treatment through dietary modification stabilised visual impairment and has prevented development of neurological complications to date.[ncbi.nlm.nih.gov]
  • Treatment for RD is aimed at lowering the serum levels of phytanic acid.[doi.org]
  • Although serial examinations have failed to show a definite change in the course of visual deterioration with treatment, early diagnosis is important to prevent the development of neurological disease.[ncbi.nlm.nih.gov]
  • With continued success, we believe that LT may evolve as a feasible option for the treatment of IRD. A prospective evaluation with long-term outcomes may address the ethical concerns and the validity of LDLT as a treatment of IRD.[pediatrics.aappublications.org]
  • This resulted in a significant increase in the intracellular Ca2 level, similar to the effect seen after treatment with the synthetic GPR40 agonist GW9508.[ncbi.nlm.nih.gov]

Prognosis

  • Refsum's disease phytanic acid diet peroxisome metabolic disease neuroophthalmology prognosis Statistics from Altmetric.com Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright[dx.doi.org]
  • Prognosis Prognosis in the absence of treatment is generally poor. Severe cases or late diagnosis may be life-threatening. The main cause of death is arrhythmia and heart failure. Expert reviewer(s): Pr B.T. [Bwee Tien] POLL-THE - Pr R.J.A.[orpha.net]
  • What is the prognosis of Refsum disease? Prognosis of Refsum disease varies dramatically. Strict adherence to a dietary regimen (see treatment, below) can cause the neurological symptoms to arrest, and nerve response can improve.[ulf.org]

Etiology

  • Etiology RD is caused by mutations in the PHYH gene (10p13) in more than 90% of cases, and mutations in the PEX7 gene (6q21-q22.2) in less than 10%. These genes are involved in lipid metabolism and protein transport.[orpha.net]
  • ETIOLOGY: Refsum's disease is a rare autosomal recessive condition first characterized by Sigvald Refsum in 1945 (1).[path.upmc.edu]
  • Ichthyosis is an unusual symptom. [14, 15] Etiology Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase ( PHYH ) and the PTS2 receptor ( PEX7 ) genes. This disorder is inherited in an autosomal recessive mode.[emedicine.com]

Epidemiology

  • Summary Epidemiology About 60 cases have been reported worldwide. Prevalence rates are not known but the disorder may be underdiagnosed. Prevalence has been estimated to be 1/1,000,000 in the United Kingdom. Males and females are affected equally.[orpha.net]
  • Epidemiology Frequency Refsum disease is rare, with just 60 cases published worldwide. Race No racial predominance is reported. Sex Only male cases were reported initially; however, now, neither sex predominates.[emedicine.com]
Sex distribution
Age distribution

Pathophysiology

  • Infantile Refsum disease has clinical features and a pathophysiology distinct from classic Refsum disease, despite occasionally presenting for examination later in life.[ncbi.nlm.nih.gov]
  • Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013 Jun. 17(3):187-96. [Medline]. Aubourg P, Wanders R. Peroxisomal disorders. Handb Clin Neurol. 2013. 113:1593-609. [Medline].[emedicine.com]
  • Until 1963 the pathogenesis and pathophysiology of Refsum disease was not known.[medlink.com]

Prevention

  • Subsequent treatment through dietary modification stabilised visual impairment and has prevented development of neurological complications to date.[ncbi.nlm.nih.gov]
  • Although serial examinations have failed to show a definite change in the course of visual deterioration with treatment, early diagnosis is important to prevent the development of neurological disease.[ncbi.nlm.nih.gov]
  • Early diagnosis and effective measures to keep the phytanic acid load low can probably prevent the serious sequelae of Refsum disease. Developing a method for newborn screening is desirable.[ncbi.nlm.nih.gov]
  • Immunofluorescence study of fibroblasts from the patient indicated a mosaic pattern of catalase-positive and -negative particles, and molecular analysis revealed compound heterozygous mutations of PEX6 The failure of medical management to prevent the[ncbi.nlm.nih.gov]

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